Details of the Researcher

PHOTO

Masayuki Yamamoto
Section
Tohoku Medical Megabank Organization
Job title
Specially Appointed Research Fellow
Degree

  • 医学博士（東北大学）

e-Rad No.
50166823

Research History 4

  • 2012/02 - Present
    Tohoku University　Tohoku Medical Megabank Organization　Executive Director and Professor

  • 2007/01 - 2023/03
    東北大学医学系研究科　教授

  • 1995/04 - 2006/12
    筑波大学　教授

  • 1983/10 - 1996/01
    Northwestern 大学　Research Associate

Education 2

  • Tohoku University　Graduate School of Medicine

    - 1983/03

  • Tohoku University　Faculty of Medicine

    - 1979/03/31

Committee Memberships 4

  • 日本生化学会　会長

    2017/12 - 2019/11

  • 日本生化学会　理事

    2011/12 - 2019/11

  • 日本癌学会　評議員

    2000/10 - 2019/08

  • 日本生化学会　第89回 日本生化学会大会 会頭

    2016/09 - 2016/09

Professional Memberships 14

  • 日本分子生物学会(2001/10- 評議員)

  • 日本癌学会(2000/10- 評議員)

  • 特定研究（A)転写調節機構(1997/10-2000/10 統括幹事)

  • 日本生化学会(2006/04- 理事)

  • 日本生化学会(2000/10-2004/04 代議員)

  • 日本生化学会(1996/10- 評議員)

  • アメリカ血液学会(ASH)(1998/10-)

  • アメリカ生化学・分子生物学会（ASBMB)(1998/10-)

  • 日本発生生物学会(1993/10-)

  • 日本癌学会(1990/01-)

  • 日本血液学会(1990/10-)

  • 日本分子生物学会(1989/10-)

  • マメリカ微生物学会(ASM)(1984/10-)

  • 日本生化学会(1979/04-)

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Research Interests 5

  • Genome omics analysis

  • Biobank

  • GATA 因子

  • Erythropoietin

  • KEAP1-NRF2 regulatory system

Research Areas 1

  • Life sciences / Medical biochemistry /

Awards 28

  1. Highly Cited Researcher for 2023, Clarivate Analytics

    2023/11

  2. Annual Research Award 2023

    2023/06　Society for Free Radical Research-Europe

  3. 安藤百福賞 優秀賞

    2023/03　安藤スポーツ・食文化振興財団　植物栄養素ファイトケミカルによる抗酸化生体防御作用の分子メカニズム解明

  4. Highly Cited Researcher for 2022

    2022/11　Clarivate Analytics

  5. Honorary Doctorate

    2022/06　University of Eastern Finland

  6. Highly Cited Researcher for 2021

    2021/11　Clarivate Analytics

  7. ISS Research Award for Dr Masayuki Yamamoto and MHU-3 Mission Team

    2021/08　ISS Research Conference　“Compelling Results in Biology and Medicine for their work on Nrf2 and the ToMMo project“

  8. Lester Packer Award

    2021/03　Society for Free Radical Research

  9. 河北文化賞「生体の酸化ストレス応答機構の解明」

    2021/01　河北文化事業団

  10. Highly Cited Researcher for 2020

    2020/11　Clarivate Analytics

  11. FAOBMB Research Excellence Award

    2020/06　Federation of Asia and Oceania Biochemists and Molecular Biologists (FAOBMB)

  12. Highly Cited Researcher for 2019

    2019/11　Clarivate Analytics

  13. Highly Cited Researcher for 2018

    2018/11　Clarivate Analytics

  14. 柿内三郎賞

    2017/12　日本生化学会　環境ストレス応答機構の発見とその生理的・病理的意義の解明

  15. 特別賞

    2016/06　日本毒性学会　Keap1-Nrf2制御システムの発見による毒性学への貢献

  16. the Japan Academy Prize

    2014/07　日本学士院　生体の環境ストレス応答の分子機構の解明

  17. 高峰記念第一三共賞

    2013/07/01　第一三共生命科学研究振興財団　環境ストレスに対する生体応答メカニズムの解明

  18. 日本腎臓財団学術賞

    2013/06/07　日本腎臓財団　エリスロポエチン産生の制御機構に関する研究

  19. Oxygen Club of California and Jarrow Formulas Health Sciences Prize

    2012/06　Oxygen Club of California

  20. Medal with purple ribbon

    2012/04　日本国

  21. 上原賞

    2012/03　上原記念生命科学財団　酸素や食物が内包する毒性に対する生体の応答機構の解明

  22. Leading Edge in Basic Science Award

    2011/03　Society of Toxicology

  23. 東レ科学技術賞

    2011/03　東レ科学振興会　生体の環境ストレス応答の分子機構の解明

  24. 日産科学賞

    2008/05/21　日産科学振興財団　環境適応・応答の分子機構の解明

  25. つくば賞

    2007/09/27　茨城県科学振興財団・つくばアカデミー　環境応答の分子機構の解明

  26. Thomson Scientific Research Front Award 2004

    2004/11　Thomson Scientific Co.

  27. 井上学術賞

    1996/02　井上科学振興財団　「転写因子群による赤血球特異的遺伝子発現制御機構の解析」

  28. 東北大学医学部奨学賞・金賞および坂田賞

    1995/01　東北大学医学部　「転写因子による細胞・組織特異的遺伝子発現調節機序の解明」

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Papers 1208

  1. Returning genetic risk information for hereditary cancers to participants in a population-based cohort study in Japan. International-journal

    Kinuko Ohneda, Yoichi Suzuki, Yohei Hamanaka, Shu Tadaka, Muneaki Shimada, Junko Hasegawa-Minato, Masanobu Takahashi, Nobuo Fuse, Fuji Nagami, Hiroshi Kawame, Tomoko Kobayashi, Yumi Yamaguchi-Kabata, Kengo Kinoshita, Tomohiro Nakamura, Soichi Ogishima, Kazuki Kumada, Hisaaki Kudo, Shin-Ichi Kuriyama, Yoko Izumi, Ritsuko Shimizu, Mikako Tochigi, Tokiwa Motonari, Hideki Tokunaga, Atsuo Kikuchi, Atsushi Masamune, Yoko Aoki, Chikashi Ishioka, Takanori Ishida, Masayuki Yamamoto

    Journal of human genetics　2025/01/17

    DOI： 10.1038/s10038-024-01314-w 　

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    Large-scale population cohort studies that collect genomic information are tasked with returning an assessment of genetic risk for hereditary cancers to participants. While several studies have applied to return identified genetic risks to participants, comprehensive surveys of participants' understanding, feelings, and behaviors toward cancer risk remain to be conducted. Here, we report our experience and surveys of returning genetic risks to 100 carriers of pathogenic variants for hereditary cancers identified through whole genome sequencing of 50 000 individuals from the Tohoku Medical Megabank project, a population cohort study. The participants were carriers of pathogenic variants associated with either hereditary breast and ovarian cancer (n = 79, median age=41) or Lynch syndrome (n = 21, median age=62). Of these, 28% and 38% had a history of cancer, respectively. We provided information on cancer risk, heritability, and clinical actionability to the participants in person. The comprehension assessment revealed that the information was better understood by younger (under 60 years) females than by older males. Scores on the cancer worry scale were positively related to cancer experiences and general psychological distress. Seventy-one participants were followed up at Tohoku University Hospital; six females underwent risk-reducing surgery triggered by study participation and three were newly diagnosed with cancer during surveillance. Among first-degree relatives of hereditary breast and ovarian cancer carriers, participants most commonly shared the information with daughters. This study showed the benefits of returning genetic risks to the general population and will provide insights into returning genetic risks to asymptomatic pathogenic variant carriers in both clinical and research settings.

  2. Language Registration-Based Scoring System for Handwritten Logical Memory of Wechsler Memory Scale-Revised: Developed and Validated in the Tohoku Medical Megabank Project.

    Naoko Mori, Shunji Mugikura, Atsushi Hozawa, Makiko Taira, Hiroaki Hashizume, Atsushi Sekiguchi, Mitsunari Abe, Michiyo Kasai, Tomo Saito, Kengo Kinoshita, Nobuo Fuse, Shinichi Kuriyama, Masayuki Yamamoto

    The Tohoku journal of experimental medicine　2025/01/16

    DOI： 10.1620/tjem.2025.J006 　

  3. Prevalence and Associations of Epiretinal Membrane by OCT in a Japanese Population-Based Cohort: Tohoku Medical Megabank Organization Eye Study. International-journal

    Akihiko Shiraki, Atsushi Hirayama, Nobuo Fuse, Ryo Kawasaki, Satoko Fujimoto, Tomoyuki Okazaki, Susumu Sakimoto, Takatoshi Maeno, Makiko Taira, Tomo Saito, Tomohiro Nakamura, Soichi Ogishima, Atsushi Hozawa, Kengo Kinoshita, Masayuki Yamamoto, Kohji Nishida

    Ophthalmology science　5　(4)　100752-100752　2025

    DOI： 10.1016/j.xops.2025.100752 　

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    PURPOSE: To examine the prevalence of epiretinal membrane (ERM) according to the OCT-based severity scales, and to describe associations focusing on the impact of smoking and axial length of the globe. DESIGN: Cross-sectional study. PARTICIPANTS: The baseline examination cohort comprised participants from the Tohoku Medical Megabank community cohort recruited from 2013 to 2017. METHODS: In total, 38 118 eyes of 19 486 participants were classified with ERM staging. The characteristics of ERM severity were analyzed, and the association between the prevalence of ERM and ocular and systemic parameters was investigated using logistic regression models. Cubic spline models were constructed to visualize the relationships with lifetime smoking exposure and axial lengths. Regarding ERM severity, the associations between stage 1 and stage 2 or more were analyzed with multivariate analysis. MAIN OUTCOME MEASURES: Epiretinal membrane prevalence at each stage determined via OCT and factors associated with ERM presence and severity. RESULTS: The prevalence of ERM was 2.3% per eye (3.6% per person), with a predominance at stage 1. The presence of severe ERM stages was higher in older individuals. The multivariate logistic analysis revealed that older age, female sex, and long axial length were associated with a higher prevalence of ERM. In a multivariate analysis stratified by sex, glaucoma was also identified as a significant factor associated with the prevalence of ERM in women. In the cubic spline model, no consistent trend was observed between smoking and ERM prevalence. However, a U-shaped relationship was indicated between axial length and ERM prevalence. Epiretinal membrane severity highlighted older age, alcohol consumption, and very long axial length as significantly associated compared with stage 1. CONCLUSIONS: Epiretinal membrane prevalence was significantly associated with older age, female sex, and long axial length. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

  4. Validity of a self-administered food frequency questionnaire for genomic and omics research among pregnant women: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

    Keiko Murakami, Misako Nakadate, Taku Obara, Misato Aizawa, Ippei Takahashi, Mami Ishikuro, Aoi Noda, Hisashi Ohseto, Noriyuki Iwama, Masatoshi Saito, Ribeka Takachi, Shiori Sugawara, Yudai Yonezawa, Takahiro Yamashita, Shigenori Suzuki, Junko Ishihara, Masayuki Yamamoto, Shinichi Kuriyama

    Journal of epidemiology　2024/12/21

    DOI： 10.2188/jea.JE20240293 　

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    BACKGROUND: The Tohoku Medical Megabank Project has initiated the Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study) including genomic and omics investigations, and conducted a self-administered food frequency questionnaire with the response option "constitutionally unable to eat or drink it" for individual food items (TMM-FFQ) for pregnant women. This study evaluated the validity of the TMM-FFQ among pregnant women. METHODS: Participants comprised 122 pregnant women aged ≥20 years residing in Miyagi Prefecture who completed weighed food records (WFRs) for 3 days as reference intake and the TMM-FFQ during mid-pregnancy. Correlations between nutrient or food group intakes based on the WFR and the TMM-FFQ were calculated using Spearman's rank correlation coefficients (CCs), adjusting for energy intake and correcting for random within-individual variation of WFR. Cross-classification was also conducted according to quintiles using the WFR and TMM-FFQ data. RESULTS: The percentages of participants who chose the "constitutionally unable to eat or drink it" option were >3% for seven food and drink items. CCs were >0.30 for 31 nutrients; the median across energy and 44 nutrients was 0.41. CCs were >0.30 for 14 food groups; the median across 20 food groups was 0.35. The median percentages of cross-classification into exact plus adjacent quintiles and extreme quintiles were 63.1% and 3.3% for energy and nutrients and 61.9% and 4.1% for food groups, respectively. CONCLUSIONS: The validity of the TMM-FFQ compared with the WFR was reasonable for certain nutrients and food groups among pregnant women in the TMM BirThree Cohort Study.

  5. Basic Science and Pathogenesis. International-journal

    Makiko Taira, Nobuo Fuse, Andrew J Saykin, Fuji Nagami, Kengo Kinoshita, Masayuki Yamamoto

    Alzheimer's & dementia : the journal of the Alzheimer's Association　20 Suppl 1　e093405　2024/12

    DOI： 10.1002/alz.093405 　

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    BACKGROUND: Dementia is age-related with a significant genetic contribution, yet genome-wide association studies have not fully accounted for heritability. This discrepancy may in part be due to reliance on SNPs and small indels. Whole-genome sequencing (WGS) data in the Japanese population may reveal population-specific susceptibility loci for dementia. Retinal imaging with optical coherence tomography (OCT) is noninvasive, reproducible, and can detect thinning associated with progressive neurodegeneration. Association of population-specific genetic susceptibility loci with retinal thinning and cognitive decline may reveal novel aspects of dementia risk and pathophysiology. METHOD: Among participants with WGS data from the Tohoku Medical Megabank Organization (ToMMo) Ophthalmology Study ("ToMMo Eye Study"), individuals with adequate quality data on retinal nerve fiber layer and ganglion cell layer thickness from spectral-domain optical coherence tomography (SD-OCT) scans were selected. Since retinal thinning also occurs in glaucoma, we performed a GWAS using age, sex, and 10 principal components as covariates using SAGE1.2 to obtain a set of genes responsible for glaucoma and confirm that the genotyping was successful. We then attempted to identify susceptibility loci for cognitive decline by using (1) the Mini-Mental State Examination, Japanese version (MMSE-J), (2) the Montreal Cognitive Assessment, Japanese version (MoCA-J), and (3) the Mini-COG© (a simple screening for early detection of dementia, Japanese version) scores as associated factors, respectively. Furthermore, these validation results were also compared with those obtained from GWAS using imputation data performed on custom arrays (Japonica ArrayTM, v2 or NEO) for Japanese. RESULT: 84 significant (p < 5.0E-8) genome-wide susceptibility loci (hg38) of RNFL were detected on 14K WGS-based study (the top hit locus: Chr14, SIX6 gene, P = 4.50E-46). There were many genetic loci that have already been reported to be associated with glaucoma susceptibility, including the above locus. Among the results of GWAS for cognitive decline combining the three cognitive scores after normalization to z-scores, several loci have shown significant susceptibility in both of RNFL and cognitive rating scale. Some loci suggested more than a high or moderate effect of altering protein efficacy. CONCLUSION: We present an initial WGS-based genetic study of retinal thickness and cognitive decline in the Japanese population.

  6. Sensor systems of KEAP1 uniquely detecting oxidative and electrophilic stresses separately In vivo Peer-reviewed

    Miu Sato, Nahoko Yaguchi, Takuya Iijima, Aki Muramatsu, Liam Baird, Takafumi Suzuki, Masayuki Yamamoto

    Redox Biology　2024/11

    DOI： 10.1016/j.redox.2024.103355 　

    ISSN： 2213-2317

  7. Specific cancer types and prognosis in patients with variations in the <scp>KEAP1</scp>‐<scp>NRF2</scp> system: A retrospective cohort study Peer-reviewed

    Tomoyuki Iwasaki, Hidekazu Shirota, Keiju Sasaki, Kota Ouchi, Yuki Nakayama, Hiroyuki Oshikiri, Akihito Otsuki, Takafumi Suzuki, Masayuki Yamamoto, Chikashi Ishioka

    Cancer Science　2024/09/26

    DOI： 10.1111/cas.16355 　

    ISSN： 1347-9032 1349-7006

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    <jats:title>Abstract</jats:title><jats:p>The KEAP1–NRF2 system induces the expression of antioxidant genes in response to various types of oxidative stress. Some cancer cells activate this system, which increases their malignancy through genetic mutations. We performed a retrospective cohort study using the C‐CAT database, which contains the gene‐panel sequence data from 60,056 cases of diagnosed solid tumors. We analyzed somatic mutations in <jats:italic>NRF2</jats:italic> and <jats:italic>KEAP1</jats:italic> genes and their associations with clinical outcomes. Variants in the <jats:italic>NRF2</jats:italic> gene were clustered in exon 2, which encodes the DLG and ETGE motifs essential for KEAP1 interaction. The <jats:italic>NRF2</jats:italic> variants were frequently observed in esophageal and lung squamous cell carcinoma with frequencies of 35.9% and 19.6%, respectively. Among these mutations, the <jats:italic>NRF2</jats:italic> variants in the ETGE motif were indicators of a worse prognosis. <jats:italic>KEAP1</jats:italic> variants were found in 2.5% of all cases. The variants were frequent in lung cancer and showed a worse prognosis in lung and other types of adenocarcinomas. We then conducted gene expression analysis using TCGA data. While cancers with DLG and ETGE variants were similar in terms of gene expression profiles, there were significant differences between cancers with <jats:italic>KEAP1</jats:italic> and <jats:italic>NRF2</jats:italic> variants. Our results indicate that genetic alteration of the KEAP1–NRF2 pathway is a major factor in patient prognosis for each cancer type and its genetic variant. Variants in <jats:italic>NRF2</jats:italic> and <jats:italic>KEAP1</jats:italic> genes can characterize the biological basis of each cancer type and are involved in carcinogenesis, resistance to therapy, and other biological differences.</jats:p>

  8. Estrogen, via ESR2 receptor, prevents oxidative stress-induced Müller cell death and stimulates FGF2 production independently of NRF2, attenuating retinal degeneration. International-journal

    Hiroshi Tawarayama, Keiko Uchida, Hirokazu Hasegawa, Masaaki Yoshida, Maki Inoue-Yanagimachi, Wataru Sato, Noriko Himori, Masayuki Yamamoto, Toru Nakazawa

    Experimental eye research　248　110103-110103　2024/09/18

    DOI： 10.1016/j.exer.2024.110103 　

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    In this study, we aimed to investigate the effects of the deficient antioxidative gene, nuclear factor-erythroid 2-related factor 2 (Nrf2), on 17β-estradiol (E2)-mediated oxidative stress response, with a specific focus on growth factor production and cell death in Müller cells and retinal tissue. Administration of hydrogen peroxide (H2O2) reduced the viability of Müller cells derived from Nrf2 wild-type (WT) and knockout (KO) mice. However, this effect was more significant in the KO cells than in the WT cells. Pretreatment with E2 inhibited H2O2-induced cell death in both Nrf2 WT and KO Müller cell genotypes. Small interfering RNA-mediated gene silencing of estrogen receptor 2 (Esr2) attenuated the cell survival-promoting activity of E2 in Nrf2 KO Müller cells, while other identified estrogen receptors, Esr1 or G protein-coupled estrogen receptor 1 (Gper1), had no effect. Western blotting revealed higher ESR2 expression levels in Nrf2 KO cells than in WT Müller cells. Conditioned media from E2-and H2O2-treated Nrf2 WT or KO Müller cells enhanced the dissociated retinal cell viability compared with H2O2-treated cells. Both quantitative reverse-transcription polymerase chain reaction assay (qRT-PCR) and enzyme-linked immunosorbent assay exhibited a significant increase in fibroblast growth factor 2 (FGF2) expression levels in E2-and H2O2-treated Nrf2 WT and KO Müller cells compared to those in E2-treated cells. In vivo, administration of N-methyl-N-nitrosourea (MNU) reduced the thickness and cell density of the outer nuclear layer (ONL) in Nrf2 KO mice and enhanced the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells in the ONL. However, E2 administration attenuated these defects in MNU-treated mice. Concomitant administration of MNU and E2 enhanced FGF2 protein levels in retinal lysates of Nrf2 KO mice. In conclusion, E2 demonstrated a significant role in preventing oxidative stress-induced retinal cell death by stimulating FGF2 production in Müller cells, independent of the Nrf2 gene. Based on these findings, we anticipate that exogenous administration of estrogens or ESR2-selective agonists could aid in treating patients with oxidative stress-related retinal degenerative diseases such as age-related macular degeneration and retinitis pigmentosa.

  9. Genetic Risk, Lifestyle Adherence, and Risk of Developing Hyperuricaemia in a Japanese Population. International-journal

    Masato Takase, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Sayuri Tokioka, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Akira Narita, Taku Obara, Mami Ishikuro, Hisashi Ohseto, Akira Uruno, Tomoko Kobayashi, Eiichi N Kodama, Yohei Hamanaka, Masatsugu Orui, Soichi Ogishima, Satoshi Nagaie, Nobuo Fuse, Junichi Sugawara, Shinichi Kuriyama, Biobank Japan Project Koichi Matsuda, Yoko Izumi, Kengo Kinoshita, Gen Tamiya, Atsushi Hozawa, Masayuki Yamamoto

    Rheumatology (Oxford, England)　2024/09/13

    DOI： 10.1093/rheumatology/keae492 　

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    OBJECTIVE: To investigate the inter-relationships among genetic risk, healthy lifestyle adherence, and hyperuricaemia susceptibility. METHODS: This prospective cohort study was conducted with 7,241 hyperuricaemia-free individuals aged ≥ 20 years from the Tohoku Medical Megabank Community-based cohort study. A comprehensive lifestyle score included body mass index, smoking, drinking, and physical activity, and a polygenic risk score (PRS) was constructed based on uric acid loci from a previous genome-wide association study meta-analysis. A multiple logistic regression model was used to estimate the association between genetic risk, healthy lifestyle, and hyperuricaemia incidence and calculate the area under the receiver operating characteristic curve (AUROC). Hyperuricaemia was defined as a uric acid level ≥7.0 mg/dl or a self-reported history of hyperuricaemia. RESULTS: Of the 7,241 adults (80.7% females; mean [SD] age: 57.7 [12.6] years), 217 (3.0%) developed hyperuricaemia during 3.5 years of follow-up. Genetic risk correlated with hyperuricaemia development (P for interaction = 0.287), and lifestyle risks were independently associated. Those with a high genetic risk and poor lifestyle had the highest risk (odds ratio: 5.34; 95% confidence interval [CI]: 2.61-12.10). Although not statistically significant, incorporating the PRS in the model with lifestyle information improved predictive ability (AUROC = 0.771, 95% CI: 0.736-0.806 for lifestyle; AUROC = 0.785, 95% CI: 0.751-0.819 for lifestyle and PRS; p = 0.07). CONCLUSION: : A healthy lifestyle to prevent hyperuricaemia, irrespective of genetic risk, may mitigate the genetic risk. Genetic risk may complement lifestyle factors in identifying individuals at a heightened hyperuricaemia risk.

  10. The NRF2 inducer CDDO-2P-Im provokes a reduction in amyloid β levels in Alzheimer's disease model mice. International-journal

    Akira Uruno, Shiori Kadoguchi-Igarashi, Ritsumi Saito, Shohei Koiso, Daisuke Saigusa, Ching-Tung Chu, Takafumi Suzuki, Takashi Saito, Takaomi C Saido, Antonio Cuadrado, Masayuki Yamamoto

    Journal of biochemistry　2024/09/11

    DOI： 10.1093/jb/mvae060 　

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    Alzheimer's disease (AD) is the most common etiology of dementia. The transcription factor NF-E2-related factor 2 (NRF2) induces the expression of genes encoding phase II detoxification and antioxidant genes. NRF2 is regulated by Kelch-like ECH-associated protein 1 (KEAP1), and the KEAP1-NRF2 system is the key regulatory system involved in cytoprotection. To examine whether pharmacological induction of NRF2 expression alleviates AD phenotypes in vivo, we employed two AD mouse models, i.e., App  NL-G-F/NL-G-F (AppNLGF) and APPV717I::TAUP301L (APP/TAU) mice. As the synthetic oleanane triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11-dien-28-oyl)] (CDDO)-4(-pyridin-2-yl)-imidazole (CDDO-2P-Im) exhibits strong NRF2-inducing activity, we treated AD model mice with CDDO-2P-Im. We found that Aβ42 levels were markedly greater in the brains of AppNLGF mice than in those of APP/TAU mice. CDDO-2P-Im treatment significantly decreased Aβ42 levels, but not Aβ40 levels, in APP/TAU mice. Consequently, CDDO-2P-Im also decreased the ratio of Aβ42/Aβ40, a vital marker of amyloid plaque formation. LC-MS/MS analyses revealed that CDDO-2P-Im was delivered to the brains of the APP/TAU mice. CDDO-2P-Im induced the expression of detoxification and antioxidant gene targets of NRF2 and elevated reduced glutathione (GSH) levels in the mouse brain. These results support the notion that CDDO-2P-Im ameliorates AD-related pathologic changes.

  11. Mutations of CYP1B1 and FOXC1 genes for childhood glaucoma in Japanese individuals.

    Nobuo Fuse, Masae Kimura, Ai Shimizu, Seizo Koshiba, Teruhiko Hamanaka, Makoto Nakamura, Nobuo Ishida, Hiroshi Sakai, Yoko Ikeda, Kazuhiko Mori, Atsushi Endo, Masao Nagasaki, Fumiki Katsuoka, Jun Yasuda, Yoichi Matsubara, Toru Nakazawa, Masayuki Yamamoto

    Japanese journal of ophthalmology　2024/08/19

    DOI： 10.1007/s10384-024-01103-0 　

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    PURPOSE: To explore the frequency and positions of genetic mutations in CYP1B1 and FOXC1 in a Japanese population. STUDY DESIGN: Molecular genetic analysis. METHODS: Genomic DNA was extracted from 31 Japanese patients with childhood glaucoma (CG) from 29 families. We examined the CYP1B, FOXC1, and MYOC genes using Sanger sequencing and whole-exome sequencing (WES). RESULTS: For CYP1B1, we identified 9 families that harbored novel mutations, p.A202T, p.D274E, p.Q340*, and p.V420G; the remaining mutations had been previously reported. When mapped to the CYP1B1 protein structure, all mutations appeared to influence the enzymatic activity of CYP1B1 by provoking structural deformity. Five patients were homozygotes or compound heterozygotes, supporting the recessive inheritance of the CYP1B1 mutations in CG. In contrast, four patients were heterozygous for the CYP1B1 mutation, suggesting the presence of regulatory region mutations or strong modifiers. For the FOXC1 gene, we identified 3 novel mutations, p.Q23fs, p.Q70R, and p.E163*, all of which were identified in a heterozygous state. No mutation was found in the MYOC gene in these CG patients. All individuals with CYP1B1 and FOXC1 mutations were severely affected by early-onset CG. In the CYP1B1-, FOXC1-, and MYOC-negative families, we also searched for variants in the other candidate genes reported for CG through WES, but could not find any mutations in these genes. CONCLUSIONS: Our analyses of 29 CG families revealed 9 families with point mutations in the CYP1B1 gene, and four of those patients appeared to be heterozygotes, suggesting the presence of complex pathogenic mechanisms. FOXC1 appears to be another major causal gene of CG, indicating that panel sequencing of CYP1B1 and FOXC1 will be useful for diagnosis of CG in Japanese individuals.

  12. How Healthy Lifestyle Habits Have Interacted with SARS-CoV-2 Infection and the Effectiveness of COVID-19 Vaccinations: Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

    Masatsugu Orui, Taku Obara, Mami Ishikuro, Aoi Noda, Genki Shinoda, Keiko Murakami, Tomohiro Nakamura, Hirohito Metoki, Soichi Ogishima, Yoko Izumi, Naoki Nakaya, Atsushi Hozawa, Tadashi Ishii, Fuji Nagami, Masayuki Yamamoto, Shinichi Kuriyama

    JMA journal　7　(3)　353-363　2024/07/16

    DOI： 10.31662/jmaj.2024-0043 　

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    INTRODUCTION: To examine the interaction between lifestyle habits and the COVID-19 vaccinations for preventing SARS-CoV-2 infection, we analyzed 11,016 adult participants registered in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. METHODS: Lifestyle variables, including regular exercise, smoking and drinking habits, sleep status, body mass index, and daily breakfast consumption, were assessed from 2014 to 2019 using baseline questionnaires. Information on SARS-CoV-2 infection and the COVID-19 vaccination were also collected from March 2020 to May 2023. The study period was divided into two in the postvaccination phase: the first period (the beginning of the vaccination program) and the second period (the fourth shot onward). RESULTS: In the Cox proportional-hazards model analysis, the five-time vaccinations group showed a significantly lower risk of SARS-CoV-2 infection adjusted age, sex, underlying health condition, and lifestyle variables (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.76-0.86). Logistic regression analysis revealed that a higher number of vaccinations was significantly associated with a low risk of SARS-CoV-2 infection regardless of lifestyle habits (three times in the first period: odds ratio [OR] 0.19, 95% CI 0.15-0.24; five times in the second period: OR 0.07, 95% CI 0.05-0.11 vs. none). Regarding lifestyle habits, the risk reduction in those who had sleep satisfaction (OR 0.12, 95% CI 0.08-0.18) was slightly larger than in those who had sleep dissatisfaction (OR 0.23, 95% CI 0.17-0.32) in the group with the highest number of vaccinations in the first period; however, this interaction was hardly confirmed in the second period when the number of infected cases significantly increased. CONCLUSIONS: Our findings indicated that a higher number of COVID-19 vaccinations was associated with reduced risk of SARS-CoV-2 infection; otherwise, we may need to understand the advantages and limitations of a healthy lifestyle for preventing infection depending on the situation with vaccinations and infection spreading.

  13. Urgent Notification Intervention of Home Blood Pressure in Cohort Studies of the Tohoku Medical Megabank Project.

    Eiichi N Kodama, Makiko Taira, Hideyasu Kiyomoto, Tomohiro Nakamura, Satoshi Nagaie, Shinichi Kuriyama, Atsushi Hozawa, Junichi Sugawara, Fuji Nagami, Akira Uruno, Jun Nakaya, Hirohito Metoki, Masaki Sakaida, Masahiro Kikuya, Yoichi Suzuki, Kiyoshi Ito, Yohei Hamanaka, Kichiya Suzuki, Shigeo Kure, Nobuo Yaegashi, Nobuo Fuse, Ritsuko Shimizu, Masayuki Yamamoto

    JMA journal　7　(3)　342-352　2024/07/16

    DOI： 10.31662/jmaj.2023-0215 　

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    INTRODUCTION: The Tohoku Medical Megabank (TMM) was established for creative reconstruction from the Great East Japan Earthquake and tsunami in 2011. Two prospective genome cohort studies in Miyagi prefecture have successfully recruited approximately 127,000 participants. The health status of these individuals was evaluated at the initial recruitment, and follow-up health checkups have been conducted every 5 years. During these health checkups, unexpected critical values were encountered, which prompted us to develop an urgent notification system. METHODS: We analyzed the frequency of critical values observed in home blood pressure (HBP) test in an urgent notification office (UNO). We returned the critical values by urgent notification before the notifications of regular results. In addition, the impact of the TMM urgent notification on the participants was evaluated. RESULTS: We issued urgent notifications of the critical values of extremely high HBP. Of the 21,061 participants who underwent HBP measurements, 256 (1.2%) met the criteria for urgent notification. It was found that abnormalities in blood sugar levels, renal function, and lipid values were frequently concurrent with the abnormal HBP readings. Annual questionnaires administered after the urgent notification, approximately 60% of those went to hospitals or clinics. CONCLUSIONS: The urgent notification system for hypertensive emergency with HBP in the TMM was well accepted by the participants and encouraged them to seek medical care. The system has been useful in addressing the prolonged healthcare problems and in promoting health care in large-scale disaster damaged areas.

  14. Identifying critical age and gender-based metabolomic shifts in a Japanese population of the Tohoku Medical Megabank cohort. International-journal

    Miyuki Sakurai, Ikuko N Motoike, Eiji Hishinuma, Yuichi Aoki, Shu Tadaka, Mana Kogure, Masatsugu Orui, Mami Ishikuro, Taku Obara, Naoki Nakaya, Kazuki Kumada, Atsushi Hozawa, Shinichi Kuriyama, Masayuki Yamamoto, Seizo Koshiba, Kengo Kinoshita

    Scientific reports　14　(1)　15681-15681　2024/07/08

    DOI： 10.1038/s41598-024-66180-0 　

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    Understanding the physiological changes associated with aging and the associated disease risks is essential to establish biomarkers as indicators of biological aging. This study used the NMR-measured plasma metabolome to calculate age-specific metabolite indices. In doing so, the scope of the study was deliberately simplified to capture general trends and insights into age-related changes in metabolic patterns. In addition, changes in metabolite concentrations with age were examined in detail, with the period from 55-59 to 60-64 years being a period of significant metabolic change, particularly in men, and from 45-49 to 50-54 years in females. These results illustrate the different variations in metabolite concentrations by sex and provide new insights into the relationship between age and metabolic diseases.

  15. Associations of combined genetic and lifestyle risks with hypertension and home hypertension. International-journal

    Masato Takase, Takumi Hirata, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Akira Narita, Hirohito Metoki, Michihiro Satoh, Taku Obara, Mami Ishikuro, Hisashi Ohseto, Akira Uruno, Tomoko Kobayashi, Eiichi N Kodama, Yohei Hamanaka, Masatsugu Orui, Soichi Ogishima, Satoshi Nagaie, Nobuo Fuse, Junichi Sugawara, Shinichi Kuriyama, Gen Tamiya, Atsushi Hozawa, Masayuki Yamamoto

    Hypertension research : official journal of the Japanese Society of Hypertension　2024/06/24

    DOI： 10.1038/s41440-024-01705-8 　

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    No study, to our knowledge, has constructed a polygenic risk score based on clinical blood pressure and investigated the association of genetic and lifestyle risks with home hypertension. We examined the associations of combined genetic and lifestyle risks with hypertension and home hypertension. In a cross-sectional study of 7027 Japanese individuals aged ≥20 years, we developed a lifestyle score based on body mass index, alcohol consumption, physical activity, and sodium-to-potassium ratio, categorized into ideal, intermediate, and poor lifestyles. A polygenic risk score was constructed with the target data (n = 1405) using publicly available genome-wide association study summary statistics from BioBank Japan. Using the test data (n = 5622), we evaluated polygenic risk score performance and examined the associations of combined genetic and lifestyle risks with hypertension and home hypertension. Hypertension and home hypertension were defined as blood pressure measured at a community-support center ≥140/90 mmHg or at home ≥135/85 mmHg, respectively, or self-reported treatment for hypertension. In the test data, 2294 and 2322 participants had hypertension and home hypertension, respectively. Both polygenic risk and lifestyle scores were independently associated with hypertension and home hypertension. Compared with those of participants with low genetic risk and an ideal lifestyle, the odds ratios for hypertension and home hypertension in the low genetic risk and poor lifestyle group were 1.94 (95% confidence interval, 1.34-2.80) and 2.15 (1.60-2.90), respectively. In summary, lifestyle is important to prevent hypertension; nevertheless, participants with high genetic risk should carefully monitor their blood pressure despite a healthy lifestyle.

  16. Genetic Risk, Healthy Lifestyle Adherence, and Risk of Developing Diabetes in the Japanese Population.

    Masato Takase, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Akira Narita, Taku Obara, Mami Ishikuro, Akira Uruno, Tomoko Kobayashi, Eiichi N Kodama, Yohei Hamanaka, Masatsugu Orui, Soichi Ogishima, Satoshi Nagaie, Nobuo Fuse, Junichi Sugawara, Shinichi Kuriyama, Koichi Matsuda, Yoko Izumi, Kengo Kinoshita, Gen Tamiya, Atsushi Hozawa, Masayuki Yamamoto

    Journal of atherosclerosis and thrombosis　2024/06/22

    DOI： 10.5551/jat.64906 　

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    AIM: This study examined the relationship between genetic risk, healthy lifestyle, and risk of developing diabetes. METHODS: This prospective cohort study included 11,014 diabetes-free individuals ≥ 20 years old from the Tohoku Medical Megabank Community-based cohort study. Lifestyle scores, including the body mass index, smoking, physical activity, and gamma-glutamyl transferase (marker of alcohol consumption), were assigned, and participants were categorized into ideal, intermediate, and poor lifestyles. A polygenic risk score (PRS) was constructed based on the type 2 diabetes loci from the BioBank Japan study. A multiple logistic regression model was used to estimate the association between genetic risk, healthy lifestyle, and diabetes incidence and to calculate the area under the receiver operating characteristic curve (AUROC). RESULT: Of the 11,014 adults included (67.8% women; mean age [standard deviation], 59.1 [11.3] years old), 297 (2.7%) developed diabetes during a mean 4.3 (0.8) years of follow-up. Genetic and lifestyle score is independently associated with the development of diabetes. Compared with the low genetic risk and ideal lifestyle groups, the odds ratio was 3.31 for the low genetic risk and poor lifestyle group. When the PRS was integrated into a model including the lifestyle and family history, the AUROC significantly improved to 0.719 (95% confidence interval [95% CI]: 0.692-0.747) compared to a model including only the lifestyle and family history (0.703 [95% CI, 0.674-0.732]). CONCLUSION: Our findings indicate that adherence to a healthy lifestyle is important for preventing diabetes, regardless of genetic risk. In addition, genetic risk might provide information beyond lifestyle and family history to stratify individuals at high risk of developing diabetes.

  17. Body mass index stratification optimizes polygenic prediction of type 2 diabetes in cross-biobank analyses Peer-reviewed

    Takafumi Ojima, Shinichi Namba, Ken Suzuki, Kenichi Yamamoto, Kyuto Sonehara, Akira Narita, Yoichiro Kamatani, Gen Tamiya, Masayuki Yamamoto, Toshimasa Yamauchi, Takashi Kadowaki, Yukinori Okada

    Nature Genetics　2024/06/11

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41588-024-01782-y 　

    ISSN： 1061-4036

    eISSN： 1546-1718

  18. Bag1 protein loss sensitizes mouse embryonic fibroblasts to glutathione depletion. International-journal

    Atsushi Inose-Maruyama, Hayato Irokawa, Kouki Takeda, Keiko Taguchi, Masanobu Morita, Masayuki Yamamoto, Masato Sasaki, Shusuke Kuge

    Cell stress & chaperones　29　(3)　497-509　2024/06

    DOI： 10.1016/j.cstres.2024.05.003 　

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    Bcl2-associated athanogene-1 protein (Bag1) acts as a co-chaperone of heat shock protein 70 and heat shock cognate 70 and regulates multiple cellular processes, including cell proliferation, apoptosis, environmental stress response, and drug resistance. Since Bag1 knockout mice exhibited fetal lethality, the in vivo function of Bag1 remains unclear. In this study, we established a mouse line expressing Bag1 gene missing exon 5, which corresponds to an encoding region for the interface of heat shock protein 70/heat shock cognate 70. Despite mice carrying homoalleles of the Bag1 mutant (Bag1Δex5) expressing undetectable levels of Bag1, Bag1Δex5 homozygous mice developed without abnormalities. Bag1Δex5 protein was found to be highly unstable in cells and in vitro. We found that the growth of mouse embryonic fibroblasts derived from Bag1Δex5-homo mice was attenuated by doxorubicin and a glutathione (GSH) synthesis inhibitor, buthionine sulfoximine. In response to buthionine sulfoximine, Bag1Δex5-mouse embryonic fibroblasts exhibited a higher dropping rate of GSH relative to the oxidized glutathione level. In addition, Bag1 might mitigate cellular hydrogen peroxide levels. Taken together, our results demonstrate that the loss of Bag1 did not affect mouse development and that Bag1 is involved in intracellular GSH homeostasis, namely redox homeostasis.

  19. The drug-specific properties of hypoxia-inducible factor-prolyl hydroxylase inhibitors in mice reveal a significant contribution of the kidney compared to the liver to erythropoietin induction

    Taku Nakai, Daisuke Saigusa, Koichiro Kato, Tomoko Fukuuchi, Seizo Koshiba, Masayuki Yamamoto, Norio Suzuki

    Life Sciences　346　122641-122641　2024/06

    Publisher: Elsevier BV

    DOI： 10.1016/j.lfs.2024.122641 　

    ISSN： 0024-3205

  20. PNPO–PLP axis senses prolonged hypoxia in macrophages by regulating lysosomal activity

    Hiroki Sekine, Haruna Takeda, Norihiko Takeda, Akihiro Kishino, Hayato Anzawa, Takayuki Isagawa, Nao Ohta, Shohei Murakami, Hideya Iwaki, Nobufumi Kato, Shu Kimura, Zun Liu, Koichiro Kato, Fumiki Katsuoka, Masayuki Yamamoto, Fumihito Miura, Takashi Ito, Masatomo Takahashi, Yoshihiro Izumi, Hiroyuki Fujita, Hitoshi Yamagata, Takeshi Bamba, Takaaki Akaike, Norio Suzuki, Kengo Kinoshita, Hozumi Motohashi

    Nature Metabolism　2024/05/31

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s42255-024-01053-4 　

    eISSN： 2522-5812

  21. A fine-scale genetic map of the Japanese population. International-journal

    Jun Takayama, Satoshi Makino, Takamitsu Funayama, Masao Ueki, Akira Narita, Keiko Murakami, Masatsugu Orui, Mami Ishikuro, Taku Obara, Shinichi Kuriyama, Masayuki Yamamoto, Gen Tamiya

    Clinical genetics　2024/05/08

    DOI： 10.1111/cge.14536 　

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    Genetic maps are fundamental resources for linkage and association studies. A fine-scale genetic map can be constructed by inferring historical recombination events from the genome-wide structure of linkage disequilibrium-a non-random association of alleles among loci-by using population-scale sequencing data. We constructed a fine-scale genetic map and identified recombination hotspots from 10 092 551 bi-allelic high-quality autosomal markers segregating among 150 unrelated Japanese individuals whose genotypes were determined by high-coverage (30×) whole-genome sequencing, and the genotype quality was carefully controlled by using their parents' and offspring's genotypes. The pedigree information was also utilized for haplotype phasing. The resulting genome-wide recombination rate profiles were concordant with those of the worldwide population on a broad scale, and the resolution was much improved. We identified 9487 recombination hotspots and confirmed the enrichment of previously known motifs in the hotspots. Moreover, we demonstrated that the Japanese genetic map improved the haplotype phasing and genotype imputation accuracy for the Japanese population. The construction of a population-specific genetic map will help make genetics research more accurate.

  22. GWAS meta-analysis of kidney function traits in Japanese populations.

    Asahi Hishida, Masahiro Nakatochi, Yoichi Sutoh, Shiori Nakano, Yukihide Momozawa, Akira Narita, Kozo Tanno, Atsushi Shimizu, Atsushi Hozawa, Kengo Kinoshita, Taiki Yamaji, Atsushi Goto, Mitsuhiko Noda, Norie Sawada, Hiroaki Ikezaki, Mako Nagayoshi, Megumi Hara, Sadao Suzuki, Teruhide Koyama, Chihaya Koriyama, Sakurako Katsuura-Kamano, Aya Kadota, Kiyonori Kuriki, Masayuki Yamamoto, Makoto Sasaki, Motoki Iwasaki, Keitaro Matsuo, Kenji Wakai

    Journal of epidemiology　2024/04/06

    DOI： 10.2188/jea.JE20230281 　

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    BACKGROUND: Genetic epidemiological evidence for the kidney function traits in East Asian population including Japanese remain still relatively unclarified. Especially, the number of GWASs for kidney traits reported still remains limited, and the sample size of each independent study is relatively small. Given the genetic variability between ancestries/ethnicities, implementation of GWAS with sufficiently large sample sizes in specific population of Japanese is considered meaningful. METHODS: We conducted the GWAS meta-analyses of kidney traits by leveraging the GWAS summary data of the representative large genome cohort studies with about 200,000 Japanese participants (n = 202,406 for estimated glomerular filtration rate [eGFR] and n = 200,845 for serum creatinine [SCr]). RESULTS: In the present GWAS meta-analysis, we identified 110 loci with 169 variants significantly associated with eGFR (on chromosomes 1-13 and 15-22; p < 5×10-8), whereas we also identified 112 loci with 176 variants significantly associated with SCr (on chromosomes 1-22; p < 5×10-8), of which one locus (more than 1Mb distant from known loci) with one variant (CD36 rs146148222 on chromosome 7) for SCr was considered as the truly novel finding. CONCLUSIONS: The present GWAS meta-analysis of largest genome cohort studies in Japanese provided some original genomic loci associated with kidney function in Japanese, which may contribute to the possible development of personalized prevention of kidney diseases based on genomic information in the near future.

  23. Differential squamous cell fates elicited by NRF2 gain of function versus KEAP1 loss of function Peer-reviewed

    Jun Takahashi, Takafumi Suzuki, Miu Sato, Shuji Nitta, Nahoko Yaguchi, Tatsuki Muta, Kouhei Tsuchida, Hiromi Suda, Masanobu Morita, Shin Hamada, Atsushi Masamune, Satoru Takahashi, Takashi Kamei, Masayuki Yamamoto

    Cell Reports　2024/04

    DOI： 10.1016/j.celrep.2024.114104 　

  24. The Health History of First-Degree Relatives’ Dyslipidemia Can Affect Preferences and Intentions following the Return of Genomic Results for Monogenic Familial Hypercholesterolemia Peer-reviewed

    Tomoharu Tokutomi, Akiko Yoshida, Akimune Fukushima, Kayono Yamamoto, Yasushi Ishigaki, HIROSHI KAWAME, Nobuo Fuse, Fuji Nagami, Yoichi Suzuki, Mika Sakurai-Yageta, Akira Uruno, Kichiya Suzuki, Kozo Tanno, Hideki Ohmomo, Atsushi Shimizu, Masayuki Yamamoto, Makoto Sasaki

    Genes　2024/03/21

    DOI： 10.3390/genes15030384 　

  25. Development of phenotyping algorithms for hypertensive disorders of pregnancy (HDP) and their application in more than 22,000 pregnant women. International-journal

    Satoshi Mizuno, Maiko Wagata, Satoshi Nagaie, Mami Ishikuro, Taku Obara, Gen Tamiya, Shinichi Kuriyama, Hiroshi Tanaka, Nobuo Yaegashi, Masayuki Yamamoto, Junichi Sugawara, Soichi Ogishima

    Scientific reports　14　(1)　6292-6292　2024/03/15

    DOI： 10.1038/s41598-024-55914-9 　

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    Recently, many phenotyping algorithms for high-throughput cohort identification have been developed. Prospective genome cohort studies are critical resources for precision medicine, but there are many hurdles in the precise cohort identification. Consequently, it is important to develop phenotyping algorithms for cohort data collection. Hypertensive disorders of pregnancy (HDP) is a leading cause of maternal morbidity and mortality. In this study, we developed, applied, and validated rule-based phenotyping algorithms of HDP. Two phenotyping algorithms, algorithms 1 and 2, were developed according to American and Japanese guidelines, and applied into 22,452 pregnant women in the Birth and Three-Generation Cohort Study of the Tohoku Medical Megabank project. To precise cohort identification, we analyzed both structured data (e.g., laboratory and physiological tests) and unstructured clinical notes. The identified subtypes of HDP were validated against reference standards. Algorithms 1 and 2 identified 7.93% and 8.08% of the subjects as having HDP, respectively, along with their HDP subtypes. Our algorithms were high performing with high positive predictive values (0.96 and 0.90 for algorithms 1 and 2, respectively). Overcoming the hurdle of precise cohort identification from large-scale cohort data collection, we achieved both developed and implemented phenotyping algorithms, and precisely identified HDP patients and their subtypes from large-scale cohort data collection.

  26. Dietary habits and plasma lipid concentrations in a general Japanese population. International-journal

    Mitsuharu Sato, Eiji Hishinuma, Naomi Matsukawa, Yoshiko Shima, Daisuke Saigusa, Ikuko N Motoike, Mana Kogure, Naoki Nakaya, Atsushi Hozawa, Shinichi Kuriyama, Masayuki Yamamoto, Seizo Koshiba, Kengo Kinoshita

    Metabolomics : Official journal of the Metabolomic Society　20　(2)　34-34　2024/03/05

    DOI： 10.1007/s11306-024-02087-1 　

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    INTRODUCTION: Accumulating data on the associations between food consumption and lipid composition in the body is essential for understanding the effects of dietary habits on health. OBJECTIVES: As part of omics research in the Tohoku Medical Megabank Community-Based Cohort Study, this study sought to reveal the dietary impact on plasma lipid concentration in a Japanese population. METHODS: We conducted a correlation analysis of food consumption and plasma lipid concentrations measured using mass spectrometry, for 4032 participants in Miyagi Prefecture, Japan. RESULTS: Our analysis revealed 83 marked correlations between six food categories and the concentrations of plasma lipids in nine subclasses. Previously reported associations, including those between seafood consumption and omega-3 fatty acids, were validated, while those between dairy product consumption and odd-carbon-number fatty acids (odd-FAs) were validated for the first time in an Asian population. Further analysis suggested that dairy product consumption is associated with odd-FAs via sphingomyelin (SM), which suggests that SM is a carrier of odd-FAs. These results are important for understanding odd-FA metabolism with regards to dairy product consumption. CONCLUSION: This study provides insight into the dietary impact on plasma lipid concentration in a Japanese population.

  27. Strain-dependent modifiers exacerbate familial leukemia caused by GATA1-deficiency. International-journal

    Ikuo Hirano, Kanako Abe, James Douglas Engel, Masayuki Yamamoto, Ritsuko Shimizu

    Experimental hematology & oncology　13　(1)　23-23　2024/02/26

    DOI： 10.1186/s40164-024-00491-w 　

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    GATA1 plays a critical role in differentiation, proliferation, and apoptosis during erythropoiesis. We developed a Gata1 knock-down allele (Gata1.05) that results in GATA1 expression at 5% of endogenous level. In female mice heterozygous for both the Gata1.05 and wild-type alleles, we observed a predisposition to erythroblastic leukemia three to six months after birth. Since no male Gata1.05 progeny survive gestation, we originally maintained heterozygous females in a mixed genetic background of C57BL/6J and DBA/2 strains. Around 30% of these mice reproducibly develop leukemia, but the other subset did not develop leukemia, even though they harbor a high number of preleukemic erythroblasts. These observations prompted us to hypothesize that there may be potential influence of genetic determinants on the progression of Gata1.05-driven hematopoietic precursors to full-blown leukemia. In an initial examination of Gata1.05/X mice backcrossed into C3H/He, BALB/c, DBA/2, C57BL/6J and 129X1/SvJ strains, we discerned that the backgrounds of C57BL/6J and 129X1/SvJ significantly expedited leukemia onset in Gata1.05/X mice. Conversely, backgrounds of C3H/He, BALB/c and DBA/2 did not substantially modify the effect of the Gata1 mutation. This indicates the existence of genetic modifiers that accentuate Gata1.05 leukemogenesis. Subsequent cohort studies evaluated Gata1.05/X mice within mix backgrounds of BALB/c:129X1/SvJ and BALB/c:C57BL/6J. In these settings, Gata1.05-driven leukemia manifested in autosomal dominant patterns within the 129X1/SvJ background and in autosomal recessive patterns within C57BL/6J background. To the best of our knowledge, this study provides the inaugural evidence of genetic modifiers that can reshape the outcome based on leukemia-associated gene signatures.

  28. The abundance of the short GATA1 isoform affects megakaryocyte differentiation and leukemic predisposition in mice. International-journal

    Daishi Ishihara, Atsushi Hasegawa, Ikuo Hirano, James Douglas Engel, Masayuki Yamamoto, Ritsuko Shimizu

    Experimental hematology & oncology　13　(1)　24-24　2024/02/26

    DOI： 10.1186/s40164-024-00492-9 　

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    Transcription factor GATA1 controls the delicate balance between proliferation, differentiation and apoptosis in both the erythroid and megakaryocytic lineages. In addition to full-length GATA1, there is an GATA1 isoform, GATA1s, that lacks the amino-terminal transactivation domain. Somatic GATA1 mutations that lead to the exclusive production of GATA1s appear to be necessary and sufficient for the development of a preleukemic condition called transient myeloproliferative disorder (TMD) in Down syndrome newborns. Subsequent clonal evolution among latent TMD blasts leads to the development of acute megakaryoblastic leukemia (AMKL). We originally established transgenic mice that express only GATA1s, which exhibit hyperproliferation of immature megakaryocytes, thus mimicking human TMD; however, these mice never developed AMKL. Here, we report that transgenic mice expressing moderate levels of GATA1s, i.e., roughly comparable levels to endogenous GATA1, were prone to develop AMKL in young adults. However, when GATA1s is expressed at levels significantly exceeding that of endogenous GATA1, the development of leukemia was restrained in a dose dependent manner. If the transgenic increase of GATA1s in progenitors remains small, GATA1s supports the terminal maturation of megakaryocyte progenitors insufficiently, and consequently the progenitors persisted, leading to an increased probability for acquisition of additional genetic modifications. In contrast, more abundant GATA1s expression compensates for this maturation block, enabling megakaryocytic progenitors to fully differentiate. This study provides evidence for the clinical observation that the abundance of GATA1s correlates well with the progression to AMKL in Down syndrome.

  29. Progress report of the Tohoku Medical Megabank Community-Based Cohort Study: Study profile of the repeated center-based survey during second period in Miyagi Prefecture.

    Atsushi Hozawa, Kumi Nakaya, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Ippei Chiba, Ikumi Kanno, Junichi Sugawara, Eiichi Kodama, Yohei Hamanaka, Tomoko Kobayashi, Akira Uruno, Naho Tsuchiya, Takumi Hirata, Akira Narita, Akito Tsuboi, Toru Tamahara, Akihito Otsuki, Maki Goto, Makiko Taira, Ritsuko Shimizu, Kichiya Suzuki, Taku Obara, Masahiro Kikuya, Hirohito Metoki, Mami Ishikuro, Inaho Danjoh, Soichi Ogishima, Satoshi Nagaie, Naoko Minegishi, Masahiro Hiratsuka, Kazuki Kumada, Ichiko Nishijima, Takahiro Nobukuni, Yumi Yamaguchi-Kabata, Fuji Nagami, Shigeo Kure, Nobuo Fuse, Kengo Kinoshita, Yoko Izumi, Shinichi Kuriyama, Masayuki Yamamoto

    Journal of epidemiology　2024/02/24

    DOI： 10.2188/jea.JE20230241 　

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    BACKGROUND: The purpose of this study was to report the basic profile of the Miyagi Prefecture part of a repeated center-based survey during the second period (2nd period survey) of the Tohoku Medical Megabank Community-Based Cohort Study (TMM CommCohort Study), as well as the participants' characteristics based on their participation type in the baseline survey. METHODS: The 2nd period survey, conducted from June 2017 to March 2021, included participants of the TMM CommCohort Study (May 2013 to March 2016). In addition to the questionnaire, blood, urine, and physiological function tests were performed during the 2nd period survey. There were three main ways of participation in the baseline survey: Type 1, Type 1 additional, or Type 2 survey. The 2nd period survey was conducted in the same manner as the Type 2 survey, which was based on the community support center (CSC). RESULTS: In Miyagi Prefecture, 29,383 (57.7%) of 50,967 participants participated in the 2nd period survey. The participation rate among individuals who had visited the CSC was approximately 80%. Although some factors differed depending on the participation type in the baseline survey, the 2nd period survey respondents in the Type 1 and Type 2 survey groups at baseline had similar traits. CONCLUSIONS: The 2nd period survey of the TMM CommCohort Study provided detailed follow-up information. Following up on the health conditions of the participants will clarify the long-term effects of disasters and contribute to personalized prevention.

  30. Whole blood transcriptome analysis for age- and gender-specific gene expression profiling in Japanese individuals. International-journal

    Yu-Ichi Aoki, Keiko Taguchi, Hayato Anzawa, Junko Kawashima, Noriko Ishida, Akihito Otuki, Atsushi Hasegawa, Liam Baird, Takafumi Suzuki, Ikuko N Motoike, Kinuko Ohneda, Kazuki Kumada, Fumiki Katsuoka, Kengo Kinoshita, Masayuki Yamamoto

    Journal of biochemistry　2024/01/24

    DOI： 10.1093/jb/mvae008 　

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    Whole blood transcriptome analysis is a valuable approach in medical research, primarily due to the ease of sample collection and the richness of the information obtained. Since the expression profile of individual genes in the analysis is influenced by medical traits and demographic attributes such as age and gender, there has been a growing demand for a comprehensive database for blood transcriptome analysis. Here, we performed whole blood RNA sequencing (RNA-seq) analysis on 576 participants stratified by age (20-30s and 60-70s) and gender from cohorts of the Tohoku Medical Megabank (TMM). A part of female segment included pregnant women. We did not exclude the globin gene family in our RNA-seq study, which enabled us to identify instances of hereditary persistence of fetal hemoglobin based on the HBG1 and HBG2 expression information. Comparing stratified populations allowed us to identify groups of genes associated with age-related changes and gender differences. We also found that the immune response status, particularly measured by neutrophil-to-lymphocyte ratio (NLR), strongly influences the diversity of individual gene expression profiles in whole blood transcriptome analysis. This stratification has resulted in a dataset that will be highly beneficial for future whole blood transcriptome analysis in the Japanese population.

  31. Author Correction: Reduced glutathione level in the aqueous humor of patients with primary open-angle glaucoma and normal-tension glaucoma. International-journal

    Kota Sato, Daisuke Saigusa, Taiki Kokubun, Amane Fujioka, Qiwei Feng, Ritsumi Saito, Akira Uruno, Naomi Matsukawa, Michiko Ohno-Oishi, Hiroshi Kunikata, Yu Yokoyama, Masayuki Yasuda, Noriko Himori, Kazuko Omodaka, Satoru Tsuda, Shigeto Maekawa, Masayuki Yamamoto, Toru Nakazawa

    npj aging　10　(1)　8-8　2024/01/20

    DOI： 10.1038/s41514-024-00137-5 　

  32. Next-generation sequencing analysis with a population-specific human reference genome

    Tomohisa Suzuki, Kota Ninomiya, Takamitsu Funayama, Yasunobu Okamura, Shu Tadaka, Kengo Kinoshita, Masayuki Yamamoto, Shigeo Kure, Atsuo Kikuchi, Gen Tamiya, Jun Takayama

    Genes &amp; Genetic Systems　2024

    Publisher: Genetics Society of Japan

    DOI： 10.1266/ggs.24-00112 　

    ISSN： 1341-7568

    eISSN： 1880-5779

  33. Detection and Correction of Sample Misidentifications in a Biobank Using the MassARRAY System and Genomic Information. International-journal

    Hisaaki Kudo, Noriko Ishida, Takahiro Nobukuni, Yuichi Aoki, Sakae Saito, Ichiko Nishijima, Takahiro Terakawa, Masayuki Yamamoto, Naoko Minegishi, Riu Yamashita, Kazuki Kumada

    Biopreservation and biobanking　2023/12/11

    DOI： 10.1089/bio.2022.0211 　

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    With the number of samples increasing in many biobanks, one of the most pressing tasks is recording the correct relationships between information and the specimens. Genomic information is useful in determining the identity of these specimens. The Tohoku Medical Megabank Organization is running one of the largest biobanks in Japan. Here, we introduce a management system, which includes the development of a new probe set for the MassARRAY system for use during the production of proliferating T cells (T cells) and lymphoblastoid cell lines (LCLs). We selected single nucleotide variants that could be detected by next-generation sequencing and showed high resolution with ∼0.5 minor allele frequencies. After checking the set of probes against 96 samples from 48 people, we obtained no contradictory results in comparison with our genome sequence information. When we applied the set to our 3035 LCLs and 2256 T cells, the result showed 98.93% consistency with the corresponding genomic information. We surveyed the handling records of the 1.07% of samples that showed inconsistencies, and found that most had resulted from human errors (ID swapping between samples) during manual operations. After improving a few error-prone protocols, the error rate dropped to 0.47% for LCLs and 0% for T cells. Overall, the system that we developed shows high accuracy with easy and fast operability, and provides a good opportunity to improve the validation procedure to facilitate high-quality banking, especially in cases involving genomic information.

  34. Reduced glutathione level in the aqueous humor of patients with primary open-angle glaucoma and normal-tension glaucoma. International-journal

    Kota Sato, Daisuke Saigusa, Taiki Kokubun, Amane Fujioka, Qiwei Feng, Ritsumi Saito, Akira Uruno, Naomi Matsukawa, Michiko Ohno-Oishi, Hiroshi Kunikata, Yu Yokoyama, Masayuki Yasuda, Noriko Himori, Kazuko Omodaka, Satoru Tsuda, Shigeto Maekawa, Masayuki Yamamoto, Toru Nakazawa

    npj aging　9　(1)　28-28　2023/11/21

    DOI： 10.1038/s41514-023-00124-2 　

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    Glaucoma is a leading cause of blindness worldwide in older people. Profiling the aqueous humor, including the metabolites it contains, is useful to understand physiological and pathological conditions in the eye. In the current study, we used mass spectrometry (MS) to characterize the aqueous humor metabolomic profile and biological features of patients with glaucoma. Aqueous humor samples were collected during trabeculectomy surgery or cataract surgery and analyzed with global metabolomics. We included 40 patients with glaucoma (32 with POAG, 8 with NTG) and 37 control subjects in a discovery study. VIP analysis revealed five metabolites that were elevated and three metabolites that were reduced in the glaucoma patients. The identified metabolomic profile had an area under the receiver operating characteristic curve of 0.953. Among eight selected metabolites, the glutathione level was significantly decreased in association with visual field defects. Moreover, in a validation study to confirm the reproducibility of our findings, the glutathione level was reduced in NTG and POAG patients compared with a cataract control group. Our findings demonstrate that aqueous humor profiling can help to diagnose glaucoma and that various aqueous humor metabolites are correlated with clinical parameters in glaucoma patients. In addition, glutathione is clearly reduced in the aqueous humor of glaucoma patients with both IOP-dependent and IOP-independent disease subtypes. These findings indicate that antioxidant agents in the aqueous humor reflect glaucomatous optic nerve damage and that excessive oxidative stress may be involved in the pathogenesis of glaucoma.

  35. Effects of NRF2 polymorphisms on safety and efficacy of bardoxolone methyl: subanalysis of TSUBAKI study Peer-reviewed

    Kazuaki Ikejiri, Takafumi Suzuki, Satsuki Muto, Hirotaka Takama, Kengo Yamawaki, Tatsuya Miyazawa, Itaru Urakawa, Yuichi Aoki, Akihito Otsuki, Fumiki Katsuoka, Kengo Kinoshita, Masaomi Nangaku, Tadao Akizawa, Masayuki Yamamoto

    Clinical and Experimental Nephrology　2023/11/14

    DOI： 10.1007/s10157-023-02427-w 　

  36. 未発症のBRCA1/2病的バリアント保持者に対するサーベイランスの課題

    濱中 洋平, 多田 寛, 原田 成美, 宮下 穣, 江幡 明子, 佐藤 未来, 柳垣 美歌, 本成 登貴和, 川目 裕, 鈴木 洋一, 長神 風二, 布施 昇男, 大根田 絹子, 山本 雅之, 石田 孝宣

    日本乳癌検診学会学術総会プログラム抄録集　33回　148-148　2023/11

    Publisher: (NPO)日本乳癌検診学会

  37. 未発症のBRCA1/2病的バリアント保持者に対するサーベイランスの課題

    濱中 洋平, 多田 寛, 原田 成美, 宮下 穣, 江幡 明子, 佐藤 未来, 柳垣 美歌, 本成 登貴和, 川目 裕, 鈴木 洋一, 長神 風二, 布施 昇男, 大根田 絹子, 山本 雅之, 石田 孝宣

    日本乳癌検診学会学術総会プログラム抄録集　33回　148-148　2023/11

    Publisher: (NPO)日本乳癌検診学会

  38. jMorp: Japanese Multi-Omics Reference Panel update report 2023. International-journal

    Shu Tadaka, Junko Kawashima, Eiji Hishinuma, Sakae Saito, Yasunobu Okamura, Akihito Otsuki, Kaname Kojima, Shohei Komaki, Yuichi Aoki, Takanari Kanno, Daisuke Saigusa, Jin Inoue, Matsuyuki Shirota, Jun Takayama, Fumiki Katsuoka, Atsushi Shimizu, Gen Tamiya, Ritsuko Shimizu, Masahiro Hiratsuka, Ikuko N Motoike, Seizo Koshiba, Makoto Sasaki, Masayuki Yamamoto, Kengo Kinoshita

    Nucleic acids research　2023/11/01

    DOI： 10.1093/nar/gkad978 　

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    Modern medicine is increasingly focused on personalized medicine, and multi-omics data is crucial in understanding biological phenomena and disease mechanisms. Each ethnic group has its unique genetic background with specific genomic variations influencing disease risk and drug response. Therefore, multi-omics data from specific ethnic populations are essential for the effective implementation of personalized medicine. Various prospective cohort studies, such as the UK Biobank, All of Us and Lifelines, have been conducted worldwide. The Tohoku Medical Megabank project was initiated after the Great East Japan Earthquake in 2011. It collects biological specimens and conducts genome and omics analyses to build a basis for personalized medicine. Summary statistical data from these analyses are available in the jMorp web database (https://jmorp.megabank.tohoku.ac.jp), which provides a multidimensional approach to the diversity of the Japanese population. jMorp was launched in 2015 as a public database for plasma metabolome and proteome analyses and has been continuously updated. The current update will significantly expand the scale of the data (metabolome, genome, transcriptome, and metagenome). In addition, the user interface and backend server implementations were rewritten to improve the connectivity between the items stored in jMorp. This paper provides an overview of the new version of the jMorp.

  39. Immunoediting of KEAP1-NRF2 mutant tumours is required to circumvent NRF2-mediated immune surveillance

    Liam Baird, Masayuki Yamamoto

    Redox Biology　67　102904-102904　2023/11

    Publisher: Elsevier BV

    DOI： 10.1016/j.redox.2023.102904 　

    ISSN： 2213-2317

  40. Sulforaphane decreases serum selenoprotein P levels through enhancement of lysosomal degradation independent of Nrf2

    Xinying Ye, Takashi Toyama, Keiko Taguchi, Kotoko Arisawa, Takayuki Kaneko, Ryouhei Tsutsumi, Masayuki Yamamoto, Yoshiro Saito

    Communications Biology　6　(1)　2023/10/19

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s42003-023-05449-y 　

    eISSN： 2399-3642

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    Abstract Selenoprotein P (SeP) is a major selenoprotein in serum predominantly produced in the liver. Excess SeP impairs insulin secretion from the pancreas and insulin sensitivity in skeletal muscle, thus inhibition of SeP could be a therapeutic strategy for type 2 diabetes. In this study, we examine the effect of sulforaphane (SFN), a phytochemical of broccoli sprouts and an Nrf2 activator, on SeP expression in vitro and in vivo. Treatment of HepG2 cells with SFN decreases inter- and intra-cellular SeP levels. SFN enhances lysosomal acidification and expression of V-ATPase, and inhibition of this process cancels the decrease of SeP by SFN. SFN activates Nrf2 in the cells, while Nrf2 siRNA does not affect the decrease of SeP by SFN or lysosomal acidification. These results indicate that SFN decreases SeP by enhancing lysosomal degradation, independent of Nrf2. Injection of SFN to mice results in induction of cathepsin and a decrease of SeP in serum. The findings from this study are expected to contribute to developing SeP inhibitors in the future, thereby contributing to treating and preventing diseases related to increased SeP.

  41. Influence of Diabetes Family History on the Associations of Combined Genetic and Lifestyle Risks with Diabetes in the Tohoku Medical Megabank Community-Based Cohort Study.

    Masato Takase, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Akira Narita, Taku Obara, Mami Ishikuro, Akira Uruno, Tomoko Kobayashi, Eiichi N Kodama, Yohei Hamanaka, Masatsugu Orui, Soichi Ogishima, Satoshi Nagaie, Nobuo Fuse, Junichi Sugawara, Shinichi Kuriyama, Ichiro Tsuji, Gen Tamiya, Atsushi Hozawa, Masayuki Yamamoto

    Journal of atherosclerosis and thrombosis　2023/10/06

    DOI： 10.5551/jat.64425 　

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    AIM: The influence of family history of diabetes, probably reflecting genetic and lifestyle factors, on the association of combined genetic and lifestyle risks with diabetes is unknown. We examined these associations. METHODS: This cross-sectional study included 9,681 participants in the Tohoku Medical Megabank Community-based Cohort Study. A lifestyle score, which was categorized into ideal, intermediate, and poor lifestyles, was given. Family history was obtained through a self-reported questionnaire. A polygenic risk score (PRS) was constructed in the target data (n=1,936) using publicly available genome-wide association study summary statistics from BioBank Japan. For test data (n=7,745), we evaluated PRS performance and examined the associations of combined family history and genetic and lifestyle risks with diabetes. Diabetes was defined as non-fasting blood glucose ≥ 200 mmHg, HbA1c ≥ 6.5%, and/or self-reported diabetes treatment. RESULTS: In test data, 467 (6.0%) participants had diabetes. Compared with a low genetic risk and an ideal lifestyle without a family history, the odds ratio (OR) was 3.73 (95% confidence interval [CI], 1.92-7.00) for a lower genetic risk and a poor lifestyle without a family history. Family history was significantly associated with diabetes (OR, 3.58 [95% CI, 1.73-6.98]), even in those with a low genetic risk and an ideal lifestyle. Even among participants who had an ideal lifestyle without a family history, a high genetic risk was associated with diabetes (OR, 2.49 [95% CI, 1.65-3.85]). Adding PRS to family history and conventional lifestyle risk factors improved the prediction ability for diabetes. CONCLUSIONS: Our findings support the notion that a healthy lifestyle is important to prevent diabetes regardless of genetic risk.

  42. Nrf2 activation improves experimental rheumatoid arthritis Peer-reviewed

    Anqi Zhang, Takafumi Suzuki, Saki Adachi, Eiki Yoshida, Shimon Sakaguchi, Masayuki Yamamoto

    Free Radical Biology and Medicine　2023/10

    DOI： 10.1016/j.freeradbiomed.2023.07.016 　

  43. A NRF2-induced secretory phenotype activates immune surveillance to remove irreparably damaged cells

    Liam Baird, Keiko Taguchi, Anqi Zhang, Yushi Takahashi, Takafumi Suzuki, Thomas W. Kensler, Masayuki Yamamoto

    Redox Biology　66　102845-102845　2023/10

    Publisher: Elsevier BV

    DOI： 10.1016/j.redox.2023.102845 　

    ISSN： 2213-2317

  44. Establishment of the early prediction models of low-birth-weight reveals influential genetic and environmental factors: a prospective cohort study. International-journal

    Satoshi Mizuno, Satoshi Nagaie, Gen Tamiya, Shinichi Kuriyama, Taku Obara, Mami Ishikuro, Hiroshi Tanaka, Kengo Kinoshita, Junichi Sugawara, Masayuki Yamamoto, Nobuo Yaegashi, Soichi Ogishima

    BMC pregnancy and childbirth　23　(1)　628-628　2023/08/31

    DOI： 10.1186/s12884-023-05919-5 　

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    BACKGROUND: Low birth weight (LBW) is a leading cause of neonatal morbidity and mortality, and increases various disease risks across life stages. Prediction models of LBW have been developed before, but have limitations including small sample sizes, absence of genetic factors and no stratification of neonate into preterm and term birth groups. In this study, we challenged the development of early prediction models of LBW based on environmental and genetic factors in preterm and term birth groups, and clarified influential variables for LBW prediction. METHODS: We selected 22,711 neonates, their 21,581 mothers and 8,593 fathers from the Tohoku Medical Megabank Project Birth and Three-Generation cohort study. To establish early prediction models of LBW for preterm birth and term birth groups, we trained AI-based models using genetic and environmental factors of lifestyles. We then clarified influential environmental and genetic factors for predicting LBW in the term and preterm groups. RESULTS: We identified 2,327 (10.22%) LBW neonates consisting of 1,077 preterm births and 1,248 term births. Our early prediction models archived the area under curve 0.96 and 0.95 for term LBW and preterm LBW models, respectively. We revealed that environmental factors regarding eating habits and genetic features related to fetal growth were influential for predicting LBW in the term LBW model. On the other hand, we identified that genomic features related to toll-like receptor regulations and infection reactions are influential genetic factors for prediction in the preterm LBW model. CONCLUSIONS: We developed precise early prediction models of LBW based on lifestyle factors in the term birth group and genetic factors in the preterm birth group. Because of its accuracy and generalisability, our prediction model could contribute to risk assessment of LBW in the early stage of pregnancy and control LBW risk in the term birth group. Our prediction model could also contribute to precise prediction of LBW based on genetic factors in the preterm birth group. We then identified parental genetic and maternal environmental factors during pregnancy influencing LBW prediction, which are major targets for understanding the LBW to address serious burdens on newborns' health throughout life.

  45. Metabolic reprogramming in Nrf2-driven proliferation of normal rat hepatocytes. International-journal

    Marta Anna Kowalik, Keiko Taguchi, Marina Serra, Andrea Caddeo, Elisabetta Puliga, Marina Bacci, Seizo Koshiba, Jin Inoue, Eiji Hishinuma, Andrea Morandi, Silvia Giordano, Andrea Perra, Masayuki Yamamoto, Amedeo Columbano

    Hepatology (Baltimore, Md.)　2023/08/21

    DOI： 10.1097/HEP.0000000000000568 　

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    BACKGROUND AIMS: Cancer cells reprogram their metabolic pathways to support bioenergetic and biosynthetic needs and to maintain their redox balance. In several human tumors the Keap1-Nrf2 system controls proliferation and metabolic reprogramming by regulating the pentose phosphate pathway (PPP). However, whether this metabolic reprogramming also occurs in normal proliferating cells is unclear. APPROACH AND RESULTS: To define the metabolic phenotype in normal proliferating hepatocytes, we induced cell proliferation in the liver by three distinct stimuli: liver regeneration by partial hepatectomy (PH) and hepatic hyperplasia induced by two direct mitogens, lead nitrate (LN) or triiodothyronine (T3). Following LN treatment, well-established features of cancer metabolic reprogramming including enhanced glycolysis, oxidative PPP, nucleic acid synthesis, NAD+/NADH synthesis and altered amino acid content as well as downregulated oxidative phosphorylation (OXPHOS) occurred in normal proliferating hepatocytes displaying Nrf2 activation. Genetic deletion of Nrf2 blunted LN-induced PPP activation and suppressed hepatocyte proliferation. Moreover, Nrf2 activation and following metabolic reprogramming did not occur when hepatocyte proliferation was induced by PH or T3. CONCLUSION: Many metabolic changes in cancer cells are shared by proliferating normal hepatocytes in response to a hostile environment. Nrf2 activation is essential for bridging metabolic changes with crucial components of cancer metabolic reprogramming including the activation of oxidative PPP. Our study demonstrates that matured hepatocytes exposed to LN undergo a cancer-like metabolic reprogramming and offers a rapid and useful in vivo model to study the molecular alterations underpinning the differences/similarities of metabolic changes in normal and neoplastic hepatocytes.

  46. Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy in mice Peer-reviewed

    Shimizu R, Hirano I, Hasegawa A, Suzuki M, Otsuki A, Taguchi K, Katsuoka F, Uruno A, Suzuki N, Yumoto A, Okada R, Shrakawa M, Shiba D, Takahashi S, Suzuki T, Yamamoto M

    Commun Biol　6　2023/08

    DOI： 10.1038/s42003-022-03316-w 　

  47. Associations between birth weight and lung function in a Japanese adult population: The tohoku medical megabank community-based cohort study. International-journal

    Takashi Ohe, Mitsuhiro Yamada, Atsushi Hozawa, Naoki Nakaya, Tomohiro Nakamura, Naho Tsuchiya, Akira Narita, Mana Kogure, Nobuo Fuse, Shinichi Kuriyama, Ayumi Mitsune, Ayumi Suzuki, Shuichiro Matsumoto, Tetsuya Hatakeyama, Chikashi Iwasaki, Manami Suzuki, Naoya Fujino, Tadahisa Numakura, Tomohiro Ichikawa, Akira Koarai, Tsutomu Tamada, Masayuki Yamamoto, Masakazu Ichinose, Hisatoshi Sugiura

    Respiratory investigation　61　(5)　588-600　2023/07/08

    DOI： 10.1016/j.resinv.2023.06.004 　

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    BACKGROUND: Birth weight, as a measure of intrauterine growth, is commonly used in epidemiological studies and is reported to be associated with adult lung function. However, findings regarding this association in previous studies have been inconsistent. Furthermore, no studies have reported associations stratified by age or smoking status, or adjusted for eosinophil count or other parameters related to type 2 airway inflammation. METHODS: This cross-sectional study included 2632 men and 7237 women aged ≥20 years living in Miyagi Prefecture, Japan. Lung function was assessed based on spirometry. Birth weight data were obtained through a questionnaire survey. Analysis of covariance was used to evaluate the associations between birth weight and lung function, adjusting for potential confounders. Stratified analyses by age and smoking status were also conducted, together with a sub-analysis for low birth-weight participants. RESULTS: Birth weight was positively associated with forced expiratory volume in 1 s (FEV1) for both sexes and with vital capacity in women, after adjusting for height, age, smoking status, and parameters related to type 2 airway inflammation. The stratified analysis for smoking status revealed associations in never-smokers and ex-smokers. When stratified by age, the associations were confirmed in middle-aged participants. The effect of smoking status on the FEV1 of low birth-weight participants was not significant. CONCLUSIONS: Our analysis of a large, Japanese adult population showed that birth weight was independently and positively associated with adult lung function, even after adjustment for age, height, smoking status, and parameters related to type 2 airway inflammation.

  48. Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study: Rationale, Design, and Background Peer-reviewed

    Makiko Taira, Shunji Mugikura, Naoko Mori, Atsushi Hozawa, Tomo Saito, Tomohiro Nakamura, Hideyasu Kiyomoto, Tadao Kobayashi, Soichi Ogishima, Fuji Nagami, Akira Uruno, Ritsuko Shimizu, Tomoko Kobayashi, Jun Yasuda, Shigeo Kure, Miyuki Sakurai, Ikuko N. Motoike, Kazuki Kumada, Naoki Nakaya, Taku Obara, Kentaro Oba, Atsushi Sekiguchi, Benjamin Thyreau, Tatsushi Mutoh, Yuji Takano, Mitsunari Abe, Norihide Maikusa, Yasuko Tatewaki, Yasuyuki Taki, Nobuo Yaegashi, Hiroaki Tomita, Kengo Kinoshita, Shinichi Kuriyama, Nobuo Fuse, Masayuki Yamamoto

    JMA Journal　6　(3)　246-264　2023/07

    Publisher: Japan Medical Association

    DOI： 10.31662/jmaj.2022-0220 　

    ISSN： 2433-328X

    eISSN： 2433-3298

  49. Role of Nrf2 in 1,2-dichloropropane-induced cell proliferation and DNA damage in the mouse liver. International-journal

    Yusuke Kimura, Frederick Adams Ekuban, Cai Zong, Shigeyuki Sugie, Xiao Zhang, Ken Itoh, Masayuki Yamamoto, Sahoko Ichihara, Seiichiro Ohsako, Gaku Ichihara

    Toxicological sciences : an official journal of the Society of Toxicology　2023/06/16

    DOI： 10.1093/toxsci/kfad059 　

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    1,2-Dichloropropane (1,2-DCP) is recognized as the causative chemical of occupational cholangiocarcinoma in printing workers in Japan. However, the cellular and molecular mechanisms of 1,2-DCP-induced carcinogenesis remains elusive. The present study investigated cellular proliferation, DNA damage, apoptosis and expression of antioxidant and proinflammatory genes in the liver of mice exposed daily to 1,2-DCP for 5 weeks, and the role of Nrf2 in these responses. Wild-type and Nrf2-knockout (Nrf2-/-) mice were administered 1,2-DCP by gastric gavage, and then the livers were collected for analysis. Immunohistochemistry for BrdU or KI67 and TUNEL assay revealed that exposure to 1,2-DCP dose-dependently increased proliferative cholangiocytes, while decreased apoptotic cholangiocytes in wild-type mice but not in Nrf2-/- mice. Western blot and quantitative real time PCR showed that exposure to 1,2-DCP increased the levels of DNA double-strand break marker γ-H2AX and mRNA expression levels of NQO1, xCT, GSTM1, and G6PD in the livers of wild-type mice in a dose-dependent manner, but no such changes were noted in Nrf2-/- mice. 1,2-DCP increased glutathione levels in the liver of both the wild-type and Nrf2-/- mice, suggesting that a Nrf2-independent mechanism contributes to 1,2-DCP-induced increase in glutathione level. In conclusion, the study demonstrated that exposure to 1,2-DCP induced proliferation but reduced apoptosis in cholangiocytes, and induced double-strand DNA breaks and upregulation of antioxidant genes in the liver in an Nrf2-dependent manner. The study suggests a role of Nrf2 in 1,2-DCP-induced cell proliferation, antiapoptotic effect and DNA damage which are recognized as key characteristics of carcinogens.

  50. Comprehensive evaluation of machine learning algorithms for predicting sleep–wake conditions and differentiating between the wake conditions before and after sleep during pregnancy based on heart rate variability

    Xue Li, Chiaki Ono, Noriko Warita, Tomoka Shoji, Takashi Nakagawa, Hitomi Usukura, Zhiqian Yu, Yuta Takahashi, Kei Ichiji, Norihiro Sugita, Natsuko Kobayashi, Saya Kikuchi, Ryoko Kimura, Yumiko Hamaie, Mizuki Hino, Yasuto Kunii, Keiko Murakami, Mami Ishikuro, Taku Obara, Tomohiro Nakamura, Fuji Nagami, Takako Takai, Soichi Ogishima, Junichi Sugawara, Tetsuro Hoshiai, Masatoshi Saito, Gen Tamiya, Nobuo Fuse, Susumu Fujii, Masaharu Nakayama, Shinichi Kuriyama, Masayuki Yamamoto, Nobuo Yaegashi, Noriyasu Homma, Hiroaki Tomita

    Frontiers in Psychiatry　14　2023/06/06

    Publisher: Frontiers Media SA

    DOI： 10.3389/fpsyt.2023.1104222 　

    eISSN： 1664-0640

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    Introduction Perinatal women tend to have difficulties with sleep along with autonomic characteristics. This study aimed to identify a machine learning algorithm capable of achieving high accuracy in predicting sleep–wake conditions and differentiating between the wake conditions before and after sleep during pregnancy based on heart rate variability (HRV). Methods Nine HRV indicators (features) and sleep–wake conditions of 154 pregnant women were measured for 1 week, from the 23rd to the 32nd weeks of pregnancy. Ten machine learning and three deep learning methods were applied to predict three types of sleep–wake conditions (wake, shallow sleep, and deep sleep). In addition, the prediction of four conditions, in which the wake conditions before and after sleep were differentiated—shallow sleep, deep sleep, and the two types of wake conditions—was also tested. Results and Discussion In the test for predicting three types of sleep–wake conditions, most of the algorithms, except for Naïve Bayes, showed higher areas under the curve (AUCs; 0.82–0.88) and accuracy (0.78–0.81). The test using four types of sleep–wake conditions with differentiation between the wake conditions before and after sleep also resulted in successful prediction by the gated recurrent unit with the highest AUC (0.86) and accuracy (0.79). Among the nine features, seven made major contributions to predicting sleep–wake conditions. Among the seven features, “the number of interval differences of successive RR intervals greater than 50 ms (NN50)” and “the proportion dividing NN50 by the total number of RR intervals (pNN50)” were useful to predict sleep–wake conditions unique to pregnancy. These findings suggest alterations in the vagal tone system specific to pregnancy.

  51. Insights into the regulation of glomerular filtration rate by the Keap1-Nrf2 pathway.

    Kidokoro K, Kadoya H, Cherney DZI, Kondo M, Wada Y, Umeno R, Kishi S, Nagasu H, Nagai K, Suzuki T, Sasaki T, Yamamoto M, Kanwar YS, Kashihara N

    Kidney360　2023/06/02

    DOI： 10.34067/kid.0000000000000171 　 10.34067/KID.0000000000000171 　

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    <h4>Background</h4>Literature data suggest that the activation of the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway increases glomerular filtration rate (GFR) in patients with type 2 diabetes and chronic kidney disease. However, the mechanisms whereby the Keap1-Nrf2 pathway regulates GFR are unknown. Methods: Various renal physiological parameters were assessed in C57BL/6 mice (WT), Nrf2-deficient mice, and Nrf2-activated Keap1-knockdown mice. Also, these parameters were assessed following the administration of RTA dh404 (CDDO-dhTFEA), a Nrf2 activator.<h4>Results</h4>Pharmacological and genetic Keap1-Nrf2 activation increased renal blood flow (p <0.05), glomerular volume (p <0.05) and GFR (p <0.05), but did not alter the afferent-to-efferent arteriolar diameter ratio or glomerular permeability. Calcium influx into the podocytes through TRPC channels in response to H2O2 was suppressed by Keap1-Nrf2 activation and TRPCs inhibition. Treatment with a TRPC6 and TRPC5 inhibitors increased single-nephron GFR in WT mice.<h4>Conclusion</h4>In conclusion, the Keap1-Nrf2 pathway regulates GFR through changes in ultrafiltration by modulating redox-sensitive intracellular calcium signaling and cellular contractility, mediated through TRPC activity, in glomerular cells, in particular the podocytes.

  52. ゲノムコホート研究参加者5万人を対象としたBRCA1/2遺伝情報の回付と医療への連携

    濱中 洋平, 大根田 絹子, 川目 裕, 布施 昇男, 長神 風二, 鈴木 洋一, 山口 由美, 多田 寛, 原田 成美, 宮下 穣, 江幡 明子, 佐藤 未来, 柳垣 美歌, 山本 雅之, 石田 孝宣

    日本乳癌学会総会プログラム抄録集　31回　89-89　2023/06

    Publisher: (一社)日本乳癌学会

  53. Author Correction: The power of genetic diversity in genome-wide association studies of lipids. International-journal

    Sarah E Graham, Shoa L Clarke, Kuan-Han H Wu, Stavroula Kanoni, Greg J M Zajac, Shweta Ramdas, Ida Surakka, Ioanna Ntalla, Sailaja Vedantam, Thomas W Winkler, Adam E Locke, Eirini Marouli, Mi Yeong Hwang, Sohee Han, Akira Narita, Ananyo Choudhury, Amy R Bentley, Kenneth Ekoru, Anurag Verma, Bhavi Trivedi, Hilary C Martin, Karen A Hunt, Qin Hui, Derek Klarin, Xiang Zhu, Gudmar Thorleifsson, Anna Helgadottir, Daniel F Gudbjartsson, Hilma Holm, Isleifur Olafsson, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M Brumpton, Humaira Rasheed, Sanni E Ruotsalainen, Aki S Havulinna, Yogasudha Veturi, QiPing Feng, Elisabeth A Rosenthal, Todd Lingren, Jennifer Allen Pacheco, Sarah A Pendergrass, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E Miller, Archie Campbell, Kuang Lin, Iona Y Millwood, George Hindy, Asif Rasheed, Jessica D Faul, Wei Zhao, David R Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Anubha Mahajan, Michael R Brown, Weihua Zhang, Ketian Yu, Ellen M Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian'an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Gonneke Willemsen, Andrew R Wood, Yingji Ji, Zishan Gao, Simon Haworth, Ruth E Mitchell, Jin Fang Chai, Mette Aadahl, Jie Yao, Ani Manichaikul, Helen R Warren, Julia Ramirez, Jette Bork-Jensen, Line L Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Carlo Sidore, Edoardo Fiorillo, Aaron F McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T Møllehave, Betina H Thuesen, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E Galesloot, Jonathan P Bradfield, E Warwick Daw, Joseph M Zmuda, Jonathan S Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A Brody, Mary F Feitosa, Mary K Wojczynski, Michael Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W Benjamins, Jorgen Engmann, Rachel L Kember, Roderick C Slieker, Ken Sin Lo, Nuno R Zilhao, Phuong Le, Marcus E Kleber, Graciela E Delgado, Shaofeng Huo, Daisuke D Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Hampton L Leonard, Jonathan Marten, Börge Schmidt, Marina Arendt, Laura J Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Meraj Ahmed, Anne U Jackson, Noha A Yousri, Marguerite R Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R H J Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A Lange, Xiaoran Chai, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C Warner, Ya Xing Wang, Wen B Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Yi-Jen Hung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A Kentistou, Mathias Gorski, Marco Brumat, Karina Meidtner, Lawrence F Bielak, Jennifer A Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Chao Xue, Jifeng Zhang, Maria Pina Concas, Simona Vaccargiu, Peter J van der Most, Niina Pitkänen, Brian E Cade, Jiwon Lee, Sander W van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Martina E Zimmermann, Jong Young Lee, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W Rayner, Carol A Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hildalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O Obura, Jessica van Setten, Xiaoyin Li, Karen Schwander, Natalie Terzikhan, Jae Hun Shin, Rebecca D Jackson, Alexander P Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Heather M Highland, Kristin L Young, Takahisa Kawaguchi, Joachim Thiery, Joshua C Bis, Girish N Nadkarni, Lenore J Launer, Huaixing Li, Mike A Nalls, Olli T Raitakari, Sahoko Ichihara, Sarah H Wild, Christopher P Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Konain Fatima Bhatti, Dominique de Kleijn, Gert J de Borst, Eung Kweon Kim, Hieab H H Adams, M Arfan Ikram, Xiaofeng Zhu, Folkert W Asselbergs, Adriaan O Kraaijeveld, Joline W J Beulens, Xiao-Ou Shu, Loukianos S Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E Pennell, Trevor A Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M Heid, Klaus J Stark, Henry Völzke, Georg Homuth, Michele K Evans, Alan B Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E Hoefer, Susan Redline, Katja Pahkala, Albertine J Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Y Eugene Chen, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L R Kardia, Norihiro Kato, Matthias B Schulze, Giorgia Girotto, Bettina Jung, Carsten A Böger, Peter K Joshi, David A Bennett, Philip L De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J Caulfield, Patricia B Munroe, Xiuqing Guo, Marina Ciullo, Jost B Jonas, Nilesh J Samani, Jaakko Kaprio, Päivi Pajukanta, Linda S Adair, Sonny Augustin Bechayda, H Janaka de Silva, Ananda R Wickremasinghe, Ronald M Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke I den Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G Wilson, Lars Lind, Chew-Kiat Heng, Amanda E Nelson, Yvonne M Golightly, James F Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J Scott, D C Rao, Donna K Arnett, Steven C Hunt, Mark Walker, Heikki A Koistinen, Giriraj R Chandak, Chittaranjan S Yajnik, Josep M Mercader, Teresa Tusié-Luna, Carlos A Aguilar-Salinas, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, E Shyong Tai, Rob M van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I McCarthy, Colin N A Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M van Duijn, Fan Lu, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Esteban J Parra, Miguel Cruz, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M 't Hart, Petra J M Elders, Scott M Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D Spector, Ruth J F Loos, Michael A Province, Bruce M Psaty, Ivan Brandslund, Peter P Pramstaller, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F A Grant, Lambertus A L M Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W Franks, Allan Linneberg, J Wouter Jukema, Amit V Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Francesco Cucca, Dennis O Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P Strachan, Niels Grarup, Peter Sever, Neil Poulter, Jerome I Rotter, Thomas M Dantoft, Fredrik Karpe, Matt J Neville, Nicholas J Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T Hattersley, Nancy L Pedersen, Patrik K E Magnusson, Dorret I Boomsma, Eco J C de Geus, L Adrienne Cupples, Joyce B J van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C Chambers, Jaspal S Kooner, Paul S de Vries, Alanna C Morrison, Kari E North, Martha Daviglus, Peter Kraft, Nicholas G Martin, John B Whitfield, Shahid Abbas, Danish Saleheen, Robin G Walters, Michael V Holmes, Corri Black, Blair H Smith, Anne E Justice, Aris Baras, Julie E Buring, Paul M Ridker, Daniel I Chasman, Charles Kooperberg, Wei-Qi Wei, Gail P Jarvik, Bahram Namjou, M Geoffrey Hayes, Marylyn D Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Unnur Thorsteinsdottir, Kari Stefansson, Yuk-Lam Ho, Julie A Lynch, Daniel J Rader, Philip S Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J O'Donnell, John M Gaziano, Peter Wilson, Charles N Rotimi, Scott Hazelhurst, Michèle Ramsay, Richard C Trembath, David A van Heel, Gen Tamiya, Masayuki Yamamoto, Bong-Jo Kim, Karen L Mohlke, Timothy M Frayling, Joel N Hirschhorn, Sekar Kathiresan, Michael Boehnke, Pradeep Natarajan, Gina M Peloso, Christopher D Brown, Andrew P Morris, Themistocles L Assimes, Panos Deloukas, Yan V Sun, Cristen J Willer

    Nature　618　(7965)　E19-E20　2023/05/26

    DOI： 10.1038/s41586-023-06194-2 　

  54. A Point Mutation at C151 of Keap1 of Mice Abrogates NRF2 Signaling, Cytoprotection in Vitro, and Hepatoprotection in Vivo by Bardoxolone Methyl (CDDO-Me).

    Gatbonton-Schwager T, Yagishita Y, Joshi T, Nobunao Wakabayashi, Srinivasan H, Suzuki T, Yamamoto M, Thomas Kensler

    Molecular pharmacology　2023/05/15

    DOI： 10.1124/molpharm.123.000671 　

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    Bardoxolone methyl (CDDO-Me) is an oleanane triterpenoid in late-stage clinical development for the treatment of patients with diabetic kidney disease. Preclinical studies in rodents demonstrate the efficacy of triterpenoids against carcinogenesis and other diseases, including renal ischemia-reperfusion injury, hyperoxia-induced acute lung injury, and immune hepatitis. Genetic disruption of Nrf2 abrogates protection by triterpenoids, suggesting that induction of the NRF2 pathway may drive this protection. Herein, we examined the effect of a point mutation (C151S) in KEAP1, a repressor of NRF2 signaling, at cysteine 151 in mouse embryo fibroblasts and mouse liver. Induction of target gene transcripts and enzyme activity by CDDO-Me was lost in C151S mutant fibroblasts compared with wild-type. Protection against menadione toxicity was also nullified in the mutant fibroblasts. In mouse liver, CDDO-Me evoked the nuclear translocation of NRF2, followed by increased transcript and activity levels of a prototypic target gene, Nqo1, in wild-type, but not C151S mutant, mice. To test the role of KEAP1 Cys151 in governing the broader pharmacodynamic action of CDDO-Me, wild-type and C151S mutant mice were challenged with concanavalin A to induce immune hepatitis. Strong protection was seen in wild-type but not C151S mutant mice. RNA-seq analysis of mouse liver from wild-type, C151S mutant, and Nrf2-knockout mice revealed a vigorous response of the NRF2 transcriptome in wild-type, but in neither C151S mutant nor Nrf2-knockout, mice. Activation of "off-target" pathways by CDDO were not observed. These data highlight the singular importance of the KEAP1 cysteine 151 sensor for activation of NRF2 signaling by CDDO-Me. SIGNIFICANCE STATEMENT: KEAP1 serves as a key sensor for induction of the cytoprotective signaling pathway driven by the transcription factor NRF2. Mutation of a single cysteine (C151) in KEAP1 abrogates the induction of NRF2 signaling and its downstream cytoprotective actions in vitro and in vivo by bardoxolone methyl (CDDO-Me), a drug in late-stage clinical development. Further, at these bioeffective concentrations/doses, activation of "off-target" pathways by CDDO-Me are not observed, highlighting the singular importance of NRF2 in its mode of action.

  55. Association between low levels of anti-inflammatory cytokines during pregnancy and postpartum depression. International-journal

    Chiaki T Ono, Zhiqian Yu, Taku Obara, Mami Ishikuro, Keiko Murakami, Masahiro Kikuya, Saya Kikuchi, Natsuko Kobayashi, Hisaaki Kudo, Soichi Ogishima, Naoko Minegishi, Junichi Sugawara, Shinichi Kuriyama, Masayuki Yamamoto, Nobuo Yaegashi, Hiroaki Tomita

    Psychiatry and clinical neurosciences　77　(8)　434-441　2023/05/13

    DOI： 10.1111/pcn.13566 　

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    AIM: Previous studies based on a relatively limited number of subjects have indicated potential associations between plasma cytokine concentrations in perinatal women and postpartum depression (PPD). This report aimed to examine alterations in cytokine levels during pregnancy and after delivery by measuring nine cytokines in prenatal and postnatal plasma samples in a large cohort. METHODS: A nested, case-control study was conducted using plasma samples from 247 women with PPD (Edinburgh Postnatal Depression Scale: EPDS ≥9) and 243 age-matched control (EPDS ≤2) women from among perinatal women who participated in the Tohoku Medical Megabank three-generation cohort. Concentrations of nine plasma cytokines (IFN-γ, IL-1β, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, IL-13, and TNF-α) in plasma collected at the time of enrollment during pregnancy and one month after delivery were determined using an immunoassay kit. RESULTS: Cross-sectional comparisons of cytokine levels during pregnancy and after delivery indicated that the PPD group maintained significantly lower plasma IL-4 levels during pregnancy and after delivery than the control group, and that plasma IL-4 levels decreased significantly during pregnancy regardless of PPD status. Plasma IL-10 levels were significantly higher during pregnancy than after delivery only among healthy controls, and plasma IL-10 levels were significantly higher in the control group than in the PPD group. Moreover, IFN-γ, IL-6, IL-12p40, and TNF-α levels were significantly lower during pregnancy compared with after delivery regardless of PPD status. CONCLUSIONS AND RELEVANCE: These results suggest a potential protective effect of the anti-inflammatory cytokines IL-4 and IL-10 during pregnancy against the development of PPD. This article is protected by copyright. All rights reserved.

  56. Drugs activating hypoxia-inducible factors correct erythropoiesis and hepcidin levels via renal EPO induction in mice. International-journal

    Taku Nakai, Yuma Iwamura, Koichiro Kato, Ikuo Hirano, Yotaro Matsumoto, Yoshihisa Tomioka, Masayuki Yamamoto, Norio Suzuki

    Blood advances　2023/05/05

    DOI： 10.1182/bloodadvances.2023009798 　

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    The erythroid growth factor erythropoietin (EPO) is mainly produced by the kidneys in adult mammals and induces expansion of erythroid cells and iron use for hemoglobin synthesis. The liver also produces EPO at a lower level than the kidneys. Renal and hepatic EPO production is fundamentally regulated by hypoxia-inducible transcription factors (HIFs) in a hypoxia/anemia-inducible manner. Recently, small compounds that activate HIFs and EPO production in the kidneys by inhibiting HIF-prolyl hydroxylases (HIF-PHIs) have been launched to treat EPO-deficiency anemia in patients suffering from kidney disease. However, the roles of the liver in the HIF-PHI-mediated induction of erythropoiesis and iron mobilization remain controversial. Here, to elucidate the liver contributions to the therapeutic effects of HIF-PHIs, genetically modified mouse lines lacking renal EPO-production ability were analyzed. In the mutant mice, HIF-PHI administration marginally increased plasma EPO concentrations and peripheral erythrocytes by inducing hepatic EPO production. The effects of HIF-PHIs on the mobilization of stored iron and on the suppression of hepatic hepcidin, an inhibitory molecule for iron release from iron-storage cells, were not observed in the mutant mice. These findings demonstrate that adequate induction of EPO mainly in the kidney is essential for achieving the full therapeutic effects of HIF-PHIs, which include hepcidin suppression. The data also show that HIF-PHIs directly induce the expression of duodenal genes related to dietary iron intake. Additionally, hepatic EPO induction is considered to partially contribute to the erythropoietic effects of HIF-PHIs but to be insufficient to compensate for the abundant EPO induction by the kidneys.

  57. Recent progress in analyses of GATA1 in hematopoietic disorders: a mini-review

    Ritsuko Shimizu, Masayuki Yamamoto

    Frontiers in Hematology　2　2023/05/03

    Publisher: Frontiers Media SA

    DOI： 10.3389/frhem.2023.1181216 　

    eISSN： 2813-3935

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    GATA1 is an essential master regulator of erythropoiesis and megakaryopoiesis. Accumulating lines of evidence have shown that dynamic changes in GATA1 gene expression levels during erythropoiesis are crucial for proper erythroid differentiation. Since GATA1 is an X-chromosome gene, GATA1 knockout leads to embryonic lethal dyserythropoiesis in male mice, while heterozygous female mice can survive. In the past decade, it has become clear that germline GATA1 gene mutations leading to structural changes in the GATA1 protein are involved in congenital dyserythropoiesis in males. In contrast, decreased GATA1 expression levels, which cause embryonic lethal dyserythropoiesis in male mice, increase the risk of erythroleukemia development in female mice, while female GATA1-knockout mice do not show substantial phenotypic alterations in erythroid or megakaryocyte lineages. In this review, we summarize the recent progress in elucidating the roles of GATA1 in normal and pathogenetic erythropoiesis and discuss the possible mechanisms of pathogenesis of dyserythropoiesis and erythroleukemia.

  58. Relationship between age-related hearing loss and consumption of coffee and tea.

    Gosuke Watarai, Jun Suzuki, Ikuko N Motoike, Miyuki Sakurai, Ryoukichi Ikeda, Tetsuaki Kawase, Kengo Kinoshita, Atsushi Hozawa, Shinichi Kuriyama, Nobuo Fuse, Masayuki Yamamoto, Yukio Katori

    Geriatrics & gerontology international　2023/05/03

    DOI： 10.1111/ggi.14589 　

  59. The KEAP1-NRF2 System and Neurodegenerative Diseases

    Akira Uruno, Masayuki Yamamoto

    Antioxidants & Redox Signaling　2023/05/01

    DOI： 10.1089/ars.2023.0234 　

  60. Investigating the association between glycaemic traits and colorectal cancer in the Japanese population using Mendelian randomisation. International-journal

    Akiko Hanyuda, Atsushi Goto, Ryoko Katagiri, Yuriko N Koyanagi, Masahiro Nakatochi, Yoichi Sutoh, Shiori Nakano, Isao Oze, Hidemi Ito, Taiki Yamaji, Norie Sawada, Masao Iwagami, Aya Kadota, Teruhide Koyama, Sakurako Katsuura-Kamano, Hiroaki Ikezaki, Keitaro Tanaka, Toshiro Takezaki, Issei Imoto, Midori Suzuki, Yukihide Momozawa, Kenji Takeuchi, Akira Narita, Atsushi Hozawa, Kengo Kinoshita, Atsushi Shimizu, Kozo Tanno, Keitaro Matsuo, Shoichiro Tsugane, Kenji Wakai, Makoto Sasaki, Masayuki Yamamoto, Motoki Iwasaki

    Scientific reports　13　(1)　7052-7052　2023/04/29

    DOI： 10.1038/s41598-023-33966-7 　

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    Observational studies suggest that abnormal glucose metabolism and insulin resistance contribute to colorectal cancer; however, the causal association remains unknown, particularly in Asian populations. A two-sample Mendelian randomisation analysis was performed to determine the causal association between genetic variants associated with elevated fasting glucose, haemoglobin A1c (HbA1c), and fasting C-peptide and colorectal cancer risk. In the single nucleotide polymorphism (SNP)-exposure analysis, we meta-analysed study-level genome-wide associations of fasting glucose (~ 17,289 individuals), HbA1c (~ 52,802 individuals), and fasting C-peptide (1,666 individuals) levels from the Japanese Consortium of Genetic Epidemiology studies. The odds ratios of colorectal cancer were 1.01 (95% confidence interval [CI], 0.99-1.04, P = 0.34) for fasting glucose (per 1 mg/dL increment), 1.02 (95% CI, 0.60-1.73, P = 0.95) for HbA1c (per 1% increment), and 1.47 (95% CI, 0.97-2.24, P = 0.06) for fasting C-peptide (per 1 log increment). Sensitivity analyses, including Mendelian randomisation-Egger and weighted-median approaches, revealed no significant association between glycaemic characteristics and colorectal cancer (P > 0.20). In this study, genetically predicted glycaemic characteristics were not significantly related to colorectal cancer risk. The potential association between insulin resistance and colorectal cancer should be validated in further studies.

  61. Prevalence, Associated Factors, and Inter-Eye Differences of Refractive Errors in a Population-Based Japanese Cohort: The Tohoku Medical Megabank Eye Study. International-journal

    Atsuya Miki, Nobuo Fuse, Satoko Fujimoto, Makiko Taira, Tomo Saito, Tomoyuki Okazaki, Akihiko Shiraki, Shigeru Sato, Ryo Kawasaki, Tomohiro Nakamura, Kengo Kinoshita, Kohji Nishida, Masayuki Yamamoto

    Ophthalmic epidemiology　1-9　2023/04/24

    DOI： 10.1080/09286586.2023.2203226 　

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    PURPOSE: To investigate the prevalence, associated factors, and inter-eye differences of myopia and astigmatism in an adult Japanese population-based cohort. METHODS: A total of 4282 participants from the Tohoku Medical Megabank Organization Eye Study (ToMMo Eye Study) underwent comprehensive ocular examinations as well as extensive physiological tests and a lifestyle questionnaire. The spherical equivalent (SE) and cylinder power were obtained as refractive parameters. The age- and gender-stratified prevalences of high myopia (SE < -5D), myopia (SE < -0.5D), hyperopia (SE > 0.5D), astigmatism (cylinder power < -0.5D), and anisometropia (SE difference >1D) were calculated. Multivariable analyses were performed to identify associated factors for refractive error (RE). Distribution and associated factors of the inter-eye difference in RE were also investigated. RESULTS: The age-adjusted prevalence of high myopia, myopia, hyperopia, astigmatism, and anisometropia was 15.9%, 63.5%, 14.7%, 51.1%, and 14.7%, respectively. Both myopia and high myopia were more prevalent in the younger age group, while astigmatism was more prevalent in the older age group. Age, education, blood pressure, intraocular pressure, and corneal thickness are significantly associated with myopic refraction. Age, gender, intraocular pressure, and corneal thickness are correlated with astigmatism. Older age was associated with against-the-rule astigmatism. Older age, myopia, and longer education showed a significant correlation with large inter-eye differences in SERE. CONCLUSIONS: This study demonstrated the high prevalence of myopia in young Japanese, which may be caused by a generational shift. This study also confirmed the influence of age and education on both the prevalence and inter-eye differences of RE.

  62. Molecular Basis of the KEAP1-NRF2 Signaling Pathway

    Takafumi Suzuki, Jun Takahashi, Masayuki Yamamoto

    Molecules and Cells　2023/03/31

    DOI： 10.14348/molcells.2023.0028 　

  63. CFH-CFHR1 hybrid genes in two cases of atypical hemolytic uremic syndrome

    Yuka Sugawara, Hideki Kato, Masao Nagasaki, Yoko Yoshida, Madoka Fujisawa, Naoko Minegishi, Masayuki Yamamoto, Masaomi Nangaku

    Journal of Human Genetics　2023/02/09

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s10038-023-01129-1 　

    ISSN： 1434-5161

    eISSN： 1435-232X

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    Abstract Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated disease that manifests as the triad of thrombotic microangiopathy. We identified two aHUS patients with neither anti-complement factor H (CFH) antibodies nor causative variants of seven aHUS-related genes (CFH, CFI, CFB, C3, MCP, THBD, and DGKE); however, their plasma showed increased levels of hemolysis by hemolytic assay, which strongly suggests CFH-related abnormalities. Using a copy number variation (CNV) analysis of the CFH/CFHR gene cluster, we identified CFH-CFHR1 hybrid genes in these patients. We verified the absence of aHUS-related abnormal CNVs of the CFH gene in control genomes of 2036 individuals in the general population, which suggests that pathogenicity is related to these hybrid genes. Our study emphasizes that, for patients suspected of having aHUS, it is important to perform an integrated analysis based on a clinical examination, functional analysis, and detailed genetic investigation.

  64. Improving the Signal Intensity of Cryosections Using a Conductive Adhesive Film in Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging

    Daisuke Saigusa, Ritsumi Saito, Komei Kawamoto, Akira Uruno, Kuniyuki Kano, Shuichi Shimma, Junken Aoki, Masayuki Yamamoto, Tadafumi Kawamoto

    Mass Spectrometry　2023

    Publisher: The Mass Spectrometry Society of Japan

    DOI： 10.5702/massspectrometry.a0137 　

    ISSN： 2187-137X

    eISSN： 2186-5116

  65. Toxicity manifestations and sex differences due to MARTA olanzapine.

    Natsumi Hattori-Usami, Asuka Kaizaki-Mitsumoto, Takashi Ashino, Masayuki Yamamoto, Satoshi Numazawa

    The Journal of toxicological sciences　48　(4)　191-202　2023

    DOI： 10.2131/jts.48.191 　

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    Olanzapine is widely used as a treatment for schizophrenia and other psychiatric disorders. Its metabolic side effects, including weight gain and hyperglycemia, are a clinical problem; however, their full mechanism is not yet clearly understood. Recently, it was reported that the accumulation of oxidative stress in the hypothalamus may cause obesity and diabetes mellitus. Epidemiologically, metabolic side effects are known to be more likely to occur in women. In the present study, we investigated and tested the hypothesis that olanzapine induces oxidative stress in the hypothalamus and induces metabolic side effects. We also examined its association with sex differences. Olanzapine was administered intraperitoneally to male and female C57BL/6 mice, and the expression levels of oxidative stress-responsible genes in the hypothalamus and cerebral cortex were measured by qRT-PCR. In addition, olanzapine was administered intraperitoneally to C57BL/6 and Nrf2 KO mice, and the expression level of total glutathione was measured. Gene expressions induced by the Keap1-Nrf2-regulated system showed different responses to olanzapine for each gene. Under the conditions of this experiment, cystine-glutamate transporter was decreased although heme oxygenase-1 and γ-glutamylcysteine synthetase were increased. It was also clear that these responses were not hypothalamus-specific. Long-term feeding with olanzapine suppressed weight gain in males but not females. No glucose intolerance was observed at 13 weeks of administration. Furthermore, deaths occurred only in females. In conclusion, this study failed to provide evidence that olanzapine induces oxidative stress in a hypothalamic-specific manner. Instead, sex differences were observed in response to long-term and high-dose olanzapine administration, suggesting that individual susceptibility to olanzapine toxicity occurred in female mice.

  66. A knowledge representation model for family relationship to three generation Peer-reviewed

    Kazuro Shimokawa, Mami Ishikuro, Taku Obara, Hirohito Metoki, Satoshi Mizuno, Satoshi Nagaie, Masato Nagai, Chizuru Yamanaka, Hiroko Matsubara, Mayumi Kato, Yuki Sato, Soichi Ogishima, Takako Takai, Masahiro Kikuya, Atsushi Hozawa, Fuji Nagami, Shinichi Kuriyama, Takashi Suzuki, Kengo Kinoshita, Masayuki Yamamoto, Hiroshi Tanaka

    Bioinformation　18　(12)　1166-1172　2022/12/31

    Publisher: Biomedical Informatics

    DOI： 10.6026/973206300181166 　

    ISSN： 0973-8894

    eISSN： 0973-2063

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    A system for inputting and storing family information, named “BirThree Enrollment,” was developed to promote a birth and three-generation cohort study (BirThree Cohort Study). In this cohort study, it was necessary to satisfy many operational demands while constantly overwriting and changing input information. Complex kinship information must be quickly and accurately inputed and corrected, and information on those families not yet recruited must be retrieved. For these purposes, many devices are needed, from an input interface to the internal data structure. In the field of genetic statistics, a simple standard expressive form (describe father-child relation and mother-child relation) is used for describing family structure. However, this form doesn't have sufficient information. So we developed a new form in conducting the BirThree Cohort Study. Hence, we expanded the data structure, and constructed the Input control system. Family pedigree information is stored along with initial clinical information, and this enabled the input of all self-reported information to the data base. Operators are able to input this family information before the day is out. As a result, when recruitment is completed, family information will be completed concurrently. Therefore, operators can immediately know certain person's family structure. In this model data correction was improved dramatically, and the system was operated successfully. This study is the first report of the method for storing three generations of family data.

  67. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

    Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, Gina M. Peloso

    Genome Biology　23　(1)　2022/12/27

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1186/s13059-022-02837-1 　

    eISSN： 1474-760X

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    Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

  68. Familial Paget's disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27).

    Akiko Saito-Hakoda, Atsuo Kikuchi, Tadahisa Takahashi, Yu Yokoyama, Noriko Himori, Mika Adachi, Ryoukichi Ikeda, Yuri Nomura, Jun Takayama, Junko Kawashima, Fumiki Katsuoka, Fumiyoshi Fujishima, Takehiko Yamaguchi, Akiyo Ito, Takushi Hanita, Junko Kanno, Toshimi Aizawa, Toru Nakazawa, Tetsuaki Kawase, Gen Tamiya, Masayuki Yamamoto, Ikuma Fujiwara, Shigeo Kure

    Journal of bone and mineral metabolism　41　(2)　193-202　2022/12/15

    DOI： 10.1007/s00774-022-01392-w 　

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    INTRODUCTION: Paget's disease of bone (PDB) is a skeletal disorder characterized by disorganized bone remodeling due to abnormal osteoclasts. Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) gene encodes the receptor activator of nuclear factor kappa B (RANK), which has a critical role in osteoclast function. There are five types of rare PDB and related osteolytic disorders due to TNFRSF11A tandem duplication variants so far, including familial expansile osteolysis (84dup18), expansile skeletal hyperphosphatasia (84dup15), early-onset familial PDB (77dup27), juvenile PDB (87dup15), and panostotic expansile bone disease (90dup12). MATERIALS AND METHODS: We reviewed a Japanese family with PDB, and performed whole-genome sequencing to identify a causative variant. RESULTS: This family had bone symptoms, hyperphosphatasia, hearing loss, tooth loss, and ocular manifestations such as angioid streaks or early-onset glaucoma. We identified a novel duplication variant of TNFRSF11A (72dup27). Angioid streaks were recognized in Juvenile Paget's disease due to loss-of-function variants in the gene TNFRSF11B, and thought to be specific for this disease. However, the novel recognition of angioid streaks in our family raised the possibility of occurrence even in bone disorders due to TNFRSF11A duplication variants and the association of RANKL-RANK signal pathway as the pathogenesis. Glaucoma has conversely not been reported in any case of Paget's disease. It is not certain whether glaucoma is coincidental or specific for PDB with 72dup27. CONCLUSION: Our new findings might suggest a broad spectrum of phenotypes in bone disorders with TNFRSF11A duplication variants.

  69. Structural basis of transcription regulation by CNC family transcription factor, Nrf2 Peer-reviewed

    Toru Sengoku, Masaaki Shiina, Kae Suzuki, Keisuke Hamada, Ko Sato, Akiko Uchiyama, Shunsuke Kobayashi, Asako Oguni, Hayato Itaya, Kota Kasahara, Hirotomo Moriwaki, Chiduru Watanabe, Teruki Honma, Chikako Okada, Shiho Baba, Tsutomu Ohta, Hozumi Motohashi, Masayuki Yamamoto, Kazuhiro Ogata

    Nucleic Acids Research　50　(21)　12543-12557　2022/12/01

    Publisher: Oxford University Press (OUP)

    DOI： 10.1093/nar/gkac1102 　

    ISSN： 0305-1048

    eISSN： 1362-4962

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    Abstract Several basic leucine zipper (bZIP) transcription factors have accessory motifs in their DNA-binding domains, such as the CNC motif of CNC family or the EHR motif of small Maf (sMaf) proteins. CNC family proteins heterodimerize with sMaf proteins to recognize CNC–sMaf binding DNA elements (CsMBEs) in competition with sMaf homodimers, but the functional role of the CNC motif remains elusive. In this study, we report the crystal structures of Nrf2/NFE2L2, a CNC family protein regulating anti-stress transcriptional responses, in a complex with MafG and CsMBE. The CNC motif restricts the conformations of crucial Arg residues in the basic region, which form extensive contact with the DNA backbone phosphates. Accordingly, the Nrf2–MafG heterodimer has approximately a 200-fold stronger affinity for CsMBE than canonical bZIP proteins, such as AP-1 proteins. The high DNA affinity of the CNC–sMaf heterodimer may allow it to compete with the sMaf homodimer on target genes without being perturbed by other low-affinity bZIP proteins with similar sequence specificity.

  70. Plasma metabolic disturbances during pregnancy and postpartum in women with depression Peer-reviewed

    Zhiqian Yu, Naomi Matsukawa, Daisuke Saigusa, Ikuko N. Motoike, Chiaki Ono, Yasunobu Okamura, Tomomi Onuma, Yuta Takahashi, Mai Sakai, Hisaaki Kudo, Taku Obara, Keiko Murakami, Matusyuki Shirota, Saya Kikuchi, Natsuko Kobayashi, Yoshie Kikuchi, Junichi Sugawara, Naoko Minegishi, Soichi Ogishima, Kengo Kinoshita, Masayuki Yamamoto, Nobuo Yaegashi, Shinichi Kuriyama, Seizo Koshiba, Hiroaki Tomita

    iScience　25　(12)　105666-105666　2022/12

    Publisher: Elsevier BV

    DOI： 10.1016/j.isci.2022.105666 　

    ISSN： 2589-0042

  71. Design and Progress of Child Health Assessments at Community Support Centers in the Birth and Three-Generation Cohort Study of the Tohoku Medical Megabank Project.

    Tomoko Kobayashi, Mika Kobayashi, Naoko Minegishi, Masahiro Kikuya, Taku Obara, Mami Ishikuro, Chizuru Yamanaka, Tomomi Onuma, Keiko Murakami, Fumihiko Ueno, Aoi Noda, Akira Uruno, Junichi Sugawara, Kichiya Suzuki, Eiichi N Kodama, Yohei Hamanaka, Naho Tsuchiya, Mana Kogure, Naoki Nakaya, Makiko Taira, Mika Sakurai-Yageta, Toru Tamahara, Junko Kawashima, Maki Goto, Akihito Otsuki, Ritsuko Shimizu, Soichi Ogishima, Hiroaki Hashizume, Fuji Nagami, Tomohiro Nakamura, Atsushi Hozawa, Tadao Kobayashi, Nobuo Fuse, Shinichi Kuriyama, Shigeo Kure, Masayuki Yamamoto

    The Tohoku journal of experimental medicine　259　(2)　93-105　2022/12/01

    DOI： 10.1620/tjem.2022.J103 　

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    The Tohoku Medical Megabank Project (TMM) has been conducting a birth and three-generation cohort study (the BirThree Cohort Study). We recruited 73,529 pregnant women and their family members for this cohort study, which included 23,143 newborns and 9,459 of their siblings. We designed and are in the process of conducting three-step health assessments for each newborn at approximately ages of 5, 10 and 16. These health assessments are administered at seven community support centers. Trained genome medical research coordinators conduct physical examinations of and collect biological specimens from each participant. The Sendai Children's Health Square has been established as the headquarters for these child health assessments and is utilized to accumulate knowledge that can facilitate the proper practice of child health assessments. We designed all the relevant health assessments facilities to allow parents and their children to participate in the health assessments concomitantly. Our centers serve as places where child participants and their parents can feel at ease as a result of the implementation of safety measures and child hospitality measures. The TMM BirThree Cohort Study is in the process of conducting strategically detailed health assessments and genome analysis, which can facilitate studies concerning the gene-environment interactions relevant to noncommunicable diseases. Through these operations, our study allows for a significant depth of data to be collected in terms of the number of biospecimens under study and the comprehensiveness of both basic and clinical data alongside relevant family information.

  72. Genome-wide association study of the risk of chronic kidney disease and kidney-related traits in the Japanese population: J-Kidney-Biobank. International-journal

    Yuka Sugawara, Yosuke Hirakawa, Hajime Nagasu, Akira Narita, Akihiro Katayama, Jun Wada, Miho Shimizu, Takashi Wada, Hiromasa Kitamura, Toshiaki Nakano, Hideki Yokoi, Motoko Yanagita, Shin Goto, Ichiei Narita, Seizo Koshiba, Gen Tamiya, Masaomi Nangaku, Masayuki Yamamoto, Naoki Kashihara

    Journal of human genetics　68　(2)　55-64　2022/11/21

    DOI： 10.1038/s10038-022-01094-1 　

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    Chronic kidney disease (CKD) is a syndrome characterized by a gradual loss of kidney function with decreased estimated glomerular filtration rate (eGFR), which may be accompanied by an increase in the urine albumin-to-creatinine ratio (UACR). Although trans-ethnic genome-wide association studies (GWASs) have been conducted for kidney-related traits, there have been few analyses in the Japanese population, especially for the UACR trait. In this study, we conducted a GWAS to identify loci related to multiple kidney-related traits in Japanese individuals. First, to detect loci associated with CKD, eGFR, and UACR, we performed separate GWASs with the following two datasets: 475 cases of CKD diagnosed at seven university hospitals and 3471 healthy subjects (dataset 1) and 3664 cases of CKD-suspected individuals with eGFR <60 ml/min/1.73 m2 or urinary protein ≥ 1+ and 5952 healthy subjects (dataset 2). Second, we performed a meta-analysis between these two datasets and detected the following associated loci: 10 loci for CKD, 9 loci for eGFR, and 22 loci for UACR. Among the loci detected, 22 have never been reported previously. Half of the significant loci for CKD were shared with those for eGFR, whereas most of the loci associated with UACR were different from those associated with CKD or eGFR. The GWAS of the Japanese population identified novel genetic components that were not previously detected. The results also suggest that the group primarily characterized by increased UACR possessed genetically different features from the group characterized by decreased eGFR.

  73. Changes in glial cells and neurotrophic factors due to rotenone-induced oxidative stress in Nrf2 knockout mice. International-journal

    Maki Inoue-Yanagimachi, Noriko Himori, Keiko Uchida, Hiroshi Tawarayama, Kota Sato, Masayuki Yamamoto, Kazuhiko Namekata, Takayuki Harada, Toru Nakazawa

    Experimental eye research　226　109314-109314　2022/11/15

    DOI： 10.1016/j.exer.2022.109314 　

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    Glaucoma is one of the most common causes of blindness worldwide. It is thought to be a multifactorial disease with underlying mechanisms that include mitochondrial dysfunction and oxidative stress. Here, we used NF-E2 related factor 2 (Nrf2) knockout (KO) mice, which are vulnerable to oxidative stress, to examine a neuroprotective effect against oxidative stress due to rotenone, a mitochondrial complex I inhibitor. Wild-type (WT) and Nrf2 KO mice received an oral solution of rotenone for 30 days. We then extracted the retinas and performed immunohistochemistry and quantitative RT-PCR. We also prepared a primary Müller cell culture of samples from each mouse, added 30 μM rotenone, and then measured cell viability, cytotoxicity and CellRox absorbance. We also examined gene expression. We found a significant increase in the number of 8-OHdG-positive retinal ganglion cells (RGCs) after rotenone administration in both the WT and Nrf2 KO mice. There was no difference in the number of RNA-binding protein with multiple splicing (RBPMS)-positive RGCs in the WT and Nrf2 KO mice, but Nrf2 KO mice that were given rotenone had significantly less retinal gene expression of RBPMS than Nrf2 KO mice given a control. Moreover, there was significantly higher mRNA gene expression of vimentin and glial fibrillary acidic protein (GFAP) in Nrf2 KO mice that received rotenone than WT mice that received rotenone. A statistical analysis of the in vitro experiment showed that cell viability was lower, cytotoxicity was higher, and oxidative stress was higher in the Müller cells of the Nrf2 KO mice than the WT mice. Finally, brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF) were significantly higher in the Müller cells of the Nrf2 KO mice than the WT mice. These findings suggest that in Nrf2 KO mice under oxidative stress caused by rotenone, temporary neurotrophic factors are secreted from the Müller cells, conferring neuroprotection in these cells.

  74. Establishment of Neh2-Cre:tdTomato reporter mouse for monitoring the exposure history to electrophilic stress. International-journal

    Hiroshi Kitamura, Tetsuya Oishi, Shohei Murakami, Tomoe Yamada-Kato, Isao Okunishi, Masayuki Yamamoto, Yukio Katori, Hozumi Motohashi

    Free radical biology & medicine　193　(Pt 2)　610-619　2022/11/09

    DOI： 10.1016/j.freeradbiomed.2022.11.004 　

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    Cells are often exposed to exogenous and endogenous redox disturbances and exert their protective mechanisms in response to stimuli. The KEAP1-NRF2 system plays pivotal roles in counteracting oxidative damage. Due to the transient nature of NRF2 activation, the identification of cells in which NRF2 is activated in response to systemic stimuli is sometimes not easy. To examine the electrophilic stress response at a single-cell resolution, we aimed to develop a new reporter mouse in this study. A cell-tracing strategy exploiting Cre recombinase-mediated activation of a reporter gene was chosen for stable detection of reporter expression instead of real-time monitoring of the cellular response. We established a transgenic mouse line expressing the Neh2-Cre recombinase fusion protein. As Neh2 is an amino-terminal domain of NRF2 that serves as a degron and mediates KEAP1-dependent degradation and electrophile-inducible stabilization, Neh2-Cre was expected to be activated in response to electrophiles. The Neh2-Cre transgenic mouse was crossed with the ROSA26-loxP-stop-loxP-tdTomato reporter mouse (ROSA-LSL-tdTomato mouse). The compound mutant reporter mice exhibited accumulation of tdTomato-positive cells in various organs after repeated administration of CDDO-Im, one of the NRF2-inducing electrophiles. The mice were also successfully used for the detection of cells that experienced a cisplatin-induced electrophilic stress response.

  75. 遺伝・生活習慣が日本人の血中代謝プロファイルに与える影響の解析

    小柴 生造, 元池 育子, 井上 仁, 菱沼 英史, 青木 裕一, 櫻井 美由紀, 佐藤 允治, 七谷 圭, 田高 周, 城田 松之, 木下 賢吾, 山本 雅之

    日本生化学会大会プログラム・講演要旨集　95回　1T17e-02　2022/11

    Publisher: (公社)日本生化学会

  76. Protective role of Nrf2 in zinc oxide nanoparticles-induced lung inflammation in female mice and sexual dimorphism in susceptibility. International-journal

    Radwa Sehsah, Wenting Wu, Sahoko Ichihara, Naozumi Hashimoto, Cai Zong, Kyoka Yamazaki, Harue Sato, Ken Itoh, Masayuki Yamamoto, Ahmed Ali Elsayed, Soheir El-Bestar, Emily Kamel, Gaku Ichihara

    Toxicology letters　370　24-34　2022/11/01

    DOI： 10.1016/j.toxlet.2022.09.004 　

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    BACKGROUND: Zinc oxide nanoparticles (ZnO-NPs) are currently employed in various products such as rubber, paint, and cosmetics. Our group reported recently that Nrf2 protein provides protection against pulmonary inflammation induced by ZnO-NPs in male mice. The current study investigated the effect of Nrf2 deletion on the lung inflammatory response in female mice exposed to ZnO-NPs. METHODS: An equal number of female Nrf2-/- mice and female Nrf2+/+ mice (24 each) were allocated into three equal groups, and each was exposed to ZnO-NPs at either 0, 10 or 30 µg ZnO-NPs/mouse through pharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) and lungs were examined 14 days later to determine the number of inflammatory cells, the protein level, and for scoring inflammation histopathologically. The mRNA levels of Nrf2-dependent antioxidant enzymes and proinflammatory cytokine in lung tissue were also measured. RESULTS: Exposure to ZnO-NPs increased all types of BALF cells and lung inflammation scores in both of female Nrf2-null (Nrf2-/-) and wild-type (Nrf2+/+) mice, and Nrf2 deletion enhanced ZnO-NPs-induced increase in the number of eosinophils in BALF. Exposure to ZnO-NPs dose-dependently increased the level of oxidized glutathione (GSSG), and mRNA levels of proinflammatory cytokines/chemokines; KC, MIP-2, IL-6, IL-1β and MCP-1 only in wild-type mice. Nrf2 deletion decreased total glutathione levels and basal mRNA levels of SOD1 and NQO1, and increased the basal mRNA level of above proinflammatory cytokines/chemokines. Nrf2 deletion enhanced ZnO-NPs-induced downregulation of GcLc, GR and TGF-β and upregulation of HO-1 and TNF-α. Taken together with our previous results in male mice, our results showed a lower susceptibility of females to lung tissue inflammation, relative to males, irrespective of Nrf2 deletion, and that enhancement of ZnO-NPs-induced upregulation of HO-1 and TNF-α and downregulation of GcLc, GR and TGF-β by deletion of Nrf2 is specific to female mice. CONCLUSION: We conclude that Nrf2 provides protection in female mice against increase in BALF eosinophils, probably through down-regulation of proinflammatory cytokines/chemokines and upregulation of oxidative stress-related genes. The study also suggests lower susceptibility to lung tissue inflammation in female mice relative to their male counterparts and the synergistic effects of Nrf2 and exposure to ZnO-NPs on mRNA expression of GcLc, GR, HO-1, TGF-β or TNF-α in female mice.

  77. Nrf2 deficiency deteriorates diabetic kidney disease in Akita model mice. International-journal

    Yexin Liu, Akira Uruno, Ritsumi Saito, Naomi Matsukawa, Eiji Hishinuma, Daisuke Saigusa, Hong Liu, Masayuki Yamamoto

    Redox biology　58　102525-102525　2022/10/28

    DOI： 10.1016/j.redox.2022.102525 　

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    Oxidative stress is an essential component in the progression of diabetic kidney disease (DKD), and the transcription factor NF-E2-related factor-2 (Nrf2) plays critical roles in protecting the body against oxidative stress. To clarify the roles of Nrf2 in protecting against DKD, in this study we prepared compound mutant mice with diabetes and loss of antioxidative defense. Specifically, we prepared compound Ins2Akita/+ (Akita) and Nrf2 knockout (Akita::Nrf2-/-) or Akita and Nrf2 induction (Akita::Keap1FA/FA) mutant mice. Eighteen-week-old Akita::Nrf2-/- mice showed more severe diabetic symptoms than Akita mice. In the Akita::Nrf2-/- mouse kidneys, the glomeruli showed distended capillary loops, suggesting enhanced mesangiolysis. Distal tubules showed dilation and an increase in 8-hydroxydeoxyguanosine-positive staining. In the Akita::Nrf2-/- mouse kidneys, the expression of glutathione (GSH) synthesis-related genes was decreased, and the actual GSH level was decreased in matrix-assisted laser desorption/ionization mass spectrometry imaging analysis. Akita::Nrf2-/- mice exhibited severe inflammation and enhancement of infiltrated macrophages in the kidney. To further examine the progression of DKD, we compared forty-week-old Akita mouse kidney compounds with Nrf2-knockout or Nrf2 mildly induced (Akita::Keap1FA/FA) mice. Nrf2-knockout Akita (Akita::Nrf2-/-) mice displayed severe medullary cast formation, but the formation was ameliorated in Akita::Keap1FA/FA mice. Moreover, in Akita::Keap1FA/FA mice, tubule injury and inflammation-related gene expression were significantly suppressed, which was evident in Akita::Nrf2-/- mouse kidneys. These results demonstrate that Nrf2 contributes to the protection of the kidneys against DKD by suppressing oxidative stress and inflammation.

  78. Novel NRF2-activated cancer treatments utilizing synthetic lethality. International-journal

    Liam Baird, Thomas W Kensler, Masayuki Yamamoto

    IUBMB life　2022/10/05

    DOI： 10.1002/iub.2680 　

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    The KEAP1-NRF2 pathway regulates the main inducible cellular response to oxidative and electrophilic stresses. Activating mutations in the KEAP1-NRF2 pathway occur commonly in human cancer, where they contribute to the formation of aggressive tumours that are associated with a poor prognosis for patients. An important clinical feature of these tumours is their defiance to all current anti-cancer treatment regimens, highlighting the need for the development of new therapeutic strategies to target NRF2-activated cancers. In this review, we discuss the mechanisms through which acquired NRF2 hyperactivation can result in resistance of tumours to immune checkpoint inhibitor therapies in addition to classical chemotherapeutics, and propose with examples that using a synthetic lethal strategy mediated by NRF2-target gene-dependent bioactivation of prodrugs represents a promising strategy to specifically enhance toxicity to heretofore untreatable NRF2-hyperactivated human tumours.

  79. Multiomics and artificial intelligence enabled peripheral blood-based prediction of amnestic mild cognitive impairment

    Yota Tatara, Hiromi Yamazaki, Fumiki Katsuoka, Mitsuru Chiba, Daisuke Saigusa, Shuya Kasai, Tomohiro Nakamura, Jin Inoue, Yuichi Aoki, Miho Shoji, Ikuko Motoike, Yoshinori Tamada, Katsuhito Hashizume, Mikio Shoji, Kengo Kinoshita, Koichi Murashita, Shigeyuki Nakaji, Masayuki Yamamoto, Ken Itoh

    Current Research in Translational Medicine　71　(1)　103367-103367　2022/10

    Publisher: Elsevier BV

    DOI： 10.1016/j.retram.2022.103367 　

    ISSN： 2452-3186

  80. Pathological variants in genes associated with disorders of sex development and central causes of hypogonadism in a whole-genome reference panel of 8380 Japanese individuals. International-journal

    Naomi Shiga, Yumi Yamaguchi-Kabata, Saori Igeta, Jun Yasuda, Shu Tadaka, Takamichi Minato, Zen Watanabe, Junko Kanno, Gen Tamiya, Nobuo Fuse, Kengo Kinoshita, Shigeo Kure, Akiko Kondo, Masahito Tachibana, Masayuki Yamamoto, Nobuo Yaegashi, Junichi Sugawara

    Human genome variation　9　(1)　34-34　2022/09/28

    DOI： 10.1038/s41439-022-00213-w 　

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    Disorders of sex development (DSD) comprises a congenital condition in which chromosomal, gonadal, or anatomical sex development is atypical. In this study, we screened for pathogenic variants in 32 genes associated with DSDs and central causes of hypogonadism (CHG) in a whole-genome reference panel including 8380 Japanese individuals constructed by Tohoku Medical Megabank Organization. Candidate pathogenic (P) or likely pathogenic (LP) variants were extracted from the ClinVar, InterVar, and Human Gene Mutation databases. Ninety-one candidate pathological variants were found in 25 genes; 28 novel candidate variants were identified. Nearly 1 in 40 (either ClinVar or InterVar P or LP) to 157 (both ClinVar and InterVar P or LP) individuals were found to be carriers of recessive DSD and CHG alleles. In these data, genes implicated in gonadal dysfunction did not show loss-of-function variants, with a relatively high tendency of intolerance for haploinsufficiency based on pLI and Episcore, both of which can be used for estimating haploinsufficiency. We report the types and frequencies of causative variants for DSD and CHG in the general Japanese population. This study furthers our understanding of the genetic causes and helps to refine genetic counseling of DSD and CHG.

  81. The KEAP1-NRF2 System and Esophageal Cancer. International-journal

    Wataru Hirose, Hiroyuki Oshikiri, Keiko Taguchi, Masayuki Yamamoto

    Cancers　14　(19)　2022/09/27

    DOI： 10.3390/cancers14194702 　

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    NRF2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that regulates the expression of many cytoprotective genes. NRF2 activation is mainly regulated by KEAP1 (kelch-like ECH-associated protein 1) through ubiquitination and proteasome degradation. Esophageal cancer is classified histologically into two major types: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC harbors more genetic alterations in the KEAP-NRF2 system than EAC does, which results in NRF2 activation in these cancers. NRF2-addicted ESCC exhibits increased malignancy and acquisition of resistance to chemoradiotherapy. Therefore, it has been recognized that the development of drugs targeting the KEAP1-NRF2 system based on the molecular dissection of NRF2 function is important and urgent for the treatment of ESCC, along with efficient clinical screening for NRF2-addicted ESCC patients. Recently, the fate of NRF2-activated cells in esophageal tissues, which was under the influence of strong cell competition, and its relationship to the pathogenesis of ESCC, was clarified. In this review, we will summarize the current knowledge of the KEAP1-NRF2 system and the treatment of ESCC. We propose three main strategies for the treatment of NRF2-addicted cancer: (1) NRF2 inhibitors, (2) synthetic lethal drugs for NRF2-addicted cancers, and (3) NRF2 inducers of the host defense system.

  82. Returning individual genomic results to population-based cohort study participants with BRCA1/2 pathogenic variants.

    Kinuko Ohneda, Yohei Hamanaka, Hiroshi Kawame, Nobuo Fuse, Fuji Nagami, Yoichi Suzuki, Yumi Yamaguchi-Kabata, Muneaki Shimada, Atsushi Masamune, Yoko Aoki, Takanori Ishida, Masayuki Yamamoto

    Breast cancer (Tokyo, Japan)　30　(1)　110-120　2022/09/26

    DOI： 10.1007/s12282-022-01404-7 　

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    BACKGROUND: Recent advances in human genome research have provided evidence for genotype-phenotype associations, pathogenicity, and clinical actionability of variants and genomic risk prediction of disease. However, the return of individual genomic results to healthy individuals is fraught with ethical and practical complexity. METHODS: Individual genomic results were returned to BRCA1/2 pathogenic variant (PV) carriers of the Tohoku Medical Megabank cohort study participants with an information on hereditary breast and ovarian cancer syndrome (HBOC). One hundred and eighty participants, including 9 BRCA1/2 PV carriers, were asked about their willingness to receive individual genomic results, without revealing the gene name and related disorders, prior to the study. Of the 142 participants who responded, 103 showed willingness to know their genomic information. Each of the six BRCA1/2 PV carriers who consented to participate in the study received information about HBOC in person and underwent validation testing with blood resampling. RESULTS: All participants were in their 60s or 70s; of the four females and two males, two had a history of breast cancer and five had a family history of HBOC-related cancers. All participants appreciated the information, without remarkable negative psychological impact of the return, and intended to undergo clinical risk surveillance. Five participants were accompanied by family members while receiving the results, and three first-degree female relatives wished to undergo genomic testing at the hospital. CONCLUSIONS: Our results suggest that returning actionable genomic information to participants in a population-based genome cohort study is beneficial for preventing or providing early-stage intervention for associated diseases.

  83. Association Between Glycemic Traits and Primary Open-Angle Glaucoma: A Mendelian Randomization Study in the Japanese Population. International-journal

    Akiko Hanyuda, Atsushi Goto, Masahiro Nakatochi, Yoichi Sutoh, Akira Narita, Shiori Nakano, Ryoko Katagiri, Kenji Wakai, Naoyuki Takashima, Teruhide Koyama, Kokichi Arisawa, Issei Imoto, Yukihide Momozawa, Kozo Tanno, Atsushi Shimizu, Atsushi Hozawa, Kengo Kinoshita, Taiki Yamaji, Norie Sawada, Masao Iwagami, Kenya Yuki, Kazuo Tsubota, Kazuno Negishi, Keitaro Matsuo, Masayuki Yamamoto, Makoto Sasaki, Shoichiro Tsugane, Motoki Iwasaki

    American journal of ophthalmology　245　193-201　2022/09/23

    DOI： 10.1016/j.ajo.2022.09.004 　

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    PURPOSE: A meta-analysis suggests a relationship between abnormal glucose metabolism and primary open-angle glaucoma (POAG); however, the causal association between them remains controversial. We therefore conducted a Mendelian randomization (MR) study to assess the causal association between genetically predicted glycemic traits and the risk of POAG. DESIGN: Two-sample MR design. METHODS: We examined the genetically predicted measures of fasting glucose, hemoglobin A1c (HbA1c), and fasting C-peptide, in relation to POAG. For the single nucleotide polymorphism (SNP)-exposure analyses, we meta-analyzed the study-level genome-wide associations of fasting glucose levels (n = 17,289; n of SNPs = 34), HbA1c (n = 52,802; n of SNPs = 43), and fasting C-peptide levels (n=1666; n of SNPs = 17) from the Japanese Consortium of Genetic Epidemiology studies. We used summary statistics from the BioBank Japan projects (n = 3980 POAG cases and 18,815 controls) for the SNP-outcome association. RESULTS: We observed no association of genetically predicted HbA1c and fasting C-peptide with POAG. The MR inverse-variance-weighted (IVW) odds ratios (ORs) were 1.44 (95% confidence interval [CI], 0.78-2.65; P = .25) for HbA1c (per 1% increment) and 0.92 (95% CI, 0.56-1.53; P = .76) for fasting C-peptide (per 2-fold increment). A significant association between fasting glucose (per 10 mg/dL-increment) and POAG was observed according to the MR IVW analysis (OR = 1.48 [95% CI, 1.10-1.79, P = .009]); however, sensitivity analyses, including MR-Egger and weighted-median methods, did not support this association (P > .10). CONCLUSIONS: We did not observe strong evidence to support the association between genetically predicted glycemic traits and POAG in the Japanese population.

  84. Construction of a trio-based structural variation panel utilizing activated T lymphocytes and long-read sequencing technology. International-journal

    Akihito Otsuki, Yasunobu Okamura, Noriko Ishida, Shu Tadaka, Jun Takayama, Kazuki Kumada, Junko Kawashima, Keiko Taguchi, Naoko Minegishi, Shinichi Kuriyama, Gen Tamiya, Kengo Kinoshita, Fumiki Katsuoka, Masayuki Yamamoto

    Communications biology　5　(1)　991-991　2022/09/20

    DOI： 10.1038/s42003-022-03953-1 　

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    Long-read sequencing technology enable better characterization of structural variants (SVs). To adapt the technology to population-scale analyses, one critical issue is to obtain sufficient amount of high-molecular-weight genomic DNA. Here, we propose utilizing activated T lymphocytes, which can be established efficiently in a biobank to stably supply high-grade genomic DNA sufficiently. We conducted nanopore sequencing of 333 individuals constituting 111 trios with high-coverage long-read sequencing data (depth 22.2x, N50 of 25.8 kb) and identified 74,201 SVs. Our trio-based analysis revealed that more than 95% of the SVs were concordant with Mendelian inheritance. We also identified SVs associated with clinical phenotypes, all of which appear to be stably transmitted from parents to offspring. Our data provide a catalog of SVs in the general Japanese population, and the applied approach using the activated T-lymphocyte resource will contribute to biobank-based human genetic studies focusing on SVs at the population scale.

  85. Selective Elimination of NRF2-Activated Cells by Competition With Neighboring Cells in the Esophageal Epithelium. International-journal

    Wataru Hirose, Makoto Horiuchi, Donghan Li, Ikuko N Motoike, Lin Zhang, Hafumi Nishi, Yusuke Taniyama, Takashi Kamei, Mikiko Suzuki, Kengo Kinoshita, Fumiki Katsuoka, Keiko Taguchi, Masayuki Yamamoto

    Cellular and molecular gastroenterology and hepatology　15　(1)　153-178　2022/09/15

    DOI： 10.1016/j.jcmgh.2022.09.004 　

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    BACKGROUND & AIMS: NF-E2-related factor 2 (NRF2) is a transcription factor that regulates cytoprotective gene expression in response to oxidative and electrophilic stresses. NRF2 activity is mainly controlled by Kelch-like ECH-associated protein 1 (KEAP1). Constitutive NRF2 activation by NRF2 mutations or KEAP1 dysfunction results in a poor prognosis for esophageal squamous cell carcinoma (ESCC) through the activation of cytoprotective functions. However, the detailed contributions of NRF2 to ESCC initiation or promotion have not been clarified. Here, we investigated the fate of NRF2-activated cells in the esophageal epithelium. METHODS: We generated tamoxifen-inducible, squamous epithelium-specific Keap1 conditional knockout (Keap1-cKO) mice in which NRF2 was inducibly activated in a subset of cells at the adult stage. Histological, quantitative reverse-transcription polymerase chain reaction (qRT‒PCR), single-cell RNA-sequencing (RNA-seq) and carcinogen experiments were conducted to analyze the Keap1-cKO esophagus. RESULTS: KEAP1-deleted/NRF2-activated cells and cells with normal NRF2 expression (KEAP1-normal cells) coexisted in the Keap1-cKO esophageal epithelium in approximately equal numbers, and NRF2-activated cells formed dysplastic lesions. NRF2-activated cells exhibited weaker attachment to the basement membrane and gradually disappeared from the epithelium. In contrast, neighboring KEAP1-normal cells exhibited accelerated proliferation and started dominating the epithelium but accumulated DNA damage that triggered carcinogenesis upon carcinogen exposure. CONCLUSIONS: Constitutive NRF2 activation promotes the selective elimination of epithelial cells via cell competition, but this competition induces DNA damage in neighboring KEAP1-normal cells, which predisposes them to chemical-induced ESCC.

  86. 全ゲノム/全エキソーム解析による生殖細胞系列多型の探索 一般住民コホートにおけるBRCA遺伝子バリアントの探索及び結果の回付事業について(Exploration of BRCA1/2 gene variants in a general population cohort and return of genomic results to the participants)

    徳永 英樹, 安田 純, 島田 宗昭, 濱中 洋平, 重田 昌吾, 布施 昇男, 勝岡 史城, 荻島 創一, 山口 由美, 寳澤 篤, 川目 裕, 大根田 絹子, 青木 洋子, 山本 雅之, 八重樫 伸生

    日本癌学会総会記事　81回　S8-1　2022/09

    Publisher: (一社)日本癌学会

    ISSN： 0546-0476

  87. Blood lipids and the risk of colorectal cancer: Mendelian randomization analyses in the Japanese Consortium of Genetic Epidemiology studies. International-journal

    Masao Iwagami, Atsushi Goto, Ryoko Katagiri, Yoichi Sutoh, Yuriko N Koyanagi, Masahiro Nakatochi, Shiori Nakano, Akiko Hanyuda, Akira Narita, Atsushi Shimizu, Kozo Tanno, Atsushi Hozawa, Kengo Kinoshita, Isao Oze, Hidemi Ito, Taiki Yamaji, Norie Sawada, Yohko Nakamura, Sho Nakamura, Kiyonori Kuriki, Sadao Suzuki, Asahi Hishida, Yumiko Kasugai, Issei Imoto, Midori Suzuki, Yukihide Momozawa, Kenji Takeuchi, Masayuki Yamamoto, Makoto Sasaki, Keitaro Matsuo, Shoichiro Tsugane, Kenji Wakai, Motoki Iwasaki

    Cancer prevention research (Philadelphia, Pa.)　15　(12)　827-836　2022/08/30

    DOI： 10.1158/1940-6207.CAPR-22-0146 　

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    The associations between blood lipids, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides, and low-density lipoprotein cholesterol (LDL-C), and colorectal cancer risk are controversial. We evaluated potential causal relationships between blood lipids and colorectal cancer risk. Using the baseline data from the Japanese Consortium of Genetic Epidemiology studies, we estimated the single-nucleotide polymorphism (SNP)-exposure associations (n=34,546 for TC, n=50,290 for HDL-C, n=51,307 for triglycerides, and n=30,305 for LDL-C). We also estimated the SNP-outcome associations in another Japanese dataset (n=7,936 colorectal cancer cases and n=38,042 controls). We conducted Mendelian randomization analyses for the association between each blood lipid type and the risk of colorectal cancer using an inverse variance-weighted method. The total variances explained by the selected SNPs in TC (68 SNPs), HDL-C (50 SNPs), log-transformed triglycerides (26 SNPs), and LDL-C (35 SNPs) were 7.0%, 10.0%, 6.2%, and 5.7%, respectively. The odds ratios for colorectal cancer were 1.15 (95% confidence interval 1.01-1.32) per 1 standard deviation (SD) (33.3 mg/dL) increase in TC, 1.11 (0.98-1.26) per 1 SD (15.4 mg/dL) increase in HDL-C, 1.06 (0.90-1.26) per 1 SD (0.5 log-mg/dL) increase in log-transformed triglycerides, and 1.17 (0.91-1.50) per 1 SD (29.6 mg/dL) increase in LDL-C. Sensitivity analyses consistently suggested the positive association between TC and colorectal cancer, whereas results of each lipid component were inconsistent. In conclusion, this large Mendelian randomization study of a Japanese population showed a potentially causal association between high TC and colorectal cancer risk, although the association between each lipid component and colorectal cancer remained inconclusive.

  88. Genomic landscape of chemical-induced lung tumors under Nrf2 different expression levels. International-journal

    Hironori Satoh, Yasuhito Arai, Eisaku Furukawa, Takashi Moriguchi, Natsuko Hama, Tomoko Urushidate, Yasushi Totoki, Mamoru Kato, Yuichiro Ohe, Masayuki Yamamoto, Tatsuhiro Shibata

    Carcinogenesis　43　(7)　613-623　2022/08/30

    DOI： 10.1093/carcin/bgac041 　

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    The transcription factor Nrf2 plays a crucial role in the anti-oxidative stress response, protection of DNA from injury, and DNA repair mechanisms. Nrf2 activity reduces cancer initiation, but how Nrf2 affects whole-genome alterations upon carcinogenic stimulus remains unexplored. Although recent genome-wide analysis using next-generation sequencing revealed landscapes of nucleotide mutations and copy number alterations in various human cancers, genomic changes in murine cancer models have not been thoroughly examined. We elucidated the relationship between Nrf2 expression levels and whole exon mutation patterns using an ethyl-carbamate (urethane)-induced lung carcinogenesis model employing Nrf2-deficient and Keap1-kd mice, the latter of which express high levels of Nrf2. Exome analysis demonstrated that single nucleotide and trinucleotide mutation patterns and the Kras mutational signature differed significantly and were dependent on the expression level of Nrf2. The Nrf2-deficient tumors exhibited fewer copy number alterations relative to the Nrf2-wt and Keap1-kd tumors. The observed trend in genomic alterations likely prevented the Nrf2-deficient tumors from progressing into malignancy. For the first time, we present whole-exome sequencing results for chemically-induced lung tumors in the Nrf2 gain or loss of function mouse models. Our results demonstrate that different Nrf2 expression levels lead to distinct gene mutation patterns that underly different oncogenic mechanisms in each tumor genotype.

  89. A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids. International-journal

    Shweta Ramdas, Jonathan Judd, Sarah E Graham, Stavroula Kanoni, Yuxuan Wang, Ida Surakka, Brandon Wenz, Shoa L Clarke, Alessandra Chesi, Andrew Wells, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W Winkler, Adam E Locke, Eirini Marouli, Greg J M Zajac, Kuan-Han H Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M Brumpton, Humaira Rasheed, Aki S Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J Kullo, Akira Narita, Jun Takayama, Hilary C Martin, Karen A Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E Miller, Archie Campbell, Kuang Lin, Iona Y Millwood, Asif Rasheed, George Hindy, Jessica D Faul, Wei Zhao, David R Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R Brown, Weihua Zhang, Ketian Yu, Ellen M Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian'an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R Wood, Yingji Ji, Zishan Gao, Simon Haworth, Ruth E Mitchell, Jin Fang Chai, Mette Aadahl, Anne A Bjerregaard, Jie Yao, Ani Manichaikul, Wen-Jane Lee, Chao Agnes Hsiung, Helen R Warren, Julia Ramirez, Jette Bork-Jensen, Line L Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Sebastian Schönherr, Lukas Forer, Markus Scholz, Tessel E Galesloot, Jonathan P Bradfield, Sanni E Ruotsalainen, E Warwick Daw, Joseph M Zmuda, Jonathan S Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A Brody, Phuong Le, Mary F Feitosa, Mary K Wojczynski, Daiane Hemerich, Michael Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W Benjamins, Jorgen Engmann, Tsao L Noah, Anurag Verma, Roderick C Slieker, Ken Sin Lo, Nuno R Zilhao, Marcus E Kleber, Graciela E Delgado, Shaofeng Huo, Daisuke D Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L Leonard, Jonathan Marten, Carina Emmel, Börge Schmidt, Laura J Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S Nongmaithem, Alagu Sankareswaran, Marguerite R Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R H J Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C Warner, Ya Xing Wang, Wen B Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A Kentistou, Bernhard Banas, Anna Morgan, Karina Meidtner, Lawrence F Bielak, Jennifer A Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J van der Most, Niina Pitkänen, Brian E Cade, Sander W van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R Bentley, Ayo P Doumatey, Adebowale A Adeyemo, Jong Young Lee, Eva R B Petersen, Aneta A Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W Rayner, Carol A Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O Obura, Jessica van Setten, Karen Y He, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D Jackson, Alexander P Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C Bis, Lenore J Launer, Huaixing Li, Mike A Nalls, Olli T Raitakari, Sahoko Ichihara, Sarah H Wild, Christopher P Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J de Borst, Eung Kweon Kim, Hieab H H Adams, M Arfan Ikram, Xiaofeng Zhu, Folkert W Asselbergs, Adriaan O Kraaijeveld, Joline W J Beulens, Xiao-Ou Shu, Loukianos S Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E Pennell, Trevor A Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M Heid, Klaus J Stark, Martina E Zimmermann, Henry Völzke, Georg Homuth, Michele K Evans, Alan B Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E Hoefer, Susan Redline, Katja Pahkala, Albertine J Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Patricia A Peyser, Norihiro Kato, Matthias B Schulze, Giorgia Girotto, Carsten A Böger, Bettina Jung, Peter K Joshi, David A Bennett, Philip L De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J Caulfield, Patricia B Munroe, Xiuqing Guo, Marina Ciullo, Jost B Jonas, Nilesh J Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A Aguilar-Salinas, Linda S Adair, Sonny Augustin Bechayda, H Janaka de Silva, Ananda R Wickremasinghe, Ronald M Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke I den Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G Wilson, Lars Lind, Chew-Kiat Heng, Amanda E Nelson, Yvonne M Golightly, James F Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J Scott, D C Rao, Donna K Arnett, Mark Walker, Laura J Scott, Heikki A Koistinen, Giriraj R Chandak, Josep M Mercader, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, E Shyong Tai, Rob M van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I McCarthy, Colin N A Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M van Duijn, Zi-Bing Jin, Fan Lu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M T Hart, Petra J M Elders, Daniel J Rader, Scott M Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D Spector, Ruth J F Loos, Michael A Province, Esteban J Parra, Miguel Cruz, Bruce M Psaty, Ivan Brandslund, Peter P Pramstaller, Charles N Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F A Grant, Lambertus Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W Franks, Allan Linneberg, J Wouter Jukema, Amit V Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P Strachan, Niels Grarup, Peter Sever, Neil Poulter, Wayne Huey-Herng Sheu, Jerome I Rotter, Thomas M Dantoft, Fredrik Karpe, Matt J Neville, Nicholas J Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T Hattersley, Nancy L Pedersen, Patrik K E Magnusson, Dorret I Boomsma, Eco J C de Geus, L Adrienne Cupples, Joyce B J van Meurs, Arfan Ikram, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J Wareham, Claudia Langenberg, Eleftheria Zeggini, Jaakko Tuomilehto, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C Chambers, Jaspal S Kooner, Paul S de Vries, Alanna C Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E North, Martha Daviglus, Peter Kraft, Nicholas G Martin, John B Whitfield, Shahid Abbas, Danish Saleheen, Robin G Walters, Michael V Holmes, Corri Black, Blair H Smith, Aris Baras, Anne E Justice, Julie E Buring, Paul M Ridker, Daniel I Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A van Heel, Richard C Trembath, Wei-Qi Wei, Gail P Jarvik, Bahram Namjou, M Geoffrey Hayes, Marylyn D Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, Y Eugene Chen, Yuk-Lam Ho, Julie A Lynch, Philip S Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J O'Donnell, John M Gaziano, Peter Wilson, Karen L Mohlke, Timothy M Frayling, Joel N Hirschhorn, Sekar Kathiresan, Michael Boehnke, Struan Grant, Pradeep Natarajan, Yan V Sun, Andrew P Morris, Panos Deloukas, Gina Peloso, Themistocles L Assimes, Cristen J Willer, Xiang Zhu, Christopher D Brown

    American journal of human genetics　109　(8)　1366-1387　2022/08/04

    DOI： 10.1016/j.ajhg.2022.06.012 　

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    A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.

  90. Nrf2 protects against radiation-induced oral mucositis via antioxidation and keratin layer thickening. International-journal

    Shun Wakamori, Keiko Taguchi, Yuki Nakayama, Akira Ohkoshi, Michael B Sporn, Takenori Ogawa, Yukio Katori, Masayuki Yamamoto

    Free radical biology & medicine　188　206-220　2022/08/01

    DOI： 10.1016/j.freeradbiomed.2022.06.239 　

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    Radiation-induced oral mucositis is one of the most common adverse events in radiation therapy for head and neck cancers, but treatments for oral mucositis are limited to palliative and supportive care. New approaches are required to prevent radiation-induced mucositis and to improve treatments. The Keap1-Nrf2 system regulates cytoprotection against oxidative and electrophilic stresses. Nrf2 also regulates keratin layer thickness in mouse tongues. Therefore, we hypothesized that Nrf2 may protect the tongue epithelium against radiation-induced mucositis via elimination of reactive oxygen species and induction of keratin layer thickening. To test this hypothesis, we prepared a system for γ-ray exposure of restricted areas and irradiated the tongues of model mice with Nrf2 and Keap1 loss-of-function. We discovered that loss of Nrf2 expression indeed sensitized the tongue epithelium to radiation-induced ulcer formation with inflammation. Constitutive Nrf2 activation by genetic Keap1 knockdown alleviated radiation-induced DNA damage by increasing antioxidation. In agreement with the genetic Nrf2 activation model, the Nrf2 inducer CDDO-Im prevented irradiation damage to the tongue epithelium. These results demonstrate that Nrf2 activation has the potential to prevent the development of radiation-induced mucositis and that Nrf2 inducers are an important therapeutic drug for protection of the upper aerodigestive tract from radiation-induced mucositis.

  91. The β-TrCP-Mediated Pathway Cooperates with the Keap1-Mediated Pathway in Nrf2 Degradation In Vivo. International-journal

    Ayumi Kuga, Kouhei Tsuchida, Harit Panda, Makoto Horiuchi, Akihito Otsuki, Keiko Taguchi, Fumiki Katsuoka, Mikiko Suzuki, Masayuki Yamamoto

    Molecular and cellular biology　42　(7)　e0056321　2022/07/21

    DOI： 10.1128/mcb.00563-21 　

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    Nrf2 activates cytoprotective gene expression, and Nrf2 activity is regulated through at least two protein degradation pathways: the Keap1-mediated and β-TrCP-mediated pathways. To address the relative contributions of these pathways, we generated knock-in mouse lines expressing an Nrf2SA mutant that harbored two substitution mutations of serine residues interacting with β-TrCP. The homozygous (Nrf2SA/SA) mice grew normally, with Nrf2 levels comparable to those of wild-type (WT) mice under unstressed conditions. However, when Keap1 activity was suppressed, high levels of Nrf2 accumulated in Nrf2SA/SA macrophages compared with that in WT macrophages. We crossed Nrf2SA/SA mice with mice in which Keap1 was knocked down to two different levels. We found that the Nrf2SA/SA mutation induced higher Nrf2 activity when the Keap1 level was strongly reduced, and these mice showed severe growth retardation. However, activation and growth retardation were not evident when Keap1 was moderately suppressed. These increases in Nrf2 activity induced by the Nrf2SA mutation caused severe hyperplasia and hyperkeratosis in the esophageal epithelium but did not cause abnormalities in the other tissues/organs examined. These results indicate that the β-TrCP-mediated pathway cooperates with the Keap1-mediated pathway to regulate Nrf2 activity, which is apparent when the Keap1-mediated pathway is profoundly suppressed.

  92. Halofuginone micelle nanoparticles eradicate Nrf2-activated lung adenocarcinoma without systemic toxicity. International-journal

    Harit Panda, Mikiko Suzuki, Mitsuru Naito, Ritsumi Saito, Huaichun Wen, Liam Baird, Akira Uruno, Kanjiro Miyata, Masayuki Yamamoto

    Free radical biology & medicine　187　92-104　2022/07

    DOI： 10.1016/j.freeradbiomed.2022.05.017 　

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    The Keap1-Nrf2 system is the master regulator of the cellular response against oxidative and xenobiotic stresses. Constitutive activation of Nrf2 is frequently observed in various types of cancers. Nrf2 hyperactivation induces metabolic reprogramming in cancer cells, which supports the increased energy demand required for rapid proliferation and confers high-level resistance against anticancer radio/chemotherapy. Hence, Nrf2 inhibition has emerged as an attractive therapeutic strategy to counter such acquired resistance in Nrf2-activated tumors. We previously identified Halofuginone (HF) as a promising Nrf2 inhibitor. In this study, we pursued preclinical characterization of HF and found that while HF markedly reduced the viability of cancer cells, it also caused severe hematopoietic and immune cell suppression in a dose-dependent manner. Hence, to overcome this toxicity, we decided to employ a nanomedicine approach to HF. We found that encapsulation of HF into a polymeric micelle (HF micelle; HFm) largely relieved the systemic toxicity exhibited by free HF while maintaining the tumor-suppressive properties of HF. LC-MS/MS analysis revealed that the reduction in the magnitude of adverse effects was the result of the ability to release HF from the HFm core in a slow and sustained manner. These results thus support the contention that HFm will potentially counteract Nrf2-activated cancers in the clinical settings.

  93. Cyclobutane Pyrimidine Dimers Produced with Narrowband UVB Are on Average More Mutagenic than Those with Broadband UVB in Mouse Skin. International-journal

    Hironobu Ikehata, Masayuki Yamamoto

    Photochemistry and photobiology　98　(4)　916-924　2022/07

    DOI： 10.1111/php.13568 　

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    Although narrowband UVB (NB-UVB) has replaced broadband UVB (BB-UVB) because of its greater effectiveness in dermatological phototherapy, it is twice as carcinogenic as BB-UVB at an equivalent inflammatory dose. To clarify the basis of the different genotoxicities, we comparatively evaluated the mutagenicities in mouse skin of the two UVB types along with their efficiencies in the formation of cyclobutane pyrimidine dimer (CPD), which is a major mutagenic DNA photolesion specifically produced by UVR. We found that the mutagenicity averaged per single molecule of CPD was 2.5- and 1.8-fold higher in NB-UVB-exposed epidermis and dermis, respectively, which indicates that NB-UVB is more mutagenic for the skin than BB-UVB at doses producing an equimolar amount of CPD. Analysis of effective wavelengths for UV photolesion formation with each UVB source revealed a remarkable difference in the peak effective wavelengths for CPD formation: 15 nm longer for NB-UVB in the epidermis. Although the analysis of mutation profiles showed largely similar UV-specific signatures between the two UVB types, a relatively stronger preference for UVA-specific mutations was observed for NB-UVB. These results suggest that the difference in the effective wavelengths for CPD formation leads to the different mutagenicities and carcinogenicities between the UVB sources.

  94. Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. International-journal

    Helmut Sies, Vsevolod V Belousov, Navdeep S Chandel, Michael J Davies, Dean P Jones, Giovanni E Mann, Michael P Murphy, Masayuki Yamamoto, Christine Winterbourn

    Nature reviews. Molecular cell biology　23　(7)　499-515　2022/07

    DOI： 10.1038/s41580-022-00456-z 　

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    'Reactive oxygen species' (ROS) is a generic term that defines a wide variety of oxidant molecules with vastly different properties and biological functions that range from signalling to causing cell damage. Consequently, the description of oxidants needs to be chemically precise to translate research on their biological effects into therapeutic benefit in redox medicine. This Expert Recommendation article pinpoints key issues associated with identifying the physiological roles of oxidants, focusing on H2O2 and O2.-. The generic term ROS should not be used to describe specific molecular agents. We also advocate for greater precision in measurement of H2O2, O2.- and other oxidants, along with more specific identification of their signalling targets. Future work should also consider inter-organellar communication and the interactions of redox-sensitive signalling targets within organs and whole organisms, including the contribution of environmental exposures. To achieve these goals, development of tools that enable site-specific and real-time detection and quantification of individual oxidants in cells and model organisms are needed. We also stress that physiological O2 levels should be maintained in cell culture to better mimic in vivo redox reactions associated with specific cell types. Use of precise definitions and analytical tools will help harmonize research among the many scientific disciplines working on the common goal of understanding redox biology.

  95. Corrigendum to "Protracted rosiglitazone treatment exacerbates inflammation in white adipose tissues of adipocyte-specific Nfe2l1 knockout mice" [Food Chem. Toxicol. 146 (2020) 111836]. International-journal

    Suping Ren, Yongyong Hou, Zhuo Zuo, Zhiyuan Liu, Huihui Wang, Yuanyuan Xu, Masayuki Yamamoto, Qiang Zhang, Jingqi Fu, Jingbo Pi

    Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association　164　113063-113063　2022/06

    DOI： 10.1016/j.fct.2022.113063 　

  96. Heterozygous variants in GATA2 contribute to DCML deficiency in mice by disrupting tandem protein binding. International-journal

    Atsushi Hasegawa, Yuki Hayasaka, Masanobu Morita, Yuta Takenaka, Yuna Hosaka, Ikuo Hirano, Masayuki Yamamoto, Ritsuko Shimizu

    Communications biology　5　(1)　376-376　2022/04/19

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s42003-022-03316-w 　

    eISSN： 2399-3642

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    Abstract Accumulating lines of clinical evidence support the emerging hypothesis that loss-of-function mutations of GATA2 cause inherited hematopoietic diseases, including Emberger syndrome; dendritic cell, monocyte B and NK lymphoid (DCML) deficiency; and MonoMAC syndrome. Here, we show that mice heterozygous for an arginine-to-tryptophan substitution mutation in GATA2 (G2R398W/+), which was found in a patient with DCML deficiency, substantially phenocopy human DCML deficiency. Mice heterozygous for the GATA2-null mutation (G2-/+) do not show such phenotypes. The G2R398W protein possesses a decreased DNA-binding affinity but obstructs the function of coexpressed wild-type GATA2 through specific cis-regulatory regions, which contain two GATA motifs in direct-repeat arrangements. In contrast, G2R398W is innocuous in mice containing single GATA motifs. We conclude that the dominant-negative effect of mutant GATA2 on wild-type GATA2 through specific enhancer/silencer of GATA2 target genes perturbs the GATA2 transcriptional network, leading to the development of the DCML-like phenotype. The present mouse model provides an avenue for the understanding of molecular mechanisms underlying the pathogenesis of GATA2-related hematopoietic diseases.

  97. A Pilot Study for Return of Individual Pharmacogenomic Results to Population-Based Cohort Study Participants.

    Kinuko Ohneda, Masahiro Hiratsuka, Hiroshi Kawame, Fuji Nagami, Yoichi Suzuki, Kichiya Suzuki, Akira Uruno, Mika Sakurai-Yageta, Yohei Hamanaka, Makiko Taira, Soichi Ogishima, Shinichi Kuriyama, Atsushi Hozawa, Hiroaki Tomita, Naoko Minegishi, Junichi Sugawara, Inaho Danjoh, Tomohiro Nakamura, Tomoko Kobayashi, Yumi Yamaguchi-Kabata, Shu Tadaka, Taku Obara, Eiji Hishimuma, Nariyasu Mano, Masaki Matsuura, Yuji Sato, Masateru Nakasone, Yohei Honkura, Jun Suzuki, Yukio Katori, Yoichi Kakuta, Atsushi Masamune, Yoko Aoki, Masaharu Nakayama, Shigeo Kure, Kengo Kinoshita, Nobuo Fuse, Masayuki Yamamoto

    JMA journal　5　(2)　177-189　2022/04/15

    DOI： 10.31662/jmaj.2021-0156 　

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    Introduction: Pharmacogenomic (PGx) testing results provide valuable information on drug selection and appropriate dosing, maximization of efficacy, and minimization of adverse effects. Although the number of large-scale, next-generation-sequencing-based PGx studies has recently increased, little is known about the risks and benefits of returning PGx results to ostensibly healthy individuals in research settings. Methods: Single-nucleotide variants of three actionable PGx genes, namely, MT-RNR1, CYP2C19, and NUDT15, were returned to 161 participants in a population-based Tohoku Medical Megabank project. Informed consent was obtained from the participants after a seminar on the outline of this study. The results were sent by mail alongside sealed information letter intended for clinicians. As an exception, genetic counseling was performed for the MT-RNR1 m.1555A > G variant carriers by a medical geneticist, and consultation with an otolaryngologist was encouraged. Questionnaire surveys (QSs) were conducted five times to evaluate the participants' understanding of the topic, psychological impact, and attitude toward the study. Results: Whereas the majority of participants were unfamiliar with the term PGx, and none had undergone PGx testing before the study, more than 80% of the participants felt that they could acquire basic PGx knowledge sufficient to understand their genomic results and were satisfied with their potential benefit and use in future prescriptions. On the other hand, some felt that the PGx concepts or terminology was difficult to fully understand and suggested that in-person return of the results was desirable. Conclusions: These results collectively suggest possible benefits of returning preemptive PGx information to ostensibly healthy cohort participants in a research setting.

  98. 日本人成人GWASによる肺機能・FeNO関連遺伝子の同定

    山田 充啓, 元池 育子, 小島 要, 光根 歩, 大江 崇, 一ノ瀬 正和, 山本 雅之, 杉浦 久敏

    日本呼吸器学会誌　11　(増刊)　129-129　2022/04

    Publisher: (一社)日本呼吸器学会

    ISSN： 2186-5876

    eISSN： 2186-5884

  99. Target Gene Diversity of the Nrf1-MafG Transcription Factor Revealed by a Tethered Heterodimer. International-journal

    Fumiki Katsuoka, Akihito Otsuki, Nozomi Hatanaka, Haruna Okuyama, Masayuki Yamamoto

    Molecular and cellular biology　42　(3)　e0052021　2022/03/17

    DOI： 10.1128/mcb.00520-21 　

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    Members of the cap'n'collar (CNC) family of transcription factors, including Nrf1 and Nrf2, heterodimerize with small Maf (sMaf) proteins (MafF, MafG, and MafK) and regulate target gene expression through CNC-sMaf-binding elements (CsMBEs). We recently developed a unique tethered dimer assessment system combined with small Maf triple-knockout fibroblasts, which enabled the characterization of specific CNC-sMaf heterodimer functions. In this study, we evaluated the molecular function of the tethered Nrf1-MafG (T-N1G) heterodimer. We found that T-N1G activates the expression of proteasome subunit genes, well-known Nrf1 target genes, and binds specifically to CsMBEs in the proximity of these genes. T-N1G was also found to activate genes involved in proteostasis-related pathways, including endoplasmic reticulum-associated degradation, chaperone, and ubiquitin-mediated degradation pathways, indicating that the Nrf1-MafG heterodimer regulates a wide range of proteostatic stress response genes. By taking advantage of this assessment system, we found that Nrf1 has the potential to activate canonical Nrf2 target cytoprotective genes when strongly induced. Our results also revealed that transposable SINE B2 repeats harbor CsMBEs with high frequency and contribute to the target gene diversity of CNC-sMaf transcription factors.

  100. Multifaceted Roles of the KEAP1-NRF2 System in Cancer and Inflammatory Disease Milieu. International-journal

    Harit Panda, Huaichun Wen, Mikiko Suzuki, Masayuki Yamamoto

    Antioxidants (Basel, Switzerland)　11　(3)　2022/03/11

    DOI： 10.3390/antiox11030538 　

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    In a multicellular environment, many different types of cells interact with each other. The KEAP1-NRF2 system defends against electrophilic and oxidative stresses in various types of cells. However, the KEAP1-NRF2 system also regulates the expression of genes involved in cell proliferation and inflammation, indicating that the system plays cell type-specific roles. In this review, we introduce the multifarious roles of the KEAP1-NRF2 system in various types of cells, especially focusing on cancer and inflammatory diseases. Cancer cells frequently hijack the KEAP1-NRF2 system, and NRF2 activation confers cancer cells with a proliferative advantage and therapeutic resistance. In contrast, the activation of NRF2 in immune cells, especially in myeloid cells, suppresses tumor development. In chronic inflammatory diseases, such as sickle cell disease, NRF2 activation in myeloid and endothelial cells represses the expression of proinflammatory cytokine and adherent molecule genes, mitigating inflammation and organ damage. Based on these cell-specific roles played by the KEAP1-NRF2 system, NRF2 inducers have been utilized for the treatment of inflammatory diseases. In addition, the use of NRF2 inducers and/or inhibitors with canonical antineoplastic drugs is an emerging approach to cancer treatment.

  101. Genome-wide Association Study of Axial Length in Population-based Cohorts in Japan: The Tohoku Medical Megabank Organization Eye Study. International-journal

    Nobuo Fuse, Miyuki Sakurai, Ikuko N Motoike, Kaname Kojima, Takako Takai-Igarashi, Naoki Nakaya, Naho Tsuchiya, Tomohiro Nakamura, Mami Ishikuro, Taku Obara, Akiko Miyazawa, Kei Homma, Keisuke Ido, Makiko Taira, Tomoko Kobayashi, Ritsuko Shimizu, Akira Uruno, Eiichi N Kodama, Kichiya Suzuki, Yohei Hamanaka, Hiroaki Tomita, Junichi Sugawara, Yoichi Suzuki, Fuji Nagami, Soichi Ogishima, Fumiki Katsuoka, Naoko Minegishi, Atsushi Hozawa, Shinichi Kuriyama, Nobuo Yaegashi, Shigeo Kure, Kengo Kinoshita, Masayuki Yamamoto

    Ophthalmology science　2　(1)　100113-100113　2022/03

    Publisher: Elsevier BV

    DOI： 10.1016/j.xops.2022.100113 　

    ISSN： 2666-9145

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    PURPOSE: To elucidate the differences in ocular biometric parameters by generation and gender and to identify axial length (AL)-associated genetic variants in Japanese individuals, we analyzed Tohoku Medical Megabank Organization (ToMMo) Eye Study data. DESIGN: We designed the ToMMo Eye Study, examined AL variations, and conducted genome-wide association studies (GWASs). PARTICIPANTS: In total, 33 483 participants aged > 18 years who were recruited into the community-based cohort (CommCohort) and the birth and three-generation cohort (BirThree Cohort) of the ToMMo Eye Study were examined. METHODS: Each participant was screened with an interview, ophthalmic examinations, and a microarray analysis. The GWASs were performed in 22 379 participants in the CommCohort (discovery stage) and 11 104 participants in the BirThree Cohort (replication stage). We evaluated the associations of single nucleotide polymorphisms (SNPs) with AL using a genome-wide significance threshold (5 × 10-8) in each stage of the study and in the subsequent meta-analysis. MAIN OUTCOME MEASURES: We identified the association of SNPs with AL and distributions of AL in right and left eyes and individuals of different sexes and ages. RESULTS: In the discovery stage, the mean AL of the right eye (23.99 mm) was significantly greater than that of the left eye (23.95 mm). This difference was reproducible across sexes and ages. The GWASs revealed 703 and 215 AL-associated SNPs with genome-wide significance in the discovery and validation stages, respectively, and many of the SNPs in the discovery stage were replicated in the validation stage. Validated SNPs and their associated loci were meta-analyzed for statistical significance (P < 5 × 10-8). This study identified 1478 SNPs spread over 31 loci. Of the 31 loci, 5 are known AL loci, 15 are known refractive-error loci, 4 are known corneal-curvature loci, and 7 loci are newly identified loci that are not known to be associated with AL. Of note, some of them shared functional relationships with previously identified loci. CONCLUSIONS: Our large-scale GWASs exploiting ToMMo Eye Study data identified 31 loci linked to variations in AL, 7 of which are newly reported in this article. The results revealed genetic heterogeneity and similarity in SNPs related to ethnic variations in AL.

  102. Esterification promotes the intracellular accumulation of roxadustat, an activator of hypoxia-inducible factors, to extend its effective duration. International-journal

    Taku Nakai, Daisuke Saigusa, Yuma Iwamura, Yotaro Matsumoto, Keiko Umeda, Koichiro Kato, Hayato Yamaki, Yoshihisa Tomioka, Ikuo Hirano, Seizo Koshiba, Masayuki Yamamoto, Norio Suzuki

    Biochemical pharmacology　197　114939-114939　2022/03

    DOI： 10.1016/j.bcp.2022.114939 　

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    Kidney injury often causes anemia due to a lack of production of the erythroid growth factor erythropoietin (EPO) in the kidneys. Roxadustat is one of the first oral medicines inducing EPO production in patients with renal anemia by activating hypoxia-inducible factors (HIFs), which are activators of EPO gene expression. In this study, to develop prodrugs of roxadustat with improved permeability through cell membrane, we investigated the effects of 8 types of esterification on the pharmacokinetics and bioactivity of roxadustat using Hep3B hepatoma cells that HIF-dependently produce EPO. Mass spectrometry of cells incubated with the esterified roxadustat derivatives revealed that the designed compounds were deesterified after being taken up by cells and showed low cytotoxicity compared to the original compound. Esterification prolonged the effective duration of roxadustat with respect to EPO gene induction and HIF activation in cells transiently exposed to the compounds. In the kidneys and livers of mice, both of which are unique sites of EPO production, a majority of the methyl-esterified roxadustat was deesterified within 6 h after drug administration. The deesterified roxadustat derivative was continuously detectable in plasma and urine for at least 48 h after administration, while the administered compound became undetectable 24 h after administration. Additionally, we confirmed that methyl-esterified roxadustat activated erythropoiesis in mice by inducing Epo mRNA expression exclusively in renal interstitial cells, which have intrinsic EPO-producing potential. These data suggest that esterification could lead to the development of roxadustat prodrugs with improvements in cell membrane permeability, effective duration and cytotoxicity.

  103. AHR and NRF2 in Skin Homeostasis and Atopic Dermatitis. International-journal

    Tomohiro Edamitsu, Keiko Taguchi, Ryuhei Okuyama, Masayuki Yamamoto

    Antioxidants (Basel, Switzerland)　11　(2)　2022/01/25

    DOI： 10.3390/antiox11020227 　

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    Skin is constantly exposed to environmental insults, including toxic chemicals and oxidative stress. These insults often provoke perturbation of epidermal homeostasis and lead to characteristic skin diseases. AHR (aryl hydrocarbon receptor) and NRF2 (nuclear factor erythroid 2-related factor 2) are transcription factors that induce a battery of cytoprotective genes encoding detoxication and antioxidant enzymes in response to environmental insults. In addition to their basic functions as key regulators of xenobiotic and oxidant detoxification, recent investigations revealed that AHR and NRF2 also play critical roles in the maintenance of skin homeostasis. In fact, specific disruption of AHR function in the skin has been found to be associated with the pathogenesis of various skin diseases, most prevalently atopic dermatitis (AD). In this review, current knowledge on the roles that AHR and NRF2 play in epidermal homeostasis was summarized. Functional annotations of genetic variants, both regulatory and nonsynonymous SNPs, identified in the AHR and NRF2 loci in the human genome were also summarized. Finally, the possibility that AHR and NRF2 serve as therapeutic targets of AD was assessed.

  104. The isoquinoline PRL-295 increases the thermostability of Keap1 and disrupts its interaction with Nrf2. International-journal

    Sharadha Dayalan Naidu, Takafumi Suzuki, Dina Dikovskaya, Elena V Knatko, Maureen Higgins, Miu Sato, Miroslav Novak, José A Villegas, Terry W Moore, Masayuki Yamamoto, Albena T Dinkova-Kostova

    iScience　25　(1)　103703-103703　2022/01/21

    DOI： 10.1016/j.isci.2021.103703 　

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    Transcription factor Nrf2 and its negative regulator Keap1 orchestrate a cytoprotective response against oxidative, metabolic, and inflammatory stress. Keap1 is a drug target, with several small molecules in drug development. Here, we show that the isoquinoline PRL-295 increased Keap1 thermostability in lysates from cells expressing fluorescently tagged Keap1. The thermostability of endogenous Keap1 also increased in intact cells and murine liver following PRL-295 treatment. Fluorescence Lifetime Imaging-Förster Resonance Energy Transfer (FLIM-FRET) experiments in cells co-expressing sfGFP-Nrf2 and Keap1-mCherry further showed that PRL-295 prolonged the donor fluorescence lifetime, indicating disruption of the Keap1-Nrf2 protein complex. Orally administered PRL-295 to mice activated the Nrf2transcriptional target NAD(P)H:quinone oxidoreductase 1 (NQO1) in liver and decreased the levels of plasma alanine aminotransferase and aspartate aminotransferase upon acetaminophen-induced hepatic injury. Thus, PRL-295 engages the Keap1 protein target in cells and in vivo, disrupting its interaction with Nrf2, leading to activation of Nrf2-dependent transcription and hepatocellular protection.

  105. Corrigendum to "Nrf2 deficiency aggravates the increase in osteoclastogenesis and bone loss induced by inorganic arsenic" [Toxicology and applied pharmacology 367 (2019) 62-70]. International-journal

    Zhiyuan Liu, Yongyong Hou, Lu Li, Yang Yang, Jingkun Jia, Zhixuan Hong, Tingfeng Li, Yuanyuan Xu, Jingqi Fu, Yongxin Sun, Masayuki Yamamoto, Huihui Wang, Jingbo Pi

    Toxicology and applied pharmacology　435　115801-115801　2022/01/15

    DOI： 10.1016/j.taap.2021.115801 　

  106. Trans-ethnic Mendelian-randomization study reveals causal relationships between cardiometabolic factors and chronic kidney disease. International-journal

    Jie Zheng, Yuemiao Zhang, Humaira Rasheed, Venexia Walker, Yuka Sugawara, Jiachen Li, Yue Leng, Benjamin Elsworth, Robyn E Wootton, Si Fang, Qian Yang, Stephen Burgess, Philip C Haycock, Maria Carolina Borges, Yoonsu Cho, Rebecca Carnegie, Amy Howell, Jamie Robinson, Laurent F Thomas, Ben Michael Brumpton, Kristian Hveem, Stein Hallan, Nora Franceschini, Andrew P Morris, Anna Köttgen, Cristian Pattaro, Matthias Wuttke, Masayuki Yamamoto, Naoki Kashihara, Masato Akiyama, Masahiro Kanai, Koichi Matsuda, Yoichiro Kamatani, Yukinori Okada, Robin Walters, Iona Y Millwood, Zhengming Chen, George Davey Smith, Sean Barbour, Canqing Yu, Bjørn Olav Åsvold, Hong Zhang, Tom R Gaunt

    International journal of epidemiology　50　(6)　1995-2010　2022/01/06

    DOI： 10.1093/ije/dyab203 　

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    BACKGROUND: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization. METHODS: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of <60 ml/min/1.73 m2. Ultimately, 51 672 CKD cases and 958 102 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13 093 CKD cases and 238 118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo were included. RESULTS: Eight risk factors showed reliable evidence of causal effects on CKD in Europeans, including genetically predicted body mass index (BMI), hypertension, systolic blood pressure, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), type 2 diabetes (T2D) and nephrolithiasis. In East Asians, BMI, T2D and nephrolithiasis showed evidence of causality on CKD. In two independent replication analyses, we observed that increased hypertension risk showed reliable evidence of a causal effect on increasing CKD risk in Europeans but in contrast showed a null effect in East Asians. Although liability to T2D showed consistent effects on CKD, the effects of glycaemic phenotypes on CKD were weak. Non-linear Mendelian randomization indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI of >25 kg/m2. CONCLUSIONS: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD.

  107. Deficiency of the bZIP transcription factors Mafg and Mafk causes misexpression of genes in distinct pathways and results in lens embryonic developmental defects. International-journal

    Shaili D Patel, Deepti Anand, Hozumi Motohashi, Fumiki Katsuoka, Masayuki Yamamoto, Salil A Lachke

    Frontiers in cell and developmental biology　10　981893-981893　2022

    DOI： 10.3389/fcell.2022.981893 　

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    Deficiency of the small Maf proteins Mafg and Mafk cause multiple defects, namely, progressive neuronal degeneration, cataract, thrombocytopenia and mid-gestational/perinatal lethality. Previous data shows Mafg -/-:Mafk +/- compound knockout (KO) mice exhibit cataracts age 4-months onward. Strikingly, Mafg -/-:Mafk -/- double KO mice develop lens defects significantly early in life, during embryogenesis, but the pathobiology of these defects is unknown, and is addressed here. At embryonic day (E)16.5, the epithelium of lens in Mafg -/-:Mafk -/- animals appears abnormally multilayered as demonstrated by E-cadherin and nuclear staining. Additionally, Mafg -/-:Mafk -/- lenses exhibit abnormal distribution of F-actin near the "fulcrum" region where epithelial cells undergo apical constriction prior to elongation and reorientation as early differentiating fiber cells. To identify the underlying molecular changes, we performed high-throughput RNA-sequencing of E16.5 Mafg -/-:Mafk -/- lenses and identified a cohort of differentially expressed genes that were further prioritized using stringent filtering criteria and validated by RT-qPCR. Several key factors associated with the cytoskeleton, cell cycle or extracellular matrix (e.g., Cdk1, Cdkn1c, Camsap1, Col3a1, Map3k12, Sipa1l1) were mis-expressed in Mafg -/-:Mafk -/- lenses. Further, the congenital cataract-linked extracellular matrix peroxidase Pxdn was significantly overexpressed in Mafg -/-:Mafk -/- lenses, which may cause abnormal cell morphology. These data also identified the ephrin signaling receptor Epha5 to be reduced in Mafg -/-:Mafk -/- lenses. This likely contributes to the Mafg -/-:Mafk -/- multilayered lens epithelium pathology, as loss of an ephrin ligand, Efna5 (ephrin-A5), causes similar lens defects. Together, these findings uncover a novel early function of Mafg and Mafk in lens development and identify their new downstream regulatory relationships with key cellular factors.

  108. Gene expression changes related to bone mineralization, blood pressure and lipid metabolism in mouse kidneys after space travel. International-journal

    Norio Suzuki, Yuma Iwamura, Taku Nakai, Koichiro Kato, Akihito Otsuki, Akira Uruno, Daisuke Saigusa, Keiko Taguchi, Mikiko Suzuki, Ritsuko Shimizu, Akane Yumoto, Risa Okada, Masaki Shirakawa, Dai Shiba, Satoru Takahashi, Takafumi Suzuki, Masayuki Yamamoto

    Kidney international　101　(1)　92-105　2022/01

    DOI： 10.1016/j.kint.2021.09.031 　

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    Space travel burdens health by imposing considerable environmental stress associated with radioactivity and microgravity. In particular, gravity change predominantly impacts blood pressure and bone homeostasis, both of which are controlled mainly by the kidneys. Nuclear factor erythroid-2-related transcription factor 2 (Nrf2) plays essential roles in protecting the kidneys from various environmental stresses and injuries. To elucidate the effects of space travel on mammals in preparation for the upcoming space era, our study investigated the contribution of Nrf2 to kidney function in mice two days after their return from a 31-day stay in the International Space Station using Nrf2 knockout mice. Meaningfully, expression levels of genes regulating bone mineralization, blood pressure and lipid metabolism were found to be significantly altered in the kidneys after space travel in an Nrf2-independent manner. In particular, uridine diphosphate-glucuronosyltransferase 1A (Ugt1a) isoform genes were found to be expressed in an Nrf2-dependent manner and induced exclusively in the kidneys after return to Earth. Since spaceflight elevated the concentrations of fatty acids in the mouse plasma, we suggest that Ugt1a isoform expression in the kidneys was induced to promote glucuronidation of excessively accumulated lipids and excrete them into urine after the return from space. Thus, the kidneys were proven to play central roles in adaptation to gravity changes caused by going to and returning from space by controlling blood pressure and bone mineralization. Additionally, kidney Ugt1a isoform induction after space travel implies a significant role of the kidneys for space travelers in the excretion of excessive lipids.

  109. dbTMM: an integrated database of large-scale cohort, genome and clinical data for the Tohoku Medical Megabank Project. International-journal

    Soichi Ogishima, Satoshi Nagaie, Satoshi Mizuno, Ryosuke Ishiwata, Keita Iida, Kazuro Shimokawa, Takako Takai-Igarashi, Naoki Nakamura, Sachiko Nagase, Tomohiro Nakamura, Naho Tsuchiya, Naoki Nakaya, Keiko Murakami, Fumihiko Ueno, Tomomi Onuma, Mami Ishikuro, Taku Obara, Shunji Mugikura, Hiroaki Tomita, Akira Uruno, Tomoko Kobayashi, Akito Tsuboi, Shu Tadaka, Fumiki Katsuoka, Akira Narita, Mika Sakurai, Satoshi Makino, Gen Tamiya, Yuichi Aoki, Ritsuko Shimizu, Ikuko N Motoike, Seizo Koshiba, Naoko Minegishi, Kazuki Kumada, Takahiro Nobukuni, Kichiya Suzuki, Inaho Danjoh, Fuji Nagami, Kozo Tanno, Hideki Ohmomo, Koichi Asahi, Atsushi Shimizu, Atsushi Hozawa, Shinichi Kuriyama, Nobuo Fuse, Teiji Tominaga, Shigeo Kure, Nobuo Yaegashi, Kengo Kinoshita, Makoto Sasaki, Hiroshi Tanaka, Masayuki Yamamoto

    Human genome variation　8　(1)　44-44　2021/12/10

    DOI： 10.1038/s41439-021-00175-5 　

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    To reveal gene-environment interactions underlying common diseases and estimate the risk for common diseases, the Tohoku Medical Megabank (TMM) project has conducted prospective cohort studies and genomic and multiomics analyses. To establish an integrated biobank, we developed an integrated database called "dbTMM" that incorporates both the individual cohort/clinical data and the genome/multiomics data of 157,191 participants in the Tohoku Medical Megabank project. To our knowledge, dbTMM is the first database to store individual whole-genome data on a variant-by-variant basis as well as cohort/clinical data for over one hundred thousand participants in a prospective cohort study. dbTMM enables us to stratify our cohort by both genome-wide genetic factors and environmental factors, and it provides a research and development platform that enables prospective analysis of large-scale data from genome cohorts.

  110. Nrf2 plays a critical role in the metabolic response during and after spaceflight. International-journal

    Akira Uruno, Daisuke Saigusa, Takafumi Suzuki, Akane Yumoto, Tomohiro Nakamura, Naomi Matsukawa, Takahiro Yamazaki, Ristumi Saito, Keiko Taguchi, Mikiko Suzuki, Norio Suzuki, Akihito Otsuki, Fumiki Katsuoka, Eiji Hishinuma, Risa Okada, Seizo Koshiba, Yoshihisa Tomioka, Ritsuko Shimizu, Masaki Shirakawa, Thomas W Kensler, Dai Shiba, Masayuki Yamamoto

    Communications biology　4　(1)　1381-1381　2021/12/09

    DOI： 10.1038/s42003-021-02904-6 　

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    Space travel induces stresses that contribute to health problems, as well as inducing the expression of Nrf2 (NF-E2-related factor-2) target genes that mediate adaptive responses to oxidative and other stress responses. The volume of epididymal white adipose tissue (eWAT) in mice increases during spaceflight, a change that is attenuated by Nrf2 knockout. We conducted metabolome analyses of plasma from wild-type and Nrf2 knockout mice collected at pre-flight, in-flight and post-flight time points, as well as tissues collected post-flight to clarify the metabolic responses during and after spaceflight and the contribution of Nrf2 to these responses. Plasma glycerophospholipid and sphingolipid levels were elevated during spaceflight, whereas triacylglycerol levels were lower after spaceflight. In wild-type mouse eWAT, triacylglycerol levels were increased, but phosphatidylcholine levels were decreased, and these changes were attenuated in Nrf2 knockout mice. Transcriptome analyses revealed marked changes in the expression of lipid-related genes in the liver and eWAT after spaceflight and the effects of Nrf2 knockout on these changes. Based on these results, we concluded that space stress provokes significant responses in lipid metabolism during and after spaceflight; Nrf2 plays critical roles in these responses.

  111. Osteoclasts adapt to physioxia perturbation through DNA demethylation. International-journal

    Keizo Nishikawa, Shigeto Seno, Toshitada Yoshihara, Ayako Narazaki, Yuki Sugiura, Reito Shimizu, Junichi Kikuta, Reiko Sakaguchi, Norio Suzuki, Norihiko Takeda, Hiroaki Semba, Masamichi Yamamoto, Daisuke Okuzaki, Daisuke Motooka, Yasuhiro Kobayashi, Makoto Suematsu, Haruhiko Koseki, Hideo Matsuda, Masayuki Yamamoto, Seiji Tobita, Yasuo Mori, Masaru Ishii

    EMBO reports　22　(12)　e53035　2021/12/06

    DOI： 10.15252/embr.202153035 　

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    Oxygen plays an important role in diverse biological processes. However, since quantitation of the partial pressure of cellular oxygen in vivo is challenging, the extent of oxygen perturbation in situ and its cellular response remains underexplored. Using two-photon phosphorescence lifetime imaging microscopy, we determine the physiological range of oxygen tension in osteoclasts of live mice. We find that oxygen tension ranges from 17.4 to 36.4 mmHg, under hypoxic and normoxic conditions, respectively. Physiological normoxia thus corresponds to 5% and hypoxia to 2% oxygen in osteoclasts. Hypoxia in this range severely limits osteoclastogenesis, independent of energy metabolism and hypoxia-inducible factor activity. We observe that hypoxia decreases ten-eleven translocation (TET) activity. Tet2/3 cooperatively induces Prdm1 expression via oxygen-dependent DNA demethylation, which in turn activates NFATc1 required for osteoclastogenesis. Taken together, our results reveal that TET enzymes, acting as functional oxygen sensors, regulate osteoclastogenesis within the physiological range of oxygen tension, thus opening new avenues for research on in vivo response to oxygen perturbation.

  112. The power of genetic diversity in genome-wide association studies of lipids. International-journal

    Sarah E Graham, Shoa L Clarke, Kuan-Han H Wu, Stavroula Kanoni, Greg J M Zajac, Shweta Ramdas, Ida Surakka, Ioanna Ntalla, Sailaja Vedantam, Thomas W Winkler, Adam E Locke, Eirini Marouli, Mi Yeong Hwang, Sohee Han, Akira Narita, Ananyo Choudhury, Amy R Bentley, Kenneth Ekoru, Anurag Verma, Bhavi Trivedi, Hilary C Martin, Karen A Hunt, Qin Hui, Derek Klarin, Xiang Zhu, Gudmar Thorleifsson, Anna Helgadottir, Daniel F Gudbjartsson, Hilma Holm, Isleifur Olafsson, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M Brumpton, Humaira Rasheed, Sanni E Ruotsalainen, Aki S Havulinna, Yogasudha Veturi, QiPing Feng, Elisabeth A Rosenthal, Todd Lingren, Jennifer Allen Pacheco, Sarah A Pendergrass, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E Miller, Archie Campbell, Kuang Lin, Iona Y Millwood, George Hindy, Asif Rasheed, Jessica D Faul, Wei Zhao, David R Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Anubha Mahajan, Michael R Brown, Weihua Zhang, Ketian Yu, Ellen M Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian'an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Gonneke Willemsen, Andrew R Wood, Yingji Ji, Zishan Gao, Simon Haworth, Ruth E Mitchell, Jin Fang Chai, Mette Aadahl, Jie Yao, Ani Manichaikul, Helen R Warren, Julia Ramirez, Jette Bork-Jensen, Line L Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Carlo Sidore, Edoardo Fiorillo, Aaron F McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T Møllehave, Betina H Thuesen, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E Galesloot, Jonathan P Bradfield, E Warwick Daw, Joseph M Zmuda, Jonathan S Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A Brody, Mary F Feitosa, Mary K Wojczynski, Michael Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W Benjamins, Jorgen Engmann, Rachel L Kember, Roderick C Slieker, Ken Sin Lo, Nuno R Zilhao, Phuong Le, Marcus E Kleber, Graciela E Delgado, Shaofeng Huo, Daisuke D Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Hampton L Leonard, Jonathan Marten, Börge Schmidt, Marina Arendt, Laura J Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Meraj Ahmed, Anne U Jackson, Marguerite R Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R H J Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A Lange, Xiaoran Chai, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C Warner, Ya Xing Wang, Wen B Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Yi-Jen Hung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A Kentistou, Mathias Gorski, Marco Brumat, Karina Meidtner, Lawrence F Bielak, Jennifer A Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Chao Xue, Jifeng Zhang, Maria Pina Concas, Simona Vaccargiu, Peter J van der Most, Niina Pitkänen, Brian E Cade, Jiwon Lee, Sander W van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Martina E Zimmermann, Jong Young Lee, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W Rayner, Carol A Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hildalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O Obura, Jessica van Setten, Xiaoyin Li, Karen Schwander, Natalie Terzikhan, Jae Hun Shin, Rebecca D Jackson, Alexander P Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Heather M Highland, Kristin L Young, Takahisa Kawaguchi, Joachim Thiery, Joshua C Bis, Girish N Nadkarni, Lenore J Launer, Huaixing Li, Mike A Nalls, Olli T Raitakari, Sahoko Ichihara, Sarah H Wild, Christopher P Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Konain Fatima Bhatti, Dominique de Kleijn, Gert J de Borst, Eung Kweon Kim, Hieab H H Adams, M Arfan Ikram, Xiaofeng Zhu, Folkert W Asselbergs, Adriaan O Kraaijeveld, Joline W J Beulens, Xiao-Ou Shu, Loukianos S Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E Pennell, Trevor A Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M Heid, Klaus J Stark, Henry Völzke, Georg Homuth, Michele K Evans, Alan B Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E Hoefer, Susan Redline, Katja Pahkala, Albertine J Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Y Eugene Chen, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L R Kardia, Norihiro Kato, Matthias B Schulze, Giorgia Girotto, Bettina Jung, Carsten A Böger, Peter K Joshi, David A Bennett, Philip L De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J Caulfield, Patricia B Munroe, Xiuqing Guo, Marina Ciullo, Jost B Jonas, Nilesh J Samani, Jaakko Kaprio, Päivi Pajukanta, Linda S Adair, Sonny Augustin Bechayda, H Janaka de Silva, Ananda R Wickremasinghe, Ronald M Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke I den Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G Wilson, Lars Lind, Chew-Kiat Heng, Amanda E Nelson, Yvonne M Golightly, James F Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J Scott, D C Rao, Donna K Arnett, Mark Walker, Heikki A Koistinen, Giriraj R Chandak, Chittaranjan S Yajnik, Josep M Mercader, Teresa Tusié-Luna, Carlos A Aguilar-Salinas, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, E Shyong Tai, Rob M van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I McCarthy, Colin N A Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M van Duijn, Fan Lu, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Esteban J Parra, Miguel Cruz, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M 't Hart, Petra J M Elders, Scott M Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D Spector, Ruth J F Loos, Michael A Province, Bruce M Psaty, Ivan Brandslund, Peter P Pramstaller, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F A Grant, Lambertus A L M Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W Franks, Allan Linneberg, J Wouter Jukema, Amit V Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Francesco Cucca, Dennis O Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P Strachan, Niels Grarup, Peter Sever, Neil Poulter, Jerome I Rotter, Thomas M Dantoft, Fredrik Karpe, Matt J Neville, Nicholas J Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T Hattersley, Nancy L Pedersen, Patrik K E Magnusson, Dorret I Boomsma, Eco J C de Geus, L Adrienne Cupples, Joyce B J van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C Chambers, Jaspal S Kooner, Paul S de Vries, Alanna C Morrison, Kari E North, Martha Daviglus, Peter Kraft, Nicholas G Martin, John B Whitfield, Shahid Abbas, Danish Saleheen, Robin G Walters, Michael V Holmes, Corri Black, Blair H Smith, Anne E Justice, Aris Baras, Julie E Buring, Paul M Ridker, Daniel I Chasman, Charles Kooperberg, Wei-Qi Wei, Gail P Jarvik, Bahram Namjou, M Geoffrey Hayes, Marylyn D Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Unnur Thorsteinsdottir, Kari Stefansson, Yuk-Lam Ho, Julie A Lynch, Daniel J Rader, Philip S Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J O'Donnell, John M Gaziano, Peter Wilson, Charles N Rotimi, Scott Hazelhurst, Michèle Ramsay, Richard C Trembath, David A van Heel, Gen Tamiya, Masayuki Yamamoto, Bong-Jo Kim, Karen L Mohlke, Timothy M Frayling, Joel N Hirschhorn, Sekar Kathiresan, Michael Boehnke, Pradeep Natarajan, Gina M Peloso, Christopher D Brown, Andrew P Morris, Themistocles L Assimes, Panos Deloukas, Yan V Sun, Cristen J Willer

    Nature　600　(7890)　675-679　2021/12

    DOI： 10.1038/s41586-021-04064-3 　

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    Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.

  113. One-year trajectories of postpartum depressive symptoms and associated psychosocial factors: findings from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. International-journal

    Saya Kikuchi, Keiko Murakami, Taku Obara, Mami Ishikuro, Fumihiko Ueno, Aoi Noda, Tomomi Onuma, Natsuko Kobayashi, Junichi Sugawara, Masayuki Yamamoto, Nobuo Yaegashi, Shinichi Kuriyama, Hiroaki Tomita

    Journal of affective disorders　295　632-638　2021/12/01

    DOI： 10.1016/j.jad.2021.08.118 　

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    BACKGROUND: Trajectories of postpartum depressive symptoms up to 1 year after childbirth and the related risk factors remain unclear. Accordingly, this study aimed to examine the 1-year trajectories of postpartum depressive symptoms and their associated risk factors. METHODS: A total of 22,493 pregnant women were recruited between July 2013 and September 2016 in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study in Japan. Among them, 11,668 women with no missing data were included in the analyses. Depressive symptoms were assessed at 1 month and 1 year postpartum using the Edinburgh Postnatal Depression Scale. Multinominal logistic regression analysis was conducted after adjusting for covariates. RESULTS: The prevalence of depression was 13.9% at 1 month and 12.9% at 1 year postpartum. We identified four depression trajectories, i.e., "persistent (depressed throughout the 1 year postpartum)" (6.0%), "recovered (depressed at 1 month postpartum and recovered within a year)" (7.9%), "late-onset (became depressed after 1 month postpartum)" (6.8%), and "resilient (not depressed throughout 1 year postpartum)" (79.2%). Psychological distress during pregnancy was significantly associated with all trajectories (persistent: odds ratio [OR]=10.24, 95% confidence interval (CI)=8.40-12.48; recovered: OR=3.78, 95%CI=3.28-4.36; and late-onset: OR=3.96, 95%CI=3.40-4.62). LIMITATIONS: Postpartum depression was evaluated only by a self-administered questionnaire and the dropout rate was not neglectable. CONCLUSIONS: This study highlighted the high prevalence of depressive symptoms at 1 year postpartum and found that half of the depressive symptoms at 1 year were late-onset. The findings suggest the necessity of long-term follow-up (up to 1 year) for perinatal mental health.

  114. Fundamental Biological Features of Spaceflight: Advancing the Field to Enable Deep-Space Exploration. International-journal

    Ebrahim Afshinnekoo, Ryan T Scott, Matthew J MacKay, Eloise Pariset, Egle Cekanaviciute, Richard Barker, Simon Gilroy, Duane Hassane, Scott M Smith, Sara R Zwart, Mayra Nelman-Gonzalez, Brian E Crucian, Sergey A Ponomarev, Oleg I Orlov, Dai Shiba, Masafumi Muratani, Masayuki Yamamoto, Stephanie E Richards, Parag A Vaishampayan, Cem Meydan, Jonathan Foox, Jacqueline Myrrhe, Eric Istasse, Nitin Singh, Kasthuri Venkateswaran, Jessica A Keune, Hami E Ray, Mathias Basner, Jack Miller, Martha Hotz Vitaterna, Deanne M Taylor, Douglas Wallace, Kathleen Rubins, Susan M Bailey, Peter Grabham, Sylvain V Costes, Christopher E Mason, Afshin Beheshti

    Cell　184　(24)　6002-6002　2021/11/24

    DOI： 10.1016/j.cell.2021.11.008 　

  115. Genetic loci for lung function in Japanese adults with adjustment for exhaled nitric oxide levels as airway inflammation indicator. International-journal

    Mitsuhiro Yamada, Ikuko N Motoike, Kaname Kojima, Nobuo Fuse, Atsushi Hozawa, Shinichi Kuriyama, Fumiki Katsuoka, Shu Tadaka, Matsuyuki Shirota, Miyuki Sakurai, Tomohiro Nakamura, Yohei Hamanaka, Kichiya Suzuki, Junichi Sugawara, Soichi Ogishima, Akira Uruno, Eiichi N Kodama, Naoya Fujino, Tadahisa Numakura, Tomohiro Ichikawa, Ayumi Mitsune, Takashi Ohe, Kengo Kinoshita, Masakazu Ichinose, Hisatoshi Sugiura, Masayuki Yamamoto

    Communications biology　4　(1)　1288-1288　2021/11/15

    DOI： 10.1038/s42003-021-02813-8 　

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    Lung function reflects the ability of the respiratory system and is utilized for the assessment of respiratory diseases. Because type 2 airway inflammation influences lung function, genome wide association studies (GWAS) for lung function would be improved by adjustment with an indicator of the inflammation. Here, we performed a GWAS for lung function with adjustment for exhaled nitric oxide (FeNO) levels in two independent Japanese populations. Our GWAS with genotype imputations revealed that the RNF5/AGER locus including AGER rs2070600 SNP, which introduces a G82S substitution of AGER, was the most significantly associated with FEV1/FVC. Three other rare missense variants of AGER were further identified. We also found genetic loci with three candidate genes (NOS2, SPSB2 and RIPOR2) associated with FeNO levels. Analyses with the BioBank-Japan GWAS resource revealed genetic links of FeNO and asthma-related traits, and existence of common genetic background for allergic diseases and their biomarkers. Our study identified the genetic locus most strongly associated with airway obstruction in the Japanese population and three genetic loci associated with FeNO, an indicator of type 2 airway inflammation in adults.

  116. Bach1 derepression is neuroprotective in a mouse model of Parkinson's disease. International-journal

    Manuj Ahuja, Navneet Ammal Kaidery, Otis C Attucks, Erin McDade, Dmitry M Hushpulian, Arsen Gaisin, Irina Gaisina, Young Hoon Ahn, Sergey Nikulin, Andrey Poloznikov, Irina Gazaryan, Masayuki Yamamoto, Mitsuyo Matsumoto, Kazuhiko Igarashi, Sudarshana M Sharma, Bobby Thomas

    Proceedings of the National Academy of Sciences of the United States of America　118　(45)　2021/11/09

    DOI： 10.1073/pnas.2111643118 　

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    Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by the loss of nigrostriatal dopaminergic neurons. Mounting evidence suggests that Nrf2 is a promising target for neuroprotective interventions in PD. However, electrophilic chemical properties of the canonical Nrf2-based drugs cause irreversible alkylation of cysteine residues on cellular proteins resulting in side effects. Bach1 is a known transcriptional repressor of the Nrf2 pathway. We report that Bach1 levels are up-regulated in PD postmortem brains and preclinical models. Bach1 knockout (KO) mice were protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity and associated oxidative damage and neuroinflammation. Functional genomic analysis demonstrated that the neuroprotective effects in Bach1 KO mice was due to up-regulation of Bach1-targeted pathways that are associated with both Nrf2-dependent antioxidant response element (ARE) and Nrf2-independent non-ARE genes. Using a proprietary translational technology platform, a drug library screen identified a substituted benzimidazole as a Bach1 inhibitor that was validated as a nonelectrophile. Oral administration of the Bach1 inhibitor attenuated MPTP neurotoxicity in pre- and posttreatment paradigms. Bach1 inhibitor-induced neuroprotection was associated with the up-regulation of Bach1-targeted pathways in concurrence with the results from Bach1 KO mice. Our results suggest that genetic deletion as well as pharmacologic inhibition of Bach1 by a nonelectrophilic inhibitor is a promising therapeutic approach for PD.

  117. CNC-bZIP protein NFE2L1 regulates osteoclast differentiation in antioxidant-dependent and independent manners. International-journal

    Zhiyuan Liu, Huihui Wang, Yongyong Hou, Yang Yang, Jingkun Jia, Jinzhi Wu, Zhuo Zuo, Tianchang Gao, Suping Ren, Yiying Bian, Shengnan Liu, Jingqi Fu, Yongxin Sun, Jiliang Li, Masayuki Yamamoto, Qiang Zhang, Yuanyuan Xu, Jingbo Pi

    Redox biology　48　102180-102180　2021/11/06

    DOI： 10.1016/j.redox.2021.102180 　

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    Fine-tuning of osteoclast differentiation (OD) and bone remodeling is crucial for bone homeostasis. Dissecting the mechanisms regulating osteoclastogenesis is fundamental to understanding the pathogenesis of various bone disorders including osteoporosis and arthritis. Nuclear factor erythroid 2-related factor 1 (NFE2L1, also known as NRF1), which belongs to the CNC-bZIP family of transcription factors, orchestrates a variety of physiological processes and stress responses. While Nfe2l1 gene may be transcribed into multiple alternatively spliced isoforms, the biological function of the different isoforms of NFE2L1 in bone metabolism, osteoclastogenesis in particular, has not been reported. Here we demonstrate that knockout of all isoforms of Nfe2l1 transcripts specifically in the myeloid lineage in mice [Nfe2l1(M)-KO] results in increased activity of osteoclasts, decreased bone mass and worsening of osteoporosis induced by ovariectomy and aging. In comparison, LysM-Cre-mediated Nfe2l1 deletion has no significant effect on the osteoblast and osteocytes. Mechanistic investigations using bone marrow cells and RAW 264.7 cells revealed that deficiency of Nfe2l1 leads to accelerated and elevated OD, which is attributed, at least in part, to enhanced accumulation of ROS in the early stage of OD and expression of nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1α (Nfatc1/α). In addition, NFE2L1 regulates the transcription of multiple antioxidant genes and Nfatc1/α and OD in an isoform-specific manner. While long isoforms of NFE2L1 function as accelerators of induction of Nfatc1/α and antioxidant genes and OD, the short isoform NFE2L1-453 serves as a brake that keeps the long isoforms' accelerator effects in check. These findings provide a novel insight into the regulatory roles of NFE2L1 in osteoclastogenesis and highlight that NFE2L1 is essential in regulating bone remodeling and thus may be a valuable therapeutic target for bone disorders.

  118. An erythroid-to-myeloid cell fate conversion is elicited by LSD1 inactivation. International-journal

    Lei Yu, Greggory Myers, Chia-Jui Ku, Emily Schneider, Yu Wang, Sharon A Singh, Natee Jearawiriyapaisarn, Andrew White, Takashi Moriguchi, Rami Khoriaty, Masayuki Yamamoto, Michael G Rosenfeld, Julien Pedron, John H Bushweller, Kim-Chew Lim, James Douglas Engel

    Blood　138　(18)　1691-1704　2021/11/04

    DOI： 10.1182/blood.2021011682 　

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    Histone H3 lysine 4 methylation (H3K4Me) is most often associated with chromatin activation, and removing H3K4 methyl groups has been shown to be coincident with gene repression. H3K4Me demethylase KDM1a/LSD1 is a therapeutic target for multiple diseases, including for the potential treatment of β-globinopathies (sickle cell disease and β-thalassemia), because it is a component of γ-globin repressor complexes, and LSD1 inactivation leads to robust induction of the fetal globin genes. The effects of LSD1 inhibition in definitive erythropoiesis are not well characterized, so we examined the consequences of conditional inactivation of Lsd1 in adult red blood cells using a new Gata1creERT2 bacterial artificial chromosome transgene. Erythroid-specific loss of Lsd1 activity in mice led to a block in erythroid progenitor differentiation and to the expansion of granulocyte-monocyte progenitor-like cells, converting hematopoietic differentiation potential from an erythroid fate to a myeloid fate. The analogous phenotype was also observed in human hematopoietic stem and progenitor cells, coincident with the induction of myeloid transcription factors (eg, PU.1 and CEBPα). Finally, blocking the activity of the transcription factor PU.1 or RUNX1 at the same time as LSD1 inhibition rescued myeloid lineage conversion to an erythroid phenotype. These data show that LSD1 promotes erythropoiesis by repressing myeloid cell fate in adult erythroid progenitors and that inhibition of the myeloid-differentiation pathway reverses the lineage switch induced by LSD1 inactivation.

  119. 代謝プロファイルに影響を与える遺伝要因の網羅的解析

    小柴 生造, 元池 育子, 三枝 大輔, 井上 仁, 菱沼 英史, 青木 裕一, 田高 周, 城田 松之, 木下 賢吾, 山本 雅之

    日本生化学会大会プログラム・講演要旨集　94回　[P-837]　2021/11

    Publisher: (公社)日本生化学会

  120. 温故知新;古くて新しいGATA転写因子研究の最前線 炎症制御因子としてのGATA2

    高井 淳, 大森 慎也, 大根田 絹子, 上村 聡志, 山本 雅之, 森口 尚

    日本生化学会大会プログラム・講演要旨集　94回　[2S12m-02]　2021/11

    Publisher: (公社)日本生化学会

  121. 温故知新;古くて新しいGATA転写因子研究の最前線 炎症制御因子としてのGATA2

    高井 淳, 大森 慎也, 大根田 絹子, 上村 聡志, 山本 雅之, 森口 尚

    日本生化学会大会プログラム・講演要旨集　94回　[2S12m-02]　2021/11

    Publisher: (公社)日本生化学会

  122. Distinct Regulations of HO-1 Gene Expression for Stress Response and Substrate Induction. International-journal

    Anqi Zhang, Takafumi Suzuki, Saki Adachi, Eriko Naganuma, Norio Suzuki, Tomonori Hosoya, Ken Itoh, Michael B Sporn, Masayuki Yamamoto

    Molecular and cellular biology　41　(11)　e0023621　2021/10/26

    DOI： 10.1128/MCB.00236-21 　

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    Heme oxygenase 1 (HO-1) is the key enzyme for heme catabolism and cytoprotection. Whereas HO-1 gene expression in response to various stresses has been investigated extensively, the precise mechanisms by which HO-1 gene expression is regulated by the HO-1 substrate heme remain elusive. To systematically examine whether stress-mediated induction and substrate-mediated induction of HO-1 utilize similar or distinct regulatory pathways, we developed an HO-1-DsRed-knock-in reporter mouse in which the HO-1 gene is floxed by loxP sites and the DsRed gene has been inserted. Myeloid lineage-specific recombination of the floxed locus led to fluorescence derived from expression of the HO-1-DsRed fusion protein in peritoneal macrophages. We also challenged general recombination of the locus and generated mice harboring heterozygous recombinant alleles, which enabled us to monitor HO-1-DsRed expression in the whole body in vivo and ex vivo. HO-1 inducers upregulated HO-1-DsRed expression in myeloid lineage cells isolated from the mice. Notably, analyses of peritoneal macrophages from HO-1-DsRed mice lacking NRF2, a major regulator of the oxidative/electrophilic stress response, led us to identify NRF2-dependent stress response-mediated HO-1 induction and NRF2-independent substrate-mediated HO-1 induction. Thus, the HO-1 gene is subjected to at least two distinct levels of regulation, and the available lines of evidence suggest that substrate induction in peritoneal macrophages is independent of CNC family-based regulation.

  123. NRF3 upregulates gene expression in SREBP2-dependent mevalonate pathway with cholesterol uptake and lipogenesis inhibition. International-journal

    Tsuyoshi Waku, Toru Hagiwara, Natsuko Tamura, Yuri Atsumi, Yasuomi Urano, Mikiko Suzuki, Takuya Iwami, Katsuya Sato, Masayuki Yamamoto, Noriko Noguchi, Akira Kobayashi

    iScience　24　(10)　103180-103180　2021/10/22

    DOI： 10.1016/j.isci.2021.103180 　

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    Lipids, such as cholesterol and fatty acids, influence cell signaling, energy storage, and membrane formation. Cholesterol is biosynthesized through the mevalonate pathway, and aberrant metabolism causes metabolic diseases. The genetic association of a transcription factor NRF3 with obesity has been suggested, although the molecular mechanisms remain unknown. Here, we show that NRF3 upregulates gene expression in SREBP2-dependent mevalonate pathway. We further reveal that NRF3 overexpression not only reduces lanosterol, a cholesterol precursor, but also induces the expression of the GGPS1 gene encoding an enzyme in the production of GGPP from farnesyl pyrophosphate (FPP), a lanosterol precursor. NRF3 overexpression also enhances cholesterol uptake through RAB5-mediated macropinocytosis process, a bulk and fluid-phase endocytosis pathway. Moreover, we find that GGPP treatment abolishes NRF3 knockdown-mediated increase of neutral lipids. These results reveal the potential roles of NRF3 in the SREBP2-dependent mevalonate pathway for cholesterol uptake through macropinocytosis induction and for lipogenesis inhibition through GGPP production.

  124. Trans-ethnic Mendelian-randomization study reveals causal relationships between cardiometabolic factors and chronic kidney disease. International-journal

    Jie Zheng, Yuemiao Zhang, Humaira Rasheed, Venexia Walker, Yuka Sugawara, Jiachen Li, Yue Leng, Benjamin Elsworth, Robyn E Wootton, Si Fang, Qian Yang, Stephen Burgess, Philip C Haycock, Maria Carolina Borges, Yoonsu Cho, Rebecca Carnegie, Amy Howell, Jamie Robinson, Laurent F Thomas, Ben Michael Brumpton, Kristian Hveem, Stein Hallan, Nora Franceschini, Andrew P Morris, Anna Köttgen, Cristian Pattaro, Matthias Wuttke, Masayuki Yamamoto, Naoki Kashihara, Masato Akiyama, Masahiro Kanai, Koichi Matsuda, Yoichiro Kamatani, Yukinori Okada, Robin Walters, Iona Y Millwood, Zhengming Chen, George Davey Smith, Sean Barbour, Canqing Yu, Bjørn Olav Åsvold, Hong Zhang, Tom R Gaunt

    International journal of epidemiology　2021/10/20

    DOI： 10.1093/ije/dyab203 　

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    BACKGROUND: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization. METHODS: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of <60 ml/min/1.73 m2. Ultimately, 51 672 CKD cases and 958 102 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13 093 CKD cases and 238 118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo were included. RESULTS: Eight risk factors showed reliable evidence of causal effects on CKD in Europeans, including genetically predicted body mass index (BMI), hypertension, systolic blood pressure, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), type 2 diabetes (T2D) and nephrolithiasis. In East Asians, BMI, T2D and nephrolithiasis showed evidence of causality on CKD. In two independent replication analyses, we observed that increased hypertension risk showed reliable evidence of a causal effect on increasing CKD risk in Europeans but in contrast showed a null effect in East Asians. Although liability to T2D showed consistent effects on CKD, the effects of glycaemic phenotypes on CKD were weak. Non-linear Mendelian randomization indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI of >25 kg/m2. CONCLUSIONS: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD.

  125. Nuclear Factor Erythroid 2-Related Factor 2 Depletion Sensitizes Pancreatic Cancer Cells to Gemcitabine via Aldehyde Dehydrogenase 3a1 Repression. International-journal

    Ryotaro Matsumoto, Shin Hamada, Yu Tanaka, Keiko Taguchi, Masayuki Yamamoto, Atsushi Masamune

    The Journal of pharmacology and experimental therapeutics　379　(1)　33-40　2021/10

    DOI： 10.1124/jpet.121.000744 　

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    As the central regulator of the oxidative stress response, nuclear factor erythroid 2-related factor 2 (Nrf2) is attracting great interest as a therapeutic target for various cancers, and the possible clinical applications of novel Nrf2 inhibitors have been explored in Nrf2-activated cancers. In the present study, we specifically investigated halofuginone, which is derived from a natural plant alkaloid. We found that halofuginone administration decreased the number of pancreatic intraepithelial neoplasias in pancreas-specific Kras and p53 mutant (KPC) mice. In Nrf2-activated pancreatic cancer cell lines established from KPC mice, halofuginone rapidly depleted Nrf2 in Nrf2-activated cancer cells. Both in vitro and in vivo, it sensitized Nrf2-activated pancreatic cancer cells to gemcitabine, which is the first-line chemotherapy in clinical practice. In our mechanistic study, we found that halofuginone downregulated aldehyde dehydrogenase 3a1 (ALDH3A1) in mouse pancreatic cancer cells. The Nrf2 inducer diethyl maleate upregulated ALDH3A1, and knockdown of Aldh3a1 sensitized Nrf2-activated cancer cells to gemcitabine, strongly suggesting that ALDH3A1 is regulated by Nrf2 and that it contributes to gemcitabine resistance. The current study demonstrated the therapeutic benefits of halofuginone in Nrf2-activated pancreatic cancers. SIGNIFICANCE STATEMENT: We identified nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target aldehyde dehydrogenase 3a1 (ALDH3A1) as novel therapeutic targets in pancreatic cancer. They negatively affect the efficacy of a conventional chemotherapeutic agent, gemcitabine. We confirmed that Nrf2 plays a pivotal role in the induction of ALDH3A1.

  126. Nrf2 expression in pancreatic stellate cells promotes progression of cancer. International-journal

    Yu Tanaka, Shin Hamada, Ryotaro Matsumoto, Keiko Taguchi, Masayuki Yamamoto, Atsushi Masamune

    American journal of physiology. Gastrointestinal and liver physiology　321　(4)　G378-G388　2021/10/01

    DOI： 10.1152/ajpgi.00120.2021 　

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    It was previously identified that systemic Nrf2 deletion attenuates pancreatic cancer progression in a mutant K-ras/p53-expressing mouse model (KPC mouse). In this study, the type of cell that is responsible for the retarded cancer progression was elucidated. Human pancreatic cancers were first examined, and elevated expression of NRF2-target gene products in α-smooth muscle actin-positive cells was found, suggesting that pancreatic stellate cells (PSCs) are involved in this process. Closer examination of primary cultured PSCs from Nrf2-deleted mice revealed that the cells were less proliferative and retained a lower migration capacity. The conditioned medium of Nrf2-deleted PSCs exhibited reduced growth-stimulating effects in pancreatic cancer cells. KPC mouse-derived pancreatic cancer cells coinjected with wild-type PSCs developed significantly larger subcutaneous tumors in immunodeficient mice than those coinjected with Nrf2-deleted PSCs. These results demonstrate that Nrf2 actively contributes to the function of PSCs to sustain KPC cancer progression, thus, suggesting that Nrf2 inhibition in PSCs may be therapeutically important in pancreatic cancer.NEW & NOTEWORTHY This study identified that Nrf2 contributes to PSC activation. Nrf2 deletion in PSCs resulted in attenuation of cancer-promoting role. Nrf2 in PSCs could be an attractive therapeutic target in pancreatic cancer.

  127. A cross-population atlas of genetic associations for 220 human phenotypes. International-journal

    Saori Sakaue, Masahiro Kanai, Yosuke Tanigawa, Juha Karjalainen, Mitja Kurki, Seizo Koshiba, Akira Narita, Takahiro Konuma, Kenichi Yamamoto, Masato Akiyama, Kazuyoshi Ishigaki, Akari Suzuki, Ken Suzuki, Wataru Obara, Ken Yamaji, Kazuhisa Takahashi, Satoshi Asai, Yasuo Takahashi, Takao Suzuki, Nobuaki Shinozaki, Hiroki Yamaguchi, Shiro Minami, Shigeo Murayama, Kozo Yoshimori, Satoshi Nagayama, Daisuke Obata, Masahiko Higashiyama, Akihide Masumoto, Yukihiro Koretsune, Kaoru Ito, Chikashi Terao, Toshimasa Yamauchi, Issei Komuro, Takashi Kadowaki, Gen Tamiya, Masayuki Yamamoto, Yusuke Nakamura, Michiaki Kubo, Yoshinori Murakami, Kazuhiko Yamamoto, Yoichiro Kamatani, Aarno Palotie, Manuel A Rivas, Mark J Daly, Koichi Matsuda, Yukinori Okada

    Nature genetics　53　(10)　1415-1424　2021/10

    DOI： 10.1038/s41588-021-00931-x 　

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    Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (ntotal = 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.

  128. Comparison of Kit-Based Metabolomics with Other Methodologies in a Large Cohort, towards Establishing Reference Values International-journal

    Daisuke Saigusa, Eiji Hishinuma, Naomi Matsukawa, Masatomo Takahashi, Jin Inoue, Shu Tadaka, Ikuko N. Motoike, Atsushi Hozawa, Yoshihiro Izumi, Takeshi Bamba, Kengo Kinoshita, Kim Ekroos, Seizo Koshiba, Masayuki Yamamoto

    Metabolites　11　(10)　652-652　2021/09/24

    Publisher: MDPI AG

    DOI： 10.3390/metabo11100652 　

    eISSN： 2218-1989

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    Metabolic profiling is an omics approach that can be used to observe phenotypic changes, making it particularly attractive for biomarker discovery. Although several candidate metabolites biomarkers for disease expression have been identified in recent clinical studies, the reference values of healthy subjects have not been established. In particular, the accuracy of concentrations measured by mass spectrometry (MS) is unclear. Therefore, comprehensive metabolic profiling in large-scale cohorts by MS to create a database with reference ranges is essential for evaluating the quality of the discovered biomarkers. In this study, we tested 8700 plasma samples by commercial kit-based metabolomics and separated them into two groups of 6159 and 2541 analyses based on the different ultra-high-performance tandem mass spectrometry (UHPLC-MS/MS) systems. We evaluated the quality of the quantified values of the detected metabolites from the reference materials in the group of 2541 compared with the quantified values from other platforms, such as nuclear magnetic resonance (NMR), supercritical fluid chromatography tandem mass spectrometry (SFC-MS/MS) and UHPLC-Fourier transform mass spectrometry (FTMS). The values of the amino acids were highly correlated with the NMR results, and lipid species such as phosphatidylcholines and ceramides showed good correlation, while the values of triglycerides and cholesterol esters correlated less to the lipidomics analyses performed using SFC-MS/MS and UHPLC-FTMS. The evaluation of the quantified values by MS-based techniques is essential for metabolic profiling in a large-scale cohort.

  129. Potential of NRF2 Pathway in Preventing Developmental and Reproductive Toxicity of Fine Particles International-journal

    Ying-Ji Li, Ken Takeda, Masayuki Yamamoto, Tomoyuki Kawada

    Frontiers in Toxicology　3　710225-710225　2021/09/13

    Publisher: Frontiers Media SA

    DOI： 10.3389/ftox.2021.710225 　

    eISSN： 2673-3080

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    Air pollution is associated with significant adverse health effects. Recent studies support the idea that inhalation of fine particles can instigate extrapulmonary effects on the cardiovascular system through several pathways. The systemic transfer of ultrafine particles (UFPs) or soluble particle components (organic compounds and metals) is of particular concern. An integral role of reactive oxygen species (ROS)-dependent pathways has been suggested in systemic inflammatory responses and vascular dysfunction at the molecular level. Accumulating lines of evidence suggest that fine particles affect fetal development, giving rise to low birth weight and a reduction in fetal growth, and also affect the immune, cardiovascular, and central nervous systems. Oxidative stress plays an important role in fine particles toxicity; pre-treatment with antioxidants partially suppresses the developmental toxicity of fine particles. On the other hand, Nuclear factor erythroid-derived 2-like 2 (Nfe2l2), also known as NRF2, is a transcription factor essential for inducible and/or constitutive expression of phase II and antioxidant enzymes. Studies using <italic>Nrf2</italic>-knockout mice revealed that NRF2 dysfunction is intimately involved in the pathogenesis of various human diseases. Multiple single nucleotide polymorphisms (SNPs) have been detected in human <italic>NRF2</italic> locus. An <italic>NRF2</italic> gene SNP (−617C &amp;gt; A; rs6721961), located in the upstream promoter region, affects the transcriptional level of NRF2 and thereby the protein level and downstream gene expression. It has been reported that the SNP-617 is associated with various diseases. The onset and exacerbation of the diseases are regulated by genetic predisposition and environmental factors; some people live in the air-polluted environment but are not affected and remain healthy, suggesting the presence of individual differences in the susceptibility to air pollutants. NRF2 polymorphisms may also be associated with the fetal effects of fine particles exposure. Screening high-risk pregnant women genetically susceptible to oxidative stress and prevention by antioxidant interventions to protect fetal development in air-polluted areas should be considered. This article reviews the recent advances in our understanding of the fetal health effects of fine particles and describes potential chemoprevention <italic>via</italic> the NRF2 pathway to prevent the developmental and reproductive toxicity of fine particles.

  130. Machine learning approaches to predict gestational age in normal and complicated pregnancies via urinary metabolomics analysis. International-journal

    Takafumi Yamauchi, Daisuke Ochi, Naomi Matsukawa, Daisuke Saigusa, Mami Ishikuro, Taku Obara, Yoshiki Tsunemoto, Satsuki Kumatani, Riu Yamashita, Osamu Tanabe, Naoko Minegishi, Seizo Koshiba, Hirohito Metoki, Shinichi Kuriyama, Nobuo Yaegashi, Masayuki Yamamoto, Masao Nagasaki, Satoshi Hiyama, Junichi Sugawara

    Scientific reports　11　(1)　17777-17777　2021/09/07

    DOI： 10.1038/s41598-021-97342-z 　

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    The elucidation of dynamic metabolomic changes during gestation is particularly important for the development of methods to evaluate pregnancy status or achieve earlier detection of pregnancy-related complications. Some studies have constructed models to evaluate pregnancy status and predict gestational age using omics data from blood biospecimens; however, less invasive methods are desired. Here we propose a model to predict gestational age, using urinary metabolite information. In our prospective cohort study, we collected 2741 urine samples from 187 healthy pregnant women, 23 patients with hypertensive disorders of pregnancy, and 14 patients with spontaneous preterm birth. Using gas chromatography-tandem mass spectrometry, we identified 184 urinary metabolites that showed dynamic systematic changes in healthy pregnant women according to gestational age. A model to predict gestational age during normal pregnancy progression was constructed; the correlation coefficient between actual and predicted weeks of gestation was 0.86. The predicted gestational ages of cases with hypertensive disorders of pregnancy exhibited significant progression, compared with actual gestational ages. This is the first study to predict gestational age in normal and complicated pregnancies by using urinary metabolite information. Minimally invasive urinary metabolomics might facilitate changes in the prediction of gestational age in various clinical settings.

  131. 幹細胞から赤血球への通り道 GATA転写因子群と赤血球分化(GATA transcription factors and erythroid differentiation)

    山本 雅之, 清水 律子

    日本血液学会学術集会　83回　PSY-3　2021/09

    Publisher: (一社)日本血液学会

  132. Glycyrrhizic acid suppresses early stage of adipogenesis through repression of MEK/ERK-mediated C/EBPβ and C/EBPδ expression in 3T3-L1 cells. International-journal

    Masayuki Yamamoto, Yasuna Nagasawa, Ko Fujimori

    Chemico-biological interactions　346　109595-109595　2021/09/01

    DOI： 10.1016/j.cbi.2021.109595 　

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    Glycyrrhizic acid (GA), a major constituent of the root of licorice (Glycyrrhiza glabra), and has various biological activities, including anti-obesity property. However, the molecular mechanism of anti-adipogenic effect of GA is still unclear. In this study, we investigated the anti-adipogenic effects of GA in mouse adipocytic 3T3-L1 cells and elucidated its underlying molecular mechanism. GA decreased the intracellular triglyceride level. The expression levels of the adipogenic and lipogenic genes were lowered by treatment with GA in a concertation-dependent manner. In contrast, GA did not affect the lipolytic gene expression and the released glycerol level. GA suppressed the early stage of adipogenesis when it was added for 0-3 h after initiation of adipogenesis. Moreover, GA reduced the mRNA levels of CCAAT/enhancer binding protein (C/EBP) β and C/EBPδ, both of which activate the early stage of adipogenesis. Furthermore, GA decreased phosphorylation of extracellular signal-regulated kinase [ERK: p44/42 mitogen-activated protein kinase (MAPK)] in the early stage of adipogenesis. In addition, a MAPK kinase (MEK) inhibitor, PD98059 reduced the C/EBPβ and C/EBPδ gene expression. These results indicate that GA suppressed the early stage of adipogenesis through repressing the MEK/ERK-mediated C/EBPβ and C/EBPδ expression in 3T3-L1 cells. Thus, GA has an anti-adipogenic ability and a possible agent for treatment of obesity.

  133. Blockade of the interaction between BMP9 and endoglin on erythroid progenitors promotes erythropoiesis in mice International-journal

    Ayami Yamaguchi, Ikuo Hirano, Shiho Narusawa, Kiyoshi Shimizu, Hiroyuki Ariyama, Kengo Yamawaki, Kenji Nagao, Masayuki Yamamoto, Ritsuko Shimizu

    Genes to Cells　26　(10)　782-797　2021/08/12

    Publisher: Wiley

    DOI： 10.1111/gtc.12887 　

    ISSN： 1356-9597

    eISSN： 1365-2443

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    Bone morphogenetic protein-9 (BMP9), a member of the transforming growth factor β (TGFβ) superfamily, plays important roles in the development and maintenance of various cell lineages via complexes of type I and type II TGFβ receptors. Endoglin is a coreceptor for several TGFβ family members, including BMP9, which is highly expressed in a particular stage of differentiation in erythroid cells as well as in endothelial cells. Although the importance of the interaction between BMP9 and endoglin for endothelial development has been reported, the contribution of BMP9 to endoglin-expressing erythroid cells remains to be clarified. To address this point, we prepared an anti-BMP9 antibody that blocks the BMP9-endoglin interaction. Of note, challenge with the antibody promotes erythropoiesis in wild-type mice but not in a mouse model of renal anemia in which erythropoietin (EPO) production in the kidneys is genetically ablated. While endoglin-positive erythroid progenitors are mainly maintained as progenitors when bone marrow-derived lineage-negative and cKit-positive cells are cultured in the presence of EPO and stem cell factor, the erythroid-biased accumulation of progenitors is impeded by the presence of BMP9. Our findings uncover an unrecognized role for BMP9 in attenuating erythroid differentiation via its interaction with endoglin on erythroid progenitors.

  134. Renal NG2-expressing cells have a macrophage-like phenotype and facilitate renal recovery after ischemic injury. International-journal

    Wararat Kittikulsuth, Daisuke Nakano, Kento Kitada, Norio Suzuki, Masayuki Yamamoto, Akira Nishiyama

    American journal of physiology. Renal physiology　321　(2)　F170-F178　2021/08/01

    DOI： 10.1152/ajprenal.00011.2021 　

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    Pericytes play an important role in the recovery process after ischemic injury of many tissues. Brain pericytes in the peri-infarct area express macrophage markers in response to injury stimuli and are involved in neovascularization. In the kidney, nerve/glial antigen 2 (NG2)+ pericytes have been found to accumulate after renal injury. These accumulated NG2+ cells are not involved in scar formation. However, the role of accumulated NG2+ cells in injured kidneys remains unknown. Here, using a reversible ischemia-reperfusion (I/R) model, we found that renal NG2+ cells were increased in injured kidneys and expressed macrophage markers (CD11b or F4/80) on day 3 after reperfusion. Isolated NG2+ cells from I/R kidneys also had phagocytic activity and expressed anti-inflammatory cytokine genes, including mannose receptor and IL-10. These macrophage-like NG2+ cells did not likely differentiate into myofibroblasts because they did not increase α-smooth muscle actin expression. Intravenous transfusion of renal NG2+ cells isolated from donor mice on day 3 after reperfusion into recipient mice on day 1 after I/R surgery revealed that NG2+ cell-injected mice had lower plasma blood urea nitrogen, reduced kidney injury molecule-1 mRNA expression, ameliorated renal damage, and reduced cellular debris accumulation compared with PBS-injected mice on day 5 after reperfusion. In conclusion, these data suggest that renal NG2+ cells have an M2 macrophage-like ability and play a novel role in facilitating the recovery process after renal I/R injury.NEW & NOTEWORTHY Brain pericytes have macrophage-like activities after injury. However, such properties of pericytes in peripheral tissues have not been investigated. Here, we provide evidence that nerve/glial antigen 2-positive cells increase after renal injury. The population of nerve/glial antigen 2-positive cells, which does not increase expression of myofibroblast-associated gene, express macrophage markers and anti-inflammatory cytokine genes, have phagocytic activity, and play a role in renal recovery after kidney injury.

  135. The return of individual genomic results to research participants: design and pilot study of Tohoku Medical Megabank Project. International-journal

    Hiroshi Kawame, Akimune Fukushima, Nobuo Fuse, Fuji Nagami, Yoichi Suzuki, Mika Sakurai-Yageta, Jun Yasuda, Yumi Yamaguchi-Kabata, Kengo Kinoshita, Soichi Ogishima, Takako Takai, Shinichi Kuriyama, Atsushi Hozawa, Naoki Nakaya, Tomohiro Nakamura, Naoko Minegishi, Junichi Sugawara, Kichiya Suzuki, Hiroaki Tomita, Akira Uruno, Tomoko Kobayashi, Yayoi Aizawa, Tomoharu Tokutomi, Kayono Yamamoto, Kinuko Ohneda, Shigeo Kure, Yoko Aoki, Hideki Katagiri, Yasushi Ishigaki, Shojiro Sawada, Makoto Sasaki, Masayuki Yamamoto

    Journal of human genetics　67　(1)　9-17　2021/07/08

    DOI： 10.1038/s10038-021-00952-8 　

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    Certain large genome cohort studies attempt to return the individual genomic results to the participants; however, the implementation process and psychosocial impacts remain largely unknown. The Tohoku Medical Megabank Project has conducted large genome cohort studies of general residents. To implement the disclosure of individual genomic results, we extracted the potential challenges and obstacles. Major challenges include the determination of genes/disorders based on the current medical system in Japan, the storage of results, prevention of misunderstanding, and collaboration of medical professionals. To overcome these challenges, we plan to conduct multilayer pilot studies, which deal with different disorders/genes. We finally chose familial hypercholesterolemia (FH) as a target disease for the first pilot study. Of the 665 eligible candidates, 33.5% were interested in the pilot study and provided consent after an educational "genetics workshop" on the basic genetics and medical facts of FH. The genetics professionals disclosed the results to the participants. All positive participants were referred to medical care, and a serial questionnaire revealed no significant psychosocial distress after the disclosure. Return of genomic results to research participants was implemented using a well-prepared protocol. To further elucidate the impact of different disorders, we will perform multilayer pilot studies with different disorders, including actionable pharmacogenomics and hereditary tumor syndromes.

  136. ゲノムコホート研究におけるBRCA1/2遺伝情報返却とその後の医療機関との連携の取組み

    濱中 洋平, 多田 寛, 宮下 穣, 原田 成美, 佐藤 章子, 江幡 明子, 大根田 絹子, 布施 昇男, 川目 裕, 鈴木 洋一, 長神 風二, 鈴木 吉也, 佐藤 政文, 平塚 真弘, 櫻井 美佳, 宇留野 晃, 山口 由美, 平良 摩紀子, 山本 雅之, 石田 孝宣

    日本乳癌学会総会プログラム抄録集　29回　21-21　2021/07

    Publisher: (一社)日本乳癌学会

  137. ゲノムコホート研究におけるBRCA1/2遺伝情報返却とその後の医療機関との連携の取組み

    濱中 洋平, 多田 寛, 宮下 穣, 原田 成美, 佐藤 章子, 江幡 明子, 大根田 絹子, 布施 昇男, 川目 裕, 鈴木 洋一, 長神 風二, 鈴木 吉也, 佐藤 政文, 平塚 真弘, 櫻井 美佳, 宇留野 晃, 山口 由美, 平良 摩紀子, 山本 雅之, 石田 孝宣

    日本乳癌学会総会プログラム抄録集　29回　21-21　2021/07

    Publisher: (一社)日本乳癌学会

  138. Wide-Targeted Metabolome Analysis Identifies Potential Biomarkers for Prognosis Prediction of Epithelial Ovarian Cancer. International-journal

    Eiji Hishinuma, Muneaki Shimada, Naomi Matsukawa, Daisuke Saigusa, Bin Li, Kei Kudo, Keita Tsuji, Shogo Shigeta, Hideki Tokunaga, Kazuki Kumada, Keigo Komine, Hidekazu Shirota, Yuichi Aoki, Ikuko N Motoike, Jun Yasuda, Kengo Kinoshita, Masayuki Yamamoto, Seizo Koshiba, Nobuo Yaegashi

    Toxins　13　(7)　2021/06/30

    DOI： 10.3390/toxins13070461 　

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    Epithelial ovarian cancer (EOC) is a fatal gynecologic cancer, and its poor prognosis is mainly due to delayed diagnosis. Therefore, biomarker identification and prognosis prediction are crucial in EOC. Altered cell metabolism is a characteristic feature of cancers, and metabolomics reflects an individual's current phenotype. In particular, plasma metabolome analyses can be useful for biomarker identification. In this study, we analyzed 624 metabolites, including uremic toxins (UTx) in plasma derived from 80 patients with EOC using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Compared with the healthy control, we detected 77 significantly increased metabolites and 114 significantly decreased metabolites in EOC patients. Especially, decreased concentrations of lysophosphatidylcholines and phosphatidylcholines and increased concentrations of triglycerides were observed, indicating a metabolic profile characteristic of EOC patients. After calculating the parameters of each metabolic index, we found that higher ratios of kynurenine to tryptophan correlates with worse prognosis in EOC patients. Kynurenine, one of the UTx, can affect the prognosis of EOC. Our results demonstrated that plasma metabolome analysis is useful not only for the diagnosis of EOC, but also for predicting prognosis with the variation of UTx and evaluating response to chemotherapy.

  139. Nuclear factor E2-related factor 2 (NRF2) deficiency accelerates fast fibre type transition in soleus muscle during space flight. International-journal

    Takuto Hayashi, Takashi Kudo, Ryo Fujita, Shin-Ichiro Fujita, Hirona Tsubouchi, Sayaka Fuseya, Riku Suzuki, Michito Hamada, Risa Okada, Masafumi Muratani, Dai Shiba, Takafumi Suzuki, Eiji Warabi, Masayuki Yamamoto, Satoru Takahashi

    Communications biology　4　(1)　787-787　2021/06/24

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s42003-021-02334-4 　

    eISSN： 2399-3642

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    <title>Abstract</title>Microgravity induces skeletal muscle atrophy, particularly in the soleus muscle, which is predominantly composed of slow-twitch myofibre (type I) and is sensitive to disuse. Muscle atrophy is commonly known to be associated with increased production of reactive oxygen species. However, the role of NRF2, a master regulator of antioxidative response, in skeletal muscle plasticity during microgravity-induced atrophy, is not known. To investigate the role of NRF2 in skeletal muscle within a microgravity environment, wild-type and <italic>Nrf2-</italic>knockout (KO) mice were housed in the International Space Station for 31 days. Gene expression and histological analyses demonstrated that, under microgravity conditions, the transition of type I (oxidative) muscle fibres to type IIa (glycolytic) was accelerated in <italic>Nrf2</italic>-KO mice without affecting skeletal muscle mass. Therefore, our results suggest that NRF2 affects myofibre type transition during space flight.

  140. Molecular basis for the disruption of Keap1-Nrf2 interaction via Hinge & Latch mechanism. International-journal

    Yuta Horie, Takafumi Suzuki, Jin Inoue, Tatsuro Iso, Geoffrey Wells, Terry W Moore, Tsunehiro Mizushima, Albena T Dinkova-Kostova, Takuma Kasai, Takashi Kamei, Seizo Koshiba, Masayuki Yamamoto

    Communications biology　4　(1)　576-576　2021/05/14

    DOI： 10.1038/s42003-021-02100-6 　

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    The Keap1-Nrf2 system is central for mammalian cytoprotection against various stresses and a drug target for disease prevention and treatment. One model for the molecular mechanisms leading to Nrf2 activation is the Hinge-Latch model, where the DLGex-binding motif of Nrf2 dissociates from Keap1 as a latch, while the ETGE motif remains attached to Keap1 as a hinge. To overcome the technical difficulties in examining the binding status of the two motifs during protein-protein interaction (PPI) simultaneously, we utilized NMR spectroscopy titration experiments. Our results revealed that latch dissociation is triggered by low-molecular-weight Keap1-Nrf2 PPI inhibitors and occurs during p62-mediated Nrf2 activation, but not by electrophilic Nrf2 inducers. This study demonstrates that Keap1 utilizes a unique Hinge-Latch mechanism for Nrf2 activation upon challenge by non-electrophilic PPI-inhibiting stimuli, and provides critical insight for the pharmacological development of next-generation Nrf2 activators targeting the Keap1-Nrf2 PPI.

  141. Japonica Array NEO with increased genome-wide coverage and abundant disease risk SNPs International-journal

    Mika Sakurai-Yageta, Kazuki Kumada, Chinatsu Gocho, Satoshi Makino, Akira Uruno, Shu Tadaka, Ikuko N Motoike, Masae Kimura, Shin Ito, Akihito Otsuki, Akira Narita, Hisaaki Kudo, Yuichi Aoki, Inaho Danjoh, Jun Yasuda, Hiroshi Kawame, Naoko Minegishi, Seizo Koshiba, Nobuo Fuse, Gen Tamiya, Masayuki Yamamoto, Kengo Kinoshita

    The Journal of Biochemistry　170　(3)　399-410　2021/05/13

    Publisher: Oxford University Press (OUP)

    DOI： 10.1093/jb/mvab060 　

    ISSN： 0021-924X

    eISSN： 1756-2651

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    <title>Abstract</title> Ethnic-specific SNP arrays are becoming more important to increase the power of genome-wide association studies in diverse population. In the Tohoku Medical Megabank Project, we have been developing a series of Japonica Arrays (JPA) for genotyping participants based on reference panels constructed from whole-genome sequence data of the Japanese population. Here, we designed a novel version of the SNP array for the Japanese population, called Japonica Array NEO (JPA NEO), comprising a total of 666,883 markers. Among them, 654,246 tag SNPs of autosomes and X chromosome were selected from an expanded reference panel of 3,552 Japanese, 3.5KJPNv2, using pairwise r2 of linkage disequilibrium measures. Additionally, 28,298 markers were included for the evaluation of previously identified disease risk markers from the literature and databases, and those present in the Japanese population were extracted using the reference panel. Through genotyping 286 Japanese samples, we found that the imputation quality r2 and INFO score in the minor allele frequency bin &amp;gt;2.5–5% were &amp;gt;0.9 and &amp;gt;0.8, respectively, and &amp;gt;12 million markers were imputed with an INFO score &amp;gt;0.8. From these results, JPA NEO is a promising tool for genotyping the Japanese population with genome-wide coverage, contributing to the development of genetic risk scores.

  142. Novel method for evaluating the health condition of mice in space through a video downlink.

    Akane Yumoto, Toshiaki Kokubo, Ryutaro Izumi, Michihiko Shimomura, Osamu Funatsu, Motoki N Tada, Naoko Ota-Murakami, Kayoko Iino, Masaki Shirakawa, Hiroyasu Mizuno, Takashi Kudo, Satoru Takahashi, Takafumi Suzuki, Akira Uruno, Masayuki Yamamoto, Dai Shiba

    Experimental animals　70　(2)　236-244　2021/05/13

    DOI： 10.1538/expanim.20-0102 　

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    Clarification of the criteria for managing animal health is essential to increase the reliability of experiments and ensure transparency in animal welfare. For experiments performed in space, there is no consensus on how to care for animals owing to technical issues, launch mass limitation, and human resources. Some biological processes in mammals, such as musculoskeletal or immune processes, are altered in the space environment, and mice in space can be used to simulate morbid states, such as senescence acceleration. Thus, there is a need to establish a novel evaluation method and evaluation criteria to monitor animal health. Here, we report a novel method to evaluate the health of mice in space through a video downlink in a series of space experiments using the Multiple Artificial-gravity Research System (MARS). This method was found to be more useful in evaluating animal health in space than observations and body weight changes of the same live mice following their return to Earth. We also developed criteria to evaluate health status via a video downlink. These criteria, with "Fur condition" and "Respiratory" as key items, provided information on the daily changes in the health status of mice and helped to identify malfunctions at an early stage. Our method and criteria led to the success of our missions, and they will help establish appropriate rules for space experiments in the future.

  143. Transcription Factor MAFF (MAF Basic Leucine Zipper Transcription Factor F) Regulates an Atherosclerosis Relevant Network Connecting Inflammation and Cholesterol Metabolism. International-journal

    Moritz von Scheidt, Yuqi Zhao, Thomas Q de Aguiar Vallim, Nam Che, Michael Wierer, Marcus M Seldin, Oscar Franzén, Zeyneb Kurt, Shichao Pang, Dario Bongiovanni, Masayuki Yamamoto, Peter A Edwards, Arno Ruusalepp, Jason C Kovacic, Matthias Mann, Johan L M Björkegren, Aldons J Lusis, Xia Yang, Heribert Schunkert

    Circulation　143　(18)　1809-1823　2021/05/04

    DOI： 10.1161/CIRCULATIONAHA.120.050186 　

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    BACKGROUND: Coronary artery disease (CAD) is a multifactorial condition with both genetic and exogenous causes. The contribution of tissue-specific functional networks to the development of atherosclerosis remains largely unclear. The aim of this study was to identify and characterize central regulators and networks leading to atherosclerosis. METHODS: Based on several hundred genes known to affect atherosclerosis risk in mouse (as demonstrated in knockout models) and human (as shown by genome-wide association studies), liver gene regulatory networks were modeled. The hierarchical order and regulatory directions of genes within the network were based on Bayesian prediction models, as well as experimental studies including chromatin immunoprecipitation DNA-sequencing, chromatin immunoprecipitation mass spectrometry, overexpression, small interfering RNA knockdown in mouse and human liver cells, and knockout mouse experiments. Bioinformatics and correlation analyses were used to clarify associations between central genes and CAD phenotypes in both human and mouse. RESULTS: The transcription factor MAFF (MAF basic leucine zipper transcription factor F) interacted as a key driver of a liver network with 3 human genes at CAD genome-wide association studies loci and 11 atherosclerotic murine genes. Most importantly, expression levels of the low-density lipoprotein receptor (LDLR) gene correlated with MAFF in 600 CAD patients undergoing bypass surgery (STARNET [Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task]) and a hybrid mouse diversity panel involving 105 different inbred mouse strains. Molecular mechanisms of MAFF were tested in noninflammatory conditions and showed positive correlation between MAFF and LDLR in vitro and in vivo. Interestingly, after lipopolysaccharide stimulation (inflammatory conditions), an inverse correlation between MAFF and LDLR in vitro and in vivo was observed. Chromatin immunoprecipitation mass spectrometry revealed that the human CAD genome-wide association studies candidate BACH1 (BTB domain and CNC homolog 1) assists MAFF in the presence of lipopolysaccharide stimulation with respective heterodimers binding at the MAF recognition element of the LDLR promoter to transcriptionally downregulate LDLR expression. CONCLUSIONS: The transcription factor MAFF was identified as a novel central regulator of an atherosclerosis/CAD-relevant liver network. MAFF triggered context-specific expression of LDLR and other genes known to affect CAD risk. Our results suggest that MAFF is a missing link between inflammation, lipid and lipoprotein metabolism, and a possible treatment target.

  144. Correction to: Genome-wide association study identifies new loci for albuminuria in the Japanese population.

    Hiroshi Okuda, Koji Okamoto, Michiaki Abe, Kota Ishizawa, Satoshi Makino, Osamu Tanabe, Junichi Sugawara, Atsushi Hozawa, Kozo Tanno, Makoto Sasaki, Gen Tamiya, Masayuki Yamamoto, Sadayoshi Ito, Tadashi Ishii

    Clinical and experimental nephrology　25　(5)　565-565　2021/05

    DOI： 10.1007/s10157-021-02053-4 　

  145. Genetic ablation of Nrf2 exacerbates neurotoxic effects of acrylamide in mice. International-journal

    Frederick Adams Ekuban, Cai Zong, Madoka Takikawa, Kota Morikawa, Toshihiro Sakurai, Sahoko Ichihara, Ken Itoh, Masayuki Yamamoto, Seiichiroh Ohsako, Gaku Ichihara

    Toxicology　456　152785-152785　2021/04/16

    DOI： 10.1016/j.tox.2021.152785 　

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    Acrylamide (ACR), a recognized neurotoxicant in humans and experimental animals, is widely used in industry and in food generated through Maillard reaction. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of the cellular defense system and activates antioxidants and cytoprotective genes. The exact roles of Nrf2 in environmental electrophile-induced neurotoxicity is poorly understood. The aim of this study was to determine the roles of Nrf2 in ACR-induced neurotoxicity including degeneration of monoaminergic axons and sensorimotor dysfunction. Male 10-week-old C57BL/6JJcl Nrf2-knockout mice and wild type (WT) counterparts were each divided into four groups of 12 and provided with drinking water containing acrylamide at 0, 67, 110 or 200 ppm for four weeks. The effects of acrylamide were examined by landing foot spread test, immunohistochemistry for noradrenaline (NA) and serotonin (5-HT)-containing axons and Iba1-positive microglia in the prefrontal cortex as well as quantitative real-time polymerase chain reaction (qRT-PCR) on antioxidant, proinflammatory and anti-inflammatory genes in the prefrontal cortex. Relative to the wild type, exposure of Nrf2-knockout mice to acrylamide increased hindlimb splay length, microglial area and process length as well as decreasing the density of NA and 5-HT-immunoreactive axons to a greater extent. Moreover, deletion of Nrf2 gene suppressed acrylamide-induced mRNA upregulation of Nrf2-antioxidants, NAD(P): quinone oxidoreductase 1 (NQO1), superoxide dismutase-1 (SOD-1) and heme oxygenase-1 (HO-1) as well as anti-inflammtory markers such as, arginase-1 (Arg1), found in the inflammatory zone-1 (Fizz1), chitinase-like 3 (Chi3l3), interleukin-4 receptor alpha (IL-4Rα), cluster of differentiation  206 (CD206) and tranforming growth factor beta-1 (TGFβ1) while enhancing acrylamide-induced upregulation of pro-inflammatory cytokines, interleukin-1 beta (IL-1β), tumor necrosis-alpha (TNF-α) and iducible nitric oxide synthase (iNOS) in the prefrontal cortex. The results demonstrate susceptibility of mice lacking the Nrf2 gene to acrylamide-induced neurotoxicity and neuroinflammation with the activation of microglia. Moreover, the results suggest the role of Nrf2 not only in induction of antioxidant gene expression, but also in suppression of proinflammatory cytokine gene expression.

  146. GWAS Identified IL4R and the Major Histocompatibility Complex Region as the Associated Loci of Total Serum IgE Levels in 9,260 Japanese Individuals. International-journal

    Kosuke Shido, Kaname Kojima, Matsuyuki Shirota, Kenshi Yamasaki, Ikuko N Motoike, Atsushi Hozawa, Soichi Ogishima, Naoko Minegishi, Kozo Tanno, Fumiki Katsuoka, Gen Tamiya, Setsuya Aiba, Masayuki Yamamoto, Kengo Kinoshita

    The Journal of investigative dermatology　141　(11)　2749-2752　2021/04/14

    DOI： 10.1016/j.jid.2021.02.762 　

  147. Body mass index and colorectal cancer risk: A Mendelian randomization study. International-journal

    Shiori Suzuki, Atsushi Goto, Masahiro Nakatochi, Akira Narita, Taiki Yamaji, Norie Sawada, Ryoko Katagiri, Masao Iwagami, Akiko Hanyuda, Tsuyoshi Hachiya, Yoichi Sutoh, Isao Oze, Yuriko N Koyanagi, Yumiko Kasugai, Yukari Taniyama, Hidemi Ito, Hiroaki Ikezaki, Yuichiro Nishida, Takashi Tamura, Haruo Mikami, Toshiro Takezaki, Sadao Suzuki, Etsuko Ozaki, Kiyonori Kuriki, Naoyuki Takashima, Kokichi Arisawa, Kenji Takeuchi, Kozo Tanno, Atsushi Shimizu, Gen Tamiya, Atsushi Hozawa, Kengo Kinoshita, Kenji Wakai, Makoto Sasaki, Masayuki Yamamoto, Keitaro Matsuo, Shoichiro Tsugane, Motoki Iwasaki

    Cancer science　112　(4)　1579-1588　2021/04

    DOI： 10.1111/cas.14824 　

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    Traditional observational studies have reported a positive association between higher body mass index (BMI) and the risk of colorectal cancer (CRC). However, evidence from other approaches to pursue the causal relationship between BMI and CRC is sparse. A two-sample Mendelian randomization (MR) study was undertaken using 68 single nucleotide polymorphisms (SNPs) from the Japanese genome-wide association study (GWAS) and 654 SNPs from the GWAS catalogue for BMI as sets of instrumental variables. For the analysis of SNP-BMI associations, we undertook a meta-analysis with 36 303 participants in the Japanese Consortium of Genetic Epidemiology studies (J-CGE), comprising normal populations. For the analysis of SNP-CRC associations, we utilized 7636 CRC cases and 37 141 controls from five studies in Japan, and undertook a meta-analysis. Mendelian randomization analysis of inverse-variance weighted method indicated that a one-unit (kg/m2 ) increase in genetically predicted BMI was associated with an odds ratio of 1.13 (95% confidence interval, 1.06-1.20; P value <.001) for CRC using the set of 68 SNPs, and an odds ratio of 1.07 (1.03-1.11, 0.001) for CRC using the set of 654 SNPs. Sensitivity analyses robustly showed increased odds ratios for CRC for every one-unit increase in genetically predicted BMI. Our MR analyses strongly support the evidence that higher BMI influences the risk of CRC. Although Asians are generally leaner than Europeans and North Americans, avoiding higher BMI seems to be important for the prevention of CRC in Asian populations.

  148. 転写因子Nrf2の活性化が引き起こす食道異形成と発がんにおける細胞選択性

    堀内 真, 谷山 裕亮, 田口 恵子, 鈴木 未来子, 山本 雅之, 亀井 尚

    日本外科学会定期学術集会抄録集　121回　PS-5　2021/04

    Publisher: (一社)日本外科学会

  149. Rapid-acting and long-lasting antidepressant-like action of (R)-ketamine in Nrf2 knock-out mice: a role of TrkB signaling. International-journal

    Youge Qu, Jiajing Shan, Siming Wang, Lijia Chang, Yaoyu Pu, Xingming Wang, Yunfei Tan, Masayuki Yamamoto, Kenji Hashimoto

    European archives of psychiatry and clinical neuroscience　271　(3)　439-446　2021/04

    DOI： 10.1007/s00406-020-01208-w 　

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    The transcription nuclear factor-erythroid factor 2-related factor 2 (Nrf2) plays a key role in inflammation that is involved in depression. We previously reported that Nrf2 knock-out (KO) mice exhibit depression-like phenotypes through systemic inflammation. (R)-ketamine, an enantiomer of ketamine, has rapid-acting and long-lasting antidepressant-like effects in rodents. We investigated whether (R)-ketamine can produce antidepressant-like effects in Nrf2 KO mice. Effects of (R)-ketamine on the depression-like phenotypes in Nrf2 KO mice were examined. Furthermore, the role of TrkB in the antidepressant-like actions of (R)-ketamine was also examined. In the tail-suspension test (TST) and forced swimming test (FST), (R)-ketamine (10 mg/kg) significantly attenuated the increased immobility times of TST and FST in the Nrf2 KO mice. In the sucrose preference test (SPT), (R)-ketamine significantly ameliorated the reduced preference of SPT in Nrf2 KO mice. Decreased expression of synaptic proteins (i.e., GluA1 and PSD-95) in the medial prefrontal cortex (mPFC) of Nrf2 KO mice was significantly ameliorated after a single injection of (R)-ketamine. Furthermore, the pre-treatment with the TrkB antagonist ANA-12 (0.5 mg/kg) significantly blocked the rapid and long-lasting antidepressant-like effects of (R)-ketamine in Nrf2 KO mice. Furthermore, ANA-12 significantly antagonized the beneficial effects of (R)-ketamine on decreased expression of synaptic proteins in the mPFC of Nrf2 KO mice. These findings suggest that (R)-ketamine can produce rapid and long-lasting antidepressant-like actions in Nrf2 KO mice via TrkB signaling.

  150. Defining the functionally sufficient regulatory region and liver-specific roles of the erythropoietin gene by transgene complementation. International-journal

    Shun Yamazaki, Ikuo Hirano, Koichiro Kato, Masayuki Yamamoto, Norio Suzuki

    Life sciences　269　119075-119075　2021/03/15

    DOI： 10.1016/j.lfs.2021.119075 　

    ISSN： 0024-3205

    eISSN： 1879-0631

  151. Loss of Ftsj1 perturbs codon-specific translation efficiency in the brain and is associated with X-linked intellectual disability. Peer-reviewed

    Nagayoshi Y, Chujo T, Hirata S, Nakatsuka H, Chen CW, Takakura M, Miyauchi K, Ikeuchi Y, Carlyle BC, Kitchen RR, Suzuki T, Katsuoka F, Yamamoto M, Goto Y, Tanaka M, Natsume K, Nairn AC, Suzuki T, Tomizawa K, Wei FY

    Science Advances　7　(13)　eabf3072-eabf3072　2021/03

    Publisher: American Association for the Advancement of Science (AAAS)

    DOI： 10.1126/sciadv.abf3072 　

    eISSN： 2375-2548

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    <italic>FtsJ RNA 2′-O-methyltransferase 1</italic>(<italic>FTSJ1</italic>) gene has been implicated in X-linked intellectual disability (XLID), but the molecular pathogenesis is unknown. We show that Ftsj1 is responsible for 2′-<italic>O</italic>-methylation of 11 species of cytosolic transfer RNAs (tRNAs) at the anticodon region, and these modifications are abolished in Ftsj1 knockout (KO) mice and XLID patient–derived cells. Loss of 2′-<italic>O</italic>-methylation in Ftsj1 KO mouse selectively reduced the steady-state level of tRNAPhein the brain, resulting in a slow decoding at Phe codons. Ribosome profiling showed that translation efficiency is significantly reduced in a subset of genes that need to be efficiently translated to support synaptic organization and functions. Ftsj1 KO mice display immature synaptic morphology and aberrant synaptic plasticity, which are associated with anxiety-like and memory deficits. The data illuminate a fundamental role of tRNA modification in the brain through regulation of translation efficiency and provide mechanistic insights into FTSJ1-related XLID.

  152. 環境・衛生部会シンポジウム〜多様なストレスに対する生体適応の仕組みと疾患制御〜 KEAP1-NRF2制御系の活性化とアルツハイマー病病態(Nrf2 suppresses oxidative stress and inflammation in App knock-in Alzheimer's disease model mice)

    松丸 大輔, 宇留野 晃, 領家 梨恵, 齋藤 律水, 門口 詩織, 三枝 大輔, 斉藤 貴志, 西道 隆臣, 川島 隆太, 山本 雅之

    日本薬学会年会要旨集　141年会　S16-3　2021/03

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  153. CL316243 treatment mitigates the inflammation in white adipose tissues of juvenile adipocyte-specific Nfe2l1 knockout mice. International-journal

    Zhendi Wang, Yongyong Hou, Suping Ren, Zhiyuan Liu, Zhuo Zuo, Sicui Huang, Wanqi Wang, Huihui Wang, Yanyan Chen, Yuanyuan Xu, Masayuki Yamamoto, Qiang Zhang, Jingqi Fu, Jingbo Pi

    Free radical biology & medicine　165　289-298　2021/03

    DOI： 10.1016/j.freeradbiomed.2021.01.043 　

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    Nuclear factor-erythroid 2-related factor 1 (NFE2L1) is a key transcription factor that regulates cellular adaptive responses to various stresses. Our previous studies revealed that adult adipocyte-specific Nfe2l1-knockout [Nfe2l1(f)-KO] mice show adipocyte hypertrophy and severe adipose inflammation, which can be worsened by rosiglitazone, a peroxisome proliferator-activated receptor γ agonist. To further assess the crucial roles of NFE2L1 in adipocytes, we investigated the effect of CL316243, a β3 adrenergic agonist that promotes lipolysis via a post-translational mechanism, on adipose inflammation in juvenile Nfe2l1(f)-KO mice. In contrast to adult mice, 4-week-old juvenile Nfe2l1(f)-KO mice displayed a normal fat distribution but reduced fasting plasma glycerol levels and elevated adipocyte hypertrophy and macrophage infiltration in inguinal and gonadal WAT. In addition, Nfe2l1(f)-KO mice had decreased expression of multiple lipolytic genes and reduced lipolytic activity in WAT. While 7 days of CL316243 treatment showed no significant effect on adipose inflammation in Nfe2l1-Floxed control mice, the same treatment dramatically alleviated macrophage infiltration and mRNA expression of inflammation and pyroptosis-related genes in WAT of Nfe2l1(f)-KO mice. Together with previous findings in adult mice, the current study highlights that NFE2L1 plays a fundamental regulatory role in lipolytic gene expression and thus might be an important target to improve adipose plasticity and lipid homeostasis.

  154. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries. International-journal

    Puya Gharahkhani, Eric Jorgenson, Pirro Hysi, Anthony P Khawaja, Sarah Pendergrass, Xikun Han, Jue Sheng Ong, Alex W Hewitt, Ayellet V Segrè, John M Rouhana, Andrew R Hamel, Robert P Igo Jr, Helene Choquet, Ayub Qassim, Navya S Josyula, Jessica N Cooke Bailey, Pieter W M Bonnemaijer, Adriana Iglesias, Owen M Siggs, Terri L Young, Veronique Vitart, Alberta A H J Thiadens, Juha Karjalainen, Steffen Uebe, Ronald B Melles, K Saidas Nair, Robert Luben, Mark Simcoe, Nishani Amersinghe, Angela J Cree, Rene Hohn, Alicia Poplawski, Li Jia Chen, Shi-Song Rong, Tin Aung, Eranga Nishanthie Vithana, Gen Tamiya, Yukihiro Shiga, Masayuki Yamamoto, Toru Nakazawa, Hannah Currant, Ewan Birney, Xin Wang, Adam Auton, Michelle K Lupton, Nicholas G Martin, Adeyinka Ashaye, Olusola Olawoye, Susan E Williams, Stephen Akafo, Michele Ramsay, Kazuki Hashimoto, Yoichiro Kamatani, Masato Akiyama, Yukihide Momozawa, Paul J Foster, Peng T Khaw, James E Morgan, Nicholas G Strouthidis, Peter Kraft, Jae H Kang, Chi Pui Pang, Francesca Pasutto, Paul Mitchell, Andrew J Lotery, Aarno Palotie, Cornelia van Duijn, Jonathan L Haines, Chris Hammond, Louis R Pasquale, Caroline C W Klaver, Michael Hauser, Chiea Chuen Khor, David A Mackey, Michiaki Kubo, Ching-Yu Cheng, Jamie E Craig, Stuart MacGregor, Janey L Wiggs

    Nature communications　12　(1)　1258-1258　2021/02/24

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41467-020-20851-4 　

    eISSN： 2041-1723

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    <title>Abstract</title>Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including <italic>SVEP1, RERE, VCAM1, ZNF638</italic>, <italic>CLIC5, SLC2A12, YAP1, MXRA5</italic>, and <italic>SMAD6</italic>. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

  155. Nrf2 Activation Sensitizes K-Ras Mutant Pancreatic Cancer Cells to Glutaminase Inhibition. International-journal

    Shin Hamada, Ryotaro Matsumoto, Yu Tanaka, Keiko Taguchi, Masayuki Yamamoto, Atsushi Masamune

    International journal of molecular sciences　22　(4)　2021/02/14

    DOI： 10.3390/ijms22041870 　

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    Pancreatic cancer remains intractable owing to the lack of effective therapy for unresectable cases. Activating mutations of K-ras are frequently found in pancreatic cancers, but these have not yet been targeted by cancer therapies. The Keap1-Nrf2 system plays a crucial role in mediating the oxidative stress response, which also contributes to cancer progression. Nrf2 activation reprograms the metabolic profile to promote the proliferation of cancer cells. A recent report suggested that K-ras- and Nrf2-active lung cancer cells are sensitive to glutamine depletion. This finding led to the recognition of glutaminase inhibitors as novel anticancer agents. In the current study, we used murine pancreatic cancer tissues driven by mutant K-ras and p53 to establish cell lines expressing constitutively activated Nrf2. Genetic or pharmacological Nrf2 activation in cells via Keap1 deletion or Nrf2 activation sensitized cells to glutaminase inhibition. This phenomenon was confirmed to be dependent on K-ras activation in human pancreatic cancer cell lines harboring mutant K-ras, i.e., Panc-1 and MiaPaCa-2 in response to DEM pretreatment. This phenomenon was not observed in BxPC3 cells harboring wildtype K-ras. These results indicate the possibility of employing Nrf2 activation and glutaminase inhibition as novel therapeutic interventions for K-ras mutant pancreatic cancers.

  156. Renal interstitial fibroblasts coproduce erythropoietin and renin under anaemic conditions. International-journal

    Kenichiro Miyauchi, Taku Nakai, Sakae Saito, Tae Yamamoto, Koji Sato, Koichiro Kato, Masahiro Nezu, Mariko Miyazaki, Sadayoshi Ito, Masayuki Yamamoto, Norio Suzuki

    EBioMedicine　64　103209-103209　2021/02

    DOI： 10.1016/j.ebiom.2021.103209 　

    eISSN： 2352-3964

  157. NRF2-Dependent Bioactivation of Mitomycin C as a Novel Strategy To Target KEAP1-NRF2 Pathway Activation in Human Cancer. International-journal

    Liam Baird, Masayuki Yamamoto

    Molecular and cellular biology　41　(2)　2021/01/25

    DOI： 10.1128/MCB.00473-20 　

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    Activating mutations in the KEAP1-NRF2 pathway are found in approximately 25% of lung tumors, where the hijacking of NRF2's cytoprotective functions results in aggressive tumor growth, chemoresistance, and a poor prognosis for patients. There are currently no approved drugs which target aberrant NRF2 activation, which means that there is an urgent clinical need to target this orphan oncogenic pathway in human tumors. In this study, we used an isogenic pair of wild-type and Keap1 knockout cells to screen a range of chemotherapeutic and pathway-targeted anticancer drugs in order to identify compounds which display enhanced toxicity toward cells with high levels of Nrf2 activity. Through this approach, complemented by validation across a panel of eight human cancer cell lines from a range of different tissues, we identified the DNA-damaging agent mitomycin C to be significantly more toxic in cells with aberrant Nrf2 activation. Mechanistically, we found that the NRF2 target genes for cytochrome P450 reductase, NQO1, and enzymes in the pentose phosphate pathway are all responsible for the NRF2-dependent enhanced bioactivation of mitomycin C. As mitomycin C is already approved for clinical use, it represents as excellent drug repositioning candidate to target the currently untreatable NRF2 activation in human tumors.

  158. Identification of Dominant Transcripts in Oxidative Stress Response by a Full-Length Transcriptome Analysis. International-journal

    Akihito Otsuki, Yasunobu Okamura, Yuichi Aoki, Noriko Ishida, Kazuki Kumada, Naoko Minegishi, Fumiki Katsuoka, Kengo Kinoshita, Masayuki Yamamoto

    Molecular and cellular biology　41　(2)　2021/01/25

    DOI： 10.1128/MCB.00472-20 　

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    Our body responds to environmental stress by changing the expression levels of a series of cytoprotective enzymes/proteins through multilayered regulatory mechanisms, including the KEAP1-NRF2 system. While NRF2 upregulates the expression of many cytoprotective genes, there are fundamental limitations in short-read RNA sequencing (RNA-Seq), resulting in confusion regarding interpreting the effectiveness of cytoprotective gene induction at the transcript level. To precisely delineate isoform usage in the stress response, we conducted independent full-length transcriptome profiling (isoform sequencing; Iso-Seq) analyses of lymphoblastoid cells from three volunteers under normal and electrophilic stress-induced conditions. We first determined the first exon usage in KEAP1 and NFE2L2 (encoding NRF2) and found the presence of transcript diversity. We then examined changes in isoform usage of NRF2 target genes under stress conditions and identified a few isoforms dominantly expressed in the majority of NRF2 target genes. The expression levels of isoforms determined by Iso-Seq analyses showed striking differences from those determined by short-read RNA-Seq; the latter could be misleading concerning the abundance of transcripts. These results support that transcript usage is tightly regulated to produce functional proteins under electrophilic stress. Our present study strongly argues that there are important benefits that can be achieved by long-read transcriptome sequencing.

  159. Cellular Nrf2 Levels Determine Cell Fate during Chemical Carcinogenesis in Esophageal Epithelium. International-journal

    Makoto Horiuchi, Keiko Taguchi, Wataru Hirose, Kouhei Tsuchida, Mikiko Suzuki, Yusuke Taniyama, Takashi Kamei, Masayuki Yamamoto

    Molecular and cellular biology　41　(2)　2021/01/25

    DOI： 10.1128/MCB.00536-20 　

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    Nrf2 is essential for cytoprotection against carcinogens, and through systemic Nrf2 knockout mice, Nrf2-deficient cells were shown to be susceptible to chemical carcinogens and prone to developing cancers. However, the oncogenic potential of Nrf2-deficient epithelial cells surrounded by normal cells in the esophagus could not be assessed by previous models, and the fate of Nrf2-deficient cells in such situations remains elusive. In this study, therefore, we generated mice that harbor almost equal levels of cells with Nrf2 deleted and those with Nrf2 intact in the basal layer of the esophageal epithelium, utilizing inducible Cre-mediated recombination of Nrf2 alleles in adults through moderate use of tamoxifen. In this mouse model, epithelial cells with Nrf2 deleted were maintained with no obvious decrease or phenotypic changes for 12 weeks under unstressed conditions. Upon exposure to the carcinogen 4-nitroquinoline-1-oxide (4NQO), the cells with Nrf2 deleted accumulated DNA damage and selectively disappeared from the epithelium, so almost all 4NQO-induced tumors originated from cells with Nrf2 intact and not from those with Nrf2 deleted. We propose that cells with Nrf2 deleted do not undergo carcinogenesis due to selective elimination upon exposure to 4NQO, indicating that cellular Nrf2 abundance and the epithelial environment determine the cell fate or oncogenic potential of esophageal epithelial cells in 4NQO-induced carcinogenesis.

  160. Publisher Correction: Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers. International-journal

    Keito Okazaki, Hayato Anzawa, Zun Liu, Nao Ota, Hiroshi Kitamura, Yoshiaki Onodera, Md Morshedul Alam, Daisuke Matsumaru, Takuma Suzuki, Fumiki Katsuoka, Shu Tadaka, Ikuko Motoike, Mika Watanabe, Kazuki Hayasaka, Akira Sakurada, Yoshinori Okada, Masayuki Yamamoto, Takashi Suzuki, Kengo Kinoshita, Hiroki Sekine, Hozumi Motohashi

    Nature communications　12　(1)　506-506　2021/01/15

    DOI： 10.1038/s41467-021-20927-9 　

  161. Estimation of the carrier frequencies and proportions of potential patients by detecting causative gene variants associated with autosomal recessive bone dysplasia using a whole-genome reference panel of Japanese individuals. International-journal

    Shinichi Nagaoka, Yumi Yamaguchi-Kabata, Naomi Shiga, Masahito Tachibana, Jun Yasuda, Shu Tadaka, Gen Tamiya, Nobuo Fuse, Kengo Kinoshita, Shigeo Kure, Jun Murotsuki, Masayuki Yamamoto, Nobuo Yaegashi, Junichi Sugawara

    Human genome variation　8　(1)　2-2　2021/01/15

    DOI： 10.1038/s41439-020-00133-7 　

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    Bone dysplasias are a group of rare hereditary diseases, with up to 436 disease types. Perinatal diagnosis is clinically important for adequate personalized management and counseling. There are no reports focused on pathogenic variants of bone dysplasias in the general population. In this study, we focused on autosomal recessive bone dysplasias. We identified pathogenic variants using whole-genome reference panel data from 3552 Japanese individuals. For the first time, we were able to estimate the carrier frequencies and the proportions of potential patients. For autosomal recessive bone dysplasias, we detected 198 pathogenic variants of 54 causative genes. We estimated the variant carrier frequencies and the proportions of potential patients with variants associated with four clinically important bone dysplasias: osteogenesis imperfecta (OI), hypophosphatasia (HPP), asphyxiating thoracic dysplasia (ATD), and Ellis-van Creveld syndrome (EvC). The proportions of potential patients with OI, ATD, and EvC based on pathogenic variants classified as "pathogenic" and "likely pathogenic" by InterVar were closer to the reported incidence rates in Japanese subjects. Furthermore, the proportions of potential patients with HPP variants classified as "pathogenic" and "likely pathogenic" in InterVar and "pathogenic" in ClinVar were closer to the reported incidence rates. For bone dysplasia, the findings of this study will provide a better understanding of the variant types and frequencies in the Japanese general population, and should be useful for clinical diagnosis, genetic counseling, and personalized medicine.

  162. Construction and integration of three de novo Japanese human genome assemblies toward a population-specific reference. International-journal Peer-reviewed

    Jun Takayama, Shu Tadaka, Kenji Yano, Fumiki Katsuoka, Chinatsu Gocho, Takamitsu Funayama, Satoshi Makino, Yasunobu Okamura, Atsuo Kikuchi, Sachiyo Sugimoto, Junko Kawashima, Akihito Otsuki, Mika Sakurai-Yageta, Jun Yasuda, Shigeo Kure, Kengo Kinoshita, Masayuki Yamamoto, Gen Tamiya

    Nature communications　12　(1)　226-226　2021/01/11

    Publisher: Cold Spring Harbor Laboratory

    DOI： 10.1038/s41467-020-20146-8 　

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    <title>ABSTRACT</title>The complete sequence of the human genome is used as a reference for next-generation sequencing analyses. However, some ethnic ancestries are under-represented in the international human reference genome (e.g., GRCh37), especially Asian populations, due to a strong bias toward European and African ancestries in a single mosaic haploid genome consisting chiefly of a single donor. Here, we performed <italic>de novo</italic> assembly of the genomes from three Japanese male individuals using &gt;100× PacBio long reads and Bionano optical maps per sample. We integrated the genomes using the major allele for consensus, and anchored the scaffolds using sequence-tagged site markers from conventional genetic and radiation hybrid maps to reconstruct each chromosome sequence. The resulting genome sequence, designated JG1, is highly contiguous, accurate, and carries the major allele in the majority of single nucleotide variant sites for a Japanese population. We adopted JG1 as the reference for confirmatory exome re-analyses of seven Japanese families with rare diseases and found that re-analysis using JG1 reduced false-positive variant calls versus GRCh37 while retaining disease-causing variants. These results suggest that integrating multiple genome assemblies from a single ethnic population can aid next-generation sequencing analyses of individuals originated from the population.

  163. jMorp updates in 2020: large enhancement of multi-omics data resources on the general Japanese population. International-journal

    Shu Tadaka, Eiji Hishinuma, Shohei Komaki, Ikuko N Motoike, Junko Kawashima, Daisuke Saigusa, Jin Inoue, Jun Takayama, Yasunobu Okamura, Yuichi Aoki, Matsuyuki Shirota, Akihito Otsuki, Fumiki Katsuoka, Atsushi Shimizu, Gen Tamiya, Seizo Koshiba, Makoto Sasaki, Masayuki Yamamoto, Kengo Kinoshita

    Nucleic acids research　49　(D1)　D536-D544　2021/01/08

    DOI： 10.1093/nar/gkaa1034 　

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    In the Tohoku Medical Megabank project, genome and omics analyses of participants in two cohort studies were performed. A part of the data is available at the Japanese Multi Omics Reference Panel (jMorp; https://jmorp.megabank.tohoku.ac.jp) as a web-based database, as reported in our previous manuscript published in Nucleic Acid Research in 2018. At that time, jMorp mainly consisted of metabolome data; however, now genome, methylome, and transcriptome data have been integrated in addition to the enhancement of the number of samples for the metabolome data. For genomic data, jMorp provides a Japanese reference sequence obtained using de novo assembly of sequences from three Japanese individuals and allele frequencies obtained using whole-genome sequencing of 8,380 Japanese individuals. In addition, the omics data include methylome and transcriptome data from ∼300 samples and distribution of concentrations of more than 755 metabolites obtained using high-throughput nuclear magnetic resonance and high-sensitivity mass spectrometry. In summary, jMorp now provides four different kinds of omics data (genome, methylome, transcriptome, and metabolome), with a user-friendly web interface. This will be a useful scientific data resource on the general population for the discovery of disease biomarkers and personalized disease prevention and early diagnosis.

  164. Organic synthesis and anti-influenza A virus activity of cyclobakuchiols A, B, C, and D. International-journal

    Masaki Shoji, Tomoyuki Esumi, Narue Tanaka, Misa Takeuchi, Saki Yamaji, Mihiro Watanabe, Etsuhisa Takahashi, Hiroshi Kido, Masayuki Yamamoto, Takashi Kuzuhara

    PloS one　16　(3)　e0248960　2021

    DOI： 10.1371/journal.pone.0248960 　

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    Novel antiviral agents for influenza, which poses a substantial threat to humans, are required. Cyclobakuchiols A and B have been isolated from Psoralea glandulosa, and cyclobakuchiol C has been isolated from P. corylifolia. The structural differences between cyclobakuchiol A and C arise due to the oxidation state of isopropyl group, and these compounds can be derived from (+)-(S)-bakuchiol, a phenolic isoprenoid compound present in P. corylifolia seeds. We previously reported that bakuchiol induces enantiospecific anti-influenza A virus activity involving nuclear factor erythroid 2-related factor 2 (Nrf2) activation. However, it remains unclear whether cyclobakuchiols A-C induce anti-influenza A virus activity. In this study, cyclobakuchiols A, B, and C along with cyclobakuchiol D, a new artificial compound derived from cyclobakuchiol B, were synthesized and examined for their anti-influenza A virus activities using Madin-Darby canine kidney cells. As a result, cyclobakuchiols A-D were found to inhibit influenza A viral infection, growth, and the reduction of expression of viral mRNAs and proteins in influenza A virus-infected cells. Additionally, these compounds markedly reduced the mRNA expression of the host cell influenza A virus-induced immune response genes, interferon-β and myxovirus-resistant protein 1. In addition, cyclobakuchiols A-D upregulated the mRNA levels of NAD(P)H quinone oxidoreductase 1, an Nrf2-induced gene, in influenza A virus-infected cells. Notably, cyclobakuchiols A, B, and C, but not D, induced the Nrf2 activation pathway. These findings demonstrate that cyclobakuchiols have anti-influenza viral activity involving host cell oxidative stress response. In addition, our results suggest that the suitably spatial configuration between oxidized isopropyl group and phenol moiety in the structure of cyclobakuchiols is required for their effect.

  165. Heart Rate Information-Based Machine Learning Prediction of Emotions Among Pregnant Women. International-journal

    Xue Li, Chiaki Ono, Noriko Warita, Tomoka Shoji, Takashi Nakagawa, Hitomi Usukura, Zhiqian Yu, Yuta Takahashi, Kei Ichiji, Norihiro Sugita, Natsuko Kobayashi, Saya Kikuchi, Yasuto Kunii, Keiko Murakami, Mami Ishikuro, Taku Obara, Tomohiro Nakamura, Fuji Nagami, Takako Takai, Soichi Ogishima, Junichi Sugawara, Tetsuro Hoshiai, Masatoshi Saito, Gen Tamiya, Nobuo Fuse, Shinichi Kuriyama, Masayuki Yamamoto, Nobuo Yaegashi, Noriyasu Homma, Hiroaki Tomita

    Frontiers in psychiatry　12　799029-799029　2021

    DOI： 10.3389/fpsyt.2021.799029 　

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    In this study, the extent to which different emotions of pregnant women can be predicted based on heart rate-relevant information as indicators of autonomic nervous system functioning was explored using various machine learning algorithms. Nine heart rate-relevant autonomic system indicators, including the coefficient of variation R-R interval (CVRR), standard deviation of all NN intervals (SDNN), and square root of the mean squared differences of successive NN intervals (RMSSD), were measured using a heart rate monitor (MyBeat) and four different emotions including "happy," as a positive emotion and "anxiety," "sad," "frustrated," as negative emotions were self-recorded on a smartphone application, during 1 week starting from 23rd to 32nd weeks of pregnancy from 85 pregnant women. The k-nearest neighbor (k-NN), support vector machine (SVM), logistic regression (LR), random forest (RF), naïve bayes (NB), decision tree (DT), gradient boosting trees (GBT), stochastic gradient descent (SGD), extreme gradient boosting (XGBoost), and artificial neural network (ANN) machine learning methods were applied to predict the four different emotions based on the heart rate-relevant information. To predict four different emotions, RF also showed a modest area under the receiver operating characteristic curve (AUC-ROC) of 0.70. CVRR, RMSSD, SDNN, high frequency (HF), and low frequency (LF) mostly contributed to the predictions. GBT displayed the second highest AUC (0.69). Comprehensive analyses revealed the benefits of the prediction accuracy of the RF and GBT methods and were beneficial to establish models to predict emotions based on autonomic nervous system indicators. The results implicated SDNN, RMSSD, CVRR, LF, and HF as important parameters for the predictions.

  166. Identification and Validation of Combination Plasma Biomarker of Afamin, Fibronectin and Sex Hormone-Binding Globulin to Predict Pre-eclampsia.

    Yasuo Uchida, Tomoya Higuchi, Matsuyuki Shirota, Satoshi Kagami, Daisuke Saigusa, Seizo Koshiba, Jun Yasuda, Gen Tamiya, Shinichi Kuriyama, Kengo Kinoshita, Nobuo Yaegashi, Masayuki Yamamoto, Tetsuya Terasaki, Junichi Sugawara

    Biological & pharmaceutical bulletin　44　(6)　804-815　2021

    DOI： 10.1248/bpb.b20-01043 　

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    The purpose of the present study was to identify a plasma protein biomarker able to predict pre-eclampsia (PE). Comprehensive quantitative proteomics using mass spectrometry with sequential window acquisition of all theoretical fragment ion spectra (SWATH-MS) was applied to plasma samples of 7 PE and 14 healthy pregnant women (for PE subjects, plasma samples were taken before onset of PE), and 11 proteins were selected as candidates potentially able to differentiate the two groups. Plasmas collected at gestational weeks 14-24 from 36 PE and 120 healthy pregnant women (for PE subjects, plasma samples were taken before onset of PE) were used to conduct selected reaction monitoring quantification analysis, optimize protein combinations and conduct internal validation, which consisted of 30 iterations of 10-fold cross-validation using multivariate logistic regression and receiver operating characteristic (ROC) analysis. The combination of afamin, fibronectin, and sex-hormone-binding globulin was selected as the best candidate. The 3-protein combination predictive model (predictive equation and cut-off value) generated using the internal validation subjects was successfully validated in another group of validation subjects (36 PE and 54 healthy (for PE subjects, plasma samples were taken before onset of PE)) and showed good predictive performance, with the area under the curve (AUC) 0.835 and odds ratio 13.43. In conclusion, we newly identified a 3-protein combination biomarker and established a predictive equation and cut-off value that can predict the onset of PE based on analysis of plasma samples collected during gestational weeks 14-24.

  167. Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2). International-journal

    Hideki Tokunaga, Keita Iida, Atsushi Hozawa, Soichi Ogishima, Yoh Watanabe, Shogo Shigeta, Muneaki Shimada, Yumi Yamaguchi-Kabata, Shu Tadaka, Fumiki Katsuoka, Shin Ito, Kazuki Kumada, Yohei Hamanaka, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto, Nobuo Yaegashi, Jun Yasuda

    PloS one　16　(1)　e0236907　2021

    DOI： 10.1371/journal.pone.0236907 　

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    Identification of the population frequencies of definitely pathogenic germline variants in two major hereditary breast and ovarian cancer syndrome (HBOC) genes, BRCA1/2, is essential to estimate the number of HBOC patients. In addition, the identification of moderately penetrant HBOC gene variants that contribute to increasing the risk of breast and ovarian cancers in a population is critical to establish personalized health care. A prospective cohort subjected to genome analysis can provide both sets of information. Computational scoring and prospective cohort studies may help to identify such likely pathogenic variants in the general population. We annotated the variants in the BRCA1 and BRCA2 genes from a dataset of 3,552 whole-genome sequences obtained from members of a prospective cohorts with genome data in the Tohoku Medical Megabank Project (TMM) with InterVar software. Computational impact scores (CADD_phred and Eigen_raw) and minor allele frequencies (MAFs) of pathogenic (P) and likely pathogenic (LP) variants in ClinVar were used for filtration criteria. Familial predispositions to cancers among the 35,000 TMM genome cohort participants were analyzed to verify the identified pathogenicity. Seven potentially pathogenic variants were newly identified. The sisters of carriers of these moderately deleterious variants and definite P and LP variants among members of the TMM prospective cohort showed a statistically significant preponderance for cancer onset, from the self-reported cancer history. Filtering by computational scoring and MAF is useful to identify potentially pathogenic variants in BRCA genes in the Japanese population. These results should help to follow up the carriers of variants of uncertain significance in the HBOC genes in the longitudinal prospective cohort study.

  168. The KEAP1-NRF2 System as a Molecular Target of Cancer Treatment. International-journal

    Keiko Taguchi, Masayuki Yamamoto

    Cancers　13　(1)　2020/12/26

    DOI： 10.3390/cancers13010046 　

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    The Kelch-like ECH-associated protein (KEAP1)- Nuclear factor erythroid-derived 2-like 2 (encoded by the Nfe2l2 gene; NRF2) system attracts extensive interest from scientists in basic and clinical cancer research fields, as NRF2 exhibits activity as both an oncogene and tumor suppressor, depending on the context. Especially unique and malignant, NRF2-addicted cancers exhibit high levels of NRF2 expression. Somatic mutations identified in the NRF2 or KEAP1 genes of NRF2-addicted cancers cause the stabilization and accumulation of NRF2. NRF2-addicted cancers hijack the intrinsic roles that NRF2 plays in cytoprotection, including antioxidative and anti-electrophilic responses, as well as metabolic reprogramming, and acquire a marked advantage to survive under severe and limited microenvironments. Therefore, NRF2 inhibitors are expected to have therapeutic effects in patients with NRF2-addicted cancers. In contrast, NRF2 activation in host immune cells exerts significant suppression of cancer cell growth, indicating that NRF2 inducers also have the potential to be therapeutics for cancers. Thus, the KEAP1-NRF2 system makes a broad range of contributions to both cancer development and suppression. These observations thus demonstrate that both NRF2 inhibitors and inducers are useful for the treatment of cancers with high NRF2 activity.

  169. Nrf2 is activated by disruption of mitochondrial thiol homeostasis but not by enhanced mitochondrial superoxide production. International-journal

    Filip Cvetko, Stuart T Caldwell, Maureen Higgins, Takafumi Suzuki, Masayuki Yamamoto, Hiran A Prag, Richard C Hartley, Albena Dinkova-Kostova, Michael P Murphy

    The Journal of biological chemistry　2020/12/09

    DOI： 10.1074/jbc.RA120.016551 　

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    The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of genes involved in antioxidant defenses to modulate fundamental cellular processes such as mitochondrial function and glutathione metabolism. Previous reports proposed that mitochondrial ROS production and disruption of the glutathione pool activate the Nrf2 pathway, suggesting that Nrf2 senses mitochondrial redox signals and/or oxidative damage and signals to the nucleus to respond appropriately. However, until now it has not been possible to disentangle the overlapping effects of mitochondrial superoxide/ hydrogen peroxide production as a redox signal from changes to mitochondrial thiol homeostasis on Nrf2. Recently, we developed mitochondria-targeted reagents that can independently induce mitochondrial superoxide and hydrogen peroxide production (MitoPQ), or selectively disrupt mitochondrial thiol homeostasis (MitoCDNB). Using these reagents, here we have determined how enhanced generation of mitochondrial superoxide and hydrogen peroxide, or disruption of mitochondrial thiol homeostasis affect activation of the Nrf2 system in cells, which was assessed by Nrf2 protein level, nuclear translocation and expression of its target genes. We found that selective disruption of the mitochondrial glutathione pool and inhibition of its thioredoxin system by MitoCDNB led to Nrf2 activation, while using MitoPQ to enhance production of mitochondrial superoxide and hydrogen peroxide alone did not. We further showed that Nrf2 activation by MitoCDNB requires cysteine sensors of Kelch-like ECH-associated protein 1 (Keap1). These findings provide important information on how disruption to mitochondrial redox homeostasis is sensed in the cytoplasm and signaled to the nucleus.

  170. Combining MRI and genetic data in the Tohoku Medical Megabank Organization cohort study for innovative Alzheimer’s disease research

    Makiko Taira, Nobuo Fuse, Shunji Mugikura, Kengo Kinoshita, Masayuki Yamamoto

    Alzheimer's &amp; Dementia　16　(S10)　2020/12

    Publisher: Wiley

    DOI： 10.1002/alz.045688 　

    ISSN： 1552-5260

    eISSN： 1552-5279

  171. 転写因子Nrf2の活性化が引き起こす食道異形成と発がんにおける細胞選択性

    堀内 真, 田口 恵子, 鈴木 未来子, 谷山 裕亮, 山本 雅之, 亀井 尚

    日本食道学会学術集会プログラム・抄録集　74回　110-110　2020/12

    Publisher: (NPO)日本食道学会

  172. Effects of post-renal anemia treatment with the HIF-PHD inhibitor molidustat on adenine-induced renal anemia and kidney disease in mice.

    Lei Li, Daisuke Nakano, Anqi Zhang, Wararat Kittikulsuth, Norihiko Morisawa, Hiroyuki Ohsaki, Norio Suzuki, Masayuki Yamamoto, Akira Nishiyama

    Journal of pharmacological sciences　144　(4)　229-236　2020/12

    DOI： 10.1016/j.jphs.2020.09.004 　

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    The kidneys are the major organs for erythropoietin (EPO) production in adults, and thus, kidney damage results in reduced EPO levels and anemia. Inhibitors of Hypoxia-inducible factor-prolyl hydroxylase domain-containing protein (HIF-PHD) are awaited as new therapeutic options for renal anemia. It can be predicted that most patients who receive HIF-PHD inhibitors have renal dysfunction as a cause of anemia. Therefore, in the present study, we investigated the effects of the HIF-PHD inhibitor molidustat on anemia and renal dysfunction when initiated after the onset of renal anemia. Male C57BL/6J mice received adenine orally to induce nephropathy. After the onset of nephropathy, the mice were treated with either vehicle or molidustat. After 4 weeks of administration, vehicle-treated mice displayed significant anemia, and molidustat ameliorated this anemia. Vehicle-treated mice exhibited reduced creatinine clearance and body weight, increased blood urea nitrogen levels, histopathological changes, immune cell infiltration, and dehydration. Molidustat reversed immune cell infiltration, dehydration, and renal fibrosis without improving renal functional parameters. In conclusion, molidustat treatment initiated after the onset of nephropathy and renal anemia reversed anemia in mice. Molidustat improved some parameters of renal abnormality, but it did not restore renal function.

  173. Identification of critical genetic variants associated with metabolic phenotypes of the Japanese population

    Seizo Koshiba, Ikuko N. Motoike, Daisuke Saigusa, Jin Inoue, Yuichi Aoki, Shu Tadaka, Matsuyuki Shirota, Fumiki Katsuoka, Gen Tamiya, Naoko Minegishi, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto

    Communications Biology　3　(1)　2020/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s42003-020-01383-5 　

    eISSN： 2399-3642

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    <title>Abstract</title> We performed a metabolome genome-wide association study for the Japanese population in the prospective cohort study of Tohoku Medical Megabank. By combining whole-genome sequencing and nontarget metabolome analyses, we identified a large number of novel associations between genetic variants and plasma metabolites. Of the identified metabolite-associated genes, approximately half have already been shown to be involved in various diseases. We identified metabolite-associated genes involved in the metabolism of xenobiotics, some of which are from intestinal microorganisms, indicating that the identified genetic variants also markedly influence the interaction between the host and symbiotic bacteria. We also identified five associations that appeared to be female-specific. A number of rare variants that influence metabolite levels were also found, and combinations of common and rare variants influenced the metabolite levels more profoundly. These results support our contention that metabolic phenotyping provides important insights into how genetic and environmental factors provoke human diseases.

  174. Landscape of electrophilic and inflammatory stress-mediated gene regulation in human lymphoblastoid cell lines. International-journal

    Noriko Ishida, Yuichi Aoki, Fumiki Katsuoka, Ichiko Nishijima, Takahiro Nobukuni, Hayato Anzawa, Li Bin, Miyuki Tsuda, Kazuki Kumada, Hisaaki Kudo, Takahiro Terakawa, Akihito Otsuki, Kengo Kinoshita, Riu Yamashita, Naoko Minegishi, Masayuki Yamamoto

    Free radical biology & medicine　161　71-83　2020/12

    DOI： 10.1016/j.freeradbiomed.2020.09.023 　

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    Human lymphoblastoid cell lines (LCLs) are valuable for the functional analyses of diseases. We have established more than 4200 LCLs as one of the resources of an integrated biobank. While oxidative and inflammatory stresses play critical roles in the onset and progression of various diseases, the responsiveness of LCLs, especially that of biobank-made LCLs, to these stresses has not been established. To address how LCLs respond to these stresses, in this study, we performed RNA sequencing of eleven human LCLs that were treated with an electrophile, diethyl maleate (DEM) and/or an inflammatory mediator, lipopolysaccharide (LPS). We found that over two thousand genes, including those regulated by a master regulator of the electrophilic/oxidative stress response, NRF2, were upregulated in LCLs treated with DEM, while approximately three hundred genes, including inflammation-related genes, were upregulated in LPS-treated LCLs. Of the LPS-induced genes, a subset of proinflammatory genes was repressed by DEM, supporting the notion that DEM suppresses the expression of proinflammatory genes through NRF2 activation. Conversely, a part of DEM-induced gene was repressed by LPS, suggesting reciprocal interference between electrophilic and inflammatory stress-mediated pathways. These data clearly demonstrate that LCLs maintain, by and large, responsive pathways against oxidative and inflammatory stresses and further endorse the usefulness of the LCL supply from the biobank.

  175. Environmental pollutants and the immune response. International-journal

    Takafumi Suzuki, Takanori Hidaka, Yoshito Kumagai, Masayuki Yamamoto

    Nature immunology　21　(12)　1486-1495　2020/12

    DOI： 10.1038/s41590-020-0802-6 　

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    Environmental pollution is one of the most serious challenges to health in the modern world. Pollutants alter immune responses and can provoke immunotoxicity. In this Review, we summarize the major environmental pollutants that are attracting wide-ranging concern and the molecular basis underlying their effects on the immune system. Xenobiotic receptors, including the aryl hydrocarbon receptor (AHR), sense and respond to a subset of environmental pollutants by activating the expression of detoxification enzymes to protect the body. However, chronic activation of the AHR leads to immunotoxicity. KEAP1-NRF2 is another important system that protects the body against environmental pollutants. KEAP1 is a sensor protein that detects environmental pollutants, leading to activation of the transcription factor NRF2. NRF2 protects the body from immunotoxicity by inducing the expression of genes involved in detoxification, antioxidant and anti-inflammatory activities. Intervening in these sensor-response systems could protect the body from the devastating immunotoxicity that can be induced by environmental pollutants.

  176. Machine learning for effectively avoiding overfitting is a crucial strategy for the genetic prediction of polygenic psychiatric phenotypes Peer-reviewed

    Yuta Takahashi, Masao Ueki, Gen Tamiya, Soichi Ogishima, Kengo Kinoshita, Atsushi Hozawa, Naoko Minegishi, Fuji Nagami, Kentaro Fukumoto, Kotaro Otsuka, Kozo Tanno, Kiyomi Sakata, Atsushi Shimizu, Makoto Sasaki, Kenji Sobue, Shigeo Kure, Masayuki Yamamoto, Hiroaki Tomita

    Translational Psychiatry　10　(1)　2020/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41398-020-00957-5 　

    eISSN： 2158-3188

  177. Improved metabolomic data-based prediction of depressive symptoms using nonlinear machine learning with feature selection Peer-reviewed

    Yuta Takahashi, Masao Ueki, Makoto Yamada, Gen Tamiya, Ikuko N. Motoike, Daisuke Saigusa, Miyuki Sakurai, Fuji Nagami, Soichi Ogishima, Seizo Koshiba, Kengo Kinoshita, Masayuki Yamamoto, Hiroaki Tomita

    Translational Psychiatry　10　(1)　2020/12/01

    DOI： 10.1038/s41398-020-0831-9 　

    eISSN： 2158-3188

  178. Fundamental Biological Features of Spaceflight: Advancing the Field to Enable Deep-Space Exploration. International-journal

    Ebrahim Afshinnekoo, Ryan T Scott, Matthew J MacKay, Eloise Pariset, Egle Cekanaviciute, Richard Barker, Simon Gilroy, Duane Hassane, Scott M Smith, Sara R Zwart, Mayra Nelman-Gonzalez, Brian E Crucian, Sergey A Ponomarev, Oleg I Orlov, Dai Shiba, Masafumi Muratani, Masayuki Yamamoto, Stephanie E Richards, Parag A Vaishampayan, Cem Meydan, Jonathan Foox, Jacqueline Myrrhe, Eric Istasse, Nitin Singh, Kasthuri Venkateswaran, Jessica A Keune, Hami E Ray, Mathias Basner, Jack Miller, Martha Hotz Vitaterna, Deanne M Taylor, Douglas Wallace, Kathleen Rubins, Susan M Bailey, Peter Grabham, Sylvain V Costes, Christopher E Mason, Afshin Beheshti

    Cell　183　(5)　1162-1184　2020/11/25

    DOI： 10.1016/j.cell.2020.10.050 　

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    Research on astronaut health and model organisms have revealed six features of spaceflight biology that guide our current understanding of fundamental molecular changes that occur during space travel. The features include oxidative stress, DNA damage, mitochondrial dysregulation, epigenetic changes (including gene regulation), telomere length alterations, and microbiome shifts. Here we review the known hazards of human spaceflight, how spaceflight affects living systems through these six fundamental features, and the associated health risks of space exploration. We also discuss the essential issues related to the health and safety of astronauts involved in future missions, especially planned long-duration and Martian missions.

  179. Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers. International-journal

    Keito Okazaki, Hayato Anzawa, Zun Liu, Nao Ota, Hiroshi Kitamura, Yoshiaki Onodera, Md Morshedul Alam, Daisuke Matsumaru, Takuma Suzuki, Fumiki Katsuoka, Shu Tadaka, Ikuko Motoike, Mika Watanabe, Kazuki Hayasaka, Akira Sakurada, Yoshinori Okada, Masayuki Yamamoto, Takashi Suzuki, Kengo Kinoshita, Hiroki Sekine, Hozumi Motohashi

    Nature communications　11　(1)　5911-5911　2020/11/20

    DOI： 10.1038/s41467-020-19593-0 　

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    Transcriptional dysregulation, which can be caused by genetic and epigenetic alterations, is a fundamental feature of many cancers. A key cytoprotective transcriptional activator, NRF2, is often aberrantly activated in non-small cell lung cancers (NSCLCs) and supports both aggressive tumorigenesis and therapeutic resistance. Herein, we find that persistently activated NRF2 in NSCLCs generates enhancers at gene loci that are not normally regulated by transiently activated NRF2 under physiological conditions. Elevated accumulation of CEBPB in NRF2-activated NSCLCs is found to be one of the prerequisites for establishment of the unique NRF2-dependent enhancers, among which the NOTCH3 enhancer is shown to be critical for promotion of tumor-initiating activity. Enhancer remodeling mediated by NRF2-CEBPB cooperativity promotes tumor-initiating activity and drives malignancy of NRF2-activated NSCLCs via establishment of the NRF2-NOTCH3 regulatory axis.

  180. Analysis of HLA-G long-read genomic sequences in mother-offspring pairs with preeclampsia. International-journal

    Ayako Nishizawa, Kazuki Kumada, Keiko Tateno, Maiko Wagata, Sakae Saito, Fumiki Katsuoka, Satoshi Mizuno, Soichi Ogishima, Masayuki Yamamoto, Jun Yasuda, Junichi Sugawara

    Scientific reports　10　(1)　20027-20027　2020/11/18

    DOI： 10.1038/s41598-020-77081-3 　

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    Preeclampsia is a pregnancy-induced disorder that is characterized by hypertension and is a leading cause of perinatal and maternal-fetal morbidity and mortality. HLA-G is thought to play important roles in maternal-fetal immune tolerance, and the associations between HLA-G gene polymorphisms and the onset of pregnancy-related diseases have been explored extensively. Because contiguous genomic sequencing is difficult, the association between the HLA-G genotype and preeclampsia onset is controversial. In this study, genomic sequences of the HLA-G region (5.2 kb) from 31 pairs of mother-offspring genomic DNA samples (18 pairs from normal pregnancies/births and 13 from preeclampsia births) were obtained by single-molecule real-time sequencing using the PacBio RS II platform. The HLA-G alleles identified in our cohort matched seven known HLA-G alleles, but we also identified two new HLA-G alleles at the fourth-field resolution and compared them with nucleotide sequences from a public database that consisted of coding sequences that cover the 3.1-kb HLA-G gene span. Intriguingly, a potential association between preeclampsia onset and the poly T stretch within the downstream region of the HLA-G*01:01:01:01 allele was found. Our study suggests that long-read sequencing of HLA-G will provide clues for characterizing HLA-G variants that are involved in the pathophysiology of preeclampsia.

  181. Preconditioning the immature lung with enhanced Nrf2 activity protects against oxidant-induced hypoalveolarization in mice. International-journal

    Chandra M Tamatam, Narsa M Reddy, Haranatha R Potteti, Aparna Ankireddy, Patrick M Noone, Masayuki Yamamoto, Thomas W Kensler, Sekhar P Reddy

    Scientific reports　10　(1)　19034-19034　2020/11/04

    DOI： 10.1038/s41598-020-75834-8 　

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    Bronchopulmonary dysplasia (BPD) is a chronic disease of preterm babies with poor clinical outcomes. Nrf2 transcription factor is crucial for cytoprotective response, whereas Keap1-an endogenous inhibitor of Nrf2 signaling-dampens these protective responses. Nrf2-sufficient (wild type) newborn mice exposed to hyperoxia develop hypoalveolarization, which phenocopies human BPD, and Nrf2 deficiency worsens it. In this study, we used PND1 pups bearing bearing hypomorphic Keap1 floxed alleles (Keap1f/f) with increased levels of Nrf2 to test the hypothesis that constitutive levels of Nrf2 in the premature lung are insufficient to mitigate hyperoxia-induced hypoalveolarization. Both wildtype and Keap1f/f pups at PND1 were exposed to hyperoxia for 72 h and then allowed to recover at room air for two weeks (at PND18), sacrificed, and lung hypoalveolarization and inflammation assessed. Hyperoxia-induced lung hypoalveolarization was remarkably lower in Keap1f/f pups than in wildtype counterparts (28.9% vs 2.4%, wildtype vs Keap1f/f). Likewise, Keap1f/f pups were protected against prolonged (96 h) hyperoxia-induced hypoalveolarization. However, there were no differences in hyperoxia-induced lung inflammatory response immediately after exposure or at PND18. Lack of hypoalveolarization in Keap1f/f pups was accompanied by increased levels of expression of antioxidant genes and GSH as assessed immediately following hyperoxia. Keap1 knockdown resulted in upregulation of lung cell proliferation postnatally but had opposing effects following hyperoxia. Collectively, our study demonstrates that augmenting endogenous Nrf2 activation by targeting Keap1 may provide a physiological way to prevent hypoalveolarization associated with prematurity.

  182. 東北メディカル・メガバンク計画(宮城)における頸動脈エコーについて

    寳澤 篤, 土屋 菜歩, 中村 智洋, 宇留野 晃, 栗山 進一, 菅原 準一, 呉 繁夫, 布施 昇男, 山本 雅之

    超音波医学　47　(Suppl.)　S532-S532　2020/11

    Publisher: (公社)日本超音波医学会

    ISSN： 1346-1176

    eISSN： 1881-9311

  183. Geldanamycin-Derived HSP90 Inhibitors Are Synthetic Lethal with NRF2. International-journal

    Liam Baird, Takafumi Suzuki, Yushi Takahashi, Eiji Hishinuma, Daisuke Saigusa, Masayuki Yamamoto

    Molecular and cellular biology　40　(22)　2020/10/26

    DOI： 10.1128/MCB.00377-20 　

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    Activating mutations in KEAP1-NRF2 are frequently found in tumors of the lung, esophagus, and liver, where they are associated with aggressive growth, resistance to cancer therapies, and low overall survival. Despite the fact that NRF2 is a validated driver of tumorigenesis and chemotherapeutic resistance, there are currently no approved drugs which can inhibit its activity. Therefore, there is an urgent clinical need to identify NRF2-selective cancer therapies. To this end, we developed a novel synthetic lethal assay, based on fluorescently labeled isogenic wild-type and Keap1 knockout cell lines, in order to screen for compounds which selectively kill cells in an NRF2-dependent manner. Through this approach, we identified three compounds based on the geldanamycin scaffold which display synthetic lethality with NRF2. Mechanistically, we show that products of NRF2 target genes metabolize the quinone-containing geldanamycin compounds into more potent HSP90 inhibitors, which enhances their cytotoxicity while simultaneously restricting the synthetic lethal effect to cells with aberrant NRF2 activity. As all three of the geldanamycin-derived compounds have been used in clinical trials, they represent ideal candidates for drug repositioning to target the currently untreatable NRF2 activity in cancer.

  184. Nrf2 Lowers the Risk of Lung Injury via Modulating the Airway Innate Immune Response Induced by Diesel Exhaust in Mice. International-journal

    Ying-Ji Li, Takako Shimizu, Yusuke Shinkai, Tomomi Ihara, Masao Sugamata, Katsuhito Kato, Maiko Kobayashi, Yukiyo Hirata, Hirofumi Inagaki, Makoto Uzuki, Toshio Akimoto, Masakazu Umezawa, Ken Takeda, Arata Azuma, Masayuki Yamamoto, Tomoyuki Kawada

    Biomedicines　8　(10)　2020/10/21

    DOI： 10.3390/biomedicines8100443 　

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    In the present study, we investigated the role of Nrf2 in airway immune responses induced by diesel exhaust (DE) inhalation in mice. C57BL/6J Nrf2+/+ and Nrf2-/- mice were exposed to DE or clean air for 8 h/day and 6 days/week for 4 weeks. After DE exposure, the number of neutrophils and macrophage inflammatory protein (MIP)-2 level in bronchoalveolar lavage fluid (BALF) and interleukin (IL)-17 level in the lung tissue increased in Nrf2-/- mice compared with Nrf2+/+ mice; however, the lack of an increase in the level of tumor necrosis factor (TNF)-α in the lung tissue in Nrf2+/+ mice and mild suppression of the level of TNF-α in Nrf2-/- mice were observed; the level of granulocyte macrophage colony-stimulating factor (GM-CSF) in the lung tissue decreased in Nrf2-/- mice than in Nrf2+/+ mice; the number of DE particle-laden alveolar macrophages in BALF were larger in Nrf2-/- mice than in Nrf2+/+ mice. The results of electron microscope observations showed alveolar type II cell injury and degeneration of the lamellar body after DE exposure in Nrf2-/- mice. Antioxidant enzyme NAD(P)H quinone dehydrogenase (NQO)1 mRNA expression level was higher in Nrf2+/+ mice than in Nrf2-/- mice after DE exposure. Our results suggested that Nrf2 reduces the risk of pulmonary disease via modulating the airway innate immune response caused by DE in mice.

  185. Maternal Baseline Characteristics and Perinatal Outcomes: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

    Junichi Sugawara, Mami Ishikuro, Taku Obara, Tomomi Onuma, Keiko Murakami, Masahiro Kikuya, Fumihiko Ueno, Aoi Noda, Satoshi Mizuno, Tomoko Kobayashi, Yohei Hamanaka, Kichiya Suzuki, Eiichi Kodama, Naho Tsuchiya, Akira Uruno, Yoichi Suzuki, Osamu Tanabe, Hideyasu Kiyomoto, Akito Tsuboi, Atsushi Shimizu, Seizo Koshiba, Naoko Minegishi, Soichi Ogishima, Gen Tamiya, Hirohito Metoki, Atsushi Hozawa, Nobuo Fuse, Kengo Kinoshita, Shigeo Kure, Nobuo Yaegashi, Shinichi Kuriyama, Masayuki Yamamoto

    Journal of epidemiology　32　(2)　69-79　2020/10/10

    DOI： 10.2188/jea.JE20200338 　

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    BACKGROUND: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study was launched in 2013 to evaluate the complex interactions of genetic and environmental factors in multifactorial diseases. The present study describes the maternal baseline profile and perinatal data of participating mothers and infants. METHODS: Expectant mothers living in Miyagi prefecture were recruited from obstetric facilities or affiliated centers between 2013 and 2017. Three sets of self-administered questionnaires were collected, and the medical records were reviewed to obtain precise information about each antenatal visit and each delivery. Biospecimens, including blood, urine, umbilical cord blood, and breast milk, were collected for the study biobank. The baseline maternal sociodemographic characteristics, results of screening tests, and obstetric outcomes were analyzed according to the maternal age group. RESULTS: A total of 23 406 pregnancies involving 23 730 fetuses resulted in 23 143 live births. Younger maternal participants had a tendency toward a higher incidence of threatened abortion and threatened premature labor, while older age groups exhibited a significantly higher rate of low lying placenta, placenta previa, gestational diabetes and hypertensive disorders of pregnancy. CONCLUSIONS: The present study clearly shows the distribution of maternal baseline characteristics and the range of perinatal outcomes according to maternal age group. This cohort study can provide strategic information for creating breakthroughs in the pathophysiology of perinatal, developmental, and noncommunicable diseases by collaborative data visiting or sharing.

  186. Author Correction: Nrf2 contributes to the weight gain of mice during space travel. International-journal

    Takafumi Suzuki, Akira Uruno, Akane Yumoto, Keiko Taguchi, Mikiko Suzuki, Nobuhiko Harada, Rie Ryoke, Eriko Naganuma, Nanae Osanai, Aya Goto, Hiromi Suda, Ryan Browne, Akihito Otsuki, Fumiki Katsuoka, Michael Zorzi, Takahiro Yamazaki, Daisuke Saigusa, Seizo Koshiba, Takashi Nakamura, Satoshi Fukumoto, Hironobu Ikehata, Keizo Nishikawa, Norio Suzuki, Ikuo Hirano, Ritsuko Shimizu, Tetsuya Oishi, Hozumi Motohashi, Hirona Tsubouchi, Risa Okada, Takashi Kudo, Michihiko Shimomura, Thomas W Kensler, Hiroyasu Mizuno, Masaki Shirakawa, Satoru Takahashi, Dai Shiba, Masayuki Yamamoto

    Communications biology　3　(1)　566-566　2020/10/07

    DOI： 10.1038/s42003-020-01292-7 　

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    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  187. ミトコンドリアComplex I阻害時のマウスミュラー細胞における神経栄養因子の検討

    柳町 真希, 檜森 紀子, 俵山 寛司, 佐藤 孝太, 行方 和彦, 原田 高幸, 山本 雅之, 中澤 徹

    日本緑内障学会抄録集　31回　72-72　2020/10

    Publisher: 日本緑内障学会

  188. A genotype imputation method for de-identified haplotype reference information by using recurrent neural network

    Kaname Kojima, Shu Tadaka, Fumiki Katsuoka, Gen Tamiya, Masayuki Yamamoto, Kengo Kinoshita

    PLOS Computational Biology　16　(10)　e1008207-e1008207　2020/10/01

    Publisher: Public Library of Science (PLoS)

    DOI： 10.1371/journal.pcbi.1008207 　

    eISSN： 1553-7358

  189. Nrf2 contributes to the weight gain of mice during space travel. International-journal

    Takafumi Suzuki, Akira Uruno, Akane Yumoto, Keiko Taguchi, Mikiko Suzuki, Nobuhiko Harada, Rie Ryoke, Eriko Naganuma, Nanae Osanai, Aya Goto, Hiromi Suda, Ryan Browne, Akihito Otsuki, Fumiki Katsuoka, Michael Zorzi, Takahiro Yamazaki, Daisuke Saigusa, Seizo Koshiba, Takashi Nakamura, Satoshi Fukumoto, Hironobu Ikehata, Keizo Nishikawa, Norio Suzuki, Ikuo Hirano, Ritsuko Shimizu, Tetsuya Oishi, Hozumi Motohashi, Hirona Tsubouchi, Risa Okada, Takashi Kudo, Michihiko Shimomura, Thomas W Kensler, Hiroyasu Mizuno, Masaki Shirakawa, Satoru Takahashi, Dai Shiba, Masayuki Yamamoto

    Communications biology　3　(1)　496-496　2020/09/08

    DOI： 10.1038/s42003-020-01227-2 　

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    Space flight produces an extreme environment with unique stressors, but little is known about how our body responds to these stresses. While there are many intractable limitations for in-flight space research, some can be overcome by utilizing gene knockout-disease model mice. Here, we report how deletion of Nrf2, a master regulator of stress defense pathways, affects the health of mice transported for a stay in the International Space Station (ISS). After 31 days in the ISS, all flight mice returned safely to Earth. Transcriptome and metabolome analyses revealed that the stresses of space travel evoked ageing-like changes of plasma metabolites and activated the Nrf2 signaling pathway. Especially, Nrf2 was found to be important for maintaining homeostasis of white adipose tissues. This study opens approaches for future space research utilizing murine gene knockout-disease models, and provides insights into mitigating space-induced stresses that limit the further exploration of space by humans.

  190. O-glycan-altered extracellular vesicles: A specific serum marker elevated in pancreatic cancer

    Takahiro Yokose, Yasuaki Kabe, Atsushi Matsuda, Minoru Kitago, Sachiko Matsuda, Miwa Hirai, Tomomi Nakagawa, Yohei Masugi, Takako Hishiki, Yuki Nakamura, Masahiro Shinoda, Hiroshi Yagi, Yuta Abe, Go Oshima, Shutaro Hori, Yutaka Nakano, Kazufumi Honda, Ayumi Kashiro, Chigusa Morizane, Satoshi Nara, Shojiro Kikuchi, Takahiko Shibahara, Makoto Itonaga, Masayuki Ono, Naoko Minegishi, Seizo Koshiba, Masayuki Yamamoto, Atsushi Kuno, Hiroshi Handa, Michiie Sakamoto, Makoto Suematsu, Yuko Kitagawa

    Cancers　12　(9)　1-17　2020/09

    DOI： 10.3390/cancers12092469 　

    eISSN： 2072-6694

  191. Microenvironmental Activation of Nrf2 Restricts the Progression of Nrf2-Activated Malignant Tumors. International-journal

    Makiko Hayashi, Ayumi Kuga, Mikiko Suzuki, Harit Panda, Hiroshi Kitamura, Hozumi Motohashi, Masayuki Yamamoto

    Cancer research　80　(16)　3331-3344　2020/08/15

    DOI： 10.1158/0008-5472.CAN-19-2888 　

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    The transcription factor Nrf2 activates transcription of cytoprotective genes during oxidative and electrophilic insults. Nrf2 activity is regulated by Keap1 in a stress-dependent manner in normal cells, and somatic loss-of-function mutations of Keap1 are known to induce constitutive Nrf2 activation, especially in lung adenocarcinomas, conferring survival and proliferative benefits to tumors. Therefore, several therapeutic strategies that aim to inhibit Nrf2 in tumors have been developed for the treatment of Nrf2-activated cancers. Here we addressed whether targeting Nrf2 activation in the microenvironment can suppress the progression of Nrf2-activated tumors. We combined two types of Keap1-flox mice expressing variable levels of Keap1 with a Kras-driven adenocarcinoma model to generate Keap1-deficient lung tumors surrounded by normal or Keap1-knockdown host cells. In this model system, activation of Nrf2 in the microenvironment prolonged the survival of Nrf2-activated tumor-bearing mice. The Nrf2-activated microenvironment suppressed tumor burden; in particular, preinvasive lesion formation was significantly suppressed. Notably, loss of Nrf2 in bone marrow-derived cells in Nrf2-activated host cells appeared to counteract the suppression of Nrf2-activated cancer progression. Thus, these results demonstrate that microenvironmental Nrf2 activation suppresses the progression of malignant Nrf2-activated tumors and that Nrf2 activation in immune cells at least partially contributes to these suppressive effects. SIGNIFICANCE: This study clarifies the importance of Nrf2 activation in the tumor microenvironment and in the host for the suppression of malignant Nrf2-activated cancers and proposes new cancer therapies utilizing inducers of Nrf2.

  192. Low birth weight and abnormal pre-pregnancy body mass index were at higher risk for hypertensive disorders of pregnancy. International-journal Peer-reviewed

    Maiko Wagata, Mami Ishikuro, Taku Obara, Masato Nagai, Satoshi Mizuno, Naoki Nakaya, Tomohiro Nakamura, Takumi Hirata, Naho Tsuchiya, Hirohito Metoki, Soichi Ogishima, Atsushi Hozawa, Kengo Kinoshita, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto, Shinichi Kuriyama, Junichi Sugawara

    Pregnancy hypertension　22　119-125　2020/08/05

    DOI： 10.1016/j.preghy.2020.08.001 　

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    Low birth weight is known to be associated with hypertension, cardiovascular disease and hypertensive disorders of pregnancy (HDP); however, this association might vary by race/ethnicity. This study aimed to clarify the association between women's own birth weight and their subsequent risk for HDP in a Japanese population, in combination with pre-pregnancy body mass index (BMI). We conducted a cohort study as part of the Tohoku Medical Megabank Birth and Three-Generation Cohort Study in Miyagi, Japan. Our study's population included 4810 women. A multivariate logistic regression analysis was performed to calculate the adjusted odds ratio (aOR) and the 95% confidence interval (CI) of the women's own birth weight for HDP, in the combination categories of birth weight and pre-pregnancy BMI. As a result, the group with a low birth weight of <2500 g had a significant association with HDP (the aOR, 1.50; 95% CI, 1.02-2.21). In the subtype analysis, the odds ratio for only preeclampsia was significantly increased in the low birth weight group (aOR, 3.37; 95% CI, 1.84-6.16). In the group with a low birth weight, the prevalence of HDP was higher in both the underweight and overweight groups. In conclusion, there was a significant association between low birth weight and subsequent HDP in Japanese women. Furthermore, a significant association with HDP was found for women born with a low birth weight who were underweight or overweight as adults. Maintaining a normal weight may be effective for preventing HDP even if a woman was born small.

  193. 産後うつ病の予測と予防のための血漿サイトカインレベルの検証

    兪 志前, 小野 千晶, 小原 拓, 菊地 沙耶, 小林 奈津子, 菅原 準一, 栗山 進一, 山本 雅之, 八重樫 伸生, 富田 博秋

    日本神経精神薬理学会年会・日本生物学的精神医学会年会・日本精神薬学会総会・学術集会合同年会プログラム・抄録集　50回・42回・4回　195-195　2020/08

    Publisher: 日本神経精神薬理学会・日本生物学的精神医学会・日本精神薬学会

  194. COPD 疫学・病因・病態 出生体重と20代成人の%FEV1は相関する 東北メディカル・メガバンク機構住民健康調査に基づく呼吸機能影響因子の探索

    大江 崇, 山田 充啓, 杉浦 久敏, 布施 昇男, 寳澤 篤, 中村 智洋, 山本 雅之, 一ノ瀬 正和

    日本呼吸器学会誌　9　(増刊)　125-125　2020/08

    Publisher: (一社)日本呼吸器学会

    ISSN： 2186-5876

    eISSN： 2186-5884

  195. 産後うつ病の予測と予防のための血漿サイトカインレベルの検証

    兪 志前, 小野 千晶, 小原 拓, 菊地 沙耶, 小林 奈津子, 菅原 準一, 栗山 進一, 山本 雅之, 八重樫 伸生, 富田 博秋

    日本神経精神薬理学会年会・日本生物学的精神医学会年会・日本精神薬学会総会・学術集会合同年会プログラム・抄録集　50回・42回・4回　195-195　2020/08

    Publisher: 日本神経精神薬理学会・日本生物学的精神医学会・日本精神薬学会

  196. Nrf2 Antioxidative System is Involved in Cytochrome P450 Gene Expression and Activity: A Delay in Pentobarbital Metabolism in Nrf2-Deficient Mice. International-journal Peer-reviewed

    Takashi Ashino, Masayuki Yamamoto, Satoshi Numazawa

    Drug metabolism and disposition: the biological fate of chemicals　48　(8)　673-680　2020/08

    DOI： 10.1124/dmd.120.000010 　

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    NF-E2-related factor 2 (Nrf2) is a transcriptional regulator of biologic defense proteins, such as antioxidant proteins and phase II detoxification enzymes. Cytochrome P450 (P450) enzymes have been shown to regulate phase I metabolism of various drugs and are partially regulated by Nrf2; however, the influence of Nrf2 on drug pharmacokinetics is not known. Here, we showed that Nrf2 depletion prolonged the effect of pentobarbital, a sleep-promoting drug. Pretreatment with phenobarbital, a P450 inducer, shortens the sleeping time associated with pentobarbital-induced sedation in wild-type (WT) mice; however, this effect was not observed in Nrf2-/- mice. Furthermore, the blood pentobarbital concentration was higher in Nrf2-/- mice than in WT mice at 30-60 minutes, and the phenobarbital-induced enhancement of its clearance was attenuated in Nrf2-/- mice compared with WT mice. Total P450 content was decreased in Nrf2-/- mouse livers, and the phenobarbital-induced increase in P450 content was lower in Nrf2-/- mice than WT mice. Cyp1a2, Cyp2a5, Cyp2c29, and Cyp2e1 gene expression levels under physiologic conditions and Cyp1a2, Cyp2a5, and Cyp2b10 gene expression levels under phenobarbital-treated conditions were lower in Nrf2-/- mice compared with WT mice. Additionally, pentobarbital metabolism in liver microsomes was attenuated by Nrf2 depletion. Taken together, these findings suggested that Nrf2 influenced pentobarbital pharmacokinetics through the regulation of drug metabolism and P450 gene expression. Thus, Nrf2-mediated regulation of P450 may contribute to the biologic defense against increased reactive oxygen species production. SIGNIFICANCE STATEMENT: NF-E2-related factor 2 (Nrf2) plays a critical role in the cellular defense against oxidative stress. Nrf2-/- mice with reduced ability to eliminate reactive oxygen species (ROS) showed a significant delay in emergence from pentobarbital-induced sleep, which was associated with decreased P450 activities and gene expression. Our findings provide that Nrf2 dysfunction or ROS that exceed a threshold level of the eliminating ability of the Nrf2 system may reduce P450 activity.

  197. Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes in a 3,552 Japanese whole-genome sequence dataset (3.5KJPNv2) Peer-reviewed

    Hideki Tokunaga, Keita Iida, Atsushi Hozawa, Soichi Ogishima, Yoh Watanabe, Shogo Shigeta, Muneaki Shimada, Yumi Yamaguchi-Kabata, Shu Tadaka, Fumiki Katsuoka, Shin Ito, Kazuki Kumada, Yohei Hamanaka, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto, Nobuo Yaegashi, Jun Yasuda

    2020/07/17

    Publisher: Cold Spring Harbor Laboratory

    DOI： 10.1101/2020.07.17.208454 　

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    <title>Abstract</title>Identification of pathogenic germline variants yet no clinical evidence in <italic>BRCA</italic> genes has become important in patient care of hereditary breast and ovarian cancer syndrome (HBOC). Computational scoring and prospective cohort studies may help to identify such pathogenic variants. We annotated the variants in the <italic>BRCA1</italic> and <italic>BRCA2</italic> genes from a dataset of 3,552 whole-genome sequences obtained from members of the genome cohorts by Tohoku Medical Megabank Project (TMM) with the InterVar software. Computational impact scores (CADD_phred and Eigen_raw) and minor allele frequencies (MAF) of pathogenic (P) and likely pathogenic (LP) variants in ClinVar are used for filtration criteria. Familial predispositions in cancers among the 35,000 TMM genome cohort participants are analyzed to verify the pathogenicity. Seven potentially pathogenic variants were newly identified. Carriers of these potential pathogenic variants and definite P and LP variants among participants of the TMM prospective cohort show a statistically significant preponderance in cancer onset in sisters in the self-reported cancer history. Filtering by computational scoring and MAF is useful to identify potential pathogenic variants in <italic>BRCA</italic> genes for Japanese population. These results will be helpful to follow up the carriers of variants of uncertain significance in the HBOC genes.

  198. 住民コホートを使った尿中アルブミン排泄量に関する量的形質遺伝子座の検討

    岡本 好司, 奥田 拓史, 石井 正, 佐々木 真理, 田宮 元, 山本 雅之, 阿部 倫明

    日本腎臓学会誌　62　(4)　261-261　2020/07

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  199. Correction: Biallelic GALM pathogenic variants cause a novel type of galactosemia. International-journal

    Yoichi Wada, Atsuo Kikuchi, Natsuko Arai-Ichinoi, Osamu Sakamoto, Yusuke Takezawa, Shinya Iwasawa, Tetsuya Niihori, Hiromi Nyuzuki, Yoko Nakajima, Erika Ogawa, Mika Ishige, Hiroki Hirai, Hideo Sasai, Ryoji Fujiki, Matsuyuki Shirota, Ryo Funayama, Masayuki Yamamoto, Tetsuya Ito, Osamu Ohara, Keiko Nakayama, Yoko Aoki, Seizo Koshiba, Toshiyuki Fukao, Shigeo Kure

    Genetics in medicine : official journal of the American College of Medical Genetics　22　(7)　1281-1281　2020/07

    DOI： 10.1038/s41436-020-0836-z 　

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    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  200. 住民コホートを使った尿中アルブミン排泄量に関する量的形質遺伝子座の検討

    岡本 好司, 奥田 拓史, 石井 正, 佐々木 真理, 田宮 元, 山本 雅之, 阿部 倫明

    日本腎臓学会誌　62　(4)　261-261　2020/07

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  201. 【婦人科医が知っておくべきがん遺伝子パネル検査の基礎知識】研究資源としてのがん組織・がんオミックス解析データ がんゲノム医療におけるバイオバンキングの役割

    島田 宗昭, 荻島 創一, 八重樫 伸生, 山本 雅之

    産婦人科の実際　69　(7)　755-759　2020/07

    Publisher: 金原出版(株)

    ISSN： 0558-4728

  202. The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway. International-journal

    Liam Baird, Masayuki Yamamoto

    Molecular and cellular biology　40　(13)　2020/06/15

    DOI： 10.1128/MCB.00099-20 　

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    The KEAP1-NRF2 pathway is the principal protective response to oxidative and electrophilic stresses. Under homeostatic conditions, KEAP1 forms part of an E3 ubiquitin ligase, which tightly regulates the activity of the transcription factor NRF2 by targeting it for ubiquitination and proteasome-dependent degradation. In response to stress, an intricate molecular mechanism facilitated by sensor cysteines within KEAP1 allows NRF2 to escape ubiquitination, accumulate within the cell, and translocate to the nucleus, where it can promote its antioxidant transcription program. Recent advances have revealed that KEAP1 contains multiple stress sensors and inactivation modalities, which together allow diverse cellular inputs, from oxidative stress and cellular metabolites to dysregulated autophagy, to regulate NRF2 activity. This integration of the KEAP1-NRF2 system into multiple cellular signaling and metabolic pathways places NRF2 activation as a critical regulatory node in many disease phenotypes and suggests that the pharmaceutical modulation of NRF2's cytoprotective activity will be beneficial for human health in a broad range of noncommunicable diseases.

  203. ゲノムコホート調査におけるゲノム薬理学(PGx)遺伝情報返却(回付)のパイロット研究

    濱中 洋平, 大根田 絹子, 布施 昇男, 川目 裕, 長神 風二, 平塚 真弘, 宇留野 晃, 櫻井 美佳, 平良 摩紀子, 鈴木 吉也, 鈴木 洋一, 山本 雅之

    日本遺伝カウンセリング学会誌　41　(2)　122-122　2020/06

    Publisher: (一社)日本遺伝カウンセリング学会

    ISSN： 1347-9628

  204. Erratum: Environmental electrophile-mediated toxicity in mice lacking nrf2, CSE, or both (Environ Health Perspect, (2019) 127, 6, 10.1289/EHP4949)

    Masahiro Akiyama, Takamitsu Unoki, Yasuhiro Shinkai, Isao Ishii, Tomoaki Ida, Takaaki Akaike, Masayuki Yamamoto, Yoshito Kumagai

    Environmental Health Perspectives　128　(6)　1　2020/06

    DOI： 10.1289/EHP7480 　

    ISSN： 0091-6765

    eISSN： 1552-9924

  205. Transethnic Meta-Analysis of Genome-Wide Association Studies Identifies Three New Loci and Characterizes Population-Specific Differences for Coronary Artery Disease. International-journal Peer-reviewed

    Hiroshi Matsunaga, Kaoru Ito, Masato Akiyama, Atsushi Takahashi, Satoshi Koyama, Seitaro Nomura, Hirotaka Ieki, Kouichi Ozaki, Yoshihiro Onouchi, Saori Sakaue, Shinichiro Suna, Soichi Ogishima, Masayuki Yamamoto, Atsushi Hozawa, Mamoru Satoh, Makoto Sasaki, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Shoichiro Tsugane, Keitaro Tanaka, Kokichi Arisawa, Hiroaki Ikezaki, Naoyuki Takashima, Mariko Naito, Kenji Wakai, Hideo Tanaka, Yasuhiko Sakata, Hiroyuki Morita, Yasushi Sakata, Koichi Matsuda, Yoshinori Murakami, Hiroshi Akazawa, Michiaki Kubo, Yoichiro Kamatani, Issei Komuro

    Circulation. Genomic and precision medicine　13　(3)　e002670　2020/06

    DOI： 10.1161/CIRCGEN.119.002670 　

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    BACKGROUND: Genome-wide association studies provided many biological insights into coronary artery disease (CAD), but these studies were mainly performed in Europeans. Genome-wide association studies in diverse populations have the potential to advance our understanding of CAD. METHODS: We conducted 2 genome-wide association studies for CAD in the Japanese population, which included 12 494 cases and 28 879 controls and 2808 cases and 7261 controls, respectively. Then, we performed transethnic meta-analysis using the results of the coronary artery disease genome-wide replication and meta-analysis plus the coronary artery disease 1000 Genomes meta-analysis with UK Biobank. We then explored the pathophysiological significance of these novel loci and examined the differences in CAD-susceptibility loci between Japanese and Europeans. RESULTS: We identified 3 new loci on chromosome 1q21 (CTSS), 10q26 (WDR11-FGFR2), and 11q22 (RDX-FDX1). Quantitative trait locus analyses suggested the association of CTSS and RDX-FDX1 with atherosclerotic immune cells. Tissue/cell type enrichment analysis showed the involvement of arteries, adrenal glands, and fat tissues in the development of CAD. We next compared the odds ratios of lead variants for myocardial infarction at 76 genome-wide significant loci in the transethnic meta-analysis and a moderate correlation between Japanese and Europeans, where 8 loci showed a difference. Finally, we performed tissue/cell type enrichment analysis using East Asian-frequent and European-frequent variants according to the risk allele frequencies and identified significant enrichment of adrenal glands in the East Asian-frequent group while the enrichment of arteries and fat tissues was found in the European-frequent group. These findings indicate biological differences in CAD susceptibility between Japanese and Europeans. CONCLUSIONS: We identified 3 new loci for CAD and highlighted the genetic differences between the Japanese and European populations. Moreover, our transethnic analyses showed both shared and unique genetic architectures between the Japanese and Europeans. While most of the underlying genetic bases for CAD are shared, further analyses in diverse populations will be needed to elucidate variations fully.

  206. Hypertensive disorders of pregnancy, obesity, and hypertension in later life by age group: a cross-sectional analysis. International-journal Peer-reviewed

    Maiko Wagata, Mana Kogure, Naoki Nakaya, Naho Tsuchiya, Tomohiro Nakamura, Takumi Hirata, Akira Narita, Hirohito Metoki, Mami Ishikuro, Masahiro Kikuya, Kozo Tanno, Akimune Fukushima, Nobuo Yaegashi, Shigeo Kure, Masayuki Yamamoto, Shinichi Kuriyama, Atsushi Hozawa, Junichi Sugawara

    Hypertension research : official journal of the Japanese Society of Hypertension　43　(11)　1277-1283　2020/05/13

    DOI： 10.1038/s41440-020-0463-8 　

    ISSN： 0916-9636

    eISSN： 1348-4214

  207. EVI1 and GATA2 misexpression induced by inv(3)(q21q26) contribute to megakaryocyte-lineage skewing and leukemogenesis. International-journal Peer-reviewed

    Ayaka Yamaoka, Mikiko Suzuki, Saori Katayama, Daiki Orihara, James Douglas Engel, Masayuki Yamamoto

    Blood advances　4　(8)　1722-1736　2020/04/28

    DOI： 10.1182/bloodadvances.2019000978 　

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    Chromosomal rearrangements between 3q21 and 3q26 elicit high-risk acute myeloid leukemia (AML), which is often associated with elevated platelet and megakaryocyte (Mk) numbers. The 3q rearrangements reposition a GATA2 enhancer near the EVI1 (or MECOM) locus, which results in both EVI1 overexpression and GATA2 haploinsufficiency. However, the mechanisms explaining how the misexpression of these 2 genes individually contribute to leukemogenesis are unknown. To clarify the characteristics of differentiation defects caused by EVI1 and GATA2 misexpression and to identify the cellular origin of leukemic cells, we generated a system to monitor both inv(3) allele-driven EVI1 and Gata2 expression in 3q-rearranged AML model mice. A cell population in which both EVI1 and Gata2 were highly induced appeared in the bone marrows before the onset of frank leukemia. This population had acquired serial colony-forming potential. Because hematopoietic stem/progenitor cells (HSPCs) and Mks were enriched in this peculiar population, we analyzed the independent EVI1 and GATA2 contributions to HSPC and Mk. We found that inv(3)-driven EVI1 promotes accumulation of Mk-biased and myeloid-biased progenitors, Mks, and platelets, and that Gata2 heterozygous deletion enhanced Mk-lineage skewing of EVI1-expressing progenitors. Notably, inv(3)-directed EVI1 expression and Gata2 haploinsufficient expression cooperatively provoke a leukemia characterized by abundant Mks and platelets. These hematological features of the mouse model phenocopy those observed in human 3q AML. On the basis of these results, we conclude that inv(3)-driven EVI1 expression in HSPCs and Mks collaborates with Gata2 haploinsufficiency to provoke Mk-lineage skewing and leukemogenesis with excessive platelets, thus mimicking an important feature of human AML.

  208. Longitudinal plasma amino acid profiling with maternal genomic background throughout human pregnancy International-journal Peer-reviewed

    Matsuyuki Shirota, Daisuke Saigusa, Riu Yamashita, Yasutake Kato, Mitsuyo Matsumoto, Junya Yamagishi, Noriko Ishida, Kazuki Kumada, Yuji Oe, Hisaaki Kudo, Junji Yokozawa, Yoko Kuroki, Ikuko Motoike, Fumiki Katsuoka, Masao Nagasaki, Seizo Koshiba, Keiko Nakayama, Osamu Tanabe, Jun Yasuda, Shigeo Kure, Kengo Kinoshita, Hirohito Metoki, Shinichi Kuriyama, Nobuo Yaegashi, Masayuki Yamamoto, Junichi Sugawara

    Medical Mass Spectrometry　4　(1)　36-49　2020/04/16

    DOI： 10.24508/mms.2020.06.001 　

  209. Metabolic basis of neuronal vulnerability to ischemia; an in vivo untargeted metabolomics approach. International-journal Peer-reviewed

    Sherif Rashad, Daisuke Saigusa, Takahiro Yamazaki, Yotaro Matsumoto, Yoshihisa Tomioka, Ritsumi Saito, Akira Uruno, Kuniyasu Niizuma, Masayuki Yamamoto, Teiji Tominaga

    Scientific reports　10　(1)　6507-6507　2020/04/16

    DOI： 10.1038/s41598-020-63483-w 　

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    Understanding the root causes of neuronal vulnerability to ischemia is paramount to the development of new therapies for stroke. Transient global cerebral ischemia (tGCI) leads to selective neuronal cell death in the CA1 sub-region of the hippocampus, while the neighboring CA3 sub-region is left largely intact. By studying factors pertaining to such selective vulnerability, we can develop therapies to enhance outcome after stroke. Using untargeted liquid chromatography-mass spectrometry, we analyzed temporal metabolomic changes in CA1 and CA3 hippocampal areas following tGCI in rats till the setting of neuronal apoptosis. 64 compounds in CA1 and 74 in CA3 were found to be enriched and statistically significant following tGCI. Pathway analysis showed that pyrimidine and purine metabolism pathways amongst several others to be enriched after tGCI in CA1 and CA3. Metabolomics analysis was able to capture very early changes following ischemia. We detected 6 metabolites to be upregulated and 6 to be downregulated 1 hour after tGCI in CA1 versus CA3. Several metabolites related to apoptosis and inflammation were differentially expressed in both regions after tGCI. We offer a new insight into the process of neuronal apoptosis, guided by metabolomic profiling that was not performed to such an extent previously.

  210. Genome-wide association study identifies new loci for albuminuria in the Japanese population. Peer-reviewed

    Hiroshi Okuda, Koji Okamoto, Michiaki Abe, Kota Ishizawa, Satoshi Makino, Osamu Tanabe, Junichi Sugawara, Atsushi Hozawa, Kozo Tanno, Makoto Sasaki, Gen Tamiya, Masayuki Yamamoto, Sadayoshi Ito, Tadashi Ishii

    Clinical and experimental nephrology　2020/04/10

    DOI： 10.1007/s10157-020-01884-x 　

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    BACKGROUND: Urinary albumin excretion (UAE) is a risk factor for cardiovascular diseases, metabolic syndrome, chronic kidney disease, etc. Only a few genome-wide association studies (GWAS) for UAE have been conducted in the European population, but not in the Asian population. Here we conducted GWAS and identified several candidate genes harboring single nucleotide polymorphisms (SNPs) responsible for UAE in the Japanese population. METHODS: We conducted GWAS for UAE in 7805 individuals of Asian ancestry from health-survey data collected by Tohoku Medical Megabank Organization (ToMMo) and Iwate Tohoku Medical Megabank Organization (IMM). The SNP genotype data were obtained with a SNP microarray. After imputation using a haplotype panel consisting of 2000 genome sequencing, 4,962,728 SNP markers were used for the GWAS. RESULTS: Eighteen SNPs at 14 loci (GRM7, EXOC1/NMU, LPA, STEAP1B/RAPGEF5, SEMA3D, PRKAG2, TRIQK, SERTM1, TPT1-AS1, OR5AU1, TSHR, FMN1/RYR3, COPRS, and BRD1) were associated with UAE in the Japanese individuals. A locus with particularly strong associations was observed on TSHR, chromosome 14 [rs116622332 (p = 3.99 × 10-10)]. CONCLUSION: In this study, we successfully identified UAE-associated variant loci in the Japanese population. Further study is required to confirm this association.

  211. Ribosome binding protein GCN1 regulates the cell cycle and cell proliferation and is essential for the embryonic development of mice. International-journal Peer-reviewed

    Hiromi Yamazaki, Shuya Kasai, Junsei Mimura, Peng Ye, Atsushi Inose-Maruyama, Kunikazu Tanji, Koichi Wakabayashi, Seiya Mizuno, Fumihiro Sugiyama, Satoru Takahashi, Tsubasa Sato, Taku Ozaki, Douglas R Cavener, Masayuki Yamamoto, Ken Itoh

    PLoS genetics　16　(4)　e1008693　2020/04

    DOI： 10.1371/journal.pgen.1008693 　

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    Amino acids exert many biological functions, serving as allosteric regulators and neurotransmitters, as constituents in proteins and as nutrients. GCN2-mediated phosphorylation of eukaryotic initiation factor 2 alpha (elF2α) restores homeostasis in response to amino acid starvation (AAS) through the inhibition of the general translation and upregulation of amino acid biosynthetic enzymes and transporters by activating the translation of Gcn4 and ATF4 in yeast and mammals, respectively. GCN1 is a GCN2-binding protein that possesses an RWD binding domain (RWDBD) in its C-terminus. In yeast, Gcn1 is essential for Gcn2 activation by AAS; however, the roles of GCN1 in mammals need to be established. Here, we revealed a novel role of GCN1 that does not depend on AAS by generating two Gcn1 mutant mouse lines: Gcn1-knockout mice (Gcn1 KO mice (Gcn1-/-)) and RWDBD-deleted mutant mice (Gcn1ΔRWDBD mice). Both mutant mice showed growth retardation, which was not observed in the Gcn2 KO mice, such that the Gcn1 KO mice died at the intermediate stage of embryonic development because of severe growth retardation, while the Gcn1ΔRWDBD embryos showed mild growth retardation and died soon after birth, most likely due to respiratory failure. Extension of pregnancy by 24 h through the administration of progesterone to the pregnant mothers rescued the expression of differentiation markers in the lungs and prevented lethality of the Gcn1ΔRWDBD pups, indicating that perinatal lethality of the Gcn1ΔRWDBD embryos was due to simple growth retardation. Similar to the yeast Gcn2/Gcn1 system, AAS- or UV irradiation-induced elF2α phosphorylation was diminished in the Gcn1ΔRWDBD mouse embryonic fibroblasts (MEFs), suggesting that GCN1 RWDBD is responsible for GCN2 activity. In addition, we found reduced cell proliferation and G2/M arrest accompanying a decrease in Cdk1 and Cyclin B1 in the Gcn1ΔRWDBD MEFs. Our results demonstrated, for the first time, that GCN1 is essential for both GCN2-dependent stress response and GCN2-independent cell cycle regulation.

  212. Public Relations and Communication Strategies in Construction of Large-Scale Cohorts and Biobank: Practice in the Tohoku Medical Megabank Project.

    Fuji Nagami, Miho Kuriki, Sachie Koreeda, Maiko Kageyama, Osamu Shimizu, Soichiro Toda, Atsushi Hozawa, Shinichi Kuriyama, Noriko Osumi, Masayuki Yamamoto

    The Tohoku journal of experimental medicine　250　(4)　253-262　2020/04

    DOI： 10.1620/tjem.250.253 　

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    The Tohoku Medical Megabank Project was designed as part of the national reconstruction project for addressing the damage from the 2011 Great East Japan Earthquake. It is an integrated project involving the genome cohort study of 150,000 participants, integrated biobank construction, and multi-omics analyses. Public relations and communication activities emerged to be extremely important in the successful development of this project. To gain insights into the contributions of these activities, we divided the public relations and communication activities for the project into three phases based on the situations surrounding the project. Prior to the start of the cohort study (Phase I), a cooperative relationship was established with a focus on concluding cooperation agreements with local governments. Until the participants reached the target number (Phase II), we actively communicated with the media to publicize the project. During the phase in which use of the constructed biobank is promoted (Phase III), for ensuring the industrial utilization of the biobank, visits from the industry are promoted. Throughout the execution of these activities, we explored the best strategies for building relationships with multiple stakeholders like local government, media and industry. By paying attention to these phases that have been changing according to the project's progress, we were able to adapt the strategies and methods of public relations and communication. The success of these activities has enabled the overall project to progress smoothly. We hope that the process of designing our project's public relations and communication activities will be useful for other similar initiatives.

  213. Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients. International-journal Peer-reviewed

    Minako Mori, Asuka Hira, Kenichi Yoshida, Hideki Muramatsu, Yusuke Okuno, Yuichi Shiraishi, Michiko Anmae, Jun Yasuda, Shu Tadaka, Kengo Kinoshita, Tomoo Osumi, Yasushi Noguchi, Souichi Adachi, Ryoji Kobayashi, Hiroshi Kawabata, Kohsuke Imai, Tomohiro Morio, Kazuo Tamura, Akifumi Takaori-Kondo, Masayuki Yamamoto, Satoru Miyano, Seiji Kojima, Etsuro Ito, Seishi Ogawa, Keitaro Matsuo, Hiromasa Yabe, Miharu Yabe, Minoru Takata

    Haematologica　105　(4)　1166-1167　2020/04

    DOI： 10.3324/haematol.2019.245720 　

  214. Author Correction: Characterizing rare and low-frequency height-associated variants in the Japanese population. International-journal Peer-reviewed

    Masato Akiyama, Kazuyoshi Ishigaki, Saori Sakaue, Yukihide Momozawa, Momoko Horikoshi, Makoto Hirata, Koichi Matsuda, Shiro Ikegawa, Atsushi Takahashi, Masahiro Kanai, Sadao Suzuki, Daisuke Matsui, Mariko Naito, Taiki Yamaji, Motoki Iwasaki, Norie Sawada, Kozo Tanno, Makoto Sasaki, Atsushi Hozawa, Naoko Minegishi, Kenji Wakai, Shoichiro Tsugane, Atsushi Shimizu, Masayuki Yamamoto, Yukinori Okada, Yoshinori Murakami, Michiaki Kubo, Yoichiro Kamatani

    Nature communications　11　(1)　1350-1350　2020/03/09

    DOI： 10.1038/s41467-020-15202-2 　

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    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  215. Amino-acid selective isotope labeling enables simultaneous overlapping signal decomposition and information extraction from NMR spectra Peer-reviewed

    Takuma Kasai, Shunsuke Ono, Seizo Koshiba, Masayuki Yamamoto, Toshiyuki Tanaka, Shiro Ikeda, Takanori Kigawa

    Journal of Biomolecular NMR　74　(2-3)　125-137　2020/03

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1007/s10858-019-00295-9 　

    ISSN： 0925-2738

    eISSN： 1573-5001

  216. Cis-element architecture of Nrf2-sMaf heterodimer binding sites and its relation to diseases. International-journal

    Akihito Otsuki, Masayuki Yamamoto

    Archives of pharmacal research　43　(3)　275-285　2020/03

    DOI： 10.1007/s12272-019-01193-2 　

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    Cellular detoxication is essential for health because it provides protection against various chemicals and xenobiotics. The KEAP1-NRF2 system is important for cellular defense against oxidative and electrophilic stresses as NRF2 activates the transcription of an array of cytoprotective genes, including drug-metabolizing and antioxidant enzymes, in a stress-dependent manner. The CNC family of transcription factors, including NRF2, form heterodimers with small Maf (sMaf) proteins and bind to consensus DNA sequences that have been referred to as antioxidant response element, electrophile response element, or NF-E2-binding element. These sequences are now collectively called CNC-sMaf binding element (CsMBE). In addition to forming a heterodimer with CNC proteins, sMaf proteins can form homodimers and recognize regulatory motifs called Maf recognition element (MARE). Although the CsMBE sequence substantially overlaps with that of MARE, the sequences differ. NRF2 selectively recognizes CsMBE, which is critical for cytoprotection. Recent advances in high-throughput sequencing and population-scale genome analysis provide new insights into the transcriptional regulation involved in the stress response. The integration of a genome-wide map of NRF2 occupancy with disease-susceptibility loci reveals the associations between polymorphisms in CsMBE and disease risk, information useful for the personalized medicine of the future.

  217. コホート調査参加者に対するゲノム薬理学(PGx)遺伝情報の返却(回付) 個別化予防・医療の確立を目指して

    大根田 絹子, 布施 昇男, 川目 裕, 長神 風二, 平塚 真弘, 櫻井 美佳, 濱中 洋平, 鈴木 吉也, 鈴木 洋一, 山本 雅之

    日本薬学会年会要旨集　140年会　27K-pm08　2020/03

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  218. Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma. International-journal

    Tatsuhide Nabeshima, Shin Hamada, Keiko Taguchi, Yu Tanaka, Ryotaro Matsumoto, Masayuki Yamamoto, Atsushi Masamune

    American journal of physiology. Gastrointestinal and liver physiology　318　(3)　G419-G427　2020/03/01

    DOI： 10.1152/ajpgi.00296.2019 　

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    The activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) pathway contributes to cancer progression in addition to oxidative stress responses. Loss-of-function Keap1 mutations were reported to activate Nrf2, leading to cancer progression. We examined the effects of Keap1 deletion in a cholangiocarcinoma mouse model using a mutant K-ras/p53 mouse. Introduction of the Keap1 deletion into liver-specific mutant K-ras/p53 expression resulted in the formation of invasive cholangiocarcinoma. Comprehensive analyses of the gene expression profiles identified broad upregulation of Nrf2-target genes such as Nqo1 and Gstm1 in the Keap1-deleted mutant K-ras/p53 expressing livers, accompanied by upregulation of cholangiocyte-related genes. Among these genes, the transcriptional factor Sox9 was highly expressed in the dysplastic bile duct. The Keap-Nrf2-Sox9 axis might serve as a novel therapeutic target for cholangiocarcinoma.NEW & NOTEWORTHY The Keap1-Nrf2 system has a wide variety of effects in addition to the oxidative stress response in cancer cells. Addition of the liver-specific Keap1 deletion to mice harboring mutant K-ras and p53 accelerated cholangiocarcinoma formation, together with the hallmarks of Nrf2 activation. This process involved the expansion of Sox9-positive cells, indicating increased differentiation toward the cholangiocyte phenotype.

  219. Nrf2 Suppresses Oxidative Stress and Inflammation in App Knock-In Alzheimer's Disease Model Mice. International-journal Peer-reviewed

    Akira Uruno, Daisuke Matsumaru, Rie Ryoke, Ritsumi Saito, Shiori Kadoguchi, Daisuke Saigusa, Takashi Saito, Takaomi C Saido, Ryuta Kawashima, Masayuki Yamamoto

    Molecular and cellular biology　40　(6)　2020/02/27

    DOI： 10.1128/MCB.00467-19 　

    ISSN： 0270-7306

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    Nrf2 (NF-E2-related-factor 2) is a stress-responsive transcription factor that protects cells against oxidative stresses. To clarify whether Nrf2 prevents Alzheimer's disease (AD), AD model AppNL-G-F/NL-G-F knock-in (AppNLGF ) mice were studied in combination with genetic Nrf2 induction model Keap1FA/FA mice. While AppNLGF mice displayed shorter latency to escape than wild-type mice in the passive-avoidance task, the impairment was improved in AppNLGF ::Keap1FA/FA mice. Matrix-assisted laser desorption ionization-mass spectrometry imaging revealed that reduced glutathione levels were elevated by Nrf2 induction in AppNLGF ::Keap1FA/FA mouse brains compared to AppNLGF mouse brains. Genetic Nrf2 induction in AppNLGF mice markedly suppressed the elevation of the oxidative stress marker 8-OHdG and Iba1-positive microglial cell number. We also determined the plasmalogen-phosphatidylethanolamine (PlsPE) level as an AD biomarker. PlsPE containing polyunsaturated fatty acids was decreased in the AppNLGF mouse brain, but Nrf2 induction attenuated this decline. To evaluate whether pharmacological induction of Nrf2 elicits beneficial effects for AD treatment, we tested the natural compound 6-MSITC [6-(methylsulfinyl)hexyl isothiocyanate]. Administration of 6-MSITC improved the impaired cognition of AppNLGF mice in the passive-avoidance task. These results demonstrate that the induction of Nrf2 ameliorates cognitive impairment in the AD model mouse by suppressing oxidative stress and neuroinflammation, suggesting that Nrf2 is an important therapeutic target of AD.

  220. Impacts of NRF2 activation in non-small-cell lung cancer cell lines on extracellular metabolites. International-journal Peer-reviewed

    Daisuke Saigusa, Ikuko N Motoike, Sakae Saito, Michael Zorzi, Yuichi Aoki, Hiroshi Kitamura, Mikiko Suzuki, Fumiki Katsuoka, Hirofumi Ishii, Kengo Kinoshita, Hozumi Motohashi, Masayuki Yamamoto

    Cancer science　111　(2)　667-678　2020/02

    DOI： 10.1111/cas.14278 　

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    Aberrant activation of NRF2 is as a critical prognostic factor that drives the malignant progression of various cancers. Cancer cells with persistent NRF2 activation heavily rely on NRF2 activity for therapeutic resistance and aggressive tumorigenic capacity. To clarify the metabolic features of NRF2-activated lung cancers, we conducted targeted metabolomic (T-Met) and global metabolomic (G-Met) analyses of non-small-cell lung cancer (NSCLC) cell lines in combination with exome and transcriptome analyses. Exome analysis of 88 cell lines (49 adenocarcinoma, 14 large cell carcinoma, 15 squamous cell carcinoma and 10 others) identified non-synonymous mutations in the KEAP1, NRF2 and CUL3 genes. Judging from the elevated expression of NRF2 target genes, these mutations are expected to result in the constitutive stabilization of NRF2. Out of the 88 cell lines, 52 NSCLC cell lines (29 adenocarcinoma, 10 large cell carcinoma, 9 squamous cell carcinoma and 4 others) were subjected to T-Met analysis. Classification of the 52 cell lines into three groups according to the NRF2 target gene expression enabled us to draw typical metabolomic signatures induced by NRF2 activation. From the 52 cell lines, 18 NSCLC cell lines (14 adenocarcinoma, 2 large cell carcinoma, 1 squamous cell carcinoma and 1 others) were further chosen for G-Met and detailed transcriptome analyses. G-Met analysis of their culture supernatants revealed novel metabolites associated with NRF2 activity, which may be potential diagnostic biomarkers of NRF2 activation. This study also provides useful information for the exploration of new metabolic nodes for selective toxicity towards NRF2-activated NSCLC.

  221. Cohort Profile: Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study): rationale, progress and perspective. International-journal Peer-reviewed

    Shinichi Kuriyama, Hirohito Metoki, Masahiro Kikuya, Taku Obara, Mami Ishikuro, Chizuru Yamanaka, Masato Nagai, Hiroko Matsubara, Tomoko Kobayashi, Junichi Sugawara, Gen Tamiya, Atsushi Hozawa, Naoki Nakaya, Naho Tsuchiya, Tomohiro Nakamura, Akira Narita, Mana Kogure, Takumi Hirata, Ichiro Tsuji, Fuji Nagami, Nobuo Fuse, Tomohiko Arai, Yoshio Kawaguchi, Shinichi Higuchi, Masaki Sakaida, Yoichi Suzuki, Noriko Osumi, Keiko Nakayama, Kiyoshi Ito, Shinichi Egawa, Koichi Chida, Eiichi Kodama, Hideyasu Kiyomoto, Tadashi Ishii, Akito Tsuboi, Hiroaki Tomita, Yasuyuki Taki, Hiroshi Kawame, Kichiya Suzuki, Naoto Ishii, Soichi Ogishima, Satoshi Mizuno, Takako Takai-Igarashi, Naoko Minegishi, Jun Yasuda, Kazuhiko Igarashi, Ritsuko Shimizu, Masao Nagasaki, Osamu Tanabe, Seizo Koshiba, Hiroaki Hashizume, Hozumi Motohashi, Teiji Tominaga, Sadayoshi Ito, Kozo Tanno, Kiyomi Sakata, Atsushi Shimizu, Jiro Hitomi, Makoto Sasaki, Kengo Kinoshita, Hiroshi Tanaka, Tadao Kobayashi, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto

    International journal of epidemiology　49　(1)　18-19　2020/02/01

    DOI： 10.1093/ije/dyz169 　

    ISSN： 0300-5771

  222. Study profile of The Tohoku Medical Megabank Community-Based Cohort Study. Peer-reviewed

    Atsushi Hozawa, Kozo Tanno, Naoki Nakaya, Tomohiro Nakamura, Naho Tsuchiya, Takumi Hirata, Akira Narita, Mana Kogure, Kotaro Nochioka, Ryohei Sasaki, Nobuyuki Takanashi, Kotaro Otsuka, Kiyomi Sakata, Shinichi Kuriyama, Masahiro Kikuya, Osamu Tanabe, Junichi Sugawara, Kichiya Suzuki, Yoichi Suzuki, Eiichi N Kodama, Nobuo Fuse, Hideyasu Kiyomoto, Hiroaki Tomita, Akira Uruno, Yohei Hamanaka, Hirohito Metoki, Mami Ishikuro, Taku Obara, Tomoko Kobayashi, Kazuyuki Kitatani, Takako Takai-Igarashi, Soichi Ogishima, Mamoru Satoh, Hideki Ohmomo, Akito Tsuboi, Shinichi Egawa, Tadashi Ishii, Kiyoshi Ito, Sadayoshi Ito, Yasuyuki Taki, Naoko Minegishi, Naoto Ishii, Masao Nagasaki, Kazuhiko Igarashi, Seizo Koshiba, Ritsuko Shimizu, Gen Tamiya, Keiko Nakayama, Hozumi Motohashi, Jun Yasuda, Atsushi Shimizu, Tsuyoshi Hachiya, Yuh Shiwa, Teiji Tominaga, Hiroshi Tanaka, Kotaro Oyama, Ryoichi Tanaka, Hiroshi Kawame, Akimune Fukushima, Yasushi Ishigaki, Tomoharu Tokutomi, Noriko Osumi, Tadao Kobayashi, Fuji Nagami, Hiroaki Hashizume, Tomohiro Arai, Yoshio Kawaguchi, Shinichi Higuchi, Masaki Sakaida, Ryujin Endo, Satoshi Nishizuka, Ichiro Tsuji, Jiro Hitomi, Motoyuki Nakamura, Kuniaki Ogasawara, Nobuo Yaegashi, Kengo Kinoshita, Shigeo Kure, Akio Sakai, Seiichiro Kobayashi, Kenji Sobue, Makoto Sasaki, Masayuki Yamamoto

    Journal of epidemiology　2020/01/11

    DOI： 10.2188/jea.JE20190271 　

    ISSN： 0917-5040

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    BackgroundWe established a community-based cohort study to assess the long-term impact of the Great East Japan Earthquake on disaster victims and gene-environmental interactions on the incidence of major diseases such as cancer and cardiovascular diseases.MethodsWe asked participants to join our cohort in the health check-up settings and assessment center based settings. Inclusion criteria was aged 20 years or over and living in Miyagi or Iwate Prefecture. We obtained information on lifestyle, effect of disaster, blood, and urine information (Type 1 survey), and some detailed measurements (Type 2 survey), for example, carotid echography, calcaneal ultrasound bone mineral density, and so on. All participants agreed to measure genome information and to distribute their information widely.ResultsAs a result, 87,865 gave their informed consent to join our study. Participation rate at health check-up site was about 70%. The participants with Type 1 survey were more likely to have psychological distress than those of Type 2 survey, and women were more likely to have psychological distress than men. Additionally, coastal residents were more likely to have higher degrees of psychological distress than inland residents regardless of sex.ConclusionThis cohort comprised large sample size and it contains information on disaster, genome information, and metabolome information. This cohort also had several detailed measurements. Using this cohort enabled us to clarify the long-term effect of disaster and also to establish personalized prevention based on genome, metabolome, and other omics information.

  223. Possible Roles of Proinflammatory Signaling in Keratinocytes Through Aryl Hydrocarbon Receptor Ligands for the Development of Squamous Cell Carcinoma. International-journal

    Yota Sato, Taku Fujimura, Takanori Hidaka, Chunbing Lyu, Kayo Tanita, Shigeto Matsushita, Masayuki Yamamoto, Setsuya Aiba

    Frontiers in immunology　11　534323-534323　2020

    DOI： 10.3389/fimmu.2020.534323 　

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    Aryl hydrocarbon receptor (AhR) provides a deeper insight into the pathogenesis of cutaneous squamous cell carcinoma (cSCC). AhR ligands, such as 6-formylindolo[3,2-b] carbazole (FICZ), and 7,12-Dimethylbenz[a]anthracene (DMBA), constitute major substrates for the cytochrome P450 (CYP) family, and influence the expression of various cytokine genes, including IL-17 and IL-23-related genes via the AhR. On the other hand, proinflammatory cytokines could drive tumor progression through the TRAF-ERK5 signaling pathway in cSCC. From the above findings, we hypothesized that AhR ligands might enhance the mRNA expression of proinflammatory cytokines via the AhR, leading to the development of cSCC. The purpose of this study was to investigate (1) the immunomodulatory effects of FICZ and DMBA on normal human keratinocytes (NHKCs), focusing on IL-17, and related cytokines/chemokines (IL-23, IL-36γ, and CCL20), (2) the expression of these factors in AhR-dependent pathways using a two-stage chemically induced skin carcinogenesis mouse model, and (3) the expression of these factors in lesion-affected skin in cSCC. Both FICZ and DMBA augmented the expression of CYP1A1, p19, CCL20, and IL-36γ mRNA in NHKCs in vitro. Moreover, the mRNA expression of these proinflammatory factors, as well as IL-17, in mouse cSCC is significantly decreased in the AhR-(fl/fl) Krt5-(Cre) mice compared to wild type mice, leading to a decrease in the number of developed cSCC lesions. Furthermore, CCL20, IL-23, as well as IL-17, are detected in the lesion-affected skin of cSCC patients. Our study demonstrates a possible mechanism for the development of cSCC involving AhR-mediated signaling by epidermal keratinocytes and recruitment of Th17 cells.

  224. Oral Microbiome Analysis in Prospective Genome Cohort Studies of the Tohoku Medical Megabank Project. International-journal

    Sakae Saito, Yuichi Aoki, Toru Tamahara, Maki Goto, Hiroyuki Matsui, Junko Kawashima, Inaho Danjoh, Atsushi Hozawa, Shinichi Kuriyama, Yoichi Suzuki, Nobuo Fuse, Shigeo Kure, Riu Yamashita, Osamu Tanabe, Naoko Minegishi, Kengo Kinoshita, Akito Tsuboi, Ritsuko Shimizu, Masayuki Yamamoto

    Frontiers in cellular and infection microbiology　10　604596-604596　2020

    DOI： 10.3389/fcimb.2020.604596 　

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    A baseline oral microbiome study of the Tohoku Medical Megabank Organization (TMM) was planned to characterize the profile of the oral microbiome in the Japanese population. The study also aimed to clarify risk factors for multifactorial diseases by integrated analysis of the oral microbiome and host genome/omics information. From 2013 to 2016, we collected three types of oral biospecimens, saliva, supragingival plaque, and tongue swab, from a total of 25,101 participants who had a dental examination in TMM. In this study, we used two independent cohorts; the Community-Based Cohort and Birth and Three-Generation Cohort as discovery and validation cohorts, respectively, and we selected participants examined by a single dentist. We found through the 16S ribosomal RNA gene sequencing analysis of 834 participants of the Community-Based Cohort Study that there are differences in the microbial composition and community structure between saliva and plaque. The species diversities in both saliva and plaque were increased in correlation with the severity of periodontal disease. These results were nicely reproduced in the analysis of 455 participants of the Birth and Three-Generation Cohort Study. In addition, strong positive and negative associations of microbial taxa in both plaque and saliva with periodontitis-associated biofilm formation were detected by co-occurrence network analysis. The classes Actinobacteria and Bacilli, including oral health-associated bacterial species, showed a positive correlation in saliva. These results revealed differences in microbial composition and community structure between saliva and plaque and a correlation between microbial species and the severity of periodontal disease. We expect that the large database of the oral microbiome in the TMM biobank will help in the discovery of novel targets for the treatment and prevention of oral diseases, as well as for the discovery of therapeutic and/or preventive targets of systemic diseases.

  225. Association of single nucleotide polymorphisms in the NRF2 promoter with vascular stiffness with aging. International-journal

    Sunao Shimizu, Junsei Mimura, Takanori Hasegawa, Eigo Shimizu, Seiya Imoto, Michiko Tsushima, Shuya Kasai, Hiromi Yamazaki, Yusuke Ushida, Hiroyuki Suganuma, Hirofumi Tomita, Masayuki Yamamoto, Shigeyuki Nakaji, Ken Itoh

    PloS one　15　(8)　e0236834　2020

    DOI： 10.1371/journal.pone.0236834 　

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    PURPOSE: Pulse wave velocity (PWV), an indicator of vascular stiffness, increases with age and is increasingly recognized as an independent risk factor for cardiovascular disease (CVD). Although many mechanical and chemical factors underlie the stiffness of the elastic artery, genetic risk factors related to age-dependent increases in PWV in apparently healthy people are largely unknown. The transcription factor nuclear factor E2 (NF-E2)-related factor 2 (Nrf2), which is activated by unidirectional vascular pulsatile shear stress or oxidative stress, regulates vascular redox homeostasis. Previous reports have shown that a SNP in the NRF2 gene regulatory region (-617C>A; hereafter called SNP-617) affects NRF2 gene expression such that the minor A allele confers lower gene expression compared to the C allele, and it is associated with various diseases, including CVD. We aimed to investigate whether SNP-617 affects vascular stiffness with aging in apparently healthy people. METHODS: Analyzing wide-ranging data obtained from a public health survey performed in Japan, we evaluated whether SNP-617 affected brachial-ankle PWV (baPWV) in never-smoking healthy subjects (n = 642). We also evaluated the effects of SNP-617 on other cardiovascular and blood test measurements. RESULTS: We have shown that not only AA carriers (n = 55) but also CA carriers (n = 247) show arterial stiffness compared to CC carriers (n = 340). Furthermore, SNP-617 also affected blood pressure indexes such as systolic blood pressure and mean arterial pressure but not the ankle brachial pressure index, an indicator of atherosclerosis. Multivariate analysis showed that SNP-617 accelerates the incremental ratio of baPWV with age. CONCLUSIONS: This study is the first to show that SNP-617 affects the age-dependent increase in vascular stiffness. Our results indicate that low NRF2 activity induces premature vascular aging and could be targeted for the prevention of cardiovascular diseases associated with aging.

  226. Design and Progress of Oral Health Examinations in the Tohoku Medical Megabank Project Peer-reviewed

    Akito Tsuboi, Hiroyuki Matsui, Naru Shiraishi, Takahisa Murakami, Akihito Otsuki, Junko Kawashima, Tomomi Kiyama, Toru Tamahara, Maki Goto, Shihoko Koyama, Junichi Sugawara, Eiichi N. Kodama, Hirohito Metoki, Atsushi Hozawa, Shinichi Kuriyama, Hiroaki Tomita, Masahiro Kikuya, Naoko Minegishi, Kichiya Suzuki, Seizo Koshiba, Gen Tamiya, Nobuo Fuse, Yuichi Aoki, Takako Takai-Igarashi, Soichi Ogishima, Tomohiro Nakamura, Mika Sakurai-Yageta, Fuji Nagami, Kengo Kinoshita, Shigeo Kure, Ritsuko Shimizu, Keiichi Sasaki, Masayuki Yamamoto

    The Tohoku Journal of Experimental Medicine　251　(2)　97-115　2020

    Publisher: Tohoku University Medical Press

    DOI： 10.1620/tjem.251.97 　

    ISSN： 0040-8727

    eISSN： 1349-3329

  227. Monitoring the autophagy-endolysosomal system using monomeric Keima-fused MAP1LC3B. International-journal Peer-reviewed

    Hideki Hayashi, Ting Wang, Masayuki Tanaka, Sanae Ogiwara, Chisa Okada, Masatoshi Ito, Nahoko Fukunishi, Yumi Iida, Ayaka Nakamura, Ayumi Sasaki, Shunji Amano, Kazuhiro Yoshida, Asako Otomo, Masato Ohtsuka, Shinji Hadano

    PloS one　15　(6)　e0234180　2020

    DOI： 10.1371/journal.pone.0234180 　

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    The autophagy-endolysosomal pathway is an evolutionally conserved degradation system that is tightly linked to a wide variety of physiological processes. Dysfunction of this system is associated with many pathological conditions such as cancer, inflammation and neurodegenerative diseases. Therefore, monitoring the cellular autophagy-endolysosomal activity is crucial for studies on the pathogenesis as well as therapeutics of such disorders. To this end, we here sought to create a novel means exploiting Keima, an acid-stable fluorescent protein possessing pH-dependent fluorescence excitation spectra, for precisely monitoring the autophagy-endolysosomal system. First, we generated three lines of transgenic (tg) mouse expressing monomeric Keima-fused MAP1LC3B (mKeima-LC3B). Then, these tg mice were subjected to starvation by food-restriction, and also challenged to neurodegeneration by genetically crossing with a mouse model of amyotrophic lateral sclerosis; i.e., SOD1H46R transgenic mouse. Unexpectedly, despite that a lipidated-form of endogenous LC3 (LC3-II) was significantly increased, those of mKeima-LC3B (mKeima-LC3B-II) were not changed under both stressed conditions. It was also noted that mKeima-LC3B-positive aggregates were progressively accumulated in the spinal cord of SOD1H46R;mKeima-LC3B double-tg mice, suggestive of acid-resistance and aggregate-prone natures of long-term overexpressed mKeima-LC3B in vivo. Next, we characterized mouse embryonic fibroblasts (MEFs) derived from mKeima-LC3B-tg mice. In contrast with in vivo, levels of mKeima-LC3B-I were decreased under starved conditions. Furthermore, when starved MEFs were treated with chloroquine (CQ), the abundance of mKeima-LC3B-II was significantly increased. Remarkably, when cultured medium was repeatedly changed between DMEM (nutrient-rich) and EBSS (starvation), acidic/neutral signal ratios of mKeima-LC3B-positive compartments were rapidly and reversibly shifted, which were suppressed by the CQ treatment, indicating that intraluminal pH of mKeima-LC3B-positive vesicles was changeable upon nutritional conditions of culture media. Taken together, although mKeima-LC3B-tg mice may not be an appropriate tool to monitor the autophagy-endolysosomal system in vivo, mKeima-LC3B must be one of the most sensitive reporter molecules for monitoring this system under in vitro cultured conditions.

  228. Two effects of GATA2 enhancer repositioning by 3q chromosomal rearrangements. International-journal Peer-reviewed

    Mikiko Suzuki, Saori Katayama, Masayuki Yamamoto

    IUBMB life　72　(1)　159-169　2020/01

    DOI： 10.1002/iub.2191 　

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    Chromosomal inversion and translocation between 3q21 and 3q26 [inv (3)(q21.3q26.2) and t(3;3)(q21.3;q26.2), respectively] give rise to acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), which have poor prognoses. The chromosomal rearrangements reposition a GATA2 distal hematopoietic enhancer from the original 3q21 locus to the EVI1 (also known as MECOM) locus on 3q26. Therefore, the GATA2 enhancer from one of two GATA2 alleles drives EVI1 gene expression in hematopoietic stem and progenitor cells, which promotes the accumulation of abnormal progenitors and induces leukemogenesis. On the other hand, one allele of the GATA2 gene loses its enhancer, which results in reduced GATA2 expression. The GATA2 gene encodes a transcription factor critical for the generation and maintenance of hematopoietic stem and progenitor cells. GATA2 haploinsufficiency has been known to cause immunodeficiency and myeloid leukemia. Notably, reduced GATA2 expression suppresses the differentiation but promotes the proliferation of EVI1-expressing leukemic cells, which accelerates EVI1-driven leukemogenesis. A series of studies have shown that the GATA2 enhancer repositioning caused by the chromosomal rearrangements between 3q21 and 3q26 provokes misexpression of both the EVI1 and GATA2 genes and that these two effects coordinately elicit high-risk leukemia.

  229. Inhibitors of the protein-protein interaction between phosphorylated p62 and Keap1 attenuate chemoresistance in a human hepatocellular carcinoma cell line Peer-reviewed

    Yasuda D., Ohe T., Takahashi, K., Imamura, R., Kojima H., Okabe T., Ichimura Y., Komatsu M., Yamamoto M., Nagano T., Mashino T.

    Free Radical Research　In Press,　2020

  230. Role of Nrf2 in inflammatory response in lung of mice exposed to zinc oxide nanoparticles. International-journal

    Radwa Sehsah, Wenting Wu, Sahoko Ichihara, Naozumi Hashimoto, Yoshinori Hasegawa, Cai Zong, Ken Itoh, Masayuki Yamamoto, Ahmed Ali Elsayed, Soheir El-Bestar, Emily Kamel, Gaku Ichihara

    Particle and fibre toxicology　16　(1)　47-47　2019/12/16

    DOI： 10.1186/s12989-019-0328-y 　

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    BACKGROUND: Zinc oxide nanoparticles (ZnO-NPs) are widely used in many industrial sectors and previous studies have reported that exposure of the lungs to ZnO-NPs induces both acute and/or chronic pulmonary inflammation, but the exact mechanism underlying such response remains elusive. This study investigated the role of nuclear factor-erythroid 2-related factor (Nrf2) in pulmonary inflammation induced by exposure to ZnO-NPs using Nrf2 null (Nrf2-/-) mice. METHODS: Twenty-four male Nrf2-/- mice and thirty male wild type C57BL/6 J mice were divided into three groups of eight and ten each respectively, and exposed once to ZnO-NPs at 0, 10, 30 μg/mouse by pharyngeal aspiration. At 14 days after the exposure to ZnO-NPs, bronchoalveolar lavage fluid (BALF) and lungs were collected to quantify protein level and the number of inflammatory cells. The mRNA levels of Nrf2-dependent antioxidant enzymes and inflammatory cytokines in lung tissue were measured. RESULTS: Exposure to ZnO-NPs dose-dependently increased the number of total cells, macrophages, lymphocytes and eosinophils in BALF both in Nrf2-/- mice and wild type mice, but the magnitude of increase was significantly higher in Nrf2-/- mice than wild type mice. The number of neutrophils in BALF increased in Nrf2-/- mice, being accompanied by marginal trend of increase in mRNA expression of MIP-2, neutrophil chemoattractant, but such changes were not observed in wild type mice. Exposure to ZnO-NPs did not dose-dependently increase mRNA level of Nrf2-dependent antioxidant enzymes both in Nrf2-/- mice and wild type mice. CONCLUSION: Pharyngeal aspiration of ZnO-NPs induced infiltration of inflammatory cells in the lung of mice, but minimally induced Nrf2-dependent antioxidant enzymes. The results suggest that Nrf2 play a role in negative regulation on ZnO-NP exposure-induced neutrophil migration, but does not demonstrate that the regulation is through suppression of oxidative stress.

  231. A low-frequency IL4R locus variant in Japanese patients with intravenous immunoglobulin therapy-unresponsive Kawasaki disease Peer-reviewed

    Yuji Amano, Yohei Akazawa, Jun Yasuda, Kazuhisa Yoshino, Katsuhiko Kojima, Norimoto Kobayashi, Satoshi Matsuzaki, Masao Nagasaki, Yosuke Kawai, Naoko Minegishi, Noriko Ishida, Noriko Motoki, Akira Hachiya, Yozo Nakazawa, Masayuki Yamamoto, Kenichi Koike, Toshikazu Takeshita

    Pediatric Rheumatology　17　(1)　34　2019/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1186/s12969-019-0337-2 　

    eISSN： 1546-0096

  232. 核酸クロマトグラフィーストリップを利用したファーマコゲノミクス検査薬の開発

    公文代 將希, 伊藤 暁生, 菱沼 英史, 齋藤 雄大, 石田 典子, 峯岸 直子, 齋藤 さかえ, 木下 賢吾, 山本 雅之, 金子 明, 平澤 典保, 平塚 真弘

    臨床薬理　50　(Suppl.)　S310-S310　2019/11

    Publisher: (一社)日本臨床薬理学会

    ISSN： 0388-1601

    eISSN： 1882-8272

  233. Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function. Peer-reviewed

    Nagasu H, Sogawa Y, Kidokoro K, Itano S, Yamamoto T, Satoh M, Sasaki T, Suzuki T, Yamamoto M, Wigley WC, Proksch JW, Meyer CJ, Kashihara N

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology　33　(11)　12253-12263　2019/11

    DOI： 10.1096/fj.201900217R 　

    ISSN： 0892-6638

  234. GATA2 and PU.1 Collaborate To Activate the Expression of the Mouse Ms4a2 Gene, Encoding FcεRIβ, through Distinct Mechanisms. International-journal Peer-reviewed

    Ohmori S, Ishijima Y, Numata S, Takahashi M, Sekita M, Sato T, Chugun K, Yamamoto M, Ohneda K

    Molecular and cellular biology　39　(22)　2019/11

    DOI： 10.1128/MCB.00314-19 　

    ISSN： 0270-7306

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    GATA factors GATA1 and GATA2 and ETS factor PU.1 are known to function antagonistically during hematopoietic development. In mouse mast cells, however, these factors are coexpressed and activate the expression of the Ms4a2 gene encoding the β chain of the high-affinity IgE receptor (FcεRI). The present study showed that these factors cooperatively regulate Ms4a2 gene expression through distinct mechanisms. Although GATA2 and PU.1 contributed almost equally to Ms4a2 gene expression, gene ablation experiments revealed that simultaneous knockdown of both factors showed neither a synergistic nor an additive effect. A chromatin immunoprecipitation analysis showed that they shared DNA binding to the +10.4-kbp region downstream of the Ms4a2 gene with chromatin looping factor LDB1, whereas the proximal -60-bp region was exclusively bound by GATA2 in a mast cell-specific manner. Ablation of PU.1 significantly reduced the level of GATA2 binding to both the +10.4-kbp and -60-bp regions. Surprisingly, the deletion of the +10.4-kbp region by genome editing completely abolished the Ms4a2 gene expression as well as the cell surface expression of FcεRI. These results suggest that PU.1 and LDB1 play central roles in the formation of active chromatin structure whereas GATA2 directly activates the Ms4a2 promoter.

  235. Quantitative and qualitative impairments in GATA2 and myeloid neoplasms. Peer-reviewed

    Shimizu R, Yamamoto M

    IUBMB life　2019/11

    DOI： 10.1002/iub.2188 　

    ISSN： 1521-6543

  236. Lipopolysaccharide-induced expansion of histidine decarboxylase-expressing Ly6G+ myeloid cells identified by exploiting histidine decarboxylase BAC-GFP transgenic mice. International-journal Peer-reviewed

    Jun Takai, Hiroshi Ohtsu, Atsushi Sato, Satoshi Uemura, Tsutomu Fujimura, Masayuki Yamamoto, Takashi Moriguchi

    Scientific reports　9　(1)　15603-15603　2019/10/30

    DOI： 10.1038/s41598-019-51716-6 　

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    Histamine is a biogenic amine that is chiefly produced in mast cells and basophils and elicits an allergic response upon stimulation. Histidine decarboxylase (HDC) is a unique enzyme that catalyzes the synthesis of histamine. Therefore, the spatiotemporally specific Hdc gene expression profile could represent the localization of histamine-producing cells under various pathophysiological conditions. Although the bioactivity of histamine is well defined, the regulatory mechanism of Hdc gene expression and the distribution of histamine-producing cell populations in various disease contexts remains unexplored. To address these issues, we generated a histidine decarboxylase BAC (bacterial artificial chromosome) DNA-directed GFP reporter transgenic mouse employing a 293-kb BAC clone containing the entire Hdc gene locus and extended flanking sequences (Hdc-GFP). We found that the GFP expression pattern in the Hdc-GFP mice faithfully recapitulated that of conventional histamine-producing cells and that the GFP expression level mirrored the increased Hdc expression in lipopolysaccharide (LPS)-induced septic lungs. Notably, a CD11b+Ly6G+Ly6Clow myeloid cell population accumulated in the lung during sepsis, and most of these cells expressed high levels of GFP and indeed contain histamine. This study reveals the accumulation of a histamine-producing myeloid cell population during sepsis, which likely participates in the immune process of sepsis.

  237. Aryl Hydrocarbon Receptor Directly Regulates Artemin Gene Expression. International-journal Peer-reviewed

    Tomohiro Edamitsu, Keiko Taguchi, Eri H Kobayashi, Ryuhei Okuyama, Masayuki Yamamoto

    Molecular and cellular biology　39　(20)　2019/10/15

    DOI： 10.1128/MCB.00190-19 　

    ISSN： 0270-7306

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    Transgenic mice expressing a constitutively active form of the aryl hydrocarbon receptor in keratinocytes (AhR-CA mice) develop severe dermatitis that substantially recapitulates the pathology of human atopic dermatitis. The neurotrophic factor artemin (Artn) is highly expressed in the epidermis of AhR-CA mice and causes hypersensitivity to itch (alloknesis) by elongating nerves into the epidermis. However, whether the Artn gene is regulated directly by AhR or indirectly through complex regulation associated with AhR remains unclear. To this end, we previously conducted chromatin immunoprecipitation-sequencing analyses of the Artn locus and found a xenobiotic response element (XRE) motif located far upstream (52 kb) of the gene. Therefore, in this study, we addressed whether the XRE actually regulates the Artn gene expression by deleting the region containing the motif. We generated two lines of ArtnΔXRE mice. In the mouse epidermis, inducible expression of the Artn gene by the AhR agonist 3-methylcholanthrene was substantially suppressed compared to that in wild-type mice. Importantly, in AhR-CA::ArtnΔXRE mice, Artn expression was significantly suppressed, and alloknesis was improved. These results demonstrate that the Artn gene is indeed regulated by the distal XRE-containing enhancer, and alloknesis in AhR-CA mice is provoked by the AhR-mediated direct induction of the Artn gene.

  238. TMM計画地域住民コホート調査(宮城)調査票項目と総死亡の関連

    寳澤 篤, 土屋 菜歩, 平田 匠, 成田 暁, 小暮 真奈, 中村 智洋, 小原 拓, 中谷 直樹, 丹野 高三, 菅原 準一, 栗山 進一, 辻 一郎, 呉 繁夫, 布施 昇男, 山本 雅之

    日本公衆衛生学会総会抄録集　78回　212-212　2019/10

    Publisher: 日本公衆衛生学会

    ISSN： 1347-8060

  239. 大規模ゲノム解析による28の新規2型糖尿病感受性領域の同定

    鈴木 顕, 秋山 雅人, 石垣 和慶, 金井 仁弘, 細江 隼, 庄嶋 伸浩, 池川 志郎, 寳澤 篤, 山本 雅之, 門田 文, 栗木 清典, 内藤 真理子, 若井 建志, 丹野 高三, 石垣 泰, 佐々木 真理, 平田 真, 松田 浩一, 村上 善則, 岩田 仲生, 池田 匡志, 澤田 典絵, 山地 太樹, 岩崎 基, 津金 昌一郎, 前田 士郎, 岡田 随象, 久保 充明, 鎌谷 洋一郎, 堀越 桃子, 山内 敏正, 門脇 孝

    肥満研究　25　(Suppl.)　246-246　2019/10

    Publisher: (一社)日本肥満学会

    ISSN： 1343-229X

  240. TMM計画地域住民コホート調査(宮城)調査票項目と総死亡の関連 Peer-reviewed

    寳澤 篤, 土屋 菜歩, 平田 匠, 成田 暁, 小暮 真奈, 中村 智洋, 小原 拓, 中谷 直樹, 丹野 高三, 菅原 準一, 栗山 進一, 辻 一郎, 呉 繁夫, 布施 昇男, 山本 雅之

    日本公衆衛生学会総会抄録集　78回　212-212　2019/10

    Publisher: 日本公衆衛生学会

    ISSN： 1347-8060

  241. Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients. International-journal Peer-reviewed

    Minako Mori, Asuka Hira, Kenichi Yoshida, Hideki Muramatsu, Yusuke Okuno, Yuichi Shiraishi, Michiko Anmae, Jun Yasuda, Shu Tadaka, Kengo Kinoshita, Tomoo Osumi, Yasushi Noguchi, Souichi Adachi, Ryoji Kobayashi, Hiroshi Kawabata, Kohsuke Imai, Tomohiro Morio, Kazuo Tamura, Akifumi Takaori-Kondo, Masayuki Yamamoto, Satoru Miyano, Seiji Kojima, Etsuro Ito, Seishi Ogawa, Keitaro Matsuo, Hiromasa Yabe, Miharu Yabe, Minoru Takata

    Haematologica　104　(10)　1962-1973　2019/10

    DOI： 10.3324/haematol.2018.207241 　

    ISSN： 0390-6078

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    Fanconi anemia is a rare recessive disease characterized by multiple congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancies. It results from mutations in one of the 22 known FANC genes. The number of Japanese Fanconi anemia patients with a defined genetic diagnosis was relatively limited. In this study, we reveal the genetic subtyping and the characteristics of mutated FANC genes in Japan and clarify the genotype-phenotype correlations. We studied 117 Japanese patients and successfully subtyped 97% of the cases. FANCA and FANCG pathogenic variants accounted for the disease in 58% and 25% of Fanconi anemia patients, respectively. We identified one FANCA and two FANCG hot spot mutations, which are found at low percentages (0.04-0.1%) in the whole-genome reference panel of 3,554 Japanese individuals (Tohoku Medical Megabank). FANCB was the third most common complementation group and only one FANCC case was identified in our series. Based on the data from the Tohoku Medical Megabank, we estimate that approximately 2.6% of Japanese are carriers of disease-causing FANC gene variants, excluding missense mutations. This is the largest series of subtyped Japanese Fanconi anemia patients to date and the results will be useful for future clinical management.

  242. Direct and Specific Functional Evaluation of the Nrf2 and MafG Heterodimer by Introducing a Tethered Dimer into Small Maf-Deficient Cells. International-journal Peer-reviewed

    Katsuoka F, Otsuki A, Takahashi M, Ito S, Yamamoto M

    Molecular and cellular biology　39　(20)　2019/10

    DOI： 10.1128/MCB.00273-19 　

    ISSN： 0270-7306

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    A group of cytoprotective genes is regulated by heterodimers composed of the cap'n'collar (CNC) family member Nrf2 and one of the small Maf (sMaf) proteins (MafF, MafG, or MafK) through the antioxidant response element (ARE, also referred to as the CNC-sMaf binding element [CsMBE]). Many lines of evidence support this model; however, a direct and specific evaluation of the Nrf2-sMaf heterodimer remains to be executed. To address this issue, we constructed a tethered Nrf2-MafG (T-N2G) heterodimer using a flexible linker peptide. We then introduced the T-N2G construct into cells lacking all three sMaf proteins to specifically evaluate the function of the tethered heterodimer without interference from other endogenous CNC-sMaf heterodimers or sMaf homodimers. In response to an Nrf2 activator, diethyl maleate, the T-N2G protein can widely activate the target genes of Nrf2 but not those of Nrf1, such as proteasome subunit genes. Genome-wide binding analysis showed that the T-N2G protein preferentially bound to the CsMBE motifs in the regulatory regions of the Nrf2 target genes. These results provide direct evidence that the Nrf2-MafG heterodimer acts as a transcriptional activator of Nrf2-dependent genes and show that this assay system will be a powerful tool to specifically examine the function of other CNC-sMaf heterodimers.

  243. コホート調査における代謝プロファイルの経時変化の解析

    小柴 生造, 元池 育子, 三枝 大輔, 井上 仁, 菱沼 英史, 青木 裕一, 田 高周, 城田 松之, 木下 賢吾, 山本 雅之

    日本生化学会大会プログラム・講演要旨集　92回　[1T12a-04]　2019/09

    Publisher: (公社)日本生化学会

  244. Establishment of Integrated Biobank for Precision Medicine and Personalized Healthcare: The Tohoku Medical Megabank Project. Peer-reviewed

    Fuse N, Sakurai-YagetaM, Katsuoka F, Danjoh I, Shimizu R, Tamiya G, Nagami F, Kawame H, Higuchi S, Kinoshita K, Kure S, Yamamoto M

    JMA Journal　2　(2)　113-122　2019/09

    DOI： 10.31662/jmaj.2019-0014. 　

  245. Dietary supplementation with sulforaphane attenuates liver damage and heme overload in a sickle cell disease murine model. Peer-reviewed

    Panda H, Keleku-Lukwete N, Kuga A, Fuke N, Suganuma H, Suzuki M, Yamamoto M

    Experimental hematology　77　51-60.e1　2019/09

    DOI： 10.1016/j.exphem.2019.08.001 　

    ISSN： 0301-472X

  246. Mouse Tryptase Gene Expression is Coordinately Regulated by GATA1 and GATA2 in Bone Marrow-Derived Mast Cells. International-journal Peer-reviewed

    Ohneda K, Ohmori S, Yamamoto M

    International journal of molecular sciences　20　(18)　2019/09

    DOI： 10.3390/ijms20184603 　

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    Mast cell tryptases have crucial roles in allergic and inflammatory diseases. The mouse tryptase genes represent a cluster of loci on chromosome 16p3.3. While their functional studies have been extensively performed, transcriptional regulation of tryptase genes is poorly understood. In this study, we examined the molecular basis of the tryptase gene expression in bone marrow-derived mast cells (BMMCs) of C57BL/6 mice and in MEDMC-BRC6 mast cells. The expression of the Tpsb2 and Tpsg1 genes, which reside at the 3'-end of the tryptase locus, is significantly decreased by the reduction of the GATA transcription factors GATA1 or GATA2. Chromatin immunoprecipitation assays have shown that the GATA factors bind at multiple regions within the locus, including 1.0 and 72.8 kb upstream of the Tpsb2 gene, and that GATA1 and GATA2 facilitate each other's DNA binding activity to these regions. Deletion of the -72.8 kb region by genome editing significantly reduced the Tpsb2 and Tpsg1 mRNA levels in MEDMC-BRC6 cells. Furthermore, binding of CTCF and the cohesin subunit Rad21 was found upstream of the -72.8 kb region and was significantly reduced in the absence of GATA1. These results suggest that mouse tryptase gene expression is coordinately regulated by GATA1 and GATA2 in BMMCs.

  247. Characterizing rare and low-frequency height-associated variants in the Japanese population. International-journal Peer-reviewed

    Akiyama M, Ishigaki K, Sakaue S, Momozawa Y, Horikoshi M, Hirata M, Matsuda K, Ikegawa S, Takahashi A, Kanai M, Suzuki S, Matsui D, Naito M, Yamaji T, Iwasaki M, Sawada N, Tanno K, Sasaki M, Hozawa A, Minegishi N, Wakai K, Tsugane S, Shimizu A, Yamamoto M, Okada Y, Murakami Y, Kubo M, Kamatani Y

    Nature communications　10　(1)　4393-4393　2019/09

    DOI： 10.1038/s41467-019-12276-5 　

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    Human height is a representative phenotype to elucidate genetic architecture. However, the majority of large studies have been performed in European population. To investigate the rare and low-frequency variants associated with height, we construct a reference panel (N = 3,541) for genotype imputation by integrating the whole-genome sequence data from 1,037 Japanese with that of the 1000 Genomes Project, and perform a genome-wide association study in 191,787 Japanese. We report 573 height-associated variants, including 22 rare and 42 low-frequency variants. These 64 variants explain 1.7% of the phenotypic variance. Furthermore, a gene-based analysis identifies two genes with multiple height-increasing rare and low-frequency nonsynonymous variants (SLC27A3 and CYP26B1; PSKAT-O < 2.5 × 10-6). Our analysis shows a general tendency of the effect sizes of rare variants towards increasing height, which is contrary to findings among Europeans, suggesting that height-associated rare variants are under different selection pressure in Japanese and European populations.

  248. A training and education program for genome medical research coordinators in the genome cohort study of the Tohoku Medical Megabank Organization. International-journal Peer-reviewed

    Mika Sakurai-Yageta, Hiroshi Kawame, Shinichi Kuriyama, Atsushi Hozawa, Naoki Nakaya, Fuji Nagami, Naoko Minegishi, Soichi Ogishima, Takako Takai-Igarashi, Inaho Danjoh, Taku Obara, Mami Ishikuro, Tomoko Kobayashi, Yayoi Aizawa, Rino Ishihara, Masayuki Yamamoto, Yoichi Suzuki

    BMC medical education　19　(1)　297-297　2019/08/02

    DOI： 10.1186/s12909-019-1725-5 　

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    BACKGROUND: Genome cohort studies are used to analyze interactions between genetic and environmental factors, providing valuable information for personalized healthcare. Large-scale and long-term cohort studies require a number of specially trained personnel, of whom those involved in obtaining informed consent play a vital role, especially during the initial phase of such studies. The Japanese Society of Human Genetics (JSHG) previously established a certification system for genome medical research coordinators (GMRCs) responsible for obtaining written consent via face-to-face explanation. Meanwhile, in the Tohoku Medical Megabank Organization (ToMMo), GMRCs are expected to play important roles not only in obtaining informed consent and conducting various assessments, but also in communicating with participants throughout the long-term follow-up. Based on the JSHG program, we therefore developed a specific education and training program for ToMMo GMRCs consisting of 17 lectures, one practical training session on the informed consent procedure, and written and interview examinations. Re-education workshops aimed at self-improvement are also carried out following certification. In this study, we evaluated the education and training program in terms of overall understanding, usefulness, and satisfaction using an anonymous questionnaire. METHODS: An anonymous questionnaire addressing each aspect of the education and training program (understanding, usefulness, and satisfaction) was distributed among 152 qualified ToMMo GMRCs. Responses were received from 94 participants (61.8%). RESULTS: There was a significant association between the level of overall understanding of lectures and medical qualification (nurse or clinical laboratory technologist), but not with age or educational background. The level of understanding and overall usefulness were lower in sessions related to genetics and epidemiology than those dealing with ToMMo practices. In the re-education workshops, GMRCs showed a preference for and hoped to learn more about both background knowledge and research progress in the ToMMo. CONCLUSIONS: The results of our questionnaire suggest that not all ToMMo GMRCs are able to understand everything during the initial education and training program, especially in terms of genomic medicine. Continuous re-education is therefore vital in improving knowledge, skills and motivation, and preparing GMRCs for a specialist role in community-based personalized healthcare.

  249. An immortalized cell line derived from renal erythropoietin-producing (REP) cells demonstrates their potential to transform into myofibroblasts. International-journal Peer-reviewed

    Koji Sato, Ikuo Hirano, Hiroki Sekine, Kenichiro Miyauchi, Taku Nakai, Koichiro Kato, Sadayoshi Ito, Masayuki Yamamoto, Norio Suzuki

    Scientific reports　9　(1)　11254-11254　2019/08/02

    DOI： 10.1038/s41598-019-47766-5 　

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    The erythroid growth factor erythropoietin (Epo) is produced by renal interstitial fibroblasts, called REP (renal Epo-producing) cells, in a hypoxia-inducible manner. In chronic kidney disease (CKD), REP cells lose their Epo-production ability, leading to renal anaemia. Concurrently, REP cells are suggested to be transformed into myofibroblasts, which are the major player of renal fibrosis. Although establishment of cultured cell lines derived from REP cells has been a long-term challenge, we here successfully established a REP-cell-derived immortalized and cultivable cell line (Replic cells) by using a genetically modified mouse line. Replic cells exhibited myofibroblastic phenotypes and lost their Epo-production ability, reflecting the situation in renal fibrosis. Additionally, we found that cell-autonomous TGFβ signalling contributes to maintenance of the myofibroblastic features of Replic cells. Furthermore, the promoters of genes for Epo and HIF2α, a major activator of Epo gene expression, were highly methylated in Replic cells. Thus, these results strongly support our contention that REP cells are the origin of myofibroblasts in fibrotic kidneys and demonstrate that cell-autonomous TGFβ signalling and epigenetic silencing are involved in renal fibrosis and renal anaemia, respectively, in CKD. The Replic cell line is a useful tool to further investigate the molecular mechanisms underlying renal fibrosis.

  250. MALDI-MSI分析における導電性粘着フィルムで作製した生体組織切片の有用性について

    三枝 大輔, 齋藤 律水, 川本 孔明, 宇留野 晃, 可野 邦行, 青木 淳賢, 山本 雅之, 川本 忠文

    JSBMS Letters　44　(Suppl.)　122-122　2019/08

    Publisher: (一社)日本医用マススペクトル学会

    ISSN： 1881-5464

  251. Spiral ganglion cell degeneration-induced deafness as a consequence of reduced GATA factor activity Peer-reviewed

    Hoshino, Tomofumi, Terunuma, Tsumoru, Takai, Jun, Uemura, Satoshi, Nakamura, Yasuhiro, Hamada, Michito, Takahashi, Satoru, Yamamoto, Masayuki, Engel, James Douglas, Moriguchi, Takashi

    Genes to cells : devoted to molecular & cellular mechanisms　24　(8)　534-545　2019/08

    Publisher: WILEY

    DOI： 10.1111/gtc.12705 　

    ISSN： 1365-2443

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    Zinc-finger transcription factors GATA2 and GATA3 are both expressed in the developing inner ear, although their overlapping versus distinct activities in adult definitive inner ear are not well understood. We show here that GATA2 and GATA3 are co-expressed in cochlear spiral ganglion cells and redundantly function in the maintenance of spiral ganglion cells and auditory neural circuitry. Notably, Gata2 and Gata3 compound heterozygous mutant mice had a diminished number of spiral ganglion cells due to enhanced apoptosis, which resulted in progressive hearing loss. The decrease in spiral ganglion cellularity was associated with lowered expression of neurotrophin receptor TrkC that is an essential factor for spiral ganglion cell survival. We further show that Gata2 null mutants that additionally bear a Gata2 YAC (yeast artificial chromosome) that counteracts the lethal hematopoietic deficiency due to complete Gata2 loss nonetheless failed to complement the deficiency in neonatal spiral ganglion neurons. Furthermore, cochlea-specific Gata2 deletion mice also had fewer spiral ganglion cells and resultant hearing impairment. These results show that GATA2 and GATA3 redundantly function t

  252. Spiral ganglion cell degeneration-induced deafness as a consequence of reduced GATA factor activity. International-journal Peer-reviewed

    Tomofumi Hoshino, Tsumoru Terunuma, Jun Takai, Satoshi Uemura, Yasuhiro Nakamura, Michito Hamada, Satoru Takahashi, Masayuki Yamamoto, James Douglas Engel, Takashi Moriguchi

    Genes to cells : devoted to molecular & cellular mechanisms　24　(8)　534-545　2019/08

    DOI： 10.1111/gtc.12705 　

    ISSN： 1356-9597

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    Zinc-finger transcription factors GATA2 and GATA3 are both expressed in the developing inner ear, although their overlapping versus distinct activities in adult definitive inner ear are not well understood. We show here that GATA2 and GATA3 are co-expressed in cochlear spiral ganglion cells and redundantly function in the maintenance of spiral ganglion cells and auditory neural circuitry. Notably, Gata2 and Gata3 compound heterozygous mutant mice had a diminished number of spiral ganglion cells due to enhanced apoptosis, which resulted in progressive hearing loss. The decrease in spiral ganglion cellularity was associated with lowered expression of neurotrophin receptor TrkC that is an essential factor for spiral ganglion cell survival. We further show that Gata2 null mutants that additionally bear a Gata2 YAC (yeast artificial chromosome) that counteracts the lethal hematopoietic deficiency due to complete Gata2 loss nonetheless failed to complement the deficiency in neonatal spiral ganglion neurons. Furthermore, cochlea-specific Gata2 deletion mice also had fewer spiral ganglion cells and resultant hearing impairment. These results show that GATA2 and GATA3 redundantly function to maintain spiral ganglion cells and hearing. We propose possible mechanisms underlying hearing loss in human GATA2- or GATA3-related genetic disorders.

  253. Wavelength- and Tissue-dependent Variations in the Mutagenicity of Cyclobutane Pyrimidine Dimers in Mouse Skin. Peer-reviewed

    Ikehata H, Mori T, Kamei Y, Douki T, Cadet J, Yamamoto M

    Photochemistry and photobiology　2019/08

    DOI： 10.1111/php.13159 　

    ISSN： 0031-8655

  254. Identification of Celastramycin as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension. International-journal Peer-reviewed

    Ryo Kurosawa, Kimio Satoh, Nobuhiro Kikuchi, Haruhisa Kikuchi, Daisuke Saigusa, Md Elias Al-Mamun, Mohammad A H Siddique, Junichi Omura, Taijyu Satoh, Shinichiro Sunamura, Masamichi Nogi, Kazuhiko Numano, Satoshi Miyata, Akira Uruno, Kuniyuki Kano, Yotaro Matsumoto, Takayuki Doi, Junken Aoki, Yoshiteru Oshima, Masayuki Yamamoto, Hiroaki Shimokawa

    Circulation research　125　(3)　309-327　2019/07/19

    DOI： 10.1161/CIRCRESAHA.119.315229 　

    ISSN： 0009-7330

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    RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) accompanying increased production of inflammatory factors and adaptation of the mitochondrial metabolism to a hyperproliferative state. However, all the drugs in clinical use target pulmonary vascular dilatation, which may not be effective for patients with advanced PAH. OBJECTIVE: We aimed to discover a novel drug for PAH that inhibits PASMC proliferation. METHODS AND RESULTS: We screened 5562 compounds from original library using high-throughput screening system to discover compounds which inhibit proliferation of PASMCs from patients with PAH (PAH-PASMCs). We found that celastramycin, a benzoyl pyrrole-type compound originally found in a bacteria extract, inhibited the proliferation of PAH-PASMCs in a dose-dependent manner with relatively small effects on PASMCs from healthy donors. Then, we made 25 analogs of celastramycin and selected the lead compound, which significantly inhibited cell proliferation of PAH-PASMCs and reduced cytosolic reactive oxygen species levels. Mechanistic analysis demonstrated that celastramycin reduced the protein levels of HIF-1α (hypoxia-inducible factor 1α), which impairs aerobic metabolism, and κB (nuclear factor-κB), which induces proinflammatory signals, in PAH-PASMCs, leading to reduced secretion of inflammatory cytokine. Importantly, celastramycin treatment reduced reactive oxygen species levels in PAH-PASMCs with increased protein levels of Nrf2 (nuclear factor erythroid 2-related factor 2), a master regulator of cellular response against oxidative stress. Furthermore, celastramycin treatment improved mitochondrial energy metabolism with recovered mitochondrial network formation in PAH-PASMCs. Moreover, these celastramycin-mediated effects were regulated by ZFC3H1 (zinc finger C3H1 domain-containing protein), a binding partner of celastramycin. Finally, celastramycin treatment ameliorated pulmonary hypertension in 3 experimental animal models, accompanied by reduced inflammatory changes in the lungs. CONCLUSIONS: These results indicate that celastramycin ameliorates pulmonary hypertension, reducing excessive proliferation of PAH-PASMCs with less inflammation and reactive oxygen species levels, and recovered mitochondrial energy metabolism. Thus, celastramycin is a novel drug for PAH that targets antiproliferative effects on PAH-PASMCs.

  255. Molecular Mechanism of Cellular Oxidative Stress Sensing by Keap1. International-journal Peer-reviewed

    Takafumi Suzuki, Aki Muramatsu, Ryota Saito, Tatsuro Iso, Takahiro Shibata, Keiko Kuwata, Shin-Ichi Kawaguchi, Takao Iwawaki, Saki Adachi, Hiromi Suda, Masanobu Morita, Koji Uchida, Liam Baird, Masayuki Yamamoto

    Cell reports　28　(3)　746-758　2019/07/16

    DOI： 10.1016/j.celrep.2019.06.047 　

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    The Keap1-Nrf2 system plays a central role in the oxidative stress response; however, the identity of the reactive oxygen species sensor within Keap1 remains poorly understood. Here, we show that a Keap1 mutant lacking 11 cysteine residues retains the ability to target Nrf2 for degradation, but it is unable to respond to cysteine-reactive Nrf2 inducers. Of the 11 mutated cysteine residues, we find that 4 (Cys226/613/622/624) are important for sensing hydrogen peroxide. Our analyses of multiple mutant mice lines, complemented by MEFs expressing a series of Keap1 mutants, reveal that Keap1 uses the cysteine residues redundantly to set up an elaborate fail-safe mechanism in which specific combinations of these four cysteine residues can form a disulfide bond to sense hydrogen peroxide. This sensing mechanism is distinct from that used for electrophilic Nrf2 inducers, demonstrating that Keap1 is equipped with multiple cysteine-based sensors to detect various endogenous and exogenous stresses.

  256. 遺伝教育は血縁者の健康管理のために自身の遺伝学的検査結果を共有する意識を強くする

    徳富 智明, 吉田 明子, 福島 明宗, 山本 佳世乃, 石垣 泰, 川目 裕, 布施 昇男, 長神 風二, 鈴木 吉也, 宇留野 晃, 櫻井 美佳, 沼田 早苗, 中山 文予, 山本 雅之, 佐々木 真理

    日本遺伝カウンセリング学会誌　40　(2)　76-76　2019/07

    Publisher: (一社)日本遺伝カウンセリング学会

    ISSN： 1347-9628

  257. 【次世代に向けたアンチ・ドーピング】ドーピング分析の最前線 日本アンチ・ドーピング研究コンソーシアムの挑戦

    小柴 生造, 山本 雅之

    体育の科学　69　(7)　504-509　2019/07

    Publisher: (株)杏林書院

    ISSN： 0039-8985

  258. 大規模ゲノムコホート調査におけるBRCA1/2遺伝子の病的バリアント保持者への遺伝情報回付に関する課題

    濱中 洋平, 石田 孝宣, 布施 昇男, 川目 裕, 山口 由美, 安田 純, 多田 寛, 宮下 穣, 原田 成美, 佐藤 章子, 青木 洋子, 長神 風二, 八重樫 伸生, 木下 賢吾, 呉 繁夫, 山本 雅之

    日本乳癌学会総会プログラム抄録集　27回　332-332　2019/07

    Publisher: (一社)日本乳癌学会

  259. Conductive Adhesive Film Expands the Utility of Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging. International-journal Peer-reviewed

    Saigusa D, Saito R, Kawamoto K, Uruno A, Kano K, Aoki J, Yamamoto M, Kawamoto T

    Analytical chemistry　91　(14)　8979-8986　2019/07

    DOI： 10.1021/acs.analchem.9b01159 　

    ISSN： 0003-2700

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    The matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) technique is a promising approach for detecting the distribution of small molecules in a section of biological tissue. However, when a cryosection is created from fragile, hard, or whole-body samples, obtaining a high-quality section that maintains the distribution of the various components has been difficult. Since adhesive films have the potential to obtain high-quality cryosections, we attempted to utilize a conductive adhesive film for MALDI-MSI. To this end, cryosections of the whole body of a 9-day-old mouse were directly prepared on indium tin oxide (ITO) glass slides, nonconductive adhesive films, or conductive adhesive films, and the signal intensities from each section were measured by MALDI-MSI. We measured the differences in the ion intensity among these three slides/films by means of multivariate analyses and found that both the nonconductive and conductive adhesive films gave rise to high-quality sections in comparison with the ITO glass slide. The conductive adhesive film gave higher signals that were comparable to those of the ITO glass slide in comparison with the nonconductive adhesive film. We divided the frozen sections into two groups, a freeze-dried group and a thawed group, to examine the freeze-thaw effect on the signals of representative compounds of amino acids, cholesterol, and phosphatidylcholines. The freeze-dried samples were found to be useful for the analysis. These results indicate that the sections made with the conductive adhesive film under a freeze-dried condition can expand the utility of the MALDI-MSI analysis.

  260. Genome-wide association meta-analysis and Mendelian randomization analysis confirm the influence of ALDH2 on sleep durationin the Japanese population. International-journal Peer-reviewed

    Takeshi Nishiyama, Masahiro Nakatochi, Atsushi Goto, Motoki Iwasaki, Tsuyoshi Hachiya, Yoichi Sutoh, Atsushi Shimizu, Chaochen Wang, Hideo Tanaka, Miki Watanabe, Akihiro Hosono, Yuya Tamai, Tamaki Yamada, Taiki Yamaji, Norie Sawada, Kentaro Fukumoto, Kotaro Otsuka, Kozo Tanno, Hiroaki Tomita, Kaname Kojima, Masao Nagasaki, Atsushi Hozawa, Asahi Hishida, Tae Sasakabe, Yuichiro Nishida, Megumi Hara, Hidemi Ito, Isao Oze, Yohko Nakamura, Haruo Mikami, Rie Ibusuki, Toshiro Takezaki, Teruhide Koyama, Nagato Kuriyama, Kaori Endoh, Kiyonori Kuriki, Tanvir C Turin, Takashima Naoyuki, Sakurako Katsuura-Kamano, Hirokazu Uemura, Rieko Okada, Sayo Kawai, Mariko Naito, Yukihide Momozawa, Michiaki Kubo, Makoto Sasaki, Masayuki Yamamoto, Shoichiro Tsugane, Kenji Wakai, Sadao Suzuki

    Sleep　42　(6)　2019/06/11

    DOI： 10.1093/sleep/zsz046 　

    ISSN： 0161-8105

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    Usual sleep duration has substantial heritability and is associated with various physical and psychiatric conditions as well as mortality. However, for its genetic locus, only PAX8 and VRK2 have been replicated in previous genome-wide association studies (GWAS). We conducted a GWAS meta-analysis of self-reported usual sleep duration using three population-based cohorts totaling 31 230 Japanese individuals. A genome-wide significant locus was identified at 12q24 (p-value < 5.0 × 10-8). Subsequently, a functional variant in the ALDH2 locus, rs671, was replicated in an independent sample of 5140 Japanese individuals (p-value = 0.004). The association signal, however, disappeared after adjusting for alcohol consumption, indicating the possibility that the rs671 genotype modifies sleep duration via alcohol consumption. This hypothesis explained a modest genetic correlation observed between sleep duration and alcohol consumption (rG = 0.23). A Mendelian randomization analysis using rs671 and other variants as instrumental variables confirmed this by showing a causal effect of alcohol consumption, but not of coffee consumption on sleep duration. Another genome-wide significant locus was identified at 5q33 after adjusting for drinking frequency. However, this locus was not replicated, nor was the PAX8 and VRK2. Our study has confirmed that a functional ALDH2 variant, rs671, most strongly influences on usual sleep duration possibly via alcohol consumption in the Japanese population, and presumably in East Asian populations. This highlights the importance of considering the involvement of alcohol consumption in future GWAS of usual sleep duration, even in non-East Asian populations, where rs671 is monomorphic.

  261. ゲノムワイド遺伝子多型データを用いた機械学習によるうつ状態脆弱性の予測

    高橋 雄太, 植木 優夫, 田宮 元, 荻島 創一, 長神 風二, 福本 健太郎, 大塚 耕太郎, 山本 雅之, 富田 博秋

    精神神経学雑誌　(2019特別号)　S609-S609　2019/06

    Publisher: (公社)日本精神神経学会

    ISSN： 0033-2658

  262. メタボロームデータを用いた非線形変数選択機械学習によるうつ状態の予測

    高橋 雄太, 植木 優夫, 山田 誠, 田宮 元, 元池 育子, 三枝 大輔, 櫻井 美由紀, 長神 風二, 小柴 生造, 木下 賢吾, 山本 雅之, 富田 博秋

    精神神経学雑誌　(2019特別号)　S609-S609　2019/06

    Publisher: (公社)日本精神神経学会

    ISSN： 0033-2658

  263. Keap1欠失ラットはNrf2に依存して重篤な肝障害を引き起こす

    田口 恵子, 小山内 七重, 佐藤 由莉, 真下 知士, 山本 雅之

    The Journal of Toxicological Sciences　44　(Suppl.)　S225-S225　2019/06

    Publisher: (一社)日本毒性学会

    ISSN： 0388-1350

    eISSN： 1880-3989

  264. Biallelic GALM pathogenic variants cause a novel type of galactosemia. International-journal Peer-reviewed

    Yoichi Wada, Atsuo Kikuchi, Natsuko Arai-Ichinoi, Osamu Sakamoto, Yusuke Takezawa, Shinya Iwasawa, Tetsuya Niihori, Hiromi Nyuzuki, Yoko Nakajima, Erika Ogawa, Mika Ishige, Hiroki Hirai, Hideo Sasai, Ryoji Fujiki, Matsuyuki Shirota, Ryo Funayama, Masayuki Yamamoto, Tetsuya Ito, Osamu Ohara, Keiko Nakayama, Yoko Aoki, Seizo Koshiba, Toshiyuki Fukao, Shigeo Kure

    Genetics in medicine : official journal of the American College of Medical Genetics　21　(6)　1286-1294　2019/06

    DOI： 10.1038/s41436-018-0340-x 　

    ISSN： 1098-3600

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    PURPOSE: Galactosemia is caused by metabolic disturbances at various stages of galactose metabolism, including deficiencies in enzymes involved in the Leloir pathway (GALT, GALK1, and GALE). Nevertheless, the etiology of galactosemia has not been identified in a subset of patients. This study aimed to explore the causes of unexplained galactosemia. METHODS: Trio-based exome sequencing and/or Sanger sequencing was performed in eight patients with unexplained congenital galactosemia. In vitro enzymatic assays and immunoblot assays were performed to confirm the pathogenicity of the variants. RESULTS: The highest blood galactose levels observed in each patient were 17.3-41.9 mg/dl. Bilateral cataracts were observed in two patients. In all eight patients, we identified biallelic variants (p.Arg82*, p.Ile99Leufs*46, p.Gly142Arg, p.Arg267Gly, and p.Trp311*) in the GALM encoding galactose mutarotase, which catalyzes epimerization between β- and α-D-galactose in the first step of the Leloir pathway. GALM enzyme activities were undetectable in lymphoblastoid cell lines established from two patients. Immunoblot analysis showed the absence of the GALM protein in the patients' peripheral blood mononuclear cells. In vitro GALM expression and protein stability assays revealed altered stabilities of the variant GALM proteins. CONCLUSION: Biallelic GALM pathogenic variants cause galactosemia, suggesting the existence of type IV galactosemia.

  265. Environmental electrophile-mediated toxicity in mice lacking Nrf2, CSE, or both Peer-reviewed

    Masahiro Akiyama, Takamitsu Unoki, Yasuhiro Shinkai, Isao Ishii, Tomoaki Ida, Takaaki Akaike, Masayuki Yamamoto, Yoshito Kumagai

    Environmental Health Perspectives　127　(6)　67002　2019/06

    DOI： 10.1289/EHP4949 　

    ISSN： 0091-6765

    eISSN： 1552-9924

  266. CKD合併症最新の話題 貧血状態の腎臓における酸素恒常性の維持のためのエリスロポエチンとレニン産生の誘導(Induction of erythropoietin and renin production in kidneys under anemic conditions to maintain oxygen homeostasis) Peer-reviewed

    宮内 健一郎, 伊藤 貞嘉, 山本 雅之, 鈴木 教郎

    日本腎臓学会誌　61　(3)　235-235　2019/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  267. Respiratory resistance among adults in a population-based cohort study in Northern Japan. International-journal Peer-reviewed

    Miura E, Tsuchiya N, Igarashi Y, Arakawa R, Nikkuni E, Tamai T, Tabata M, Ohkouchi S, Irokawa T, Ogawa H, Takai-Igarashi T, Suzuki Y, Kuriyama S, Tamiya G, Hozawa A, Yamamoto M, Kurosawa H

    Respiratory investigation　57　(3)　274-281　2019/05

    DOI： 10.1016/j.resinv.2018.12.008 　

    ISSN： 2212-5345

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    BACKGROUND: Forced oscillation technique (FOT) is a noninvasive method used to measure respiratory system resistance (Rrs) and reactance (Xrs) during quiet breathing, which has been extensively studied in clinical settings. The distribution of measured FOT values was previously assessed in a community-based cohort study. In this study, we aimed to confirm the distribution of measured FOT values in a different cohort in order to investigate the relationship between these values and patient clinical and biological data. METHODS: We reviewed FOT data and relevant patient clinical and biological information collected from the Community-Based Cohort Study (CommCohort Study), carried out between 2013 to 2016 as a part of the Tohoku Medical Megabank project (TMM). In total, 16,231 adults were enrolled in the study (Male/Female: 4886/11,345). RESULTS: Significant gender differences were observed in distributions of Rrs and Xrs values at 5 Hz (termed R5 and X5, respectively). R5 values in males were lower than those in females, while X5 values in males were slightly less negative. High R5 values were strongly associated with high BMI, short height, smoking status in males, high serum IgE level, and high peripheral blood eosinophil count. CONCLUSION: The present distribution values and their relation to clinical and biological data should provide useful insights for clinical settings and serve as a helpful guide in implementing FOT. Forced oscillation technique, respiratory system resistance, respiratory system reactance, gender difference, obesity.

  268. Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease. International-journal Peer-reviewed

    Koichi Kikuchi, Daisuke Saigusa, Yoshitomi Kanemitsu, Yotaro Matsumoto, Paxton Thanai, Naoto Suzuki, Koki Mise, Hiroaki Yamaguchi, Tomohiro Nakamura, Kei Asaji, Chikahisa Mukawa, Hiroki Tsukamoto, Toshihiro Sato, Yoshitsugu Oikawa, Tomoyuki Iwasaki, Yuji Oe, Tomoya Tsukimi, Noriko N Fukuda, Hsin-Jung Ho, Fumika Nanto-Hara, Jiro Ogura, Ritsumi Saito, Shizuko Nagao, Yusuke Ohsaki, Satoshi Shimada, Takehiro Suzuki, Takafumi Toyohara, Eikan Mishima, Hisato Shima, Yasutoshi Akiyama, Yukako Akiyama, Mariko Ichijo, Tetsuro Matsuhashi, Akihiro Matsuo, Yoshiaki Ogata, Ching-Chin Yang, Chitose Suzuki, Matthew C Breeggemann, Jurgen Heymann, Miho Shimizu, Susumu Ogawa, Nobuyuki Takahashi, Takashi Suzuki, Yuji Owada, Shigeo Kure, Nariyasu Mano, Tomoyoshi Soga, Takashi Wada, Jeffrey B Kopp, Shinji Fukuda, Atsushi Hozawa, Masayuki Yamamoto, Sadayoshi Ito, Jun Wada, Yoshihisa Tomioka, Takaaki Abe

    Nature communications　10　(1)　1835-1835　2019/04/23

    DOI： 10.1038/s41467-019-09735-4 　

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    Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.

  269. Construction of full-length Japanese reference panel of class I HLA genes with single-molecule, real-time sequencing Peer-reviewed

    Takahiro Mimori, Jun Yasuda, Yoko Kuroki, Tomoko F. Shibata, Fumiki Katsuoka, Sakae Saito, Naoki Nariai, Akira Ono, Naomi Nakai-Inagaki, Kazuharu Misawa, Keiko Tateno, Yosuke Kawai, Nobuo Fuse, Atsushi Hozawa, Shinichi Kuriyama, Junichi Sugawara, Naoko Minegishi, Kichiya Suzuki, Kengo Kinoshita, Masao Nagasaki, Masayuki Yamamoto

    The Pharmacogenomics Journal　19　(2)　136-146　2019/04/19

    Publisher: Springer Nature

    DOI： 10.1038/s41397-017-0010-4 　

    ISSN： 1470-269X

  270. 生体内のヘム欠乏は,ATP代謝障害によるグリコーゲン合成異常のため,耐糖能異常・インスリン抵抗性を発症させる

    中島 修, 斉藤 真一, 尾崎 司, van Wijk Koen, 木村 朋寛, 浅尾 裕信, 山本 雅之, 高橋 究, 田中 徹, 中島 元夫

    糖尿病　62　(Suppl.1)　S-316　2019/04

    Publisher: (一社)日本糖尿病学会

    ISSN： 0021-437X

    eISSN： 1881-588X

  271. Nrf2 activation in myeloid cells and endothelial cells differentially mitigates sickle cell disease pathology in mice. International-journal Peer-reviewed

    Keleku-Lukwete N, Suzuki M, Panda H, Otsuki A, Katsuoka F, Saito R, Saigusa D, Uruno A, Yamamoto M

    Blood advances　3　(8)　1285-1297　2019/04

    DOI： 10.1182/bloodadvances.2018017574 　

    ISSN： 2473-9529

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    Sickle cell disease (SCD) is caused by a monogenic mutation of the β-globin gene and affects millions of people worldwide. SCD is associated with sustained hemolytic anemia, vasoocclusion, ischemia-reperfusion injury, oxidative tissue damage, inflammatory cell activation, and systemic endothelial dysfunction. The transcription factor Nrf2 coordinates the expression of a wide variety of genes encoding antioxidant, detoxification, and metabolic enzymes. Nrf2 participates in suppressing proinflammatory cytokines and organ protection in SCD. However, little is known regarding the mechanisms by which Nrf2 ameliorates SCD pathology or how some cells respond to Nrf2 stimuli to alleviate SCD pathology. Here, we asked whether monocytes/granulocytes and/or endothelial cells are particularly critical in alleviating the pathology of SCD. By targeting these cells with a Cre recombinase system, we generated SCD::Keap1F/F::LysM-Cre and Tie1-Cre mice with constitutive Nrf2 activation in monocytes/granulocytes and endothelial cells, respectively. Analyses of SCD::Keap1F/F::LysM-Cre and SCD::Keap1F/F::Tie1-Cre mice revealed significantly reduced inflammation, along with decreased white blood cell counts and lower Tnfα and Il1β expression in the lungs. Notably, SCD::Keap1F/F::LysM-Cre mice exhibited reduced heme distribution in the liver, consistent with a decrease in the damaged areas. Vascular function in SCD::Keap1F/F::Tie1-Cre mice was significantly improved, with a 50% decrease in vascular leakage and low expression of the adhesion molecules Vcam1 and P-selectin. Thus, Nrf2 activation in monocytes/granulocytes and endothelial cells contributes differentially and cooperatively to the improvement of SCD pathology.

  272. Identification of genetic alterations in extramammary Paget disease using whole exome analysis. International-journal Peer-reviewed

    Yukiko Kiniwa, Jun Yasuda, Sakae Saito, Rumiko Saito, Ikuko N Motoike, Inaho Danjoh, Kengo Kinoshita, Nobuo Fuse, Masayuki Yamamoto, Ryuhei Okuyama

    Journal of dermatological science　94　(1)　229-235　2019/04

    DOI： 10.1016/j.jdermsci.2019.03.006 　

    ISSN： 0923-1811

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    BACKGROUND: Extramammary Paget disease (EMPD) is a rare cutaneous malignant neoplasm, and the genomic alterations underlying its pathogenesis are unknown. OBJECTIVE: To identify tumor-specific genomic alterations in EMPD. METHODS: Exome analysis was performed in specimens from three EMPD patients, and target amplicon sequencing was done for genes frequently mutated in other adenocarcinomas. RESULTS: Exome analysis revealed recurrent somatic mutations in several genes, includingTP53, PIK3CA, and ERBB2. We identified additional candidate exons by searching the COSMIC database for exons that are frequently mutated in other adenocarcinomas. We obtained 19 exons in 12 genes as candidate exons, and performed target amplicon sequencing in samples obtained from EMPD patients. New somatic mutations in the TP53 gene were identified in six EMPD patients. Single nucleotide polymorphism analysis revealed multiple chromosomal alterations in three EMPD specimens, and two specimens exhibited amplification of chromosome 12p13 and losses of 3p21-24, 7q22 and 13q12-21. CONCLUSION: Our comprehensive genetic analysis identified novel genomic alterations, and will inform treatment options for EMPD.

  273. Generation and Molecular Characterization of Human Ring Sideroblasts: a Key Role of Ferrous Iron in Terminal Erythroid Differentiation and Ring Sideroblast Formation. International-journal Peer-reviewed

    Saito K, Fujiwara T, Hatta S, Morita M, Ono K, Suzuki C, Fukuhara N, Onishi Y, Nakamura Y, Kawamata S, Shimizu R, Yamamoto M, Harigae H

    Molecular and cellular biology　39　(7)　2019/04

    DOI： 10.1128/MCB.00387-18 　

    ISSN： 0270-7306

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    Ring sideroblasts are a hallmark of sideroblastic anemia, although little is known about their characteristics. Here, we first generated mutant mice by disrupting the GATA-1 binding motif at the intron 1 enhancer of the ALAS2 gene, a gene responsible for X-linked sideroblastic anemia (XLSA). Although heterozygous female mice showed an anemic phenotype, ring sideroblasts were not observed in their bone marrow. We next established human induced pluripotent stem cell-derived proerythroblast clones harboring the same ALAS2 gene mutation. Through coculture with sodium ferrous citrate, mutant clones differentiated into mature erythroblasts and became ring sideroblasts with upregulation of metal transporters (MFRN1, ZIP8, and DMT1), suggesting a key role for ferrous iron in erythroid differentiation. Interestingly, holo-transferrin (holo-Tf) did not induce erythroid differentiation as well as ring sideroblast formation, and mutant cells underwent apoptosis. Despite massive iron granule content, ring sideroblasts were less apoptotic than holo-Tf-treated undifferentiated cells. Microarray analysis revealed upregulation of antiapoptotic genes in ring sideroblasts, a profile partly shared with erythroblasts from a patient with XLSA. These results suggest that ring sideroblasts exert a reaction to avoid cell death by activating antiapoptotic programs. Our model may become an important tool to clarify the pathophysiology of sideroblastic anemia.

  274. 生体内でのヘム欠乏は、グリコーゲン合成異常を伴うインスリン抵抗性を惹起する

    中島 修, 斉藤 真一, 尾崎 司, 木村 朋寛, 岡野 聡, 山本 雅之, 高橋 究, 田中 徹, 中島 元夫

    糖尿病　62　(3)　203-203　2019/03

    Publisher: (一社)日本糖尿病学会

    ISSN： 0021-437X

    eISSN： 1881-588X

  275. Nrf2 Suppresses Allergic Lung Inflammation by Attenuating the Type 2 Innate Lymphoid Cell Response. International-journal Peer-reviewed

    Nagashima R, Kosai H, Masuo M, Izumiyama K, Noshikawaji T, Morimoto M, Kumaki S, Miyazaki Y, Motohashi H, Yamamoto M, Tanaka N

    Journal of immunology (Baltimore, Md. : 1950)　202　(5)　1331-1339　2019/03

    DOI： 10.4049/jimmunol.1801180 　

    ISSN： 0022-1767

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    The Keap1-Nrf2 system plays a pivotal role in the oxidative stress response by inducing a number of cytoprotective genes. Under stress, damaged epithelial cells release cytokines that activate type 2 innate lymphoid cells (ILC2s), which mediate the allergic immune response. In this article, we investigated the role of the Keap1-Nrf2 pathway in ILC2 homeostasis and allergic inflammation using Nrf2 knockout mice. ILC2s from Nrf2-deficient mice showed a transient, upregulated IL-33 response and underwent hyperproliferation in response to a combined stimulation of IL-33 with IL-2, IL-7, or TSLP. This enhanced proliferation was correlated with an increased activation of downstream signals, including JAK1, Akt, and Erk1/2. In contrast, activating Nrf2 with a chemical inducer (CDDO-Im) decreased the viability of the wild-type but not of the Nrf2-deficient ILC2s. This effect on viability resembled that exerted by the corticosteroid dexamethasone; however, unlike the latter, the Nrf2-dependent cell death was mediated by neither caspase 3-dependent apoptosis nor necroptosis. Using a mouse intratracheal IL-33 administration allergy model, we found that the activation of Nrf2 by CDDO-Im in vivo decreased the number of pulmonary ILC2s and eosinophils. These findings indicated that Nrf2 is an important regulator of the allergic response by determining the survival and death of ILC2s, and these findings suggest that Nrf2 activation is a potential therapeutic strategy for steroid-resistant allergy alleviation.

  276. Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population. Peer-reviewed

    Suzuki K, Akiyama M, Ishigaki K, Kanai M, Hosoe J, Shojima N, Hozawa A, Kadota A, Kuriki K, Naito M, Tanno K, Ishigaki Y, Hirata M, Matsuda K, Iwata N, Ikeda M, Sawada N, Yamaji T, Iwasaki M, Ikegawa S, Maeda S, Murakami Y, Wakai K, Tsugane S, Sasaki M, Yamamoto M, Okada Y, Kubo M, Kamatani Y, Horikoshi M, Yamauchi T, Kadowaki T

    Nature genetics　51　(3)　379-386　2019/03

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41588-018-0332-4 　

    ISSN： 1061-4036

    eISSN： 1546-1718

  277. New insights into nuclear factor erythroid 2-related factors in toxicology and pharmacology. Peer-reviewed

    Pi J, Hayes JD, Yamamoto M

    Toxicology and applied pharmacology　367　33-35　2019/03

    DOI： 10.1016/j.taap.2019.01.014 　

    ISSN： 0041-008X

  278. Nrf2 deficiency aggravates the increase in osteoclastogenesis and bone loss induced by inorganic arsenic. Peer-reviewed

    Liu Z, Hou Y, Li L, Yang Y, Jia J, Hong Z, Li T, Xu Y, Fu J, Sun Y, Yamamoto M, Wang H, Pi J

    Toxicology and applied pharmacology　367　62-70　2019/03

    DOI： 10.1016/j.taap.2019.02.003 　

    ISSN： 0041-008X

  279. Outlier detection for questionnaire data in biobanks. Peer-reviewed

    Sakurai R, Ueki M, Makino S, Hozawa A, Kuriyama S, Takai-Igarashi T, Kinoshita K, Yamamoto M, Tamiya G

    International journal of epidemiology　48　(4)　1305-1315　2019/03

    Publisher: Oxford University Press (OUP)

    DOI： 10.1093/ije/dyz012 　

    ISSN： 0300-5771

    eISSN： 1464-3685

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    <title>Abstract</title> <sec> <title>Background</title> Biobanks increasingly collect, process and store omics with more conventional epidemiologic information necessitating considerable effort in data cleaning. An efficient outlier detection method that reduces manual labour is highly desirable. </sec> <sec> <title>Method</title> We develop an unsupervised machine-learning method for outlier detection, namely kurPCA, that uses principal component analysis combined with kurtosis to ascertain the existence of outliers. In addition, we propose a novel regression adjustment approach to improve detection, namely the regression adjustment for data by systematic missing patterns (RAMP). </sec> <sec> <title>Result</title> Application to epidemiological record data in a large-scale biobank (Tohoku Medical Megabank Organization, Japan) shows that a combination of kurPCA and RAMP effectively detects known errors or inconsistent patterns. </sec> <sec> <title>Conclusions</title> We confirm through the results of the simulation and the application that our methods showed good performance. The proposed methods are useful for many practical analysis scenarios. </sec>

  280. Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals. International-journal Peer-reviewed

    Yamaguchi-Kabata Y, Yasuda J, Uruno A, Shimokawa K, Koshiba S, Suzuki Y, Fuse N, Kawame H, Tadaka S, Nagasaki M, Kojima K, Katsuoka F, Kumada K, Tanabe O, Tamiya G, Yaegashi N, Kinoshita K, Yamamoto M, Kure S, Tohoku Medical Megabank Project, Study Group

    Human genetics　138　(4)　389-409　2019/03

    DOI： 10.1007/s00439-019-01998-7 　

    ISSN： 0340-6717

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    Incidence rates of Mendelian diseases vary among ethnic groups, and frequencies of variant types of causative genes also vary among human populations. In this study, we examined to what extent we can predict population frequencies of recessive disorders from genomic data, and explored better strategies for variant interpretation and classification. We used a whole-genome reference panel from 3552 general Japanese individuals constructed by the Tohoku Medical Megabank Organization (ToMMo). Focusing on 32 genes for 17 congenital metabolic disorders included in newborn screening (NBS) in Japan, we identified reported and predicted pathogenic variants through variant annotation, interpretation, and multiple ways of classifications. The estimated carrier frequencies were compared with those from the Japanese NBS data based on 1,949,987 newborns from a previous study. The estimated carrier frequency based on genomic data with a recent guideline of variant interpretation for the PAH gene, in which defects cause hyperphenylalaninemia (HPA) and phenylketonuria (PKU), provided a closer estimate to that by the observed incidence than the other methods. In contrast, the estimated carrier frequencies for SLC25A13, which causes citrin deficiency, were much higher compared with the incidence rate. The results varied greatly among the 11 NBS diseases with single responsible genes; the possible reasons for departures from the carrier frequencies by reported incidence rates were discussed. Of note, (1) the number of pathogenic variants increases by including additional lines of evidence, (2) common variants with mild effects also contribute to the actual frequency of patients, and (3) penetrance of each variant remains unclear.

  281. Maternity Log study: a longitudinal lifelog monitoring and multiomics analysis for the early prediction of complicated pregnancy. International-journal Peer-reviewed

    Junichi Sugawara, Daisuke Ochi, Riu Yamashita, Takafumi Yamauchi, Daisuke Saigusa, Maiko Wagata, Taku Obara, Mami Ishikuro, Yoshiki Tsunemoto, Yuki Harada, Tomoko Shibata, Takahiro Mimori, Junko Kawashima, Fumiki Katsuoka, Takako Igarashi-Takai, Soichi Ogishima, Hirohito Metoki, Hiroaki Hashizume, Nobuo Fuse, Naoko Minegishi, Seizo Koshiba, Osamu Tanabe, Shinichi Kuriyama, Kengo Kinoshita, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto, Satoshi Hiyama, Masao Nagasaki

    BMJ open　9　(2)　e025939　2019/02/19

    DOI： 10.1136/bmjopen-2018-025939 　

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    PURPOSE: A prospective cohort study for pregnant women, the Maternity Log study, was designed to construct a time-course high-resolution reference catalogue of bioinformatic data in pregnancy and explore the associations between genomic and environmental factors and the onset of pregnancy complications, such as hypertensive disorders of pregnancy, gestational diabetes mellitus and preterm labour, using continuous lifestyle monitoring combined with multiomics data on the genome, transcriptome, proteome, metabolome and microbiome. PARTICIPANTS: Pregnant women were recruited at the timing of first routine antenatal visits at Tohoku University Hospital, Sendai, Japan, between September 2015 and November 2016. Of the eligible women who were invited, 65.4% agreed to participate, and a total of 302 women were enrolled. The inclusion criteria were age ≥20 years and the ability to access the internet using a smartphone in the Japanese language. FINDINGS TO DATE: Study participants uploaded daily general health information including quality of sleep, condition of bowel movements and the presence of nausea, pain and uterine contractions. Participants also collected physiological data, such as body weight, blood pressure, heart rate and body temperature, using multiple home healthcare devices. The mean upload rate for each lifelog item was ranging from 67.4% (fetal movement) to 85.3% (physical activity), and the total number of data points was over 6 million. Biospecimens, including maternal plasma, serum, urine, saliva, dental plaque and cord blood, were collected for multiomics analysis. FUTURE PLANS: Lifelog and multiomics data will be used to construct a time-course high-resolution reference catalogue of pregnancy. The reference catalogue will allow us to discover relationships among multidimensional phenotypes and novel risk markers in pregnancy for the future personalised early prediction of pregnancy complications.

  282. Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals Peer-reviewed

    Nishiyama T, Nakatochi M, Goto A, Iwasaki M, Hachiya T, Sutoh Y, Shimizu A, Wang C, Tanaka H, Watanabe M, Hosono A, Tamai Y, Yamada T, Yamaji T, Sawada N, Fukumoto K, Otsuka K, Tanno K, Tomita H, Kojima K, Nagasaki M, Hozawa A, Hishida A, Sasakabe T, Nishida Y, Hara M, Ito H, Oze I, Nakamura Y, Mikami H, Ibusuki R, Takezaki T, Koyama T, Kuriyama N, Endoh K, Kuriki K, Turin TC, Naoyuki T, Katsuura-Kamano S, Uemura H, Okada R, Kawai S, Naito M, Momozawa Y, Kubo M, Sasaki M, Yamamoto M, Tsugane S, Wakai K, Suzuki S

    Sleep　42　(6)　2019/02

    DOI： 10.1093/sleep/zsz046 　

  283. Genome analyses for the Tohoku Medical Megabank Project towards establishment of personalized healthcare. International-journal Peer-reviewed

    Jun Yasuda, Kengo Kinoshita, Fumiki Katsuoka, Inaho Danjoh, Mika Sakurai-Yageta, Ikuko N Motoike, Yoko Kuroki, Sakae Saito, Kaname Kojima, Matsuyuki Shirota, Daisuke Saigusa, Akihito Otsuki, Junko Kawashima, Yumi Yamaguchi-Kabata, Shu Tadaka, Yuichi Aoki, Takahiro Mimori, Kazuki Kumada, Jin Inoue, Satoshi Makino, Miho Kuriki, Nobuo Fuse, Seizo Koshiba, Osamu Tanabe, Masao Nagasaki, Gen Tamiya, Ritsuko Shimizu, Takako Takai-Igarashi, Soichi Ogishima, Atsushi Hozawa, Shinichi Kuriyama, Junichi Sugawara, Akito Tsuboi, Hideyasu Kiyomoto, Tadashi Ishii, Hiroaki Tomita, Naoko Minegishi, Yoichi Suzuki, Kichiya Suzuki, Hiroshi Kawame, Hiroshi Tanaka, Yasuyuki Taki, Nobuo Yaegashi, Shigeo Kure, Fuji Nagami, Kenjiro Kosaki, Yoichi Sutoh, Tsuyoshi Hachiya, Atsushi Shimizu, Makoto Sasaki, Masayuki Yamamoto

    Journal of biochemistry　165　(2)　139-158　2019/02/01

    DOI： 10.1093/jb/mvy096 　

    ISSN： 0021-924X

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    Personalized healthcare (PHC) based on an individual's genetic make-up is one of the most advanced, yet feasible, forms of medical care. The Tohoku Medical Megabank (TMM) Project aims to combine population genomics, medical genetics and prospective cohort studies to develop a critical infrastructure for the establishment of PHC. To date, a TMM CommCohort (adult general population) and a TMM BirThree Cohort (birth+three-generation families) have conducted recruitments and baseline surveys. Genome analyses as part of the TMM Project will aid in the development of a high-fidelity whole-genome Japanese reference panel, in designing custom single-nucleotide polymorphism (SNP) arrays specific to Japanese, and in estimation of the biological significance of genetic variations through linked investigations of the cohorts. Whole-genome sequencing from >3,500 unrelated Japanese and establishment of a Japanese reference genome sequence from long-read data have been done. We next aim to obtain genotype data for all TMM cohort participants (>150,000) using our custom SNP arrays. These data will help identify disease-associated genomic signatures in the Japanese population, while genomic data from TMM BirThree Cohort participants will be used to improve the reference genome panel. Follow-up of the cohort participants will allow us to test the genetic markers and, consequently, contribute to the realization of PHC.

  284. Sulforaphane enriched transcriptome of lung mitochondrial energy metabolism and provided pulmonary injury protection via Nrf2 in mice. Peer-reviewed

    Cho HY, Miller-DeGraff L, Blankenship-Paris T, Wang X, Bell DA, Lih F, Deterding L, Panduri V, Morgan DL, Yamamoto M, Reddy AJ, Talalay P, Kleeberger SR

    Toxicology and applied pharmacology　364　29-44　2019/02

    DOI： 10.1016/j.taap.2018.12.004 　

    ISSN： 0041-008X

  285. GATA2 hypomorphism induces chronic myelomonocytic leukemia in mice. Peer-reviewed

    Harada N, Hasegawa A, Hirano I, Yamamoto M, Shimizu R

    Cancer science　110　(4)　1183-1193　2019/02

    DOI： 10.1111/cas.13959 　

    ISSN： 1347-9032

  286. The Keap1-Nrf2 pathway: From mechanism to medical applications

    Liam Baird, Masayuki Yamamoto

    Oxidative Stress: Eustress and Distress　125-147　2019/01/01

    Publisher: Elsevier

    DOI： 10.1016/B978-0-12-818606-0.00009-2 　

  287. Nrf2 and CSE act as critical molecules in parallel pathways for regulation of electrophilic stress in mice

    AKIYAMA Masahiro, UNOKI Takamitsu, SHINKAI Yasuhiro, ISHII Isao, AKAIKE Takaaki, YAMAMOTO Masayuki, KUMAGAI Yoshito

    Annual Meeting of the Japanese Society of Toxicology　46.1　P-229　2019

    Publisher: The Japanese Society of Toxicology

    DOI： 10.14869/toxpt.46.1.0_p-229 　

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    [in Japanese]

  288. Management of family relationship information for a three-generation cohort study

    Shimokawa K, Ishikuro M, Obara T, Metoki H, Mizuno S, Nagaie S, Nagai M, Yamanaka C, Matsubara H, Kato M, Sato Y, Ogishima S, Takai-Igarashi T, Kikuya M, Hozawa A, Nagami F, Kuriyama S, Kinoshita K, Yamamoto M, Tanaka H

    bioRxiv　2019/01

  289. Biobank Establishment and Sample Management in the Tohoku Medical Megabank Project Peer-reviewed

    Naoko Minegishi, Ichiko Nishijima, Takahiro Nobukuni, Hisaaki Kudo, Noriko Ishida, Takahiro Terakawa, Kazuki Kumada, Riu Yamashita, Fumiki Katsuoka, Soichi Ogishima, Kichiya Suzuki, Makoto Sasaki, Mamoru Satoh, Tohoku Medical Megabank Project Study Group, Masayuki Yamamoto

    The Tohoku Journal of Experimental Medicine　248　(1)　45-55　2019

    Publisher: Tohoku University Medical Press

    DOI： 10.1620/tjem.248.45 　

    ISSN： 0040-8727

    eISSN： 1349-3329

  290. Nrf2 represses the onset of type 1 diabetes in non-obese diabetic mice. International-journal Peer-reviewed

    Yagishita Y, Uruno A, Chartoumpekis DV, Kensler TW, Yamamoto M

    The Journal of endocrinology　2019/01

    DOI： 10.1530/JOE-18-0355 　

    ISSN： 0022-0795

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    The transcription factor Nrf2 (NF-E2-related factor 2) plays a critical role in oxidative stress responses. While activation of Nrf2 signaling is known to exert anti-inflammatory effects, Nrf2 function in inflammation-mediated autoimmune disorders, such as type 1 diabetes, is not well established. To address the roles of Nrf2 in protection against autoreactive T-cell-induced type 1 diabetes, we used non-obese diabetic (NOD) mice, a polygenic model of human type 1 diabetes, to generate a genetic model that allowed us to assess the contribution of Nrf2 activation to preventing and/or treating type 1 diabetes. As Keap1 negatively regulates Nrf2, we used Keap1 gene knockdown driven by either hypomorphic or knockout alleles of Keap1,which enhances Nrf2 signaling to moderate and excess levels, respectively. We found that Nrf2 activation in NOD::Keap1FA/- mice inhibited T-cell infiltration within or near the islets, ameliorated impairment of insulin secretion, and prevented development of diabetes mellitus in the NOD mice. Notably, Nrf2 activation decreased both plasma interferon-γ (IFN-γ) levels and IFN-γ-positive cell numbers in the pancreatic islets. These findings were also observed in mice with two hypomorphic Keap1 alleles (Keap1FA/FA). Both NOD::Keap1FA/- and NOD::Keap1FA/FA mice had decreased incidence of diabetes mellitus, demonstrating that the activation of Nrf2 signaling prevents the onset of type 1 diabetes mellitus in NOD mice. Thus, Nrf2 appears to be a potential target for preventing and treating type 1 diabetes.

  291. Construction of JRG (Japanese reference genome) with single-molecule real-time sequencing. International-journal Peer-reviewed

    Masao Nagasaki, Yoko Kuroki, Tomoko F Shibata, Fumiki Katsuoka, Takahiro Mimori, Yosuke Kawai, Naoko Minegishi, Atsushi Hozawa, Shinichi Kuriyama, Yoichi Suzuki, Hiroshi Kawame, Fuji Nagami, Takako Takai-Igarashi, Soichi Ogishima, Kaname Kojima, Kazuharu Misawa, Osamu Tanabe, Nobuo Fuse, Hiroshi Tanaka, Nobuo Yaegashi, Kengo Kinoshita, Shiego Kure, Jun Yasuda, Masayuki Yamamoto

    Human genome variation　6　27-27　2019

    DOI： 10.1038/s41439-019-0057-7 　

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    In recent genome analyses, population-specific reference panels have indicated important. However, reference panels based on short-read sequencing data do not sufficiently cover long insertions. Therefore, the nature of long insertions has not been well documented. Here, we assembled a Japanese genome using single-molecule real-time sequencing data and characterized insertions found in the assembled genome. We identified 3691 insertions ranging from 100 bps to ~10,000 bps in the assembled genome relative to the international reference sequence (GRCh38). To validate and characterize these insertions, we mapped short-reads from 1070 Japanese individuals and 728 individuals from eight other populations to insertions integrated into GRCh38. With this result, we constructed JRGv1 (Japanese Reference Genome version 1) by integrating the 903 verified insertions, totaling 1,086,173 bases, shared by at least two Japanese individuals into GRCh38. We also constructed decoyJRGv1 by concatenating 3559 verified insertions, totaling 2,536,870 bases, shared by at least two Japanese individuals or by six other assemblies. This assembly improved the alignment ratio by 0.4% on average. These results demonstrate the importance of refining the reference assembly and creating a population-specific reference genome. JRGv1 and decoyJRGv1 are available at the JRG website.

  292. 3.5KJPNv2: an allele frequency panel of 3552 Japanese individuals including the X chromosome. International-journal Peer-reviewed

    Shu Tadaka, Fumiki Katsuoka, Masao Ueki, Kaname Kojima, Satoshi Makino, Sakae Saito, Akihito Otsuki, Chinatsu Gocho, Mika Sakurai-Yageta, Inaho Danjoh, Ikuko N Motoike, Yumi Yamaguchi-Kabata, Matsuyuki Shirota, Seizo Koshiba, Masao Nagasaki, Naoko Minegishi, Atsushi Hozawa, Shinichi Kuriyama, Atsushi Shimizu, Jun Yasuda, Nobuo Fuse, Gen Tamiya, Masayuki Yamamoto, Kengo Kinoshita

    Human genome variation　6　28-28　2019

    DOI： 10.1038/s41439-019-0059-5 　

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    The first step towards realizing personalized healthcare is to catalog the genetic variations in a population. Since the dissemination of individual-level genomic information is strictly controlled, it will be useful to construct population-level allele frequency panels with easy-to-use interfaces. In the Tohoku Medical Megabank Project, we sequenced nearly 4000 individuals from a Japanese population and constructed an allele frequency panel of 3552 individuals after removing related samples. The panel is called the 3.5KJPNv2. It was constructed by using a standard pipeline including the 1KGP and gnomAD algorithms to reduce technical biases and to allow comparisons to other populations. Our database is the first large-scale panel providing the frequencies of variants present on the X chromosome and on the mitochondria in the Japanese population. All the data are available on our original database at https://jmorp.megabank.tohoku.ac.jp.

  293. Roles of the KEAP1-NRF2 system in mammalian skin exposed to UV radiation. Peer-reviewed

    Ikehata H, Yamamoto M

    Toxicology and applied pharmacology　360　69-77　2018/12

    DOI： 10.1016/j.taap.2018.09.038 　

    ISSN： 0041-008X

  294. Development and application of a rapid and sensitive genotyping method for pharmacogene variants using the single-stranded tag hybridization chromatographic printed-array strip (STH-PAS). International-journal Peer-reviewed

    Kumondai M, Ito A, Hishinuma E, Kikuchi A, Saito T, Takahashi M, Tsukada C, Saito S, Yasuda J, Nagasaki M, Minegishi N, Yamamoto M, Kaneko A, Teramoto I, Kimura M, Hirasawa N, Hiratsuka M

    Drug metabolism and pharmacokinetics　33　(6)　258-263　2018/12

    DOI： 10.1016/j.dmpk.2018.08.003 　

    ISSN： 1347-4367

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    Genetic polymorphisms contribute to inter-individual variability in the metabolism of multiple clinical drugs, including warfarin, thiopurines, primaquine, and aminoglycosides. A rapid and sensitive clinical assessment of various genome biomarkers is, therefore, required to predict the individual responsiveness of each patient to these drugs. In this study, we developed a novel genotyping method for the detection of nine pharmacogene variants that are important in the prediction of drug efficiency and toxicity. This genotyping method uses competitive allele-specific PCR and a single-stranded tag hybridization chromatographic printed-array strip (STH-PAS) that can unambiguously determine the presence or absence of the gene variant by displaying visible blue lines on the chromatographic printed-array strip. Notably, the results of our STH-PAS method were in 100% agreement with those obtained using standard Sanger sequencing and KASP assay genotyping methods for CYP4F2 gene deletion. Moreover, the results were obtained within 90 min, including the PCR amplification and signal detection processes. The sensitive and rapid nature of this novel method make it ideal for clinical genetic testing to predict drug efficacy and toxicity, and in doing so will aid in the development of individualized medicine and better patient care.

  295. Sulforaphane ameliorates steroid insensitivity through an Nrf2-dependent pathway in cigarette smoke-exposed asthmatic mice. International-journal Peer-reviewed

    Sakurai H, Morishima Y, Ishii Y, Yoshida K, Nakajima M, Tsunoda Y, Hayashi SY, Kiwamoto T, Matsuno Y, Kawaguchi M, Yamamoto M, Hizawa N

    Free radical biology & medicine　129　473-485　2018/12

    DOI： 10.1016/j.freeradbiomed.2018.10.400 　

    ISSN： 0891-5849

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    Oxidative stress induced by cigarette smoke and other environmental pollutants contributes to refractory asthma. To better understand the role of smoking in asthma, we investigated the effects of cigarette smoke on allergic airway responses in mice and examined expression of nuclear factor-E2-related factor-2 (Nrf2) and its downstream factors, because Nrf2 is known to play a pivotal role in antioxidant responses. OVA-sensitized and challenged BALB/c mice were exposed to cigarette smoke and then treated with dexamethasone, sulforaphane (an activator of Nrf2), or their combination. Upon exposure to cigarette smoke, Nrf2 and associated transcripts were upregulated in response to oxidative stress, and asthmatic responses were steroid resistant. In OVA-sensitized and challenged mice exposed to cigarette smoke and treated with sulforaphane, Nrf2-mediated antioxidant responses were upregulated to a greater extent, and steroid sensitivity of asthmatic responses was restored. Moreover, the expression and activity of histone deacetylase 2 (HDAC2), a key regulator of steroid responsiveness, was reduced in mice exposed to cigarette smoke, but restored by sulforaphane treatment. No effects of sulforaphane were observed in Nrf2-deficient mice. These findings indicate that cigarette smoke induces steroid unresponsiveness in asthmatic airways, and that sulforaphane restores steroid sensitivity via upregulation of Nrf2 and enhancement of HDAC2 expression and activity. Thus, Nrf2 may serve as a potential molecular target for cigarette smoke-related refractory asthma resistant to steroid therapy.

  296. Tumors sweeten macrophages with acids. International-journal Peer-reviewed

    Hiroki Sekine, Masayuki Yamamoto, Hozumi Motohashi

    Nature immunology　19　(12)　1281-1283　2018/12

    DOI： 10.1038/s41590-018-0258-0 　

    ISSN： 1529-2908

  297. C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape Peer-reviewed

    Sharadha Dayalan Naidu, Aki Muramatsu, Ryota Saito, Soichiro Asami, Tadashi Honda, Tomonori Hosoya, Ken Itoh, Masayuki Yamamoto, Takafumi Suzuki, Albena T. Dinkova-Kostova

    Scientific Reports　8　(1)　8037　2018/12/01

    Publisher: Nature Publishing Group

    DOI： 10.1038/s41598-018-26269-9 　

    ISSN： 2045-2322

  298. Interethnic analyses of blood pressure loci in populations of East Asian and European descent. International-journal Peer-reviewed

    Fumihiko Takeuchi, Masato Akiyama, Nana Matoba, Tomohiro Katsuya, Masahiro Nakatochi, Yasuharu Tabara, Akira Narita, Woei-Yuh Saw, Sanghoon Moon, Cassandra N Spracklen, Jin-Fang Chai, Young-Jin Kim, Liang Zhang, Chaolong Wang, Huaixing Li, Honglan Li, Jer-Yuarn Wu, Rajkumar Dorajoo, Jovia L Nierenberg, Ya Xing Wang, Jing He, Derrick A Bennett, Atsushi Takahashi, Yukihide Momozawa, Makoto Hirata, Koichi Matsuda, Hiromi Rakugi, Eitaro Nakashima, Masato Isono, Matsuyuki Shirota, Atsushi Hozawa, Sahoko Ichihara, Tatsuaki Matsubara, Ken Yamamoto, Katsuhiko Kohara, Michiya Igase, Sohee Han, Penny Gordon-Larsen, Wei Huang, Nanette R Lee, Linda S Adair, Mi Yeong Hwang, Juyoung Lee, Miao Li Chee, Charumathi Sabanayagam, Wanting Zhao, Jianjun Liu, Dermot F Reilly, Liang Sun, Shaofeng Huo, Todd L Edwards, Jirong Long, Li-Ching Chang, Chien-Hsiun Chen, Jian-Min Yuan, Woon-Puay Koh, Yechiel Friedlander, Tanika N Kelly, Wen Bin Wei, Liang Xu, Hui Cai, Yong-Bing Xiang, Kuang Lin, Robert Clarke, Robin G Walters, Iona Y Millwood, Liming Li, John C Chambers, Jaspal S Kooner, Paul Elliott, Pim van der Harst, Zhengming Chen, Makoto Sasaki, Xiao-Ou Shu, Jost B Jonas, Jiang He, Chew-Kiat Heng, Yuan-Tsong Chen, Wei Zheng, Xu Lin, Yik-Ying Teo, E-Shyong Tai, Ching-Yu Cheng, Tien Yin Wong, Xueling Sim, Karen L Mohlke, Masayuki Yamamoto, Bong-Jo Kim, Tetsuro Miki, Toru Nabika, Mitsuhiro Yokota, Yoichiro Kamatani, Michiaki Kubo, Norihiro Kato

    Nature communications　9　(1)　5052-5052　2018/11/28

    DOI： 10.1038/s41467-018-07345-0 　

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    Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.

  299. Severity of eczema and mental health problems in Japanese schoolchildren: The ToMMo Child Health Study. International-journal Peer-reviewed

    Yasutaka Kuniyoshi, Masahiro Kikuya, Masako Miyashita, Chizuru Yamanaka, Mami Ishikuro, Taku Obara, Hirohito Metoki, Naoki Nakaya, Fuji Nagami, Hiroaki Tomita, Atsushi Hozawa, Ichiro Tsuji, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto, Shinichi Kuriyama

    Allergology international : official journal of the Japanese Society of Allergology　67　(4)　481-486　2018/10

    DOI： 10.1016/j.alit.2018.02.009 　

    ISSN： 1323-8930

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    BACKGROUND: The association between eczema and mental health problems in schoolchildren has been underexplored. We aimed to investigate this association with the validated questionnaires. METHODS: Of 46,648 invited children, we analyzed 9954 (21.3%) in the 2nd to the 8th grades from the ToMMo Child Health Study conducted in 2014 and 2015, a cross-sectional survey in Miyagi Prefecture, Japan. We defined eczema status as "normal," "mild/moderate," or "severe," based on the presence of persistent flexural eczema and sleep disturbance, according to the International Study of Asthma and Allergies in Childhood (ISAAC) Eczema Symptom Questionnaire. Clinical ranges of Strengths and Difficulties Questionnaire (SDQ) total difficulties scores and four SDQ subcategories of emotional symptoms, conduct problems, hyperactivity/inattention, and peer problems were defined as scores ≥16, ≥5, ≥5, ≥7, and ≥5, respectively. RESULTS: The mean SDQ total difficulties score significantly increased as eczema status worsened (all P ≤ 0.004 for trend). The OR of scores in the clinical range for SDQ total difficulties were 1.51 (95% CI, 1.31-1.74) for mild/moderate eczema and 2.63 (95% CI, 1.91-3.63) for severe eczema (P < 0.001 for trend), adjusted for sex, school grade, current wheeze, and disaster-related factors, using normal eczema as a reference. The association between severity of eczema and four SDQ subcategories showed a similar trend (all P ≤ 0.017 for trend). CONCLUSIONS: We found a significant association between severity of eczema and mental health problems. The presence of eczema was associated with four SDQ subcategories.

  300. Global metabolomicsを用いた腎癌の臨床的因子と関連代謝物の解析(The value of global metabolomics in association with clinical factors for diagnosis of renal cell carcinoma)

    佐藤 友紀, 川崎 芳英, 前川 正充, 高崎 新也, 三塚 浩二, 伊藤 明宏, 山本 雅之, 荒井 陽一

    日本癌学会総会記事　77回　1625-1625　2018/09

    Publisher: 日本癌学会

    ISSN： 0546-0476

  301. ヒスチジン脱炭酸酵素レポーターマウスを用いたアレルギー・炎症反応のイメージングの試み

    高井 淳, 森口 尚, 大津 浩, 山本 雅之

    日本生化学会大会プログラム・講演要旨集　91回　[3P-330]　2018/09

    Publisher: (公社)日本生化学会

  302. 転写因子GATA2によるサイトカイン産生亢進を介した腎臓での炎症促進メカニズム

    森口 尚, 于 磊, 金子 寛, 山本 雅之, 清水 律子

    日本生化学会大会プログラム・講演要旨集　91回　[1T13m-336)]　2018/09

    Publisher: (公社)日本生化学会

  303. メタボロームGWASによる日本人の代謝プロファイルの解析

    小柴 生造, 元池 育子, 三枝 大輔, 井上 仁, 青木 裕一, 田高 周, 城田 松之, 木下 賢吾, 山本 雅之

    日本生化学会大会プログラム・講演要旨集　91回　[3T14a-314)]　2018/09

    Publisher: (公社)日本生化学会

  304. ALA欠乏マウスにおける糖代謝異常の発症メカニズムの解析

    斉藤 真一, 岡野 聡, 木村 朋寛, 尾崎 司, 山本 雅之, ケリー・ビンセント P., 高橋 究, 田中 徹, 中島 元夫, 中島 修

    日本生化学会大会プログラム・講演要旨集　91回　[3T14a-295)]　2018/09

    Publisher: (公社)日本生化学会

  305. 腎エリスロポエチン産生細胞(REP細胞)由来の細胞株は、細胞自律性TGFβ発現により筋線維芽細胞の形質を有する Peer-reviewed

    佐藤 浩司, 平野 育生, 関根 弘樹, 宮内 健一郎, 中井 啄, 加藤 幸一郎, 伊藤 貞嘉, 山本 雅之, 鈴木 教郎

    日本生化学会大会プログラム・講演要旨集　91回　[3T12m-019)]　2018/09

    Publisher: (公社)日本生化学会

  306. Phenethyl Isothiocyanate, a Dual Activator of Transcription Factors NRF2 and HSF1. Peer-reviewed

    Dayalan Naidu S, Suzuki T, Yamamoto M, Fahey JW, Dinkova-Kostova AT

    Molecular nutrition & food research　62　(18)　e1700908-1700908　2018/09

    Publisher: Wiley

    DOI： 10.1002/mnfr.201700908 　

    ISSN： 1613-4125

  307. O-GlcNAcylation Signal Mediates Proteasome Inhibitor Resistance in Cancer Cells by Stabilizing NRF1. International-journal Peer-reviewed

    Hiroki Sekine, Keito Okazaki, Koichiro Kato, M Morshedul Alam, Hiroki Shima, Fumiki Katsuoka, Tadayuki Tsujita, Norio Suzuki, Akira Kobayashi, Kazuhiko Igarashi, Masayuki Yamamoto, Hozumi Motohashi

    Molecular and cellular biology　38　(17)　2018/09/01

    DOI： 10.1128/MCB.00252-18 　

    ISSN： 0270-7306

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    Cancer cells often heavily depend on the ubiquitin-proteasome system (UPS) for their growth and survival. Irrespective of their strong dependence on the proteasome activity, cancer cells, except for multiple myeloma, are mostly resistant to proteasome inhibitors. A major cause of this resistance is the proteasome bounce-back response mediated by NRF1, a transcription factor that coordinately activates proteasome subunit genes. To identify new targets for efficient suppression of UPS, we explored, using immunoprecipitation and mass spectrometry, the possible existence of nuclear proteins that cooperate with NRF1 and identified O-linked N-acetylglucosamine transferase (OGT) and host cell factor C1 (HCF-1) as two proteins capable of forming a complex with NRF1. O-GlcNAcylation catalyzed by OGT was essential for NRF1 stabilization and consequent upregulation of proteasome subunit genes. Meta-analysis of breast and colorectal cancers revealed positive correlations in the relative protein abundance of OGT and proteasome subunits. OGT inhibition was effective at sensitizing cancer cells to a proteasome inhibitor both in culture cells and a xenograft mouse model. Since active O-GlcNAcylation is a feature of cancer metabolism, our study has clarified a novel linkage between cancer metabolism and UPS function and added a new regulatory axis to the regulation of the proteasome activity.

  308. Deficiency in the transcription factor NRF2 worsens inflammatory parameters in a mouse model with combined tauopathy and amyloidopathy. Peer-reviewed

    Rojo AI, Pajares M, García-Yagüe AJ, Buendia I, Van Leuven F, Yamamoto M, López MG, Cuadrado A

    Redox biology　18　173-180　2018/09

    DOI： 10.1016/j.redox.2018.07.006 　

  309. Metabolomic Analysis of Mouse Brain after a Transient Middle Cerebral Artery Occlusion by Mass Spectrometry Imaging. Peer-reviewed

    Abe T, Niizuma K, Kanoke A, Saigusa D, Saito R, Uruno A, Fujimura M, Yamamoto M, Tominaga T

    Neurologia medico-chirurgica　58　(9)　384-392　2018/09

    DOI： 10.2176/nmc.oa.2018-0054 　

    ISSN： 0470-8105

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    We performed metabolomic analyses of mouse brain using a transient middle cerebral artery occlusion (tMCAO) model with Matrix Assisted Laser Desorption/Ionization (MALDI)-mass spectrometry imaging (MSI) to reveal metabolite changes after cerebral ischemia. We selected and analyzed three metabolites, namely creatine (Cr), phosphocreatine (P-Cr), and ceramides (Cer), because these metabolites contribute to cell life and death. Eight-week-old male C57BL/6J mice were subjected to tMCAO via the intraluminal blockade of the middle cerebral artery (MCA) and reperfusion 60 min after the induction of ischemia. Each mouse was randomly assigned to one of the three groups; the groups were defined by the survival period after reperfusion: control, 1 h, and 24 h. Corrected samples were analyzed using MALDI-MSI. Results of MSI analysis showed the presence of several ionized substances and revealed spatial changes in some metabolites identified as precise substances, including Cr, P-Cr, Cer d18:1/18:0, phosphatidylcholine, L-glutamine, and L-histidine. Cr, P-Cr, and Cer d18:1/18:0 were changed after tMCAO, and P-Cr and Cer d18:1/18:0 accumulated over time in ischemic cores and surrounding areas following ischemia onset. The upregulation of P-Cr and Cer d18:1/18:0 was detected 1 h after tMCAO when no changes were evident on hematoxylin and eosin staining and immunofluorescence assay. P-Cr and Cer d18:1/18:0 can serve as neuroprotective therapies because they are biomarker candidates for cerebral ischemia.

  310. Functional characterization of 40 CYP2B6 allelic variants by assessing efavirenz 8-hydroxylation. International-journal Peer-reviewed

    Watanabe T, Saito T, Rico EMG, Hishinuma E, Kumondai M, Maekawa M, Oda A, Saigusa D, Saito S, Yasuda J, Nagasaki M, Minegishi N, Yamamoto M, Yamaguchi H, Mano N, Hirasawa N, Hiratsuka M

    Biochemical pharmacology　156　420-430　2018/09

    DOI： 10.1016/j.bcp.2018.09.010 　

    ISSN： 0006-2952

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    Genetic variations within cytochrome P450 2B6 (CYP2B6) contribute to inter-individual variation in the metabolism of clinically important drugs, including cyclophosphamide, bupropion, methadone and efavirenz (EFZ). In this study, we performed an in vitro analysis of 40 CYP2B6 allelic variant proteins including seven novel variants identified in 1070 Japanese individuals. Wild-type and 39 variant proteins were heterologously expressed in 293FT cells to estimate the kinetic parameters (Km, Vmax, and CLint) of EFZ 8-hydroxylation and 7-ethoxy-4-trifluoromethylcoumarin (7-ETC) O-deethylation activities. The concentrations of CYP2B6 variant holo-enzymes were measured by using carbon monoxide (CO)-reduced difference spectroscopy, and the wild-type and 28 variants showed a peak at 450 nm. The kinetic parameters were measured for the wild-type and 24 variant proteins. The values for the remaining 15 variants could not be determined because the enzymatic activity was not detected at the highest substrate concentration used. Compared to wild-type, six variants showed significantly decreased EFZ 8-hydroxylation CLint values, while these values were significantly increased in another six variants, including CYP2B6.6. Although 7-ETC O-deethylation CLint values of CYP2B6 variants did not differ significantly from that of CYP2B6.1, the CLint ratios obtained for 7-ETC O-deethylation were highly correlated with EFZ 8-hydroxylation. Furthermore, three-dimensional structural modeling analysis was performed to elucidate the mechanism of changes in the kinetics of CYP2B6 variants. Our findings could provide evidence of the specific metabolic activities of the CYP2B6 proteins encoded by these variant alleles.

  311. Nrf2 Activation Ameliorates Hepatotoxicity Induced by a Heme Synthesis Inhibitor. International-journal Peer-reviewed

    Taguchi K, Masui S, Itoh T, Miyajima A, Yamamoto M

    Toxicological sciences : an official journal of the Society of Toxicology　167　(1)　227-238　2018/09

    DOI： 10.1093/toxsci/kfy233 　

    ISSN： 1096-6080

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    Transcription factor Nrf2 protects hepatocytes against various toxicants by upregulating cytoprotective genes. The heme synthesis inhibitor 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) leads to liver injury around the portal vein, unlike other groups of toxicants that cause hemorrhage and necrosis in the centrilobular area. To examine whether and how Nrf2 protects livers from the injury, we fed DDC to Nrf2 knockout (Nrf2KO), wild-type (WT), Keap1flox/flox (Keap1-knockdown; Keap1KD), and liver-specific Keap1 knockout (Keap1-Alb) mice, as these lines of mice exhibit stepwise increases in Nrf2 protein expression levels. Liver-specific Keap1::Nrf2 double-knockout (Keap1::Nrf2-Alb) mice were also exploited to examine the contribution of Nrf2. Two weeks after DDC feeding, Keap1-Alb mice were fully recovered from body weight loss, but the WT and Nrf2KO mice were not. The liver-to-body-weight ratio of Keap1-Alb mice was significantly larger than that of WT and Nrf2KO mice. Two indicators of hepatotoxicity, alanine aminotransferase and bilirubin in plasma, were both elevated in WT mice, but downregulated in Keap1-Alb mice after the DDC-feeding. DDC-induced porphyrin accumulation was reduced in the livers of Keap1-Alb and Keap1KD mice compared with that of WT mice. When assessed by the Nqo1 level, Nrf2 expression was further enhanced by DDC in Keap1-Alb mice, suggesting that DDC may have a Keap1 independent potential to activate Nrf2. Genetic activation of Nrf2 in Keap1-Alb mice increased the extracellular excretion of porphyrins, but contrary to our expectation, hepatic damages in Nrf2KO mice appeared to be similar to that of WT mice. Based on these observations, we conclude that Nrf2 activation protects livers against DDC-elicited hepatotoxicity.

  312. Genome-wide analysis of polymorphism × sodium interaction effect on blood pressure identifies a novel 3'-BCL11B gene desert locus. International-journal Peer-reviewed

    Hachiya T, Narita A, Ohmomo H, Sutoh Y, Komaki S, Tanno K, Satoh M, Sakata K, Hitomi J, Nakamura M, Ogasawara K, Yamamoto M, Sasaki M, Hozawa A, Shimizu A

    Scientific reports　8　(1)　14162-14162　2018/09

    DOI： 10.1038/s41598-018-32074-1 　

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    Excessive sodium intake is a global risk factor for hypertension. Sodium effects on blood pressure vary from person to person; hence, high-risk group targeting based on personal genetic information can play a complementary role to ongoing population preventive approaches to reduce sodium consumption. To identify genetic factors that modulate sodium effects on blood pressure, we conducted a population-based genome-wide interaction analysis in 8,768 Japanese subjects, which was >3 times larger than a similar previous study. We tested 7,135,436 polymorphisms in the discovery cohort, and loci that met suggestive significance were further examined in an independent replication cohort. We found that an interaction between a novel 3'-BCL11B gene desert locus and daily sodium consumption was significantly associated with systolic blood pressure in both discovery and replication cohorts under the recessive model. Further statistical analysis of rs8022678, the sentinel variant of the 3'-BCL11B gene desert locus, showed that differences in mean systolic blood pressure between high and low sodium consumption subgroups were 5.9 mm Hg (P = 8.8 × 10-12) in rs8022678 A carriers and -0.3 mm Hg (P = 0.27) in rs8022678 A non-carriers, suggesting that the rs8022678 genotype can classify persons into sodium-sensitive (A carriers) and sodium-insensitive (A non-carriers) subgroups. Our results implied that rs8022678 A carriers may receive a greater benefit from sodium-lowering interventions than non-carriers.

  313. Iron attenuates erythropoietin production by decreasing hypoxia-inducible transcription factor 2α concentrations in renal interstitial fibroblasts. Peer-reviewed

    Suzuki N, Matsuo-Tezuka Y, Sasaki Y, Sato K, Miyauchi K, Kato K, Saito S, Shimonaka Y, Hirata M, Yamamoto M

    Kidney international　94　(5)　900-911　2018/09

    Publisher: Elsevier BV

    DOI： 10.1016/j.kint.2018.06.028 　

    ISSN： 0085-2538

  314. NRF2 mitigates acute alcohol-induced hepatic and pancreatic injury in mice. Peer-reviewed

    Sun J, Fu J, Zhong Y, Li L, Chen C, Wang X, Wang L, Hou Y, Wang H, Zhao R, Zhang X, Yamamoto M, Xu Y, Pi J

    Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association　121　495-503　2018/09

    DOI： 10.1016/j.fct.2018.09.042 　

    ISSN： 0278-6915

  315. Metabolomic changes in the mouse retina after optic nerve injury. International-journal Peer-reviewed

    Kota Sato, Daisuke Saigusa, Ritsumi Saito, Amane Fujioka, Yurika Nakagawa, Koji M Nishiguchi, Taiki Kokubun, Ikuko N Motoike, Kazuichi Maruyama, Kazuko Omodaka, Yukihiro Shiga, Akira Uruno, Seizo Koshiba, Masayuki Yamamoto, Toru Nakazawa

    Scientific reports　8　(1)　11930-11930　2018/08/09

    DOI： 10.1038/s41598-018-30464-z 　

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    In glaucoma, although axonal injury drives retinal ganglion cell (RGC) death, little is known about the underlying pathomechanisms. To provide new mechanistic insights and identify new biomarkers, we combined latest non-targeting metabolomics analyses to profile altered metabolites in the mouse whole retina 2, 4, and 7 days after optic nerve crush (NC). Ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry and liquid chromatography Fourier transform mass spectrometry covering wide spectrum of metabolites in combination highlighted 30 metabolites that changed its concentration after NC. The analysis displayed similar changes for purine nucleotide and glutathione as reported previously in another animal model of axonal injury and detected multiple metabolites that increased after the injury. After studying the specificity of the identified metabolites to RGCs in histological sections using imaging mass spectrometry, two metabolites, i.e., L-acetylcarnitine and phosphatidylcholine were increased not only preceding the peak of RGC death in the whole retina but also at the RGC layer (2.3-fold and 1.2-fold, respectively). These phospholipids propose novel mechanisms of RGC death and may serve as early biomarkers of axonal injury. The combinatory metabolomics analyses promise to illuminate pathomechanisms, reveal biomarkers, and allow the discovery of new therapeutic targets of glaucoma.

  316. Functional Characterization of 21 Allelic Variants of Dihydropyrimidine Dehydrogenase Identified in 1070 Japanese Individuals. International-journal Peer-reviewed

    Hishinuma E, Narita Y, Saito S, Maekawa M, Akai F, Nakanishi Y, Yasuda J, Nagasaki M, Yamamoto M, Yamaguchi H, Mano N, Hirasawa N, Hiratsuka M

    Drug metabolism and disposition: the biological fate of chemicals　46　(8)　1083-1090　2018/08

    DOI： 10.1124/dmd.118.081737 　

    ISSN： 0090-9556

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    Dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2), encoded by the DPYD gene, is the rate-limiting enzyme in the degradation pathway of endogenous pyrimidine and fluoropyrimidine drugs such as 5-fluorouracil (5-FU). DPD catalyzes the reduction of uracil, thymine, and 5-FU. In Caucasians, DPYD mutations, including DPYD*2A, DPYD*13, c.2846A>T, and c.1129-5923C>G/hapB3, are known to contribute to interindividual variations in the toxicity of 5-FU; however, none of these DPYD polymorphisms has been identified in the Asian population. Recently, 21 DPYD allelic variants, including some novel single-nucleotide variants (SNVs), were identified in 1070 healthy Japanese individuals by analyzing their whole-genome sequences (WGSs), but the functional alterations caused by these variants remain unknown. In this study, in vitro analysis was performed on 22 DPD allelic variants by transiently expressing wild-type DPD and 21 DPD variants in 293FT cells and characterizing their enzymatic activities using 5-FU as a substrate. DPD expression levels and dimeric forms were determined using immunoblotting and blue-native PAGE, respectively. Additionally, the values of three kinetic parameters-the Michaelis constant (Km ), maximum velocity (Vmax ), and intrinsic clearance (CLint = Vmax/Km )-were determined for the reduction of 5-FU. Eleven variants exhibited significantly decreased intrinsic clearance compared with wild-type DPD. Moreover, the band patterns observed in the immunoblots of blue-native gels indicated that DPD dimerization is required for enzymatic activity in DPD. Thus, the detection of rare DPYD variants might facilitate severe adverse effect prediction of 5-FU-based chemotherapy in the Japanese population.

  317. Intracellular S1P Levels Dictate Fate of Different Regions of the Hippocampus following Transient Global Cerebral Ischemia Peer-reviewed

    Sherif Rashad, Kuniyasu Niizuma, Daisuke Saigusa, Xiaobo Han, Mika Sato-Maeda, Ritsumi Saito, Akira Uruno, Miki Fujimura, Shuntaro Ikawa, Masayuki Yamamoto, Teiji Tominaga

    Neuroscience　384　188-202　2018/08/01

    Publisher: Elsevier Ltd

    DOI： 10.1016/j.neuroscience.2018.05.015 　

    ISSN： 1873-7544 0306-4522

  318. A Gata3 3' distal otic vesicle enhancer directs inner ear-specific Gata3 expression. International-journal Peer-reviewed

    Moriguchi T, Hoshino T, Rao A, Yu L, Takai J, Uemura S, Ise K, Nakamura Y, Lim KC, Shimizu R, Yamamoto M, Engel JD

    Molecular and cellular biology　38　(21)　2018/08

    DOI： 10.1128/MCB.00302-18 　

    ISSN： 0270-7306

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    Transcription factor GATA3 plays vital roles in inner ear development, while regulatory mechanisms controlling its inner ear-specific expression are undefined. We demonstrate that a cis-regulatory element lying 571 kb 3' to the Gata3 gene directs inner ear-specific Gata3 expression, which we refer to as the Gata3 otic vesicle enhancer (OVE). In transgenic murine embryos, a 1.5-kb OVE-directed lacZ reporter (TgOVE-LacZ) exhibited robust lacZ expression specifically in the otic vesicle (OV), an inner ear primordial tissue, and its derivative semicircular canal. To further define the regulatory activity of this OVE, we generated Cre transgenic mice in which Cre expression was directed by a 246-bp core sequence within the OVE element (TgcoreOVE-Cre). TgcoreOVE-Cre successfully marked the OV-derived inner ear tissues, including cochlea, semicircular canal and spiral ganglion, when crossed with ROSA26 lacZ reporter mice. Furthermore, Gata3 conditionally mutant mice, when crossed with the TgcoreOVE-Cre, showed hypoplasia throughout the inner ear tissues. These results demonstrate that OVE has a sufficient regulatory activity to direct Gata3 expression specifically in the otic vesicle and semicircular canal and that Gata3 expression driven by the OVE is crucial for normal inner ear development.

  319. Regional genetic differences among Japanese populations and performance of genotype imputation using whole-genome reference panel of the Tohoku Medical Megabank Project. International-journal Peer-reviewed

    Jun Yasuda, Fumiki Katsuoka, Inaho Danjoh, Yosuke Kawai, Kaname Kojima, Masao Nagasaki, Sakae Saito, Yumi Yamaguchi-Kabata, Shu Tadaka, Ikuko N Motoike, Kazuki Kumada, Mika Sakurai-Yageta, Osamu Tanabe, Nobuo Fuse, Gen Tamiya, Koichiro Higasa, Fumihiko Matsuda, Nobufumi Yasuda, Motoki Iwasaki, Makoto Sasaki, Atsushi Shimizu, Kengo Kinoshita, Masayuki Yamamoto

    BMC genomics　19　(1)　551-551　2018/07/24

    DOI： 10.1186/s12864-018-4942-0 　

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    BACKGROUND: Genotype imputation from single-nucleotide polymorphism (SNP) genotype data using a haplotype reference panel consisting of thousands of unrelated individuals from populations of interest can help to identify strongly associated variants in genome-wide association studies. The Tohoku Medical Megabank (TMM) project was established to support the development of precision medicine, together with the whole-genome sequencing of 1070 human genomes from individuals in the Miyagi region (Northeast Japan) and the construction of the 1070 Japanese genome reference panel (1KJPN). Here, we investigated the performance of 1KJPN for genotype imputation of Japanese samples not included in the TMM project and compared it with other population reference panels. RESULTS: We found that the 1KJPN population was more similar to other Japanese populations, Nagahama (south-central Japan) and Aki (Shikoku Island), than to East Asian populations in the 1000 Genomes Project other than JPT, suggesting that the large-scale collection (more than 1000) of Japanese genomes from the Miyagi region covered many of the genetic variations of Japanese in mainland Japan. Moreover, 1KJPN outperformed the phase 3 reference panel of the 1000 Genomes Project (1KGPp3) for Japanese samples, and IKJPN showed similar imputation rates for the TMM and other Japanese samples for SNPs with minor allele frequencies (MAFs) higher than 1%. CONCLUSIONS: 1KJPN covered most of the variants found in the samples from areas of the Japanese mainland outside the Miyagi region, implying 1KJPN is representative of the Japanese population's genomes. 1KJPN and successive reference panels are useful genome reference panels for the mainland Japanese population. Importantly, the addition of whole genome sequences not included in the 1KJPN panel improved imputation efficiencies for SNPs with MAFs under 1% for samples from most regions of the Japanese archipelago.

  320. Macrophages Switch Their Phenotype by Regulating Maf Expression during Different Phases of Inflammation. International-journal Peer-reviewed

    Kenta Kikuchi, Mayumi Iida, Naoki Ikeda, Shigetaka Moriyama, Michito Hamada, Satoru Takahashi, Hiroshi Kitamura, Takashi Watanabe, Yoshinori Hasegawa, Koji Hase, Takeshi Fukuhara, Hideyo Sato, Eri H Kobayashi, Takafumi Suzuki, Masayuki Yamamoto, Masato Tanaka, Kenichi Asano

    Journal of immunology (Baltimore, Md. : 1950)　201　(2)　635-651　2018/07/15

    DOI： 10.4049/jimmunol.1800040 　

    ISSN： 0022-1767

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    Macrophages manifest distinct phenotype according to the organs in which they reside. In addition, they flexibly switch their character in adaptation to the changing environment. However, the molecular basis that explains the conversion of the macrophage phenotype has so far been unexplored. We find that CD169+ macrophages change their phenotype by regulating the level of a transcription factor Maf both in vitro and in vivo in C57BL/6J mice. When CD169+ macrophages were exposed to bacterial components, they expressed an array of acute inflammatory response genes in Maf-dependent manner and simultaneously start to downregulate Maf. This Maf suppression is dependent on accelerated degradation through proteasome pathway and microRNA-mediated silencing. The downregulation of Maf unlocks the NF-E2-related factor 2-dominant, cytoprotective/antioxidative program in the same macrophages. The present study provides new insights into the previously unanswered question of how macrophages initiate proinflammatory responses while retaining their capacity to repair injured tissues during inflammation.

  321. The KEAP1-NRF2 system: A thiol-based sensor-effector apparatus for maintaining redox homeostasis Peer-reviewed

    Masayuki Yamamoto, Thomas W. Kensler, Hozumi Motohashi

    Physiological Reviews　98　(3)　1169-1203　2018/07/01

    Publisher: American Physiological Society

    DOI： 10.1152/physrev.00023.2017 　

    ISSN： 1522-1210 0031-9333

  322. Omics research project on prospective cohort studies from the Tohoku Medical Megabank Project. International-journal Peer-reviewed

    Seizo Koshiba, Ikuko Motoike, Daisuke Saigusa, Jin Inoue, Matsuyuki Shirota, Yasutake Katoh, Fumiki Katsuoka, Inaho Danjoh, Atsushi Hozawa, Shinichi Kuriyama, Naoko Minegishi, Masao Nagasaki, Takako Takai-Igarashi, Soichi Ogishima, Nobuo Fuse, Shigeo Kure, Gen Tamiya, Osamu Tanabe, Jun Yasuda, Kengo Kinoshita, Masayuki Yamamoto

    Genes to cells : devoted to molecular & cellular mechanisms　23　(6)　406-417　2018/06

    DOI： 10.1111/gtc.12588 　

    ISSN： 1356-9597

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    Population-based prospective cohort studies are indispensable for modern medical research as they provide important knowledge on the influences of many kinds of genetic and environmental factors on the cause of disease. Although traditional cohort studies are mainly conducted using questionnaires and physical examinations, modern cohort studies incorporate omics and genomic approaches to obtain comprehensive physical information, including genetic information. Here, we report the design and midterm results of multi-omics analysis on population-based prospective cohort studies from the Tohoku Medical Megabank (TMM) Project. We have incorporated genomic and metabolomic studies in the TMM cohort study as both metabolome and genome analyses are suitable for high-throughput analysis of large-scale cohort samples. Moreover, an association study between the metabolome and genome show that metabolites are an important intermediate phenotype connecting genetic and lifestyle factors to physical and pathologic phenotypes. We apply our metabolome and genome analyses to large-scale cohort samples in the following studies.

  323. NFE2-Related transcription factor 2 coordinates antioxidant defense with thyroglobulin production and iodination in the thyroid gland Peer-reviewed

    Panos G. Ziros, Ioannis G. Habeos, Dionysios V. Chartoumpekis, Eleni Ntalampyra, Emmanuel Somm, Cédric O. Renaud, Massimo Bongiovanni, Ioannis P. Trougakos, Masayuki Yamamoto, Thomas W. Kensler, Pilar Santisteban, Nancy Carrasco, Carrie Ris-Stalpers, Elena Amendola, Xiao-Hui Liao, Luciano Rossich, Lisa Thomasz, Guillermo J. Juvenal, Samuel Refetoff, Gerasimos P. Sykiotis

    Thyroid　28　(6)　780-798　2018/06/01

    Publisher: Mary Ann Liebert Inc.

    DOI： 10.1089/thy.2018.0018 　

    ISSN： 1557-9077 1050-7256

  324. Erratum: Detection of novel metabolite for roxadustat doping by global metabolomics (Journal of Biochemistry (2018) DOI: 10.1093/jb/mvy028) Peer-reviewed

    Daisuke Saigusa, Norio Suzuki, Yotaro Matsumoto, Keiko Umeda, Yoshihisa Tomioka, Seizo Koshiba, Masayuki Yamamoto

    Journal of Biochemistry　163　(6)　e1　2018/06/01

    Publisher: Oxford University Press

    DOI： 10.1093/jb/mvy036 　

    ISSN： 1756-2651 0021-924X

  325. Deletion of both p62 and Nrf2 spontaneously results in the development of nonalcoholic steatohepatitis. Peer-reviewed

    Akiyama K, Warabi E, Okada K, Yanagawa T, Ishii T, Kose K, Tokushige K, Ishige K, Mizokami Y, Yamagata K, Onizawa K, Ariizumi SI, Yamamoto M, Shoda J

    Experimental animals　67　(2)　201-218　2018/05

    DOI： 10.1538/expanim.17-0112 　

    ISSN： 1341-1357

  326. Nrf2 deficiency promotes the progression from acute tubular damage to chronic renal fibrosis following unilateral ureteral obstruction Peer-reviewed

    Weiwei Kong, Jingqi Fu, Nan Liu, Congcong Jiao, Guangying Guo, Junjun Luan, Huihui Wang, Li Yao, Lining Wang, Masayuki Yamamoto, Jingbo Pi, Hua Zhou

    Nephrology Dialysis Transplantation　33　(5)　771-783　2018/05/01

    Publisher: Oxford University Press

    DOI： 10.1093/ndt/gfx299 　

    ISSN： 1460-2385 0931-0509

  327. KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy Peer-reviewed

    Tawfeeq Shekh-Ahmad, Ramona Eckel, Sharadha Dayalan Naidu, Maureen Higgins, Masayuki Yamamoto, Albena T. DInkova-Kostova, Stjepana Kovac, Andrey Y. Abramov, Matthew C. Walker

    Brain　141　(5)　1390-1403　2018/05/01

    Publisher: Oxford University Press

    DOI： 10.1093/brain/awy071 　

    ISSN： 1460-2156 0006-8950

  328. Hyperactivation of Nrf2 leads to hypoplasia of bone in vivo Peer-reviewed

    Eiki Yoshida, Takafumi Suzuki, Masanobu Morita, Keiko Taguchi, Kohei Tsuchida, Hozumi Motohashi, Minoru Doita, Masayuki Yamamoto

    Genes to Cells　23　(5)　386-392　2018/05/01

    Publisher: Blackwell Publishing Ltd

    DOI： 10.1111/gtc.12579 　

    ISSN： 1365-2443 1356-9597

  329. ゲノミクスを基盤とした生活習慣病解析最前線 ゲノム情報と連携した日本人多層オミックス参照パネルの意義

    小柴 生造, 元池 育子, 三枝 大輔, 井上 仁, 城田 松之, 青木 裕一, 田高 周, 斎藤 智, 木下 賢吾, 山本 雅之

    糖尿病　61　(Suppl.1)　S-48　2018/04

    Publisher: (一社)日本糖尿病学会

    ISSN： 0021-437X

    eISSN： 1881-588X

  330. Nrf2 activation attenuates genetic endoplasmic reticulum stress induced by a mutation in the phosphomannomutase 2 gene in zebrafish. International-journal Peer-reviewed

    Katsuki Mukaigasa, Tadayuki Tsujita, Vu Thanh Nguyen, Li Li, Hirokazu Yagi, Yuji Fuse, Yaeko Nakajima-Takagi, Koichi Kato, Masayuki Yamamoto, Makoto Kobayashi

    Proceedings of the National Academy of Sciences of the United States of America　115　(11)　2758-2763　2018/03/13

    DOI： 10.1073/pnas.1714056115 　

    ISSN： 0027-8424

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    Nrf2 plays critical roles in animals' defense against electrophiles and oxidative stress by orchestrating the induction of cytoprotective genes. We previously isolated the zebrafish mutant it768, which displays up-regulated expression of Nrf2 target genes in an uninduced state. In this paper, we determine that the gene responsible for it768 was the zebrafish homolog of phosphomannomutase 2 (Pmm2), which is a key enzyme in the initial steps of N-glycosylation, and its mutation in humans leads to PMM2-CDG (congenital disorders of glycosylation), the most frequent type of CDG. The pmm2 it768 larvae exhibited mild defects in N-glycosylation, indicating that the pmm2 it768 mutation is a hypomorph, as in human PMM2-CDG patients. A gene expression analysis showed that pmm2 it768 larvae display up-regulation of endoplasmic reticulum (ER) stress, suggesting that the activation of Nrf2 was induced by the ER stress. Indeed, the treatment with the ER stress-inducing compounds up-regulated the gstp1 expression in an Nrf2-dependent manner. Furthermore, the up-regulation of gstp1 by the pmm2 inactivation was diminished by knocking down or out double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK), one of the main ER stress sensors, suggesting that Nrf2 was activated in response to the ER stress via the PERK pathway. ER stress-induced activation of Nrf2 was reported previously, but the results have been controversial. Our present study clearly demonstrated that ER stress can indeed activate Nrf2 and this regulation is evolutionarily conserved among vertebrates. Moreover, ER stress induced in pmm2 it768 mutants was ameliorated by the treatment of the Nrf2-activator sulforaphane, indicating that Nrf2 plays significant roles in the reduction of ER stress.

  331. 他分野の基礎研究から学ぶ最先端研究 メタボローム解析を応用した個別化医療

    三枝 大輔, 佐藤 孝太, 齋藤 律水, 元池 育子, 中澤 徹, 山本 雅之

    日本眼科学会雑誌　122　(臨増)　30-30　2018/03

    Publisher: (公財)日本眼科学会

    ISSN： 0029-0203

  332. 東北メディカル・メガバンク地域住民コホート調査に基づく、日本人呼気一酸化窒素濃度の分布と影響因子の解析(中間報告) Peer-reviewed

    山田 充啓, 杉浦 久敏, 布施 昇男, 寳澤 篤, 高井 貴子, 土屋 奈歩, 光根 歩, 栗山 進一, 山本 雅之, 一ノ瀬 正和

    日本呼吸器学会誌　7　(増刊)　213-213　2018/03

    Publisher: (一社)日本呼吸器学会

    ISSN： 2186-5876

    eISSN： 2186-5884

  333. YTH-RNA-binding protein prevents deleterious expression of meiotic proteins by tethering their mRNAs to nuclear foci Peer-reviewed

    Yuichi Shichino, Yoko Otsubo, Yoshitaka Kimori, Masayuki Yamamoto, Akira Yamashita

    eLife　7　2018/02/09

    Publisher: eLife Sciences Publications Ltd

    DOI： 10.7554/eLife.32155 　

    ISSN： 2050-084X

  334. Identification of somatic genetic alterations in ovarian clear cell carcinoma with next generation sequencing Peer-reviewed

    Yusuke Shibuya, Hideki Tokunaga, Sakae Saito, Kazurou Shimokawa, Fumiki Katsuoka, Li Bin, Kaname Kojima, Masao Nagasaki, Masayuki Yamamoto, Nobuo Yaegashi, Jun Yasuda

    GENES CHROMOSOMES & CANCER　57　(2)　51-60　2018/02

    DOI： 10.1002/gcc.22507 　

    ISSN： 1045-2257

    eISSN： 1098-2264

  335. Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals. International-journal Peer-reviewed

    Yumi Yamaguchi-Kabata, Jun Yasuda, Osamu Tanabe, Yoichi Suzuki, Hiroshi Kawame, Nobuo Fuse, Masao Nagasaki, Yosuke Kawai, Kaname Kojima, Fumiki Katsuoka, Sakae Saito, Inaho Danjoh, Ikuko N Motoike, Riu Yamashita, Seizo Koshiba, Daisuke Saigusa, Gen Tamiya, Shigeo Kure, Nobuo Yaegashi, Yoshio Kawaguchi, Fuji Nagami, Shinichi Kuriyama, Junichi Sugawara, Naoko Minegishi, Atsushi Hozawa, Soichi Ogishima, Hideyasu Kiyomoto, Takako Takai-Igarashi, Kengo Kinoshita, Masayuki Yamamoto

    Journal of human genetics　63　(2)　213-230　2018/02

    DOI： 10.1038/s10038-017-0347-1 　

    ISSN： 1434-5161

    More details Close

    Clarifying allele frequencies of disease-related genetic variants in a population is important in genomic medicine; however, such data is not yet available for the Japanese population. To estimate frequencies of actionable pathogenic variants in the Japanese population, we examined the reported pathological variants in genes recommended by the American College of Medical Genetics and Genomics (ACMG) in our reference panel of genomic variations, 2KJPN, which was created by whole-genome sequencing of 2049 individuals of the resident cohort of the Tohoku Medical Megabank Project. We searched for pathogenic variants in 2KJPN for 57 autosomal ACMG-recommended genes responsible for 26 diseases and then examined their frequencies. By referring to public databases of pathogenic variations, we identified 143 reported pathogenic variants in 2KJPN for the 57 ACMG recommended genes based on a classification system. At the individual level, 21% of the individuals were found to have at least one reported pathogenic allele. We then conducted a literature survey to review the variants and to check for evidence of pathogenicity. Our results suggest that a substantial number of people have reported pathogenic alleles for the ACMG genes, and reviewing variants is indispensable for constructing the information infrastructure of genomic medicine for the Japanese population.

  336. Detection of novel metabolite for Roxadustat doping by global metabolomics. International-journal Peer-reviewed

    Saigusa D, Suzuki N, Matsumoto Y, Umeda K, Tomioka Y, Koshiba S, Yamamoto M

    Journal of biochemistry　2018/02

    DOI： 10.1093/jb/mvy028 　

    ISSN： 0021-924X

    More details Close

    Roxadustat (FG-4592, Rox) is a stabilizer for hypoxia-inducible transcription factors (HIFs), which induce production of the erythroid growth factor erythropoietin, and has been listed by the World Anti-Doping Agency as a prohibited substance for athletes since 2011. Although the detection technologies for Rox and its glucuronide-conjugated metabolite (Rox-Gluc) have been developed exploiting triple quadrupole mass spectrometry (MS/MS), the production of metabolites from Rox in the human body remains to be clarified. Here, we established a protocol for the detection of unknown metabolites in plasma and urine samples from Rox-doping mice by global metabolomics using an ultra high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). We identified methylated Rox (Rox-Methyl), a novel metabolite, and Rox-Gluc in mouse urine by principal component analysis and orthogonal partial least squares discriminant analysis based on detected features by UHPLC-QTOF/MS analysis. The estimated pharmacokinetic parameters of Rox-Methyl and Rox-Gluc in mouse plasma showed similar profiles to that of Rox and both compounds showed similar biological activities. Of note, Rox-Methyl showed shorter half-life than Rox-Gluc in vivo, implying the easy escape from anti-doping screen. These results demonstrate that the global metabolomics method introduced in this study will contribute to the identification and detection of HIF-analog doping.

  337. jMorp: Japanese Multi Omics Reference Panel. International-journal Peer-reviewed

    Shu Tadaka, Daisuke Saigusa, Ikuko N Motoike, Jin Inoue, Yuichi Aoki, Matsuyuki Shirota, Seizo Koshiba, Masayuki Yamamoto, Kengo Kinoshita

    Nucleic acids research　46　(D1)　D551-D557-D557　2018/01/04

    DOI： 10.1093/nar/gkx978 　

    ISSN： 0305-1048

    More details Close

    We developed jMorp, a new database containing metabolome and proteome data for plasma obtained from >5000 healthy Japanese volunteers from the Tohoku Medical Megabank Cohort Study, which is available at https://jmorp.megabank.tohoku.ac.jp. Metabolome data were measured by proton nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS), while proteome data were obtained by nanoLC-MS. We released the concentration distributions of 37 metabolites identified by NMR, distributions of peak intensities of 257 characterized metabolites by LC-MS, and observed frequencies of 256 abundant proteins. Additionally, correlation networks for the metabolites can be observed using an interactive network viewer. Compared with some existing databases, jMorp has some unique features: (i) Metabolome data were obtained using a single protocol in a single institute, ensuring that measurement biases were significantly minimized; (ii) The database contains large-scale data for healthy volunteers with various health records and genome data and (iii) Correlations between metabolites can be easily observed using the graphical viewer. Metabolites data are becoming important intermediate markers for evaluating the health states of humans, and thus jMorp is an outstanding resource for a wide range of researchers, particularly those in the fields of medical science, applied molecular biology, and biochemistry.

  338. Structural instability of IκB kinase β promotes autophagic degradation through enhancement of Keap1 binding. Peer-reviewed

    Kanamoto M, Tsuchiya Y, Nakao Y, Suzuki T, Motohashi H, Yamamoto M, Kamata H

    PloS one　13　(11)　e0203978　2018

    DOI： 10.1371/journal.pone.0203978 　

  339. Simultaneous K-ras activation and Keap1 deletion cause atrophy of pancreatic parenchyma Peer-reviewed

    Shin Hamada, Tooru Shimosegawa, Keiko Taguchi, Tatsuhide Nabeshima, Masayuki Yamamoto, Atsushi Masamune

    American Journal of Physiology - Gastrointestinal and Liver Physiology　314　(1)　G65-G74　2018/01/01

    Publisher: American Physiological Society

    DOI： 10.1152/ajpgi.00228.2017 　

    ISSN： 1522-1547 0193-1857

  340. 5-aminolevulinic acid (ALA) deficiency causes impaired glucose tolerance and insulin resistance coincident with an attenuation of mitochondrial function in aged mice Peer-reviewed

    Shinichi Saitoh, Satoshi Okano, Hidekazu Nohara, Hiroshi Nakano, Nobuyuki Shirasawa, Akira Naito, Masayuki Yamamoto, Vincent P. Kelly, Kiwamu Takahashi, Tohru Tanaka, Motowo Nakajima, Osamu Nakajima

    PLoS ONE　13　(1)　e0189593　2018/01/01

    Publisher: Public Library of Science

    DOI： 10.1371/journal.pone.0189593 　

    ISSN： 1932-6203

  341. Quantitative analysis of UV photolesions suggests that cyclobutane pyrimidine dimers produced in mouse skin by UVB are more mutagenic than those produced by UVC Peer-reviewed

    Hironobu Ikehata, Toshio Mori, Thierry Douki, Jean Cadet, Masayuki Yamamoto

    Photochemical and Photobiological Sciences　17　(4)　404-413　2018

    Publisher: Royal Society of Chemistry

    DOI： 10.1039/c7pp00348j 　

    ISSN： 1474-9092 1474-905X

  342. Genetic inactivation of Nrf2 prevents clonal expansion of initiated cells in a nutritional model of rat hepatocarcinogenesis Peer-reviewed

    Claudia Orrù, Marta Szydlowska, Keiko Taguchi, Patrizia Zavattari, Andrea Perra, Masayuki Yamamoto, Amedeo Columbano

    Journal of Hepatology　69　(3)　635-643　2018

    Publisher: Elsevier B.V.

    DOI： 10.1016/j.jhep.2018.05.010 　

    ISSN： 1600-0641 0168-8278

  343. Palmitate deranges erythropoietin production via transcription factor ATF4 activation of unfolded protein response Peer-reviewed

    Thitinun Anusornvongchai, Masaomi Nangaku, Tzu-Ming Jao, Chia-Hsien Wu, Yu Ishimoto, Hiroshi Maekawa, Tetsuhiro Tanaka, Akira Shimizu, Masayuki Yamamoto, Norio Suzuki, Ryoji Sassa, Reiko Inagi

    Kidney International　94　(3)　536-550　2018

    Publisher: Elsevier B.V.

    DOI： 10.1016/j.kint.2018.03.011 　

    ISSN： 1523-1755 0085-2538

  344. Adipocyte-specific deficiency of Nfe2l1 disrupts plasticity of white adipose tissues and metabolic homeostasis in mice Peer-reviewed

    Yongyong Hou, Zhiyuan Liu, Zhuo Zuo, Tianchang Gao, Jingqi Fu, Huihui Wang, Yuanyuan Xu, Dianxin Liu, Masayuki Yamamoto, Beibei Zhu, Yiguo Zhang, Melvin E. Andersen, Qiang Zhang, Jingbo Pi

    Biochemical and Biophysical Research Communications　503　(1)　264-270　2018

    Publisher: Elsevier B.V.

    DOI： 10.1016/j.bbrc.2018.06.013 　

    ISSN： 1090-2104 0006-291X

  345. 妊娠高血圧症候群の原因解明を目指した長鎖型シークエンサーによるHLA-G遺伝子解析技術の開発

    西澤 絢子, 熊田 和貴, 舘野 恵子, 和形 麻衣子, 勝岡 史城, 山本 雅之, 菅原 準一, 安田 純

    生命科学系学会合同年次大会　2017年度　[2P-1139]　2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  346. 高精度日本人多層オミックス参照パネルの提供

    小柴 生造, 元池 育子, 三枝 大輔, 井上 仁, 城田 松之, 斎藤 智, 木下 賢吾, 山本 雅之

    生命科学系学会合同年次大会　2017年度　[3P-1369]　2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  347. ヘム欠乏は骨格筋での細胞内ATPレベル上昇を介してグリコーゲン合成異常を惹起する

    斉藤 真一, 尾崎 司, 中野 博, 野原 豪和, 岡野 聡, 一瀬 白帝, 白澤 信行, 内藤 輝, 山本 雅之, Vincent Kelly, 高橋 究, 田中 徹, 中島 元夫, 中島 修

    生命科学系学会合同年次大会　2017年度　[4P1T06-1073)]　2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  348. 3番染色体転座・逆位を伴う白血病におけるGATA2遺伝子発現減少の貢献

    鈴木 未来子, 山岡 彩香, 片山 紗乙莉, 山本 雅之

    生命科学系学会合同年次大会　2017年度　[2P-0884]　2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  349. 骨髄球系細胞における転写因子Nrf2活性化がエラスターゼ誘導性肺気腫の形成を阻害する

    佐藤 慶, 鈴木 隆史, 長沼 絵理子, 杉浦 久敏, 一ノ瀬 正和, 山本 雅之

    生命科学系学会合同年次大会　2017年度　[2LBA-103]　2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  350. 貧血は低血圧を招来し腎レニン発現を誘導する Peer-reviewed

    宮内 健一郎, 加藤 幸一郎, 祢津 昌宏, 齋藤 さかえ, 佐藤 浩司, 山本 雅之, 鈴木 教郎

    生命科学系学会合同年次大会　2017年度　[2LBA-101]　2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  351. Effects of in vivo deletion of GATA2 in bone marrow stromal cells Peer-reviewed

    Shin Hasegawa, Tohru Fujiwara, Yoko Okitsu, Hiroki Kato, Yuki Sato, Noriko Fukuhara, Yasushi Onishi, Ritsuko Shimizu, Masayuki Yamamoto, Hideo Harigae

    EXPERIMENTAL HEMATOLOGY　56　31-45　2017/12

    DOI： 10.1016/j.exphem.2017.08.004 　

    ISSN： 0301-472X

    eISSN： 1873-2399

  352. Genetic analysis of Japanese primary open-angle glaucoma patients and clinical characterization of risk alleles near CDKN2B-AS1, SIX6 and GAS7 Peer-reviewed

    Yukihiro Shiga, Japan Glaucoma Society Omics Group (JGS-OG), Koji M. Nishiguchi, Yosuke Kawai, Kaname Kojima, Kota Sato, Kosuke Fujita, Mai Takahashi, Kazuko Omodaka, Makoto Araie, Kenji Kashiwagi, Makoto Aihara, Takeshi Iwata, Fumihiko Mabuchi, Mitsuko Takamoto, Mineo Ozaki, Kazuhide Kawase, Nobuo Fuse, Masayuki Yamamoto, Jun Yasuda, Masao Nagasaki, Toru Nakazawa

    PLoS ONE　12　(12)　e0186678　2017/12/01

    Publisher: Public Library of Science

    DOI： 10.1371/journal.pone.0186678 　

    ISSN： 1932-6203

  353. Reducing Inflammatory Cytokine Production from Renal Collecting Duct Cells by Inhibiting GATA2 Ameliorates Acute Kidney Injury Peer-reviewed

    Lei Yu, Takashi Moriguchi, Hiroshi Kaneko, Makiko Hayashi, Atsushi Hasegawa, Masahiro Nezu, Hideyuki Saya, Masayuki Yamamoto, Ritsuko Shimizu

    MOLECULAR AND CELLULAR BIOLOGY　37　(22)　2017/11

    DOI： 10.1128/MCB.00211-17 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  354. Discovery of benzo[g]indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor Peer-reviewed

    Daisuke Yasuda, Akihiro Yuasa, Rika Obata, Mao Nakajima, Kyoko Takahashi, Tomoyuki Ohe, Yoshinobu Ichimura, Masaaki Komatsu, Masayuki Yamamoto, Riyo Imamura, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano, Tadahiko Mashino

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS　27　(22)　5006-5009　2017/11

    DOI： 10.1016/j.bmcl.2017.10.008 　

    ISSN： 0960-894X

    eISSN： 1464-3405

  355. Induction of erythropoietin gene expression in epithelial cells by chemicals identified in GATA inhibitor screenings Peer-reviewed

    Hiroshi Kaneko, Takehide Katoh, Ikuo Hirano, Atsushi Hasegawa, Tadayuki Tsujita, Masayuki Yamamoto, Ritsuko Shimizu

    GENES TO CELLS　22　(11)　939-952　2017/11

    DOI： 10.1111/gtc.12537 　

    ISSN： 1356-9597

    eISSN： 1365-2443

  356. Genome-wide meta-analysis in Japanese populations identifies novel variants at the TMC6-TMC8 and SIX3-SIX2 loci associated with HbA(1c) Peer-reviewed

    Tsuyoshi Hachiya, Shohei Komaki, Yutaka Hasegawa, Hideki Ohmomo, Kozo Tanno, Atsushi Hozawa, Gen Tamiya, Masayuki Yamamoto, Kuniaki Ogasawara, Motoyuki Nakamura, Jiro Hitomi, Yasushi Ishigaki, Makoto Sasaki, Atsushi Shimizu

    SCIENTIFIC REPORTS　7　(1)　16147　2017/11

    DOI： 10.1038/s41598-017-16493-0 　

    ISSN： 2045-2322

  357. NRF2 Activation Impairs Quiescence and Bone Marrow Reconstitution Capacity of Hematopoietic Stem Cells Peer-reviewed

    Shohei Murakami, Takuma Suzuki, Hideo Harigae, Paul-Henri Romeo, Masayuki Yamamoto, Hozumi Motohashi

    MOLECULAR AND CELLULAR BIOLOGY　37　(19)　2017/10

    DOI： 10.1128/MCB.00086-17 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  358. NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology Peer-reviewed

    Ana I. Rojo, Marta Pajares, Patricia Rada, Angel Nunez, Alejo J. Nevado-Holgado, Richard Killik, Fred Van Leuven, Elena Ribe, Simon Lovestone, Masayuki Yamamoto, Antonio Cuadrado

    REDOX BIOLOGY　13　444-451　2017/10

    DOI： 10.1016/j.redox.2017.07.006 　

    ISSN： 2213-2317

  359. Stress-sensing mechanisms and the physiological roles of the Keap1-Nrf2 system during cellular stress Peer-reviewed

    Takafumi Suzuki, Masayuki Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　292　(41)　16817-16824　2017/10

    DOI： 10.1074/jbc.R117.800169 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  360. Genome-wide association study identifies 112 new loci for body mass index in the Japanese population Peer-reviewed

    Masato Akiyama, Yukinori Okada, Masahiro Kanai, Atsushi Takahashi, Yukihide Momozawa, Masashi Ikeda, Nakao Iwata, Shiro Ikegawa, Makoto Hirata, Koichi Matsuda, Motoki Iwasaki, Taiki Yamaji, Norie Sawada, Tsuyoshi Hachiya, Kozo Tanno, Atsushi Shimizu, Atsushi Hozawa, Naoko Minegishi, Shoichiro Tsugane, Masayuki Yamamoto, Michiaki Kubo, Yoichiro Kamatani

    NATURE GENETICS　49　(10)　1458-+　2017/10

    DOI： 10.1038/ng.3951 　

    ISSN： 1061-4036

    eISSN： 1546-1718

  361. An Overview of the Advantages of KEAP1-NRF2 System Activation During Inflammatory Disease Treatment. Peer-reviewed

    Keleku-Lukwete N, Suzuki M, Yamamoto M

    Antioxidants & redox signaling　2017/10

    DOI： 10.1089/ars.2017.7358 　

    ISSN： 1523-0864

  362. Nuclear factor (erythroid derived 2)-like 2 activation increases exercise endurance capacity via redox modulation in skeletal muscles Peer-reviewed

    Sechang Oh, Shoichi Komine, Eiji Warabi, Kentaro Akiyama, Akiko Ishii, Kazunori Ishige, Yuji Mizokami, Keisuke Kuga, Masaki Horie, Yoshihiro Miwa, Takao Iwawaki, Masayuki Yamamoto, Junichi Shoda

    SCIENTIFIC REPORTS　7　(1)　12902　2017/10

    DOI： 10.1038/s41598-017-12926-y 　

    ISSN： 2045-2322

  363. Effects of deficiency of Kelch-like ECH-associated protein 1 on skeletal organization: a mechanism for diminished nuclear factor of activated T cells cytoplasmic 1 during osteoclastogenesis Peer-reviewed

    Eiko Sakai, Masanobu Morita, Masahiro Ohuchi, Mizuho A. Kido, Yutaka Fukuma, Kazuhisa Nishishita, Kuniaki Okamoto, Ken Itoh, Masayuki Yamamoto, Takayuki Tsukuba

    FASEB JOURNAL　31　(9)　4011-4022　2017/09

    DOI： 10.1096/fj.201700177R 　

    ISSN： 0892-6638

    eISSN： 1530-6860

  364. Selective termination of lncRNA transcription promotes heterochromatin silencing and cell differentiation Peer-reviewed

    Leila Touat-Todeschini, Yuichi Shichino, Mathieu Dangin, Nicolas Thierry-Mieg, Benoit Gilquin, Edwige Hiriart, Ravi Sachidanandam, Emeline Lambert, Janine Brettschneider, Michael Reuter, Jan Kadlec, Ramesh Pillai, Akira Yamashita, Masayuki Yamamoto, Andre Verdel

    EMBO JOURNAL　36　(17)　2626-2641　2017/09

    DOI： 10.15252/embj.201796571 　

    ISSN： 0261-4189

    eISSN： 1460-2075

  365. Low-Dose Irradiation Promotes Persistent Oxidative Stress and Decreases Self-Renewal in Hematopoietic Stem Cells Peer-reviewed

    Sarah Rodrigues-Moreira, Stephanie G. Moreno, Giulia Ghinatti, Daniel Lewandowski, Francoise Hoffschir, Federica Ferri, Anne-Sophie Gallouet, Denise Gay, Hozumi Motohashi, Masayuki Yamamoto, Michael C. Joiner, Nathalie Gault, Paul-Henri Romeo

    CELL REPORTS　20　(13)　3199-3211　2017/09

    DOI： 10.1016/j.celrep.2017.09.013 　

    ISSN： 2211-1247

  366. FANTOM5 CAGE profiles of human and mouse samples. International-journal Peer-reviewed

    Shuhei Noguchi, Takahiro Arakawa, Shiro Fukuda, Masaaki Furuno, Akira Hasegawa, Fumi Hori, Sachi Ishikawa-Kato, Kaoru Kaida, Ai Kaiho, Mutsumi Kanamori-Katayama, Tsugumi Kawashima, Miki Kojima, Atsutaka Kubosaki, Ri-Ichiroh Manabe, Mitsuyoshi Murata, Sayaka Nagao-Sato, Kenichi Nakazato, Noriko Ninomiya, Hiromi Nishiyori-Sueki, Shohei Noma, Eri Saijyo, Akiko Saka, Mizuho Sakai, Christophe Simon, Naoko Suzuki, Michihira Tagami, Shoko Watanabe, Shigehiro Yoshida, Peter Arner, Richard A Axton, Magda Babina, J Kenneth Baillie, Timothy C Barnett, Anthony G Beckhouse, Antje Blumenthal, Beatrice Bodega, Alessandro Bonetti, James Briggs, Frank Brombacher, Ailsa J Carlisle, Hans C Clevers, Carrie A Davis, Michael Detmar, Taeko Dohi, Albert S B Edge, Matthias Edinger, Anna Ehrlund, Karl Ekwall, Mitsuhiro Endoh, Hideki Enomoto, Afsaneh Eslami, Michela Fagiolini, Lynsey Fairbairn, Mary C Farach-Carson, Geoffrey J Faulkner, Carmelo Ferrai, Malcolm E Fisher, Lesley M Forrester, Rie Fujita, Jun-Ichi Furusawa, Teunis B Geijtenbeek, Thomas Gingeras, Daniel Goldowitz, Sven Guhl, Reto Guler, Stefano Gustincich, Thomas J Ha, Masahide Hamaguchi, Mitsuko Hara, Yuki Hasegawa, Meenhard Herlyn, Peter Heutink, Kelly J Hitchens, David A Hume, Tomokatsu Ikawa, Yuri Ishizu, Chieko Kai, Hiroshi Kawamoto, Yuki I Kawamura, Judith S Kempfle, Tony J Kenna, Juha Kere, Levon M Khachigian, Toshio Kitamura, Sarah Klein, S Peter Klinken, Alan J Knox, Soichi Kojima, Haruhiko Koseki, Shigeo Koyasu, Weonju Lee, Andreas Lennartsson, Alan Mackay-Sim, Niklas Mejhert, Yosuke Mizuno, Hiromasa Morikawa, Mitsuru Morimoto, Kazuyo Moro, Kelly J Morris, Hozumi Motohashi, Christine L Mummery, Yutaka Nakachi, Fumio Nakahara, Toshiyuki Nakamura, Yukio Nakamura, Tadasuke Nozaki, Soichi Ogishima, Naganari Ohkura, Hiroshi Ohno, Mitsuhiro Ohshima, Mariko Okada-Hatakeyama, Yasushi Okazaki, Valerio Orlando, Dmitry A Ovchinnikov, Robert Passier, Margaret Patrikakis, Ana Pombo, Swati Pradhan-Bhatt, Xian-Yang Qin, Michael Rehli, Patrizia Rizzu, Sugata Roy, Antti Sajantila, Shimon Sakaguchi, Hiroki Sato, Hironori Satoh, Suzana Savvi, Alka Saxena, Christian Schmidl, Claudio Schneider, Gundula G Schulze-Tanzil, Anita Schwegmann, Guojun Sheng, Jay W Shin, Daisuke Sugiyama, Takaaki Sugiyama, Kim M Summers, Naoko Takahashi, Jun Takai, Hiroshi Tanaka, Hideki Tatsukawa, Andru Tomoiu, Hiroo Toyoda, Marc van de Wetering, Linda M van den Berg, Roberto Verardo, Dipti Vijayan, Christine A Wells, Louise N Winteringham, Ernst Wolvetang, Yoko Yamaguchi, Masayuki Yamamoto, Chiyo Yanagi-Mizuochi, Misako Yoneda, Yohei Yonekura, Peter G Zhang, Silvia Zucchelli, Imad Abugessaisa, Erik Arner, Jayson Harshbarger, Atsushi Kondo, Timo Lassmann, Marina Lizio, Serkan Sahin, Thierry Sengstag, Jessica Severin, Hisashi Shimoji, Masanori Suzuki, Harukazu Suzuki, Jun Kawai, Naoto Kondo, Masayoshi Itoh, Carsten O Daub, Takeya Kasukawa, Hideya Kawaji, Piero Carninci, Alistair R R Forrest, Yoshihide Hayashizaki

    Scientific data　4　170112-170112　2017/08/29

    DOI： 10.1038/sdata.2017.112 　

    More details Close

    In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.

  367. Systemic Activation of NRF2 Alleviates Lethal Autoimmune Inflammation in Scurfy Mice Peer-reviewed

    Takuma Suzuki, Shohei Murakami, Shyam S. Biswal, Shimon Sakaguchi, Hideo Harigae, Masayuki Yamamoto, Hozumi Motohashi

    MOLECULAR AND CELLULAR BIOLOGY　37　(15)　2017/08

    DOI： 10.1128/MCB.00063-17 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  368. GATA2 haploinsufficiency accelerates EVI1-driven leukemogenesis Peer-reviewed

    Saori Katayama, Mikiko Suzuki, Ayaka Yamaoka, Nadine Keleku-Lukwete, Fumiki Katsuoka, Akihito Otsuki, Shigeo Kure, James Douglas Engel, Masayuki Yamamoto

    BLOOD　130　(7)　908-919　2017/08

    DOI： 10.1182/blood-2016-12-756767 　

    ISSN： 0006-4971

    eISSN： 1528-0020

  369. Infiltration of M1, but not M2, macrophages is impaired after unilateral ureter obstruction in Nrf2-deficient mice Peer-reviewed

    Yuji Sogawa, Hajime Nagasu, Shigeki Iwase, Chieko Ihoriya, Seiji Itano, Atsushi Uchida, Kengo Kidokoro, Shun'ichiro Taniguchi, Masafumi Takahashi, Minoru Satoh, Tamaki Sasaki, Takafumi Suzuki, Masayuki Yamamoto, Tiffany Horng, Naoki Kashihara

    SCIENTIFIC REPORTS　7　(1)　8801　2017/08

    DOI： 10.1038/s41598-017-08054-2 　

    ISSN： 2045-2322

  370. Development of a Questionnaire Method of Screening for Citrin Deficiency in Schoolchildren Peer-reviewed

    Miyashita M, Ishikuro M, Kikuya M, Yamanaka C, Mizuno S, Nagai M, Sato Y, Obara T, Metoki H, Kikuchi A, Nakaya N, Hozawa A, Tsuji I, Yaegashi N, Yamamoto M, Kure S, Kuriyama S

    Journal of Pediatrics and Congenital Disorders　4　101　2017/07

  371. Regulation of hypoxia-inducible gene expression after HIF activation Peer-reviewed

    Norio Suzuki, Katarina Gradin, Lorenz Poellinger, Masayuki Yamamoto

    EXPERIMENTAL CELL RESEARCH　356　(2)　182-186　2017/07

    DOI： 10.1016/j.yexcr.2017.03.013 　

    ISSN： 0014-4827

    eISSN： 1090-2422

  372. Security controls in an integrated Biobank to protect privacy in data sharing: rationale and study design Peer-reviewed

    Takako Takai-Igarashi, Kengo Kinoshita, Masao Nagasaki, Soichi Ogishima, Naoki Nakamura, Sachiko Nagase, Satoshi Nagaie, Tomo Saito, Fuji Nagami, Naoko Minegishi, Yoichi Suzuki, Kichiya Suzuki, Hiroaki Hashizume, Shinichi Kuriyama, Atsushi Hozawa, Nobuo Yaegashi, Shigeo Kure, Gen Tamiya, Yoshio Kawaguchi, Hiroshi Tanaka, Masayuki Yamamoto

    BMC MEDICAL INFORMATICS AND DECISION MAKING　17　(1)　100　2017/07

    DOI： 10.1186/s12911-017-0494-5 　

    ISSN： 1472-6947

  373. Exome sequencing deciphers a germline MET mutation in familial epidermal growth factor receptor-mutant lung cancer. International-journal Peer-reviewed

    Naoki Tode, Toshiaki Kikuchi, Tomohiro Sakakibara, Taizou Hirano, Akira Inoue, Shinya Ohkouchi, Tsutomu Tamada, Tatsuma Okazaki, Akira Koarai, Hisatoshi Sugiura, Tetsuya Niihori, Yoko Aoki, Keiko Nakayama, Kunio Matsumoto, Yoichi Matsubara, Masayuki Yamamoto, Akira Watanabe, Toshihiro Nukiwa, Masakazu Ichinose

    Cancer science　108　(6)　1263-1270　2017/06

    DOI： 10.1111/cas.13233 　

    ISSN： 1347-9032

    More details Close

    Lung cancer accompanied by somatic activating mutations in the epidermal growth factor receptor (EGFR) gene, which is associated with a significant clinical response to the targeted therapy, is frequently found in never-smoking Asian women with adenocarcinoma. Although this implies genetic factors underlying the carcinogenesis, the etiology remains unclear. To gain insight into the pathogenic mechanisms, we sequenced the exomes in the peripheral-blood DNA from six siblings, four affected and two unaffected siblings, of a family with familial EGFR-mutant lung adenocarcinoma. We identified a heterozygous missense mutation in MET proto-oncogene, p.Asn375Lys, in all four affected siblings. Combined with somatic loss of heterozygosity for MET, the higher allele frequency in a Japanese sequencing database supports a causative role of the MET mutation in EGFR-mutant lung cancer. Functional assays showed that the mutation reduces the binding affinity of MET for its ligand, hepatocyte growth factor, and damages the subsequent cellular processes, including proliferation, clonogenicity, motility and tumorigenicity. The MET mutation was further observed to abrogate the ERBB3-mediated AKT signal transduction, which is shared downstream by EGFR. These findings provide an etiological view that the MET mutation is involved in the pathogenesis of EGFR-mutant lung cancer because it generates oncogenic stress that induces compensatory EGFR activation. The identification of MET in a family with familial EGFR-mutant lung cancer is insightful to explore the pathogenic mechanism of not only familial, but also sporadic EGFR-mutant lung cancer by underscoring MET-related signaling molecules.

  374. Identification of six new genetic loci associated with atrial fibrillation in the Japanese population Peer-reviewed

    Siew-Kee Low, Atsushi Takahashi, Yusuke Ebana, Kouichi Ozaki, Ingrid E. Christophersen-, Patrick T. Ellinor, Soichi Ogishima, Masayuki Yamamoto, Mamoru Satoh, Makoto Sasaki, Taiki Yamaji, Motoki Iwasaki, Shoichiro Tsugane, Keitaro Tanaka, Mariko Naito, Kenji Wakai, Hideo Tanaka, Tetsushi Furukawa, Michiaki Kubo, Kaoru Ito, Yoichiro Kamatani, Toshihiro Tanaka

    NATURE GENETICS　49　(6)　953-+　2017/06

    DOI： 10.1038/ng.3842 　

    ISSN： 1061-4036

    eISSN： 1546-1718

  375. Nrf2 promotes mutant K-ras/p53-driven pancreatic carcinogenesis Peer-reviewed

    Shin Hamada, Keiko Taguchi, Atsushi Masamune, Masayuki Yamamoto, Tooru Shimosegawa

    CARCINOGENESIS　38　(6)　661-670　2017/06

    DOI： 10.1093/carcin/bgx043 　

    ISSN： 0143-3334

    eISSN： 1460-2180

  376. Nrf2 inactivation enhances placental angiogenesis in a preeclampsia mouse model and improves maternal and fetal outcomes. International-journal Peer-reviewed

    Masahiro Nezu, Tomokazu Souma, Lei Yu, Hiroki Sekine, Nobuyuki Takahashi, Andrew Zu-Sern Wei, Sadayoshi Ito, Akiyoshi Fukamizu, Zsuzsanna K Zsengeller, Tomohiro Nakamura, Atsushi Hozawa, S Ananth Karumanchi, Norio Suzuki, Masayuki Yamamoto

    Science signaling　10　(479)　2017/05/16

    DOI： 10.1126/scisignal.aam5711 　

    ISSN： 1945-0877

    More details Close

    Placental activation of the renin-angiotensin system (RAS) plays a key role in the pathogenesis of preeclampsia. Reactive oxygen species (ROS) are thought to affect placental angiogenesis, which is critical for preventing preeclampsia pathology. We examined the role of ROS in preeclampsia by genetically modifying the Keap1-Nrf2 pathway, a cellular antioxidant defense system, in a mouse model of RAS-induced preeclampsia. Nrf2 deficiency would be expected to impair cellular antioxidant responses; however, Nrf2 deficiency in preeclamptic mice improved maternal and fetal survival, ameliorated intra-uterine growth retardation, and augmented oxidative DNA damage. Furthermore, the placentas of Nrf2-deficient mice had increased endothelial cell proliferation with dense vascular networks. In contrast, the placentas of preeclamptic mice with overactive Nrf2 showed repressed angiogenesis, which was associated with decreased expression of genes encoding angiogenic chemokines and cytokines. Our findings support the notion that ROS-mediated signaling is essential for maintaining placental angiogenesis in preeclampsia and may provide mechanistic insight into the negative results of clinical trials for antioxidants in preeclampsia.

  377. The KEAP1NRF2 system in cancer Peer-reviewed

    Keiko Taguchi, Masayuki Yamamoto

    Frontiers in Oncology　7　(MAY)　85　2017/05/04

    Publisher: Frontiers Media S.A.

    DOI： 10.3389/fonc.2017.00085 　

    ISSN： 2234-943X

  378. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. International-journal Peer-reviewed

    Akiyoshi Nakayama, Hirofumi Nakaoka, Ken Yamamoto, Masayuki Sakiyama, Amara Shaukat, Yu Toyoda, Yukinori Okada, Yoichiro Kamatani, Takahiro Nakamura, Tappei Takada, Katsuhisa Inoue, Tomoya Yasujima, Hiroaki Yuasa, Yuko Shirahama, Hiroshi Nakashima, Seiko Shimizu, Toshihide Higashino, Yusuke Kawamura, Hiraku Ogata, Makoto Kawaguchi, Yasuyuki Ohkawa, Inaho Danjoh, Atsumi Tokumasu, Keiko Ooyama, Toshimitsu Ito, Takaaki Kondo, Kenji Wakai, Blanka Stiburkova, Karel Pavelka, Lisa K Stamp, Nicola Dalbeth, Yutaka Sakurai, Hiroshi Suzuki, Makoto Hosoyamada, Shin Fujimori, Takashi Yokoo, Tatsuo Hosoya, Ituro Inoue, Atsushi Takahashi, Michiaki Kubo, Hiroshi Ooyama, Toru Shimizu, Kimiyoshi Ichida, Nariyoshi Shinomiya, Tony R Merriman, Hirotaka Matsuo

    Annals of the rheumatic diseases　76　(5)　869-877　2017/05

    DOI： 10.1136/annrheumdis-2016-209632 　

    ISSN： 0003-4967

    eISSN： 1468-2060

  379. 「遺伝の仕組み」と「多様性」を学ぶための小児を対象とした遺伝教育ツール開発の取り組み

    小林 朋子, 菅原 美智子, 石原 利乃, 本郷 一夫, 相澤 弥生, 山口 由美, 齋藤 さかえ, 田中 由佳里, 栗木 美穂, 長神 風二, 安田 純, 栗山 進一, 川目 裕, 山本 雅之, 鈴木 洋一

    日本遺伝カウンセリング学会誌　38　(2)　89-89　2017/05

    Publisher: 日本遺伝カウンセリング学会

    ISSN： 1347-9628

  380. 住民コホート研究における個人への遺伝情報回付(返却) 東北メディカル・メガバンク計画の試み

    川目 裕, 福島 明宗, 長神 風二, 鈴木 洋一, 川口 悦生, 布施 昇男, 徳富 智明, 山本 佳世乃, 沼田 早苗, 小林 朋子, 相澤 弥生, 佐々木 真理, 山本 雅之

    日本遺伝カウンセリング学会誌　38　(2)　95-95　2017/05

    Publisher: 日本遺伝カウンセリング学会

    ISSN： 1347-9628

  381. ゲノムコホート研究における個人への遺伝情報の結果返却に関する遺伝カウンセリング記録の運用についての取り組みと今後の課題

    相澤 弥生, 高井 貴子, 沼田 早苗, 山本 佳世乃, 徳富 智明, 福島 明宗, 小林 朋子, 長神 風二, 鈴木 洋一, 川口 悦生, 布施 昇男, 川目 裕, 佐々木 真理, 山本 雅之

    日本遺伝カウンセリング学会誌　38　(2)　95-95　2017/05

    Publisher: 日本遺伝カウンセリング学会

    ISSN： 1347-9628

  382. The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice Peer-reviewed

    Chika Higashi, Atsuko Kawaji, Naoto Tsuda, Makiko Hayashi, Ryota Saito, Yoko Yagishita, Takafumi Suzuki, Akira Uruno, Masaki Nakamura, Kazunari Nakao, Shoji Furusako, Masayuki Yamamoto

    EUROPEAN JOURNAL OF PHARMACOLOGY　802　76-84　2017/05

    DOI： 10.1016/j.ejphar.2017.02.044 　

    ISSN： 0014-2999

    eISSN： 1879-0712

  383. A Histologic Categorization of Aqueous Outflow Routes in Familial Open-Angle Glaucoma and Associations With Mutations in the MYOC Gene in Japanese Patients Peer-reviewed

    Teruhiko Hamanaka, Masae Kimura, Tetsuro Sakurai, Nobuo Ishida, Jun Yasuda, Masao Nagasaki, Naoki Nariai, Atsushi Endo, Kei Homma, Fumiki Katsuoka, Yoichi Matsubara, Masayuki Yamamoto, Nobuo Fuse

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　58　(5)　2818-2831　2017/05

    DOI： 10.1167/iovs.16-20646 　

    ISSN： 0146-0404

    eISSN： 1552-5783

  384. 抗酸化ストレス転写因子Nrf2による腎障害進展抑制機構の解明 Peer-reviewed

    祢津 昌広, 相馬 友和, 伊藤 貞嘉, 鈴木 教郎, 山本 雅之

    日本臨床分子医学会学術総会プログラム・抄録集　54回　53-53　2017/04

    Publisher: 日本臨床分子医学会

  385. [CNC-small Maf heterodimer: Unique cis-element recognition and biological functions]. Peer-reviewed

    Otsuki A, Yamamoto M

    Seikagaku. The Journal of Japanese Biochemical Society　89　(2)　278-281　2017/04

    ISSN： 0037-1017

  386. Derepression of the DNA Methylation Machinery of the Gata1 Gene Triggers the Differentiation Cue for Erythropoiesis Peer-reviewed

    Lei Yu, Jun Takai, Akihito Otsuki, Fumiki Katsuoka, Mikiko Suzuki, Saori Katayama, Masahiro Nezu, James Douglas Engel, Takashi Moriguchi, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　37　(8)　2017/04

    DOI： 10.1128/MCB.00592-16 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  387. Genome-wide identification of inter-individually variable DNA methylation sites improves the efficacy of epigenetic association studies Peer-reviewed

    Tsuyoshi Hachiya, Ryohei Furukawa, Yuh Shiwa, Hideki Ohmomo, Kanako Ono, Fumiki Katsuoka, Masao Nagasaki, Jun Yasuda, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto, Kozo Tanno, Mamoru Satoh, Ryujin Endo, Makoto Sasaki, Kiyomi Sakata, Seiichiro Kobayashi, Kuniaki Ogasawara, Jiro Hitomi, Kenji Sobue, Atsushi Shimizu

    NPJ GENOMIC MEDICINE　2　11　2017/04

    DOI： 10.1038/s41525-017-0016-5 　

    ISSN： 2056-7944

  388. Nrf2 regulates the risk of a diesel exhaust inhalation-induced immune response during bleomycin lung injury and fibrosis in mice International-journal

    Ying Ji Li, Takako Shimizu, Yusuke Shinkai, Yukiyo Hirata, Hirofumi Inagaki, Ken Takeda, Arata Azuma, Masayuki Yamamoto, Tomoyuki Kawada

    International Journal of Molecular Sciences　18　(3)　2017/03/17

    DOI： 10.3390/ijms18030649 　

    ISSN： 1661-6596

  389. Nrf2 Regulates the Risk of a Diesel Exhaust Inhalation-Induced Immune Response during Bleomycin Lung Injury and Fibrosis in Mice Peer-reviewed

    Ying-Ji Li, Takako Shimizu, Yusuke Shinkai, Yukiyo Hirata, Hirofumi Inagaki, Ken Takeda, Arata Azuma, Masayuki Yamamoto, Tomoyuki Kawada

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES　18　(3)　2017/03

    DOI： 10.3390/ijms18030649 　

    ISSN： 1422-0067

  390. Renal Anemia Model Mouse Established by Transgenic Rescue with an Erythropoietin Gene Lacking Kidney-Specific Regulatory Elements. International-journal Peer-reviewed

    Ikuo Hirano, Norio Suzuki, Shun Yamazaki, Hiroki Sekine, Naoko Minegishi, Ritsuko Shimizu, Masayuki Yamamoto

    Molecular and cellular biology　37　(4)　2017/02/15

    DOI： 10.1128/MCB.00451-16 　

    ISSN： 0270-7306

    More details Close

    The erythropoietin (Epo) gene is under tissue-specific inducible regulation. Because the kidney is the primary EPO-producing tissue in adults, impaired EPO production in chronic kidney disorders results in serious renal anemia. The Epo gene contains a liver-specific enhancer in the 3' region, but the kidney-specific enhancer for gene expression in renal EPO-producing (REP) cells remains elusive. Here, we examined a conserved upstream element for renal Epo regulation (CURE) region that spans 17.4 kb to 3.6 kb upstream of the Epo gene and harbors several phylogenetically conserved elements. We prepared various Epo gene-reporter constructs utilizing a bacterial artificial chromosome and generated a number of transgenic-mouse lines. We observed that deletion of the CURE region (δCURE) abrogated Epo gene expression in REP cells. Although transgenic expression of the δCURE construct rescued Epo-deficient mice from embryonic lethality, the rescued mice had severe EPO-dependent anemia. These mouse lines serve as an elaborate model for the search for erythroid stimulatory activity and are referred to as AnRED (anemic model with renal EPO deficiency) mice. We also dissected the CURE region by exploiting a minigene harboring four phylogenetically conserved elements in reporter transgenic-mouse analyses. Our analyses revealed that Epo gene regulation in REP cells is a complex process that utilizes multiple regulatory influences.

  391. Nrf2はNALP3インフラマソーム活性化を介して黄色ブドウ球菌感染を制御する(Nrf2 regulates Staphylococcus aureus infection through NLRP3 inflammasome activation)

    長島 隆一, 小齋 仁美, 小嶋 克彦, 竹下 敏一, 本橋 ほづみ, 山本 雅之, 田中 伸幸

    日本細菌学雑誌　72　(1)　154-154　2017/02

    Publisher: 日本細菌学会

    ISSN： 0021-4930

    eISSN： 1882-4110

  392. Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression Peer-reviewed

    Masahiro Nezu, Tomokazu Souma, Lei Yu, Takafumi Suzuki, Daisuke Saigusa, Sadayoshi Ito, Norio Suzuki, Masayuki Yamamoto

    KIDNEY INTERNATIONAL　91　(2)　387-401　2017/02

    DOI： 10.1016/j.kint.2016.08.023 　

    ISSN： 0085-2538

    eISSN： 1523-1755

  393. A Homeostatic Shift Facilitates Endoplasmic Reticulum Proteostasis through Transcriptional Integration of Proteostatic Stress Response Pathways Peer-reviewed

    Liam Baird, Tadayuki Tsujita, Eri H. Kobayashi, Ryo Funayama, Takeshi Nagashima, Keiko Nakayama, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　37　(4)　E00651-U199　2017/02

    DOI： 10.1128/MCB.00439.16 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  394. Genetic Predisposition to Ischemic Stroke: A Polygenic Risk Score Peer-reviewed

    Tsuyoshi Hachiya, Yoichiro Kamatani, Atsushi Takahashi, Jun Hata, Ryohei Furukawa, Yuh Shiwa, Taiki Yamaji, Megumi Hara, Kozo Tanno, Hideki Ohmomo, Kanako Ono, Naoyuki Takashima, Koichi Matsuda, Kenji Wakai, Norie Sawada, Motoki Iwasaki, Kazumasa Yamagishi, Tetsuro Ago, Toshiharu Ninomiya, Akimune Fukushima, Atsushi Hozawa, Naoko Minegishi, Mamoru Satoh, Ryujin Endo, Makoto Sasaki, Kiyomi Sakata, Seiichiro Kobayashi, Kuniaki Ogasawara, Motoyuki Nakamura, Jiro Hitomi, Yoshikuni Kita, Keitaro Tanaka, Hiroyasu Iso, Takanari Kitazono, Michiaki Kubo, Hideo Tanaka, Shoichiro Tsugane, Yutaka Kiyohara, Masayuki Yamamoto, Kenji Sobue, Atsushi Shimizu

    STROKE　48　(2)　253-258　2017/02

    DOI： 10.1161/STROKEAHA.116.014506 　

    ISSN： 0039-2499

    eISSN： 1524-4628

  395. Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation Peer-reviewed

    Kouhei Tsuchida, Tadayuki Tsujita, Makiko Hayashi, Asaka Ojima, Nadine Keleku-Lukwete, Fumiki Katsuoka, Akihito Otsuki, Haruhisa Kikuchi, Yoshiteru Oshima, Mikiko Suzuki, Masayuki Yamamoto

    FREE RADICAL BIOLOGY AND MEDICINE　103　236-247　2017/02

    DOI： 10.1016/j.freeradbiomed.2016.12.041 　

    ISSN： 0891-5849

    eISSN： 1873-4596

  396. Nrf2 Improves Leptin and Insulin Resistance Provoked by Hypothalamic Oxidative Stress Peer-reviewed

    Yoko Yagishita, Akira Uruno, Toshiaki Fukutomi, Ritsumi Saito, Daisuke Saigusa, Jingbo Pi, Akiyoshi Fukamizu, Fumihiro Sugiyama, Satoru Takahashi, Masayuki Yamamoto

    CELL REPORTS　18　(8)　2030-2044　2017/02

    DOI： 10.1016/j.celrep.2017.01.064 　

    ISSN： 2211-1247

  397. Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus Peer-reviewed

    Takafumi Suzuki, Shiori Seki, Keiichiro Hiramoto, Eriko Naganuma, Eri H. Kobayashi, Ayaka Yamaoka, Liam Baird, Nobuyuki Takahashi, Hiroshi Sato, Masayuki Yamamoto

    NATURE COMMUNICATIONS　8　14577　2017/02

    DOI： 10.1038/ncomms14577 　

    ISSN： 2041-1723

  398. 低酸素ストレスに対する生体応答機構

    平野 育生, 山本 雅之

    ファルマシア　53　(3)　201-205　2017

    Publisher: 公益社団法人 日本薬学会

    DOI： 10.14894/faruawpsj.53.3_201 　

    More details Close

    利用可能な酸素分子が低下することにより引き起こされる低酸素ストレスは、好気呼吸によるエネルギー産生を阻害し、生命活動に重大な障害を与える。そのため、我々の体は低酸素ストレスに対する全身性および細胞性の生体応答機構を備えている。本セミナーでは、低酸素ストレスに対する応答機構について、特に、赤血球産生を促進するサイトカインであるエリスロポエチンの遺伝子発現制御機構を中心に概説する。

  399. AhR links atopic dermatitis and air pollution via Artemin induction

    Hidaka T, Ogawa E, Kobayashi EH, Suzuki T, Funayama R, Nagashima T, Fujimura T, Aiba S, Nakayama K, Okuyama R, Yamamoto M

    Nat Immunol　18　64-73　2017

  400. Monitoring of minimal residual disease in early T-cell precursor acute lymphoblastic leukaemia by next-generation sequencing Peer-reviewed

    Xiaoqing Pan, Naoki Nariai, Noriko Fukuhara, Sakae Saito, Yukuto Sato, Fumiki Katsuoka, Kaname Kojima, Yoko Kuroki, Inaho Danjoh, Rumiko Saito, Shin Hasegawa, Yoko Okitsu, Aiko Kondo, Yasushi Onishi, Fuji Nagami, Hideyasu Kiyomoto, Atsushi Hozawa, Nobuo Fuse, Masao Nagasaki, Ritsuko Shimizu, Jun Yasuda, Hideo Harigae, Masayuki Yamamoto

    BRITISH JOURNAL OF HAEMATOLOGY　176　(2)　318-321　2017/01

    DOI： 10.1111/bjh.13948 　

    ISSN： 0007-1048

    eISSN： 1365-2141

  401. Inflammation and airway hyperresponsiveness after chlorine exposure are prolonged by Nrf2 deficiency in mice Peer-reviewed

    Satoshi Ano, Mice Panariti, Benoit Allard, Michael O'Sullivan, Toby K. McGovern, Yoichiro Hamamoto, Yukio Ishii, Masayuki Yamamoto, William S. Powell, James G. Martin

    FREE RADICAL BIOLOGY AND MEDICINE　102　1-15　2017/01

    DOI： 10.1016/j.freeradbiomed.2016.11.017 　

    ISSN： 0891-5849

    eISSN： 1873-4596

  402. The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin Peer-reviewed

    Takanori Hidaka, Eisaku Ogawa, Eri H. Kobayashi, Takafumi Suzuki, Ryo Funayama, Takeshi Nagashima, Taku Fujimura, Setsuya Aiba, Keiko Nakayama, Ryuhei Okuyama, Masayuki Yamamoto

    NATURE IMMUNOLOGY　18　(1)　64-73　2017/01

    DOI： 10.1038/ni.3614 　

    ISSN： 1529-2908

    eISSN： 1529-2916

  403. Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression Peer-reviewed

    Masahiro Nezu, Norio Suzuki, Masayuki Yamamoto

    AMERICAN JOURNAL OF NEPHROLOGY　45　(6)　473-483　2017

    DOI： 10.1159/000475890 　

    ISSN： 0250-8095

    eISSN： 1421-9670

  404. Absolute Amounts and Status of the Nrf2-Keap1-Cul3 Complex within Cells Peer-reviewed

    Tatsuro Iso, Takafumi Suzuki, Liam Baird, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　36　(24)　3100-3112　2016/12

    DOI： 10.1128/MCB.00389-16 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  405. Small Maf deficiency recapitulates the liver phenotypes of Nrf1-and Nrf2-deficient mice Peer-reviewed

    Fumiki Katsuoka, Hiromi Yamazaki, Masayuki Yamamoto

    GENES TO CELLS　21　(12)　1309-1319　2016/12

    DOI： 10.1111/gtc.12445 　

    ISSN： 1356-9597

    eISSN： 1365-2443

  406. Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity Peer-reviewed

    Daisuke Yasuda, Mao Nakajima, Akihiro Yuasa, Rika Obata, Kyoko Takahashi, Tomoyuki Ohe, Yoshinobu Ichimura, Masaaki Komatsu, Masayuki Yamamoto, Riyo Imamura, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano, Tadahiko Mashino

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS　26　(24)　5956-5959　2016/12

    DOI： 10.1016/j.bmcl.2016.10.083 　

    ISSN： 0960-894X

    eISSN： 1464-3405

  407. Development of Novel Inhibitors for Keap1-Nrf2 and Keap1-P62 Protein-Protein Interaction Peer-reviewed

    Yasuda Daisuke, Yuasa Akihiro, Nakajima Mao, Yoshida Taketo, Obata Rika, Takahashi Kyoko, Ohe Tomoyuki, Ichimura Yoshinobu, Komatsu Masaaki, Yamamoto Masayuki, Imamura Riyo, Kojima Hirotatsu, Okabe Takayoshi, Nagano Tetsuo, Mashino Tadahiko

    FREE RADICAL BIOLOGY AND MEDICINE　100　S76　2016/11

    DOI： 10.1016/j.freeradbiomed.2016.10.194 　

    ISSN： 0891-5849

  408. 抗酸化ストレス転写因子Nrf2過剰発現マウスの著明な肺発癌抑制能を誘導する機構

    佐藤 大希, 森口 尚, 六反 啓文, 海老名 雅人, 柴田 龍弘, 山本 雅之

    日本癌学会総会記事　75回　P-2018　2016/10

    Publisher: (一社)日本癌学会

    ISSN： 0546-0476

  409. ヘム欠乏はグリコーゲン合成障害を介して糖代謝異常を惹起する

    中島 修, 斉藤 真一, 中野 博, 野原 豪和, 白澤 信行, 岡野 聡, 山本 雅之, ケリー・ヴィンセント, 高橋 究, 田中 徹, 中島 元夫

    日本生化学会大会プログラム・講演要旨集　89回　[2T06-293)]　2016/09

    Publisher: (公社)日本生化学会

  410. 赤血球型5-アミノレブリン酸合成酵素ALAS2遺伝子ヘテロ接合体マウスにおける耐糖能異常

    斉藤 真一, 中野 博, 野原 豪和, 岡野 聡, 山本 雅之, 高橋 究, 田中 徹, 中島 元夫, 中島 修

    日本生化学会大会プログラム・講演要旨集　89回　[2P-315]　2016/09

    Publisher: (公社)日本生化学会

  411. 妊娠高血圧マウスでは、Nrf2の欠損は、胎盤血管の発育を促し、周産期合併症を改善させる Peer-reviewed

    祢津 昌広, 相馬 友和, 于 磊, 伊藤 貞嘉, 高橋 信行, 鈴木 教郎, 山本 雅之

    日本高血圧学会総会プログラム・抄録集　39回　324-324　2016/09

    Publisher: (NPO)日本高血圧学会

  412. エリスロポエチンによる赤血球の代謝制御 Peer-reviewed

    福田 愛菜, 加藤 幸一郎, 河野 あかり, 齋藤 さかえ, 山本 雅之, 鈴木 教郎

    日本生化学会大会プログラム・講演要旨集　89回　[3P-035]　2016/09

    Publisher: (公社)日本生化学会

  413. 転写因子NRF1のOGT-HCF-1複合体を介した分解制御機構 Peer-reviewed

    関根 弘樹, 加藤 幸一郎, 福田 愛菜, 鈴木 教郎, 岡崎 慶斗, アラム・モルシェッド, 辻田 忠志, 小林 聡, 山本 雅之, 本橋 ほづみ

    日本生化学会大会プログラム・講演要旨集　89回　[3P-111]　2016/09

    Publisher: (公社)日本生化学会

  414. NRF2 DEFICIENCY ALLEVIATES PERINATAL COMPLICATIONS IN PREGNANCY-ASSOCIATED HYPERTENSION MICE VIA ENHANCING PLACENTAL ANGIOGENESIS Peer-reviewed

    Nezu Masahiro, Souma Tomokazu, Yu Lei, Sekine Hiroki, Moriguchi Takashi, Takahashi Nobuyuki, Ito Sadayoshi, Suzuki Norio, Yamamoto Masayuki

    JOURNAL OF HYPERTENSION　34　E59　2016/09

    DOI： 10.1097/01.hjh.0000500005.64305.c1 　

    ISSN： 0263-6352

  415. Efficacy estimation of erythropoiesis-stimulating agents using erythropoietin-deficient anemic mice Peer-reviewed

    Norio Suzuki, Yusuke Sasaki, Koichiro Kato, Shun Yamazaki, Mitsue Kurasawa, Keigo Yorozu, Yasushi Shimonaka, Masayuki Yamamoto

    HAEMATOLOGICA　101　(9)　e356-60　2016/09

    DOI： 10.3324/haematol.2015.140814 　

    ISSN： 0390-6078

  416. Gata3 Hypomorphic Mutant Mice Rescued with a Yeast Artificial Chromosome Transgene Suffer a Glomerular Mesangial Cell Defect Peer-reviewed

    Takashi Moriguchi, Lei Yu, Akihito Otsuki, Keiko Ainoya, Kim-Chew Lim, Masayuki Yamamoto, James Douglas Engel

    MOLECULAR AND CELLULAR BIOLOGY　36　(17)　2272-2281　2016/09

    DOI： 10.1128/MCB.00173-16 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  417. The Tohoku Medical Megabank Project: Design and Mission Peer-reviewed

    Shinichi Kuriyama, Nobuo Yaegashi, Fuji Nagami, Tomohiko Arai, Yoshio Kawaguchi, Noriko Osumi, Masaki Sakaida, Yoichi Suzuki, Keiko Nakayama, Hiroaki Hashizume, Gen Tamiya, Hiroshi Kawame, Kichiya Suzuki, Atsushi Hozawa, Naoki Nakaya, Masahiro Kikuya, Hirohito Metoki, Ichiro Tsuji, Nobuo Fuse, Hideyasu Kiyomoto, Junichi Sugawara, Akito Tsuboi, Shinichi Egawa, Kiyoshi Ito, Koichi Chida, Tadashi Ishii, Hiroaki Tomita, Yasuyuki Taki, Naoko Minegishi, Naoto Ishii, Jun Yasuda, Kazuhiko Igarashi, Ritsuko Shimizu, Masao Nagasaki, Seizo Koshiba, Kengo Kinoshita, Soichi Ogishima, Takako Takai-Igarashi, Teiji Tominaga, Osamu Tanabe, Noriaki Ohuchi, Toru Shimosegawa, Shigeo Kure, Hiroshi Tanaka, Sadayoshi Ito, Jiro Hitomi, Kozo Tanno, Motoyuki Nakamura, Kuniaki Ogasawara, Seiichiro Kobayashi, Kiyomi Sakata, Mamoru Satoh, Atsushi Shimizu, Makoto Sasaki, Ryujin Endo, Kenji Sobue, Masayuki Yamamoto

    JOURNAL OF EPIDEMIOLOGY　26　(9)　493-511　2016/09

    DOI： 10.2188/jea.JE20150268 　

    ISSN： 0917-5040

  418. The role of nuclear factor E2-Related factor 2 and uncoupling protein 2 in glutathione metabolism: Evidence from an in vivo gene knockout study Peer-reviewed

    Yanyan Chen, Yuanyuan Xu, Hongzhi Zheng, Jingqi Fu, Yongyong Hou, Huihui Wang, Qiang Zhang, Masayuki Yamamoto, Jingbo Pi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　478　(1)　87-92　2016/09

    DOI： 10.1016/j.bbrc.2016.07.088 　

    ISSN： 0006-291X

    eISSN： 1090-2104

  419. GATA1 Binding Kinetics on Conformation-Specific Binding Sites Elicit Differential Transcriptional Regulation Peer-reviewed

    Atsushi Hasegawa, Hiroshi Kaneko, Daishi Ishihara, Masahiro Nakamura, Akira Watanabe, Masayuki Yamamoto, Cecelia D. Trainor, Ritsuko Shimizu

    MOLECULAR AND CELLULAR BIOLOGY　36　(16)　2151-2167　2016/08

    DOI： 10.1128/MCB.00017-16 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  420. GATA-related hematologic disorders Peer-reviewed

    Ritsuko Shimizu, Masayuki Yamamoto

    EXPERIMENTAL HEMATOLOGY　44　(8)　696-705　2016/08

    DOI： 10.1016/j.exphem.2016.05.010 　

    ISSN： 0301-472X

    eISSN： 1873-2399

  421. Functional links between SQSTM1 and ALS2 in the pathogenesis of ALS: cumulative impact on the protection against mutant SOD1-mediated motor dysfunction in mice Peer-reviewed

    Shinji Hadano, Shun Mitsui, Lei Pan, Asako Otomo, Mizuki Kubo, Kai Sato, Suzuka Ono, Wakana Onodera, Koichiro Abe, XuePing Chen, Masato Koike, Yasuo Uchiyama, Masashi Aoki, Eiji Warabi, Masayuki Yamamoto, Tetsuro Ishii, Toru Yanagawa, Hui-Fang Shang, Fumihito Yoshii

    HUMAN MOLECULAR GENETICS　25　(15)　3321-3340　2016/08

    DOI： 10.1093/hmg/ddw180 　

    ISSN： 0964-6906

    eISSN： 1460-2083

  422. The structural origin of metabolic quantitative diversity Peer-reviewed

    Seizo Koshiba, Ikuko Motoike, Kaname Kojima, Takanori Hasegawa, Matsuyuki Shirota, Tomo Saito, Daisuke Saigusa, Inaho Danjoh, Fumiki Katsuoka, Soichi Ogishima, Yosuke Kawai, Yumi Yamaguchi-Kabata, Miyuki Sakurai, Sachiko Hirano, Junichi Nakata, Hozumi Motohashi, Atsushi Hozawa, Shinichi Kuriyama, Naoko Minegishi, Masao Nagasaki, Takako Takai-Igarashi, Nobuo Fuse, Hideyasu Kiyomoto, Junichi Sugawara, Yoichi Suzuki, Shigeo Kure, Nobuo Yaegashi, Osamu Tanabe, Kengo Kinoshita, Jun Yasuda, Masayuki Yamamoto

    SCIENTIFIC REPORTS　6　31463　2016/08

    DOI： 10.1038/srep31463 　

    ISSN： 2045-2322

  423. Establishment of Protocols for Global Metabolomics by LC-MS for Biomarker Discovery Peer-reviewed

    Daisuke Saigusa, Yasunobu Okamura, Ikuko N. Motoike, Yasutake Katoh, Yasuhiro Kurosawa, Reina Saijyo, Seizo Koshiba, Jun Yasuda, Hozumi Motohashi, Junichi Sugawara, Osamu Tanabe, Kengo Kinoshita, Masayuki Yamamoto

    PLOS ONE　11　(8)　e0160555　2016/08

    DOI： 10.1371/journal.pone.0160555 　

    ISSN： 1932-6203

  424. Small Maf proteins (MafF, MafG, MafK): History, structure and function Peer-reviewed

    Fumiki Katsuoka, Masayuki Yamamoto

    GENE　586　(2)　197-205　2016/07

    DOI： 10.1016/j.gene.2016.03.058 　

    ISSN： 0378-1119

    eISSN： 1879-0038

  425. Generation of a New Model Rat: Nrf2 Knockout Rats Are Sensitive to Aflatoxin B-1 Toxicity Peer-reviewed

    Keiko Taguchi, Misaki Takaku, Patricia A. Egner, Masanobu Morita, Takehito Kaneko, Tomoji Mashimo, Thomas W. Kensler, Masayuki Yamamoto

    TOXICOLOGICAL SCIENCES　152　(1)　40-52　2016/07

    DOI： 10.1093/toxsci/kfw065 　

    ISSN： 1096-6080

    eISSN： 1096-0929

  426. GATA2 regulates dendritic cell differentiation Peer-reviewed

    Koichi Onodera, Tohru Fujiwara, Yasushi Onishi, Ari Itoh-Nakadai, Yoko Okitsu, Noriko Fukuhara, Kenichi Ishizawa, Ritsuko Shimizu, Masayuki Yamamoto, Hideo Harigae

    BLOOD　128　(4)　508-518　2016/07

    DOI： 10.1182/blood-2016-02-698118 　

    ISSN： 0006-4971

    eISSN： 1528-0020

  427. Role of Keap1-Nrf2 signaling in depression and dietary intake of glucoraphanin confers stress resilience in mice Peer-reviewed

    Wei Yao, Ji-chun Zhang, Tamaki Ishima, Chao Dong, Chun Yang, Qian Ren, Min Ma, Mei Han, Jin Wu, Hiroyuki Suganuma, Yusuke Ushida, Masayuki Yamamoto, Kenji Hashimoto

    SCIENTIFIC REPORTS　6　30659　2016/07

    DOI： 10.1038/srep30659 　

    ISSN： 2045-2322

  428. Nrf2-Mediated Regulation of Skeletal Muscle Glycogen Metabolism Peer-reviewed

    Akira Uruno, Yoko Yagishita, Fumiki Katsuoka, Yasuo Kitajima, Aki Nunomiya, Ryoichi Nagatomi, Jingbo Pi, Shyam S. Biswal, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　36　(11)　1655-1672　2016/06

    DOI： 10.1128/MCB.01095-15 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  429. p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming Peer-reviewed

    Tetsuya Saito, Yoshinobu Ichimura, Keiko Taguchi, Takafumi Suzuki, Tsunehiro Mizushima, Kenji Takagi, Yuki Hirose, Masayuki Nagahashi, Tetsuro Iso, Toshiaki Fukutomi, Maki Ohishi, Keiko Endo, Takefumi Uemura, Yasumasa Nishito, Shujiro Okuda, Miki Obata, Tsuguka Kouno, Riyo Imamura, Yukio Tada, Rika Obata, Daisuke Yasuda, Kyoko Takahashi, Tsutomu Fujimura, Jingbo Pi, Myung-Shik Lee, Takashi Ueno, Tomoyuki Ohe, Tadahiko Mashino, Toshifumi Wakai, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano, Hozumi Motohashi, Satoshi Waguri, Tomoyoshi Soga, Masayuki Yamamoto, Keiji Tanaka, Masaaki Komatsu

    NATURE COMMUNICATIONS　7　12030　2016/06

    DOI： 10.1038/ncomms12030 　

    ISSN： 2041-1723

  430. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. International-journal Peer-reviewed

    Eri H Kobayashi, Takafumi Suzuki, Ryo Funayama, Takeshi Nagashima, Makiko Hayashi, Hiroki Sekine, Nobuyuki Tanaka, Takashi Moriguchi, Hozumi Motohashi, Keiko Nakayama, Masayuki Yamamoto

    Nature communications　7　11624-11624　2016/05/23

    DOI： 10.1038/ncomms11624 　

    More details Close

    Nrf2 (NF-E2-related factor-2) transcription factor regulates oxidative/xenobiotic stress response and also represses inflammation. However, the mechanisms how Nrf2 alleviates inflammation are still unclear. Here, we demonstrate that Nrf2 interferes with lipopolysaccharide-induced transcriptional upregulation of proinflammatory cytokines, including IL-6 and IL-1β. Chromatin immunoprecipitation (ChIP)-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes in macrophages and inhibits RNA Pol II recruitment. Further, we found that Nrf2-mediated inhibition is independent of the Nrf2-binding motif and reactive oxygen species level. Murine inflammatory models further demonstrated that Nrf2 interferes with IL6 induction and inflammatory phenotypes in vivo. Thus, contrary to the widely accepted view that Nrf2 suppresses inflammation through redox control, we demonstrate here that Nrf2 opposes transcriptional upregulation of proinflammatory cytokine genes. This study identifies Nrf2 as the upstream regulator of cytokine production and establishes a molecular basis for an Nrf2-mediated anti-inflammation approach.

  431. 尿細管におけるNrf2の活性化が腎虚血再灌流障害による尿細管障害の進行を抑制する分子メカニズムの解明 Peer-reviewed

    祢津 昌広, 相馬 友和, 于 磊, 鈴木 隆史, 三枝 大輔, 伊藤 貞嘉, 鈴木 教郎, 山本 雅之

    日本腎臓学会誌　58　(3)　365-365　2016/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  432. NRF2 Intensifies Host Defense Systems to Prevent Lung Carcinogenesis, but After Tumor Initiation Accelerates Malignant Cell Growth Peer-reviewed

    Hironori Satoh, Takashi Moriguchi, Daisuke Saigusa, Liam Baird, Lei Yu, Hirofumi Rokutan, Keiko Igarashi, Masahito Ebina, Tatsuhiro Shibata, Masayuki Yamamoto

    CANCER RESEARCH　76　(10)　3088-3096　2016/05

    DOI： 10.1158/0008-5472.CAN-15-1584 　

    ISSN： 0008-5472

    eISSN： 1538-7445

  433. Nrf2/Keap1 system regulates vascular smooth muscle cell apoptosis for vascular homeostasis: role in neointimal formation after vascular injury Peer-reviewed

    Takashi Ashino, Masayuki Yamamoto, Satoshi Numazawa

    SCIENTIFIC REPORTS　6　26291　2016/05

    DOI： 10.1038/srep26291 　

    ISSN： 2045-2322

  434. 飽和脂肪酸(パルミチン酸)による小胞体ストレスを介したエリスロポエチン産生制御機能の破綻 Peer-reviewed

    Anusornvongchai Thitinun, 岡田 啓, 中谷 嘉寿, 南学 正臣, 鈴木 教郎, 山本 雅之, 稲城 玲子

    Pharma Medica　34　(4)　117-117　2016/04

    Publisher: (株)メディカルレビュー社

    ISSN： 0289-5803

  435. Partial contribution of the Keap1-Nrf2 system to cadmium-mediated metallothionein expression in vascular endothelial cells Peer-reviewed

    Yasuhiro Shinkai, Tomoki Kimura, Ayaka Itagaki, Chika Yamamoto, Keiko Taguchi, Masayuki Yamamoto, Yoshito Kumagai, Toshiyuki Kaji

    TOXICOLOGY AND APPLIED PHARMACOLOGY　295　37-46　2016/03

    DOI： 10.1016/j.taap.2016.01.020 　

    ISSN： 0041-008X

    eISSN： 1096-0333

  436. The Mediator Subunit MED16 Transduces NRF2-Activating Signals into Antioxidant Gene Expression. International-journal Peer-reviewed

    Hiroki Sekine, Keito Okazaki, Nao Ota, Hiroki Shima, Yasutake Katoh, Norio Suzuki, Kazuhiko Igarashi, Mitsuhiro Ito, Hozumi Motohashi, Masayuki Yamamoto

    Molecular and cellular biology　36　(3)　407-20　2016/02/01

    DOI： 10.1128/MCB.00785-15 　

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    The KEAP1-NRF2 system plays a central role in cytoprotection. NRF2 is stabilized in response to electrophiles and activates transcription of antioxidant genes. Although robust induction of NRF2 target genes confers resistance to oxidative insults, how NRF2 triggers transcriptional activation after binding to DNA has not been elucidated. To decipher the molecular mechanisms underlying NRF2-dependent transcriptional activation, we purified the NRF2 nuclear protein complex and identified the Mediator subunits as NRF2 cofactors. Among them, MED16 directly associated with NRF2. Disruption of Med16 significantly attenuated the electrophile-induced expression of NRF2 target genes but did not affect hypoxia-induced gene expression, suggesting a specific requirement for MED16 in NRF2-dependent transcription. Importantly, we found that 75% of NRF2-activated genes exhibited blunted inductions by electrophiles in Med16-deficient cells compared to wild-type cells, which strongly argues that MED16 is a major contributor supporting NRF2-dependent transcriptional activation. NRF2-dependent phosphorylation of the RNA polymerase II C-terminal domain was absent in Med16-deficient cells, suggesting that MED16 serves as a conduit to transmit NRF2-activating signals to RNA polymerase II. MED16 indeed turned out to be essential for cytoprotection against oxidative insults. Thus, the KEAP1-NRF2-MED16 axis has emerged as a new regulatory pathway mediating the antioxidant response through the robust activation of NRF2 target genes.

  437. Erythropoietin Synthesis in Renal Myofibroblasts Is Restored by Activation of Hypoxia Signaling. International-journal Peer-reviewed

    Tomokazu Souma, Masahiro Nezu, Daisuke Nakano, Shun Yamazaki, Ikuo Hirano, Hiroki Sekine, Takashi Dan, Kotaro Takeda, Guo-Hua Fong, Akira Nishiyama, Sadayoshi Ito, Toshio Miyata, Masayuki Yamamoto, Norio Suzuki

    Journal of the American Society of Nephrology : JASN　27　(2)　428-38　2016/02

    DOI： 10.1681/ASN.2014121184 　

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    Erythropoietin (Epo) is produced by renal Epo-producing cells (REPs) in a hypoxia-inducible manner. The conversion of REPs into myofibroblasts and coincident loss of Epo-producing ability are the major cause of renal fibrosis and anemia. However, the hypoxic response of these transformed myofibroblasts remains unclear. Here, we used complementary in vivo transgenic and live imaging approaches to better understand the importance of hypoxia signaling in Epo production. Live imaging of REPs in transgenic mice expressing green fluorescent protein from a modified Epo-gene locus revealed that healthy REPs tightly associated with endothelium by wrapping processes around capillaries. However, this association was hampered in states of renal injury-induced inflammation previously shown to correlate with the transition to myofibroblast-transformed renal Epo-producing cells (MF-REPs). Furthermore, activation of hypoxia-inducible factors (HIFs) by genetic inactivation of HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) selectively in Epo-producing cells reactivated Epo production in MF-REPs. Loss of PHD2 in REPs restored Epo-gene expression in injured kidneys but caused polycythemia. Notably, combined deletions of PHD1 and PHD3 prevented loss of Epo expression without provoking polycythemia. Mice with PHD-deficient REPs also showed resistance to LPS-induced Epo repression in kidneys, suggesting that augmented HIF signaling counterbalances inflammatory stimuli in regulation of Epo production. Thus, augmentation of HIF signaling may be an attractive therapeutic strategy for treating renal anemia by reactivating Epo synthesis in MF-REPs.

  438. Keap1/Nrf2 pathway activation leads to a repressed hepatic gluconeogenic and lipogenic program in mice on a high-fat diet Peer-reviewed

    Stephen L. Slocum, John J. Skoko, Nobunao Wakabayashi, Susan Aja, Masayuki Yamamoto, Thomas W. Kensler, Dionysios V. Chartoumpekis

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS　591　57-65　2016/02

    DOI： 10.1016/j.abb.2015.11.040 　

    ISSN： 0003-9861

    eISSN： 1096-0384

  439. Unique cistrome defined as CsMBE is strictly required for Nrf2-sMaf heterodimer function in cytoprotection Peer-reviewed

    Akihito Otsuki, Mikiko Suzuki, Fumiki Katsuoka, Kouhei Tsuchida, Hiromi Suda, Masanobu Morita, Ritsuko Shimizu, Masayuki Yamamoto

    FREE RADICAL BIOLOGY AND MEDICINE　91　45-57　2016/02

    DOI： 10.1016/j.freeradbiomed.2015.12.005 　

    ISSN： 0891-5849

    eISSN： 1873-4596

  440. Constitutive Nrf2 activation ameliorates hepatotoxicity induced by a heme synthesis Inhibitor

    TAGUCHI Keiko, MASUI Saho, YAMAMOTO Masayuki

    Annual Meeting of the Japanese Society of Toxicology　43　O-46　2016

    Publisher: The Japanese Society of Toxicology

    DOI： 10.14869/toxpt.43.1.0_O-46 　

  441. Discovery of the Keap1-Nrf2 system and contribution to toxicology

    YAMAMOTO Masayuki

    Annual Meeting of the Japanese Society of Toxicology　43　SP　2016

    Publisher: The Japanese Society of Toxicology

    DOI： 10.14869/toxpt.43.1.0_SP 　

  442. The Keap1-Nrf2 system and lung diseases

    YAMAMOTO Masayuki

    Annual Meeting of the Japanese Society of Toxicology　43　S2-2　2016

    Publisher: The Japanese Society of Toxicology

    DOI： 10.14869/toxpt.43.1.0_S2-2 　

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    Our body has ability to sense environmental insults and to activate cellular defense enzyme genes. Transcription factor Nrf2 is essential for the coordinated induction of cellular defense enzymes and protection of lung tissues through association with CNC-sMaf binding element (CsMBE or ARE/EpRE). This notion has been supported by experiments using animal models, showing that Nrf2-null mice are sensitive to a wide variety of toxic electrophiles and ROS. Keap1 acts as a subunit of ubiquitin-E3 ligase that degrades Nrf2 constitutively and as sensors for electrophilic and oxidative stresses, and covalent modifications of the cysteine residues abrogate the ubiquitin ligase activity. This system has been referred to as the Cysteine Code. The two-site recognition / hinge and latch model proposed for the Keap1-Nrf2 system describes the mechanism of nuclear accumulation of Nrf2 in a Cul3-Keap1 E3 ubiquitin ligase-dependent manner. We have verified this model through structure biology, mouse genetics, and human disease analyses. Many missense mutations have been identified in KEAP1 and NRF2 genes of human lung cancers. These mutations disrupt the KEAP1-NRF2 complex and result in constitutive activation of NRF2. Subsequently, elevated expression of NRF2 target genes confers advantages on the growth of cancer cells through the metabolic reprogramming. Thus, the Keap1-Nrf2 system opens a new avenue to the understanding of the signal transduction and regulatory processes underlying the stress response and cancer progression.

  443. A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies Peer-reviewed

    Masakazu Kohda, Yoshimi Tokuzawa, Yoshihito Kishita, Hiromi Nyuzuki, Yohsuke Moriyama, Yosuke Mizuno, Tomoko Hirata, Yukiko Yatsuka, Yzumi Yamashita-Sugahara, Yutaka Nakachi, Hidemasa Kato, Akihiko Okuda, Shunsuke Tamaru, Nurun Nahar Borna, Kengo Banshoya, Toshiro Aigaki, Yukiko Sato-Miyata, Kohei Ohnuma, Tsutomu Suzuki, Asuteka Nagao, Hazuki Maehata, Fumihiko Matsuda, Koichiro Higasa, Masao Nagasaki, Jun Yasuda, Masayuki Yamamoto, Takuya Fushimi, Masaru Shimura, Keiko Kaiho-Ichimoto, Hiroko Harashima, Taro Yamazaki, Masato Mori, Kei Murayama, Akira Ohtake, Yasushi Okazaki

    PLOS GENETICS　12　(1)　2016/01

    DOI： 10.1371/journal.pgen.1005679 　

    ISSN： 1553-7404

  444. Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response Peer-reviewed

    Ryota Saito, Takafumi Suzuki, Keiichiro Hiramoto, Soichiro Asami, Eriko Naganuma, Hiromi Suda, Tatsuro Iso, Hirotaka Yamamoto, Masanobu Morita, Liam Baird, Yuki Furusawa, Takaaki Negishi, Masakazu Ichinose, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　36　(2)　271-284　2016/01

    DOI： 10.1128/MCB.00868-15 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  445. Adjustment of Cell-Type Composition Minimizes Systematic Bias in Blood DNA Methylation Profiles Derived by DNA Collection Protocols Peer-reviewed

    Yuh Shiwa, Tsuyoshi Hachiya, Ryohei Furukawa, Hideki Ohmomo, Kanako Ono, Hisaaki Kudo, Jun Hata, Atsushi Hozawa, Motoki Iwasaki, Koichi Matsuda, Naoko Minegishi, Mamoru Satoh, Kozo Tanno, Taiki Yamaji, Kenji Wakai, Jiro Hitomi, Yutaka Kiyohara, Michiaki Kubo, Hideo Tanaka, Shoichiro Tsugane, Masayuki Yamamoto, Kenji Sobue, Atsushi Shimizu

    PLOS ONE　11　(1)　e0147519-e0147519　2016/01

    DOI： 10.1371/journal.pone.0147519 　

    ISSN： 1932-6203

  446. A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies Peer-reviewed

    Masakazu Kohda, Yoshimi Tokuzawa, Yoshihito Kishita, Hiromi Nyuzuki, Yohsuke Moriyama, Yosuke Mizuno, Tomoko Hirata, Yukiko Yatsuka, Yzumi Yamashita-Sugahara, Yutaka Nakachi, Hidemasa Kato, Akihiko Okuda, Shunsuke Tamaru, Nurun Nahar Borna, Kengo Banshoya, Toshiro Aigaki, Yukiko Sato-Miyata, Kohei Ohnuma, Tsutomu Suzuki, Asuteka Nagao, Hazuki Maehata, Fumihiko Matsuda, Koichiro Higasa, Masao Nagasaki, Jun Yasuda, Masayuki Yamamoto, Takuya Fushimi, Masaru Shimura, Keiko Kaiho-Ichimoto, Hiroko Harashima, Taro Yamazaki, Masato Mori, Kei Murayama, Akira Ohtake, Yasushi Okazaki

    PLoS Genetics　12　(1)　e1005679-e1005679　2016

    Publisher: Public Library of Science

    DOI： 10.1371/journal.pgen.1005679 　

    ISSN： 1553-7404 1553-7390

  447. Roles of renal erythropoietin-producing (REP) cells in the maintenance of systemic oxygen homeostasis Peer-reviewed

    Norio Suzuki, Masayuki Yamamoto

    PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY　468　(1)　3-12　2016/01

    DOI： 10.1007/s00424-015-1740-2 　

    ISSN： 0031-6768

    eISSN： 1432-2013

  448. Nuclear Factor Erythroid 2-Related Factor 2 Drives Podocyte-Specific Expression of Peroxisome Proliferator-Activated Receptor gamma Essential for Resistance to Crescentic GN Peer-reviewed

    Carole Henique, Guillaume Bollee, Olivia Lenoir, Neeraj Dhaun, Marine Camus, Anna Chipont, Kathleen Flosseau, Chantal Mandet, Masayuki Yamamoto, Alexandre Karras, Eric Thervet, Patrick Bruneval, Dominique Nochy, Laurent Mesnard, Pierre-Louis Tharaux

    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY　27　(1)　172-188　2016/01

    DOI： 10.1681/ASN.2014111080 　

    ISSN： 1046-6673

    eISSN： 1533-3450

  449. The Transcription Factor Bach2 Is Phosphorylated at Multiple Sites in Murine B Cells but a Single Site Prevents Its Nuclear Localization Peer-reviewed

    Ryo Ando, Hiroki Shima, Toru Tamahara, Yoshihiro Sato, Miki Watanabe-Matsui, Hiroki Kato, Nicolas Sax, Hozumi Motohashi, Keiko Taguchi, Masayuki Yamamoto, Masaki Nio, Tatsuya Maeda, Kyoko Ochiai, Akihiko Muto, Kazuhiko Igarashi

    JOURNAL OF BIOLOGICAL CHEMISTRY　291　(4)　1826-1840　2016/01

    DOI： 10.1074/jbc.M115.661702 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  450. Syndecan 4 Mediates Nrf2-dependent Expansion of Bronchiolar Progenitors That Protect Against Lung Inflammation Peer-reviewed

    Arif Santoso, Toshiaki Kikuchi, Naoki Tode, Taizou Hirano, Riyo Komatsu, Triya Damayanti, Hozumi Motohashi, Masayuki Yamamoto, Tetsuhito Kojima, Toshimitsu Uede, Toshihiro Nukiwa, Masakazu Ichinose

    MOLECULAR THERAPY　24　(1)　41-52　2016/01

    DOI： 10.1038/mt.2015.153 　

    ISSN： 1525-0016

    eISSN： 1525-0024

  451. NRF2 Is a Key Target for Prevention of Noise-Induced Hearing Loss by Reducing Oxidative Damage of Cochlea Peer-reviewed

    Yohei Honkura, Hirotaka Matsuo, Shohei Murakami, Masayuki Sakiyama, Kunio Mizutari, Akihiro Shiotani, Masayuki Yamamoto, Ichiro Morita, Nariyoshi Shinomiya, Tetsuaki Kawase, Yukio Katori, Hozumi Motohashi

    SCIENTIFIC REPORTS　6　19329　2016/01

    DOI： 10.1038/srep19329 　

    ISSN： 2045-2322

  452. Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes Peer-reviewed

    Marta Pajares, Natalia Jimenez-Moreno, Angel J. Garcia-Yague, Maribel Escoll, Maria L. de Ceballos, Fred Van Leuven, Alberto Rabano, Masayuki Yamamoto, Ana I. Rojo, Antonio Cuadrado

    AUTOPHAGY　12　(10)　1902-1916　2016

    DOI： 10.1080/15548627.2016.1208889 　

    ISSN： 1554-8627

    eISSN： 1554-8635

  453. Keap1-Nrf2 System: Potential Role in Prevention of Sickle Cell Disease Organs Damages and Inflammation Peer-reviewed

    Keleku-Lukwete Nadine, Suzuki Mikiko, Otsuki Akihito, Tsuchida Kouhei, Katayama Saori, Hayashi Makiko, Naganuma Eriko, Moriguchi Takashi, Tanabe Osamu, Engel James Doug, Imaizumi Masue, Yamamoto Masayuki

    BLOOD　126　(23)　2015/12/03

    ISSN： 0006-4971

  454. 転写因子による細胞分化・増殖抑制 造血系幹細胞におけるGata1遺伝子の不活性化の機序(Mechanisms of Gata1 gene inactivation in hematopoietic stem cells)

    森口 尚, 于 磊, 山本 雅之

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[2W9-9]　2015/12

    Publisher: (公社)日本生化学会

  455. NRF2-MED16を介した抗酸化遺伝子群の転写活性化機構 Peer-reviewed

    岡崎 慶斗, 関根 弘樹, 鈴木 教郎, 加藤 恭丈, 五十嵐 和彦, 伊藤 光宏, 本橋 ほづみ, 山本 雅之

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[4T14L-01(3P0701)]　2015/12

    Publisher: (公社)日本生化学会

  456. Whole-genome Japanese Reference Panel and future directions Peer-reviewed

    Nagasaki Masao, Yasuda Jun, Katsuoka Fumiki, Nariai Naoki, Kojima Kaname, Kawai Yosuke, Yamaguchi-Kabata Yumi, Yokozawa Junji, Danjoh Inaho, Saito Sakae, Sato Yukuto, Mimori Takahiro, Tsuda Kaoru, Saito Rumiko, Pan Xiaoqing, Nishikawa Satoshi, Ito Shin, Kuroki Yoko, Tanabe Osamu, Fuse Nobuo, Kuriyama Shinichi, Kiyomoto Hideyasu, Hozawa Atsushi, Minegishi Naoko, Kinoshita Kengo, Kure Shigeo, Yaegashi Nobuo, Yamamoto Masayuki

    GENES & GENETIC SYSTEMS　90　(6)　377　2015/12

    ISSN： 1341-7568

  457. Analysis of UVC genotoxicity for mouse skin.

    H. Ikehata, T. Mori, M. Yamamoto

    Photomed. Photobiol.　37　29-30　2015/12

  458. Eczema and Asthma Symptoms among Schoolchildren in Coastal and Inland Areas after the 2011 Great East Japan Earthquake: The ToMMo Child Health Study Peer-reviewed

    Masako Miyashita, Masahiro Kikuya, Chizuru Yamanaka, Mami Ishikuro, Taku Obara, Yuki Sato, Hirohito Metoki, Naoki Nakaya, Fuji Nagami, Hiroaki Tomita, Hideyasu Kiyomoto, Junichi Sugawara, Atsushi Hozawa, Nobuo Fuse, Yoichi Suzuki, Ichiro Tsuji, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto, Shinichi Kuriyama

    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE　237　(4)　297-305　2015/12

    DOI： 10.1620/tjem.237.297 　

    ISSN： 0040-8727

    eISSN： 1349-3329

  459. In Vivo Spectrum of UVC-induced Mutation in Mouse Skin Epidermis May Reflect the Cytosine Deamination Propensity of Cyclobutane Pyrimidine Dimers Peer-reviewed

    Hironobu Ikehata, Toshio Mori, Masayuki Yamamoto

    PHOTOCHEMISTRY AND PHOTOBIOLOGY　91　(6)　1488-1496　2015/11

    DOI： 10.1111/php.12525 　

    ISSN： 0031-8655

    eISSN： 1751-1097

  460. Molecular basis of the Keap1-Nrf2 system Peer-reviewed

    Takafumi Suzuki, Masayuki Yamamoto

    FREE RADICAL BIOLOGY AND MEDICINE　88　(Pt B)　93-100　2015/11

    DOI： 10.1016/j.freeradbiomed.2015.06.006 　

    ISSN： 0891-5849

    eISSN： 1873-4596

  461. LSD1/KDM1A promotes hematopoietic commitment of hemangioblasts through downregulation of Etv2 Peer-reviewed

    Miki Takeuchi, Yuji Fuse, Mana Watanabe, Christina-Sylvia Andrea, Miho Takeuchi, Hitomi Nakajima, Ken Ohashi, Hiroshi Kaneko, Maki Kobayashi-Osaki, Masayuki Yamamoto, Makoto Kobayashi

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　112　(45)　13922-13927　2015/11

    DOI： 10.1073/pnas.1517326112 　

    ISSN： 0027-8424

  462. The subcellular localization and activity of cortactin is regulated by acetylation and interaction with Keap1 Peer-reviewed

    Akihiro Ito, Tadahiro Shimazu, Satoko Maeda, Asad Ali Shah, Tatsuhiko Tsunoda, Shun-ichiro Iemura, Toru Natsume, Takafumi Suzuki, Hozumi Motohashi, Masayuki Yamamoto, Minoru Yoshida

    SCIENCE SIGNALING　8　(404)　ra120-ra120　2015/11

    DOI： 10.1126/scisignal.aad0667 　

    ISSN： 1945-0877

    eISSN： 1937-9145

  463. Whole-Body In Vivo Monitoring of Inflammatory Diseases Exploiting Human Interleukin 6-Luciferase Transgenic Mice Peer-reviewed

    Makiko Hayashi, Jun Takai, Lei Yu, Hozumi Motohashi, Takashi Moriguchi, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　35　(20)　3590-3601　2015/10

    DOI： 10.1128/MCB.00506-15 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  464. Japonica array: improved genotype imputation by designing a population-specific SNP array with 1070 Japanese individuals Peer-reviewed

    Yosuke Kawai, Takahiro Mimori, Kaname Kojima, Naoki Nariai, Inaho Danjoh, Rumiko Saito, Jun Yasuda, Masayuki Yamamoto, Masao Nagasaki

    JOURNAL OF HUMAN GENETICS　60　(10)　581-587　2015/10

    DOI： 10.1038/jhg.2015.68 　

    ISSN： 1434-5161

    eISSN： 1435-232X

  465. Keap1-Nrf2 regulatory system and cancer Peer-reviewed

    Keiko Taguchi, Masayuki Yamamoto

    Protein Modifications in Pathogenic Dysregulation of Signaling　269-285　2015/09/02

    Publisher: Springer Japan

    DOI： 10.1007/978-4-431-55561-2_17 　

  466. Nrf2 status affects tumor growth, HDAC3 gene promoter associations, and the response to sulforaphane in the colon Peer-reviewed

    Praveen Rajendran, Wan-Mohaiza Dashwood, Li Li, Yuki Kang, Eunah Kim, Gavin Johnson, Kay A. Fischer, Christiane V. Loehr, David E. Williams, Emily Ho, Masayuki Yamamoto, David A. Lieberman, Roderick H. Dashwood

    CLINICAL EPIGENETICS　7　(1)　102-102　2015/09

    DOI： 10.1186/s13148-015-0132-y 　

    ISSN： 1868-7083

  467. An integrative approach to analyze microarray datasets for prioritization of genes relevant to lens biology and disease Peer-reviewed

    Deepti Anand, Smriti A. Agrawal, Archana D. Siddam, Hozumi Motohashi, Masayuki Yamamoto, Salil A. Lachke

    Genomics Data　5　223-227　2015/09/01

    Publisher: Elsevier Inc

    DOI： 10.1016/j.gdata.2015.06.017 　

    ISSN： 2213-5960

  468. Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation Peer-reviewed

    Nadine Keleku-Lukwete, Mikiko Suzuki, Akihito Otsuki, Kouhei Tsuchida, Saori Katayama, Makiko Hayashi, Eriko Naganuma, Takashi Moriguchi, Osamu Tanabe, James Douglas Engel, Masue Imaizumi, Masayuki Yamamoto

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　112　(39)　12169-12174　2015/09

    DOI： 10.1073/pnas.1509158112 　

    ISSN： 0027-8424

  469. Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals Peer-reviewed

    Masao Nagasaki, Jun Yasuda, Fumiki Katsuoka, Naoki Nariai, Kaname Kojima, Yosuke Kawai, Yumi Yamaguchi-Kabata, Junji Yokozawa, Inaho Danjoh, Sakae Saito, Yukuto Sato, Takahiro Mimori, Kaoru Tsuda, Rumiko Saito, Xiaoqing Pan, Satoshi Nishikawa, Shin Ito, Yoko Kuroki, Osamu Tanabe, Nobuo Fuse, Shinichi Kuriyama, Hideyasu Kiyomoto, Atsushi Hozawa, Naoko Minegishi, James Douglas Engel, Kengo Kinoshita, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto

    NATURE COMMUNICATIONS　6　8018-8018　2015/08

    DOI： 10.1038/ncomms9018 　

    ISSN： 2041-1723

  470. Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes. International-journal Peer-reviewed

    Yutaka Tojo, Hiroki Sekine, Ikuo Hirano, Xiaoqing Pan, Tomokazu Souma, Tadayuki Tsujita, Shin-ichi Kawaguchi, Norihiko Takeda, Kotaro Takeda, Guo-Hua Fong, Takashi Dan, Masakazu Ichinose, Toshio Miyata, Masayuki Yamamoto, Norio Suzuki

    Molecular and cellular biology　35　(15)　2658-72　2015/08

    DOI： 10.1128/MCB.00161-15 　

    More details Close

    Erythropoietin (Epo) is produced in the kidney and liver in a hypoxia-inducible manner via the activation of hypoxia-inducible transcription factors (HIFs) to maintain oxygen homeostasis. Accelerating Epo production in hepatocytes is one plausible therapeutic strategy for treating anemia caused by kidney diseases. To elucidate the regulatory mechanisms of hepatic Epo production, we analyzed mouse lines harboring liver-specific deletions of genes encoding HIF-prolyl-hydroxylase isoforms (PHD1, PHD2, and PHD3) that mediate the inactivation of HIF1α and HIF2α under normal oxygen conditions. The loss of all PHD isoforms results in both polycythemia, which is caused by Epo overproduction, and fatty livers. We found that deleting any combination of two PHD isoforms induces polycythemia without steatosis complications, whereas the deletion of a single isoform induces no apparent phenotype. Polycythemia is prevented by the loss of either HIF2α or the hepatocyte-specific Epo gene enhancer (EpoHE). Chromatin analyses show that the histones around EpoHE dissociate from the nucleosome structure after HIF2α activation. HIF2α also induces the expression of HIF3α, which is involved in the attenuation of Epo production. These results demonstrate that the total amount of PHD activity is more important than the specific function of each isoform for hepatic Epo expression regulated by a PHD-HIF2α-EpoHE cascade in vivo.

  471. 【新しい腎性貧血治療ガイドラインへの期待】トピックス EPO産生制御機構 Peer-reviewed

    祢津 昌広, 鈴木 教郎, 山本 雅之

    腎と透析　79　(1)　88-93　2015/07

    Publisher: (株)東京医学社

    ISSN： 0385-2156

  472. Compound mouse mutants of bZIP transcription factors Mafg and Mafk reveal a regulatory network of non-crystallin genes associated with cataract Peer-reviewed

    Smriti A. Agrawal, Deepti Anand, Archana D. Siddam, Atul Kakrana, Soma Dash, David A. Scheiblin, Christine A. Dang, Anne M. Terrell, Stephanie M. Waters, Abhyudai Singh, Hozumi Motohashi, Masayuki Yamamoto, Salil A. Lachke

    HUMAN GENETICS　134　(7)　717-735　2015/07

    DOI： 10.1007/s00439-015-1554-5 　

    ISSN： 0340-6717

    eISSN： 1432-1203

  473. Discovery of an NRF1-specific inducer from a large-scale chemical library using a direct NRF1-protein monitoring system Peer-reviewed

    Tadayuki Tsujita, Liam Baird, Yuki Furusawa, Fumiki Katsuoka, Yoshika Hou, Satomi Gotoh, Shin-ichi Kawaguchi, Masayuki Yamamoto

    GENES TO CELLS　20　(7)　563-577　2015/07

    DOI： 10.1111/gtc.12248 　

    ISSN： 1356-9597

    eISSN： 1365-2443

  474. Inter-Individual Differences in the Oral Bacteriome Are Greater than Intra-Day Fluctuations in Individuals Peer-reviewed

    Yukuto Sato, Junya Yamagishi, Riu Yamashita, Natsuko Shinozaki, Bin Ye, Takuji Yamada, Masayuki Yamamoto, Masao Nagasaki, Akito Tsuboi

    PLOS ONE　10　(6)　e0131607-e0131607　2015/06

    DOI： 10.1371/journal.pone.0131607 　

    ISSN： 1932-6203

  475. Renal erythropoietin-producing cells in health and disease Peer-reviewed

    Tomokazu Souma, Norio Suzuki, Masayuki Yamamoto

    FRONTIERS IN PHYSIOLOGY　6　167-167　2015/06

    DOI： 10.3389/fphys.2015.00167 　

    ISSN： 1664-042X

  476. Protocol and Research Perspectives of the ToMMo Child Health Study after the 2011 Great East Japan Earthquake Peer-reviewed

    Masahiro Kikuya, Masako Miyashita, Chizuru Yamanaka, Mami Ishikuro, Yuki Sato, Taku Obara, Hirohito Metoki, Naoki Nakaya, Fuji Nagami, Hiroaki Tomita, Hideyasu Kiyomoto, Junichi Sugawara, Atsushi Hozawa, Nobuo Fuse, Yoichi Suzuki, Ichiro Tsuji, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto, Shinichi Kuriyama

    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE　236　(2)　123-130　2015/06

    DOI： 10.1620/tjem.236.123 　

    ISSN： 0040-8727

    eISSN： 1349-3329

  477. Alcohol dehydrogenase 3 contributes to the protection of liver from nonalcoholic steatohepatitis Peer-reviewed

    Maki Goto, Hiroshi Kitamura, Md Morshedul Alam, Nao Ota, Takeshi Haseba, Toshio Akimoto, Akio Shimizu, Teruko Takano-Yamamoto, Masayuki Yamamoto, Hozumi Motohashi

    GENES TO CELLS　20　(6)　464-480　2015/06

    DOI： 10.1111/gtc.12237 　

    ISSN： 1356-9597

    eISSN： 1365-2443

  478. 飽和脂肪酸(パルミチン酸)による腎臓早期老化 小胞体ストレスによる造血ホルモン産生制御機能の破綻 Peer-reviewed

    稲城 玲子, Anusonvongchai Thitinun, 鈴木 教郎, 山本 雅之, 南学 正臣

    基礎老化研究　39　(2)　55-55　2015/05

    Publisher: 日本基礎老化学会

    ISSN： 0912-8921

  479. 飽和脂肪酸(パルミチン酸)による腎臓早期老化 小胞体ストレスによる造血ホルモン産生制御機能の破綻 Peer-reviewed

    稲城 玲子, Thitinun Anusonvongchai, 鈴木 教郎, 山本 雅之, 南学 正臣

    日本抗加齢医学会総会プログラム・抄録集　15回　211-211　2015/05

    Publisher: (一社)日本抗加齢医学会

  480. 飽和脂肪酸(パルミチン酸)による腎臓早期老化 小胞体ストレスによる造血ホルモン産生制御機能の破綻 Peer-reviewed

    稲城 玲子, Anusonvongchai Thitinun, 鈴木 教郎, 山本 雅之, 南学 正臣

    日本老年医学会雑誌　52　(Suppl.)　148-148　2015/05

    Publisher: (一社)日本老年医学会

    ISSN： 0300-9173

  481. The Human GATA1 Gene Retains a 5 ' Insulator That Maintains Chromosomal Architecture and GATA1 Expression Levels in Splenic Erythroblasts Peer-reviewed

    Takashi Moriguchi, Lei Yu, Jun Takai, Makiko Hayashi, Hironori Satoh, Mikiko Suzuki, Kinuko Ohneda, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　35　(10)　1825-1837　2015/05

    DOI： 10.1128/MCB.00011-15 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  482. GATA2 is critical for the maintenance of cellular identity in differentiated mast cells derived from mouse bone marrow Peer-reviewed

    Shin'ya Ohmori, Takashi Moriguchi, Yuki Noguchi, Muneharu Ikeda, Kota Kobayashi, Nazuki Tomaru, Yasushi Ishijima, Osamu Ohneda, Masayuki Yamamoto, Kinuko Ohneda

    BLOOD　125　(21)　3306-3315　2015/05

    DOI： 10.1182/blood-2014-11-612465 　

    ISSN： 0006-4971

    eISSN： 1528-0020

  483. 飽和脂肪酸(パルミンチン酸)は小胞体ストレスを介して腎EPO産生細胞の機能破綻を招く Peer-reviewed

    Anusornvongchai Thitinun, 本西 秀太, 鈴木 教郎, 山本 雅之, 南学 正臣, 稲城 玲子

    日本腎臓学会誌　57　(3)　473-473　2015/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  484. CNC-bZIP Protein Nrf1-Dependent Regulation of Glucose-Stimulated Insulin Secretion Peer-reviewed

    Hongzhi Zheng, Jingqi Fu, Peng Xue, Rui Zhao, Jian Dong, Dianxin Liu, Masayuki Yamamoto, Qingchun Tong, Weiping Teng, Weidong Qu, Qiang Zhang, Melvin E. Andersen, Jingbo Pi

    ANTIOXIDANTS & REDOX SIGNALING　22　(10)　819-831　2015/04

    DOI： 10.1089/ars.2014.6017 　

    ISSN： 1523-0864

    eISSN： 1557-7716

  485. Molecular basis distinguishing the DNA binding profile of Nrf2-Maf heterodimer from that of Maf homodimer. Peer-reviewed

    Kimura M, Yamamoto T, Zhang J, Itoh K, Kyo M, Kamiya T, Aburatani H, Katsuoka F, Kurokawa H, Tanaka T, Motohashi H, Yamamoto M

    The Journal of biological chemistry　290　(17)　10644　2015/04

    DOI： 10.1074/jbc.A115.706863 　

    ISSN： 0021-9258

  486. Activation of the NRF2 pathway and its impact on the prognosis of anaplastic glioma patients Peer-reviewed

    Masayuki Kanamori, Tsuyoshi Higa, Yukihiko Sonoda, Shohei Murakami, Mina Dodo, Hiroshi Kitamura, Keiko Taguchi, Tatsuhiro Shibata, Mika Watanabe, Hiroyoshi Suzuki, Ichiyo Shibahara, Ryuta Saito, Yoji Yamashita, Toshihiro Kumabe, Masayuki Yamamoto, Hozumi Motohashi, Teiji Tominaga

    NEURO-ONCOLOGY　17　(4)　555-565　2015/04

    DOI： 10.1093/neuonc/nou282 　

    ISSN： 1522-8517

    eISSN： 1523-5866

  487. In Vivo Regulation of Erythropoiesis by Chemically Inducible Dimerization of the Erythropoietin Receptor Intracellular Domain Peer-reviewed

    Norio Suzuki, Harumi Y. Mukai, Masayuki Yamamoto

    PLOS ONE　10　(3)　e0119442-e0119442　2015/03

    DOI： 10.1371/journal.pone.0119442 　

    ISSN： 1932-6203

  488. DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine-producing metabolic pathway Peer-reviewed

    Keizo Nishikawa, Yoriko Iwamoto, Yasuhiro Kobayashi, Fumiki Katsuoka, Shin-ichi Kawaguchi, Tadayuki Tsujita, Takashi Nakamura, Shigeaki Kato, Masayuki Yamamoto, Hiroshi Takayanagi, Masaru Ishii

    NATURE MEDICINE　21　(3)　281-+　2015/03

    DOI： 10.1038/nm.3774 　

    ISSN： 1078-8956

    eISSN： 1546-170X

  489. Progenitor Stage-Specific Activity of a cis-Acting Double GATA Motif for Gata1 Gene Expression Peer-reviewed

    Takashi Moriguchi, Mikiko Suzuki, Lei Yu, Jun Takai, Kinuko Ohneda, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　35　(5)　805-815　2015/03

    DOI： 10.1128/MCB.01011-14 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  490. Hypoxia-Sensitive Reporter System for High-Throughput Screening Peer-reviewed

    Tadayuki Tsujita, Shin-ichi Kawaguchi, Takashi Dan, Liam Baird, Toshio Miyata, Masayuki Yamamoto

    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE　235　(2)　151-159　2015/02

    DOI： 10.1620/tjem.235.151 　

    ISSN： 0040-8727

    eISSN： 1349-3329

  491. MAFG Is a Transcriptional Repressor of Bile Acid Synthesis and Metabolism Peer-reviewed

    Thomas Q. de Aguiar Vallim, Elizabeth J. Tarling, Hannah Ahn, Lee R. Hagey, Casey E. Romanoski, Richard G. Lee, Mark J. Graham, Hozumi Motohashi, Masayuki Yamamoto, Peter A. Edwards

    CELL METABOLISM　21　(2)　298-310　2015/02

    DOI： 10.1016/j.cmet.2015.01.007 　

    ISSN： 1550-4131

    eISSN： 1932-7420

  492. Nrf2 knockout rats are sensitive to hepatic toxicity by Aflatoxin B1

    TAGUCHI Keiko, TAKAKU Misaki, KENSLER Thomas W., YAMAMOTO Masayuki

    Annual Meeting of the Japanese Society of Toxicology　42　O-12　2015

    Publisher: The Japanese Society of Toxicology

    DOI： 10.14869/toxpt.42.1.0_O-12 　

  493. NRF2-Mediated Gene Regulation and Glucose Homeostasis Peer-reviewed

    Yoko Yagishita, Akira Uruno, Masayuki Yamamoto

    Molecular Nutrition and Diabetes: A Volume in the Molecular Nutrition Series　331-348　2015

    Publisher: Elsevier Inc.

    DOI： 10.1016/B978-0-12-801585-8.00027-0 　

  494. iJGVD: an integrative Japanese genome variation database based on whole-genome sequencing. Peer-reviewed

    Yamaguchi-Kabata Y, Nariai N, Kawai Y, Sato Y, Kojima K, Tateno M, Katsuoka F, Yasuda J, Yamamoto M, Nagasaki M

    Human genome variation　2　15050　2015

    DOI： 10.1038/hgv.2015.50 　

  495. Identification of a Functional Antioxidant Response Element within the Eighth Intron of the Human ABCC3 Gene Peer-reviewed

    Mark J. Canet, Matthew D. Merrell, Bryan G. Harder, Jonathan M. Maher, Tongde Wu, Andrew J. Lickteig, Jonathan P. Jackson, Donna D. Zhang, Masayuki Yamamoto, Nathan J. Cherrington

    DRUG METABOLISM AND DISPOSITION　43　(1)　93-99　2015/01

    DOI： 10.1124/dmd.114.060103 　

    ISSN： 0090-9556

    eISSN： 1521-009X

  496. The Keap1-Nrf2 system and diabetes mellitus Peer-reviewed

    Akira Uruno, Yoko Yagishita, Masayuki Yamamoto

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS　566　76-84　2015/01

    DOI： 10.1016/j.abb.2014.12.012 　

    ISSN： 0003-9861

    eISSN： 1096-0384

  497. Nrf2 induces fibroblast growth factor 21 in diabetic mice Peer-reviewed

    Yuki Furusawa, Akira Uruno, Yoko Yagishita, Chika Higashi, Masayuki Yamamoto

    GENES TO CELLS　19　(12)　864-878　2014/12

    DOI： 10.1111/gtc.12186 　

    ISSN： 1356-9597

    eISSN： 1365-2443

  498. An efficient quantitation method of next-generation sequencing libraries by using MiSeq sequencer Peer-reviewed

    Fumiki Katsuoka, Junji Yokozawa, Kaoru Tsuda, Shin Ito, Xiaoqing Pan, Masao Nagasaki, Jun Yasuda, Masayuki Yamamoto

    ANALYTICAL BIOCHEMISTRY　466　27-29　2014/12

    DOI： 10.1016/j.ab.2014.08.015 　

    ISSN： 0003-2697

    eISSN： 1096-0309

  499. Metabolism of 8-nitro-cGMP and regulation of electrophilic signaling by reactive sulfur species Peer-reviewed

    Ida Tomoaki, Sawa Tomohiro, Ihara Hideshi, Tsuchiya Yukihiro, Watanabe Yasuo, Kumagai Yoshito, Motohashi Hozumi, Fujii Shigemoto, Matsunaga Tetsuro, Yamamoto Masayuki, Ono Katsuhiko, Fukuto Jon, Akaike Takaaki

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　42　126-127　2014/11/15

    DOI： 10.1016/j.niox.2014.09.084 　

    ISSN： 1089-8603

  500. GATA2 regulates differentiation of bone marrow-derived mesenchymal stem cells Peer-reviewed

    Mayumi Kamata, Yoko Okitsu, Tohru Fujiwara, Masahiko Kanehira, Shinji Nakajima, Taro Takahashi, Ai Inoue, Noriko Fukuhara, Yasushi Onishi, Kenichi Ishizawa, Ritsuko Shimizu, Masayuki Yamamoto, Hideo Harigae

    HAEMATOLOGICA　99　(11)　1686-1696　2014/11

    DOI： 10.3324/haematol.2014.105692 　

    ISSN： 0390-6078

  501. A regulatory network governing Gata1 and Gata2 gene transcription orchestrates erythroid lineage differentiation Peer-reviewed

    Takashi Moriguchi, Masayuki Yamamoto

    INTERNATIONAL JOURNAL OF HEMATOLOGY　100　(5)　417-424　2014/11

    DOI： 10.1007/s12185-014-1568-0 　

    ISSN： 0925-5710

    eISSN： 1865-3774

  502. EVI1陽性白血病においてEVI1発現量が白血病細胞の分化形態を規定する

    鈴木 未来子, 片山 紗乙莉, 山嵜 博未, Engel James Douglas, 山本 雅之

    日本生化学会大会プログラム・講演要旨集　87回　[3P-420]　2014/10

    Publisher: (公社)日本生化学会

  503. [Identification of erythropoietin producing cells and erythropoietin gene regulation]. Peer-reviewed

    Yamamoto M, Hirano I

    [Rinsho ketsueki] The Japanese journal of clinical hematology　55　(10)　1785-1794　2014/10

    ISSN： 0485-1439

  504. Remarkable induction of UV-signature mutations at the 3'-cytosine of dipyrimidine sites except at 5'-TCG-3' in the UVB-exposed skin epidermis of xeroderma pigmentosum variant model mice. International-journal Peer-reviewed

    Hironobu Ikehata, Yumin Chang, Masayuki Yokoi, Masayuki Yamamoto, Fumio Hanaoka

    DNA repair　22　112-22　2014/10

    DOI： 10.1016/j.dnarep.2014.07.012 　

    More details Close

    The human POLH gene is responsible for the variant form of xeroderma pigmentosum (XP-V), a genetic disease highly susceptible to cancer on sun-exposed skin areas, and encodes DNA polymerase η (polη), which is specialized for translesion DNA synthesis (TLS) of UV-induced DNA photolesions. We constructed polη-deficient mice transgenic with lacZ mutational reporter genes to study the effect of Polh null mutation (Polh(-/-)) on mutagenesis in the skin after UVB irradiation. UVB induced lacZ mutations with remarkably higher frequency in the Polh(-/-) epidermis and dermis than in the wild-type (Polh(+/+)) and heterozygote. DNA sequences of a hundred lacZ mutants isolated from the epidermis of four UVB-exposed Polh(-/-) mice were determined and compared with mutant sequences from irradiated Polh(+)(/)(+) mice. The spectra of the mutations in the two genotypes were both highly UV-specific and dominated by C→T transitions at dipyrimidines, namely UV-signature mutations. However, sequence preferences of the occurrence of UV-signature mutations were quite different between the two genotypes: the mutations occurred at a higher frequency preferentially at the 5'-TCG-3' sequence context than at the other dipyrimidine contexts in the Polh(+/+) epidermis, whereas the mutations were induced remarkably and exclusively at the 3'-cytosine of almost all dipyrimidine contexts with no preference for 5'-TCG-3' in the Polh(-/-) epidermis. In addition, in Polh(-/-) mice, a small but remarkable fraction of G→T transversions was also observed exclusively at the 3'-cytosine of dipyrimidine sites, strongly suggesting that these transversions resulted not from oxidative damage but from UV photolesions. These results would reflect the characteristics of the error-prone TLS functioning in the bypass of UV photolesions in the absence of polη, which would be mediated by mechanisms based on the two-step model of TLS. On the other hand, the deamination model would explain well the mutation spectrum in the Polh(+/+) genotype.

  505. Transcription Factor Nrf1 Negatively Regulates the Cystine/Glutamate Transporter and Lipid-Metabolizing Enzymes Peer-reviewed

    Tadayuki Tsujita, Vivian Peirce, Liam Baird, Yuka Matsuyama, Misaki Takaku, Shawn V. Walsh, Julian L. Griffin, Akira Uruno, Masayuki Yamamoto, John D. Hayes

    MOLECULAR AND CELLULAR BIOLOGY　34　(20)　3800-3816　2014/10

    DOI： 10.1128/MCB.00110-14 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  506. Fetal Globin Gene Repressors as Drug Targets for Molecular Therapies To Treat the beta-Globinopathies Peer-reviewed

    Mikiko Suzuki, Masayuki Yamamoto, James Douglas Engel

    MOLECULAR AND CELLULAR BIOLOGY　34　(19)　3560-3569　2014/10

    DOI： 10.1128/MCB.00714-14 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  507. Nuclear Factor Erythroid 2-Related Factor 2 Regulates Toll-Like Receptor 4 Innate Responses in Mouse Liver Ischemia-Reperfusion Injury Through Akt-Forkhead box Protein O1 Signaling Network Peer-reviewed

    Jing Huang, Shi Yue, Bibo Ke, Jianjun Zhu, Xiu-da Shen, Yuan Zhai, Masayuki Yamamoto, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski

    TRANSPLANTATION　98　(7)　721-728　2014/10

    DOI： 10.1097/TP.0000000000000316 　

    ISSN： 0041-1337

    eISSN： 1534-6080

  508. 薬剤によるNrf2活性化はウレタン誘導性肺腫瘍の悪性化を促進する(Drug-induced Nrf2 activation accelerates malignant progression of urethane-induced lung tumors)

    佐藤 大希, 森口 尚, 海老名 雅仁, 柴田 龍弘, 山本 雅之

    日本癌学会総会記事　73回　P-1050　2014/09

    Publisher: (一社)日本癌学会

    ISSN： 0546-0476

  509. Loss of Nrf2 in Mice Evokes a Congenital Intrahepatic Shunt That Alters Hepatic Oxygen and Protein Expression Gradients and Toxicity Peer-reviewed

    John J. Skoko, Nobunao Wakabayashi, Kentaro Noda, Shoko Kimura, Kimimasa Tobita, Norihisa Shigemura, Tadayuki Tsujita, Masayuki Yamamoto, Thomas W. Kensler

    TOXICOLOGICAL SCIENCES　141　(1)　112-119　2014/09

    DOI： 10.1093/toxsci/kfu109 　

    ISSN： 1096-6080

    eISSN： 1096-0929

  510. Proteasome Dysfunction Activates Autophagy and the Keap1-Nrf2 Pathway Peer-reviewed

    Shun Kageyama, Yu-shin Sou, Takefumi Uemura, Satoshi Kametaka, Tetsuya Saito, Ryosuke Ishimura, Tsuguka Kouno, Lynn Bedford, R. John Mayer, Myung-Shik Lee, Masayuki Yamamoto, Satoshi Waguri, Keiji Tanaka, Masaaki Komatsu

    JOURNAL OF BIOLOGICAL CHEMISTRY　289　(36)　24944-24955　2014/09

    DOI： 10.1074/jbc.M114.580357 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  511. Validation of multiple single nucleotide variation calls by additional exome analysis with a semiconductor sequencer to supplement data of whole-genome sequencing of a human population Peer-reviewed

    Ikuko N. Motoike, Mitsuyo Matsumoto, Inaho Danjoh, Fumiki Katsuoka, Kaname Kojima, Naoki Nariai, Yukuto Sato, Yumi Yamaguchi-Kabata, Shin Ito, Hisaaki Kudo, Ichiko Nishijima, Satoshi Nishikawa, Xiaoqing Pan, Rumiko Saito, Sakae Saito, Tomo Saito, Matsuyuki Shirota, Kaoru Tsuda, Junji Yokozawa, Kazuhiko Igarashi, Naoko Minegishi, Osamu Tanabe, Nobuo Fuse, Masao Nagasaki, Kengo Kinoshita, Jun Yasuda, Masayuki Yamamoto

    BMC GENOMICS　15　673-673　2014/08

    DOI： 10.1186/1471-2164-15-673 　

    ISSN： 1471-2164

  512. Transcription factor NF-E2-related factor 1 impairs glucose metabolism in mice Peer-reviewed

    Yosuke Hirotsu, Chika Higashi, Toshiaki Fukutomi, Fumiki Katsuoka, Tadayuki Tsujita, Yoko Yagishita, Yuka Matsuyama, Hozumi Motohashi, Akira Uruno, Masayuki Yamamoto

    GENES TO CELLS　19　(8)　650-665　2014/08

    DOI： 10.1111/gtc.12165 　

    ISSN： 1356-9597

    eISSN： 1365-2443

  513. Myeloid Lineage-Specific Deletion of Antioxidant System Enhances Tumor Metastasis Peer-reviewed

    Keiichiro Hiramoto, Hironori Satoh, Takafumi Suzuki, Takashi Moriguchi, Jingbo Pi, Tooru Shimosegawa, Masayuki Yamamoto

    CANCER PREVENTION RESEARCH　7　(8)　835-844　2014/08

    DOI： 10.1158/1940-6207.CAPR-14-0094 　

    ISSN： 1940-6207

    eISSN： 1940-6215

  514. Electron microscopy of primary cell cultures in solution and correlative optical microscopy using ASEM Peer-reviewed

    Kazumi Hirano, Takaaki Kinoshita, Takeshi Uemura, Hozumi Motohashi, Yohei Watanabe, Tatsuhiko Ebihara, Hidetoshi Nishiyama, Mari Sato, Mitsuo Suga, Yuusuke Maruyama, Noriko M. Tsuji, Masayuki Yamamoto, Shoko Nishihara, Chikara Sato

    ULTRAMICROSCOPY　143　52-66　2014/08

    DOI： 10.1016/J.ultramic.2013.10.010 　

    ISSN： 0304-3991

    eISSN： 1879-2723

  515. Multiple Nonglycemic Genomic Loci Are Newly Associated With Blood Level of Glycated Hemoglobin in East Asians Peer-reviewed

    Peng Chen, Fumihiko Takeuchi, Jong-Young Lee, Huaixing Li, Jer-Yuarn Wu, Jun Liang, Jirong Long, Yasuharu Tabara, Mark O. Goodarzi, Mark A. Pereira, Young Jin Kim, Min Jin Go, Daniel O. Stram, Eranga Vithana, Chiea-Chuen Khor, Jianjun Liu, Jiemin Liao, Xingwang Ye, Yiqin Wang, Ling Lu, Terri L. Young, Jeannette Lee, Ah Chuan Thai, Ching-Yu Cheng, Rob M. van Dam, Yechiel Friedlander, Chew-Kiat Heng, Woon-Puay Koh, Chien-Hsiun Chen, Li-Ching Chang, Wen-Harn Pan, Qibin Qi, Masato Isono, Wei Zheng, Qiuyin Cai, Yutang Gao, Ken Yamamoto, Keizo Ohnaka, Ryoichi Takayanagi, Yoshikuni Kita, Hirotsugu Ueshima, Chao A. Hsiung, Jinrui Cui, Wayne H. -H. Sheu, Jerome I. Rotter, Yii-Der I. Chen, Chris Hsu, Yukinori Okada, Michiaki Kubo, Atsushi Takahashi, Toshihiro Tanaka, Frank J. A. van Rooij, Santhi K. Ganesh, Jinyan Huang, Tao Huang, Jianmin Yuan, Joo-Yeon Hwang, Myron D. Gross, Themistocles L. Assimes, Tetsuro Miki, Xiao-Ou Shu, Lu Qi, Yuan-Tson Chen, Xu Lin, Tin Aung, Tien-Yin Wong, Yik-Ying Teo, Bong-Jo Kim, Norihiro Kato, E-Shyong Tai

    DIABETES　63　(7)　2551-2562　2014/07

    DOI： 10.2337/db13-1815 　

    ISSN： 0012-1797

    eISSN： 1939-327X

  516. Nrf2 enhances myocardial clearance of toxic ubiquitinated proteins Peer-reviewed

    Wenjuan Wang, Siying Li, Hui Wang, Bin Li, Lei Shao, Yimu Lai, Gary Horvath, Qian Wang, Masayuki Yamamoto, Joseph S. Janicki, Xing Li Wang, Dongqi Tang, Taixing Cui

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY　72　305-315　2014/07

    DOI： 10.1016/j.yjmcc.2014.04.006 　

    ISSN： 0022-2828

    eISSN： 1095-8584

  517. Nrf2 Positively Regulates FGF21 in Diabetic Mice: A Potential Efficacy Biomarker of Nrf2 Induction Peer-reviewed

    Yuki Furusawa, Akira Uruno, Yoko Yagishita, Masayuki Yamamoto

    DIABETES　63　A485-A485　2014/06

    ISSN： 0012-1797

    eISSN： 1939-327X

  518. Network regulation of Gata1 and Gata2 gene-dynamics underlies erythroid differentiation. Peer-reviewed

    Moriguchi, Takashi, Yamamoto, Masayuki

    Rinsho Ketsueki　55　(6)　633-642 (J-STAGE)-642　2014/06

    DOI： 10.11406/rinketsu.55.633 　

    ISSN： 0485-1439

  519. PGC-1 Coactivator Activity Is Required for Murine Erythropoiesis Peer-reviewed

    Shuaiying Cui, Osamu Tanabe, Kim-Chew Lim, H. Eric Xu, X. Edward Zhou, Jiandie D. Lin, Lihong Shi, Lindsay Schmidt, Andrew Campbell, Ritsuko Shimizu, Masayuki Yamamoto, James Douglas Engel

    MOLECULAR AND CELLULAR BIOLOGY　34　(11)　1956-1965　2014/06

    DOI： 10.1128/MCB.00247-14 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  520. NF-E2-Related Factor 2 Promotes Compensatory Liver Hypertrophy After Portal Vein Branch Ligation in Mice Peer-reviewed

    Keiichi Shirasaki, Keiko Taguchi, Michiaki Unno, Hozumi Motohashi, Masayuki Yamamoto

    HEPATOLOGY　59　(6)　2371-2382　2014/06

    DOI： 10.1002/hep.27020 　

    ISSN： 0270-9139

    eISSN： 1527-3350

  521. Isocitrate dehydrogenase mutation is frequently observed in giant cell tumor of bone Peer-reviewed

    Mika Kato Kaneko, Xing Liu, Hiroharu Oki, Satoshi Ogasawara, Takuro Nakamura, Noriko Saidoh, Yuta Tsujimoto, Yuka Matsuyama, Akira Uruno, Masato Sugawara, Takashi Tsuchiya, Mitsunori Yamakawa, Masayuki Yamamoto, Michiaki Takagi, Yukinari Kato

    CANCER SCIENCE　105　(6)　744-748　2014/06

    DOI： 10.1111/cas.12413 　

    ISSN： 1349-7006

  522. GATA2 Regulates Body Water Homeostasis through Maintaining Aquaporin 2 Expression in Renal Collecting Ducts Peer-reviewed

    Lei Yu, Takashi Moriguchi, Tomokazu Souma, Jun Takai, Hironori Satoh, Naoki Morito, James Douglas Engel, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　34　(11)　1929-1941　2014/06

    DOI： 10.1128/MCB.01659 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  523. Reactive cysteine persulfides and S-polythiolation regulate oxidative stress and redox signaling. International-journal Peer-reviewed

    Tomoaki Ida, Tomohiro Sawa, Hideshi Ihara, Yukihiro Tsuchiya, Yasuo Watanabe, Yoshito Kumagai, Makoto Suematsu, Hozumi Motohashi, Shigemoto Fujii, Tetsuro Matsunaga, Masayuki Yamamoto, Katsuhiko Ono, Nelmi O Devarie-Baez, Ming Xian, Jon M Fukuto, Takaaki Akaike

    Proceedings of the National Academy of Sciences of the United States of America　111　(21)　7606-11　2014/05/27

    DOI： 10.1073/pnas.1321232111 　

    More details Close

    Using methodology developed herein, it is found that reactive persulfides and polysulfides are formed endogenously from both small molecule species and proteins in high amounts in mammalian cells and tissues. These reactive sulfur species were biosynthesized by two major sulfurtransferases: cystathionine β-synthase and cystathionine γ-lyase. Quantitation of these species indicates that high concentrations of glutathione persulfide (perhydropersulfide >100 μM) and other cysteine persulfide and polysulfide derivatives in peptides/proteins were endogenously produced and maintained in the plasma, cells, and tissues of mammals (rodent and human). It is expected that persulfides are especially nucleophilic and reducing. This view was found to be the case, because they quickly react with H2O2 and a recently described biologically generated electrophile 8-nitroguanosine 3',5'-cyclic monophosphate. These results indicate that persulfides are potentially important signaling/effector species, and because H2S can be generated from persulfide degradation, much of the reported biological activity associated with H2S may actually be that of persulfides. That is, H2S may act primarily as a marker for the biologically active of persulfide species.

  524. 遺伝性超貧血マウスに対するエポエチン ベータ ペゴル投与後の鉄代謝亢進効果 Peer-reviewed

    佐々木 雄亮, 山嵜 瞬, 藤田 謙, 倉澤 光江, 萬 啓悟, 下中 靖, 鈴木 教郎, 山本 雅之

    日本透析医学会雑誌　47　(Suppl.1)　618-618　2014/05

    Publisher: (一社)日本透析医学会

    ISSN： 1340-3451

    eISSN： 1883-082X

  525. Transcription Factor GATA1 Is Dispensable for Mast Cell Differentiation in Adult Mice Peer-reviewed

    Kinuko Ohneda, Takashi Moriguchi, Shin'ya Ohmori, Yasushi Ishijima, Hironori Satoh, Sjaak Philipsen, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　34　(10)　1812-1826　2014/05

    DOI： 10.1128/MCB.01524 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  526. Nrf2 deficiency impairs the barrier function of mouse oesophageal epithelium Peer-reviewed

    Hao Chen, Yuhui Hu, Yu Fang, Zorka Djukic, Masayuki Yamamoto, Nicholas J. Shaheen, Roy C. Orlando, Xiaoxin Chen

    GUT　63　(5)　711-719　2014/05

    DOI： 10.1136/gutjnl-2012-303731 　

    ISSN： 0017-5749

    eISSN： 1468-3288

  527. Carbocisteine Reduces Virus-Induced Pulmonary Inflammation in Mice Exposed to Cigarette Smoke Peer-reviewed

    Yuichi Yageta, Yukio Ishii, Yuko Morishima, Satoshi Ano, Shigeo Ohtsuka, Masashi Matsuyama, Kaoru Takeuchi, Ken Itoh, Masayuki Yamamoto, Nobuyuki Hizawa

    AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY　50　(5)　963-973　2014/05

    DOI： 10.1165/rcmb.2012-0292OC 　

    ISSN： 1044-1549

    eISSN： 1535-4989

  528. GATA4 immunolocalization in breast carcinoma as a potent prognostic predictor. Peer-reviewed

    Takagi, Kiyoshi Moriguchi, Takashi Miki, Yasuhiro Nakamura, Yasuhiro Watanabe, Mika Ishida, Takanori Yamamoto, Masayuki Sasano, Hironobu Suzuki, Takashi

    Cancer Sci　105　(5)　600-607　2014/05

    DOI： 10.1111/cas.12382 　

  529. Mouse Spermatogenic Stem Cells Continually Interconvert between Equipotent Singly Isolated and Syncytial States Peer-reviewed

    Kenshiro Hara, Toshinori Nakagawa, Hideki Enomoto, Mikiko Suzuki, Masayuki Yamamoto, Benjamin D. Simons, Shosei Yoshida

    CELL STEM CELL　14　(5)　658-672　2014/05

    DOI： 10.1016/j.stem.2014.01.019 　

    ISSN： 1934-5909

    eISSN： 1875-9777

  530. 【大気圧走査電子顕微鏡(ASEM)】巨核球による血小板産生と樹状細胞による細菌貪食の液中電顕観察

    佐藤 主税, 渡邊 要平, 丸山 雄介, 佐藤 真理, 山本 雅之, 辻 典子, 本橋 ほづみ

    顕微鏡　49　(1)　14-17　2014/04

    Publisher: (公社)日本顕微鏡学会

    ISSN： 1349-0958

  531. Keap1 inhibition attenuates glomerulosclerosis. Peer-reviewed

    Miyazaki Y, Shimizu A, Pastan I, Taguchi K, Naganuma E, Suzuki T, Hosoya T, Yokoo T, Saito A, Miyata T, Yamamoto M, Matsusaka T

    Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association　29　(4)　783-791　2014/04

    DOI： 10.1093/ndt/gfu002 　

    ISSN： 0931-0509

  532. NRF2 immunolocalization in human breast cancer patients as a prognostic factor Peer-reviewed

    Yoshiaki Onodera, Hozumi Motohashi, Kiyoshi Takagi, Yasuhiro Miki, Yukiko Shibahara, Mika Watanabe, Takanori Ishida, Hisashi Hirakawa, Hironobu Sasano, Masayuki Yamamoto, Takashi Suzuki

    ENDOCRINE-RELATED CANCER　21　(2)　241-252　2014/04

    DOI： 10.1530/ERC-13-0234 　

    ISSN： 1351-0088

    eISSN： 1479-6821

  533. A Remote GATA2 Hematopoietic Enhancer Drives Leukemogenesis in inv(3)(q21;q26) by Activating EVI1 Expression Peer-reviewed

    Hiromi Yamazaki, Mikiko Suzuki, Akihito Otsuki, Ritsuko Shimizu, Emery H. Bresnick, James Douglas Engel, Masayuki Yamamoto

    CANCER CELL　25　(4)　415-427　2014/04

    DOI： 10.1016/j.ccr.2014.02.008 　

    ISSN： 1535-6108

    eISSN： 1878-3686

  534. A promoter-level mammalian expression atlas. International-journal Peer-reviewed

    Alistair R R Forrest, Hideya Kawaji, Michael Rehli, J Kenneth Baillie, Michiel J L de Hoon, Vanja Haberle, Timo Lassmann, Ivan V Kulakovskiy, Marina Lizio, Masayoshi Itoh, Robin Andersson, Christopher J Mungall, Terrence F Meehan, Sebastian Schmeier, Nicolas Bertin, Mette Jørgensen, Emmanuel Dimont, Erik Arner, Christian Schmidl, Ulf Schaefer, Yulia A Medvedeva, Charles Plessy, Morana Vitezic, Jessica Severin, Colin A Semple, Yuri Ishizu, Robert S Young, Margherita Francescatto, Intikhab Alam, Davide Albanese, Gabriel M Altschuler, Takahiro Arakawa, John A C Archer, Peter Arner, Magda Babina, Sarah Rennie, Piotr J Balwierz, Anthony G Beckhouse, Swati Pradhan-Bhatt, Judith A Blake, Antje Blumenthal, Beatrice Bodega, Alessandro Bonetti, James Briggs, Frank Brombacher, A Maxwell Burroughs, Andrea Califano, Carlo V Cannistraci, Daniel Carbajo, Yun Chen, Marco Chierici, Yari Ciani, Hans C Clevers, Emiliano Dalla, Carrie A Davis, Michael Detmar, Alexander D Diehl, Taeko Dohi, Finn Drabløs, Albert S B Edge, Matthias Edinger, Karl Ekwall, Mitsuhiro Endoh, Hideki Enomoto, Michela Fagiolini, Lynsey Fairbairn, Hai Fang, Mary C Farach-Carson, Geoffrey J Faulkner, Alexander V Favorov, Malcolm E Fisher, Martin C Frith, Rie Fujita, Shiro Fukuda, Cesare Furlanello, Masaaki Furino, Jun-ichi Furusawa, Teunis B Geijtenbeek, Andrew P Gibson, Thomas Gingeras, Daniel Goldowitz, Julian Gough, Sven Guhl, Reto Guler, Stefano Gustincich, Thomas J Ha, Masahide Hamaguchi, Mitsuko Hara, Matthias Harbers, Jayson Harshbarger, Akira Hasegawa, Yuki Hasegawa, Takehiro Hashimoto, Meenhard Herlyn, Kelly J Hitchens, Shannan J Ho Sui, Oliver M Hofmann, Ilka Hoof, Furni Hori, Lukasz Huminiecki, Kei Iida, Tomokatsu Ikawa, Boris R Jankovic, Hui Jia, Anagha Joshi, Giuseppe Jurman, Bogumil Kaczkowski, Chieko Kai, Kaoru Kaida, Ai Kaiho, Kazuhiro Kajiyama, Mutsumi Kanamori-Katayama, Artem S Kasianov, Takeya Kasukawa, Shintaro Katayama, Sachi Kato, Shuji Kawaguchi, Hiroshi Kawamoto, Yuki I Kawamura, Tsugumi Kawashima, Judith S Kempfle, Tony J Kenna, Juha Kere, Levon M Khachigian, Toshio Kitamura, S Peter Klinken, Alan J Knox, Miki Kojima, Soichi Kojima, Naoto Kondo, Haruhiko Koseki, Shigeo Koyasu, Sarah Krampitz, Atsutaka Kubosaki, Andrew T Kwon, Jeroen F J Laros, Weonju Lee, Andreas Lennartsson, Kang Li, Berit Lilje, Leonard Lipovich, Alan Mackay-Sim, Ri-ichiroh Manabe, Jessica C Mar, Benoit Marchand, Anthony Mathelier, Niklas Mejhert, Alison Meynert, Yosuke Mizuno, David A de Lima Morais, Hiromasa Morikawa, Mitsuru Morimoto, Kazuyo Moro, Efthymios Motakis, Hozumi Motohashi, Christine L Mummery, Mitsuyoshi Murata, Sayaka Nagao-Sato, Yutaka Nakachi, Fumio Nakahara, Toshiyuki Nakamura, Yukio Nakamura, Kenichi Nakazato, Erik van Nimwegen, Noriko Ninomiya, Hiromi Nishiyori, Shohei Noma, Shohei Noma, Tadasuke Noazaki, Soichi Ogishima, Naganari Ohkura, Hiroko Ohimiya, Hiroshi Ohno, Mitsuhiro Ohshima, Mariko Okada-Hatakeyama, Yasushi Okazaki, Valerio Orlando, Dmitry A Ovchinnikov, Arnab Pain, Robert Passier, Margaret Patrikakis, Helena Persson, Silvano Piazza, James G D Prendergast, Owen J L Rackham, Jordan A Ramilowski, Mamoon Rashid, Timothy Ravasi, Patrizia Rizzu, Marco Roncador, Sugata Roy, Morten B Rye, Eri Saijyo, Antti Sajantila, Akiko Saka, Shimon Sakaguchi, Mizuho Sakai, Hiroki Sato, Suzana Savvi, Alka Saxena, Claudio Schneider, Erik A Schultes, Gundula G Schulze-Tanzil, Anita Schwegmann, Thierry Sengstag, Guojun Sheng, Hisashi Shimoji, Yishai Shimoni, Jay W Shin, Christophe Simon, Daisuke Sugiyama, Takaai Sugiyama, Masanori Suzuki, Naoko Suzuki, Rolf K Swoboda, Peter A C 't Hoen, Michihira Tagami, Naoko Takahashi, Jun Takai, Hiroshi Tanaka, Hideki Tatsukawa, Zuotian Tatum, Mark Thompson, Hiroo Toyodo, Tetsuro Toyoda, Elvind Valen, Marc van de Wetering, Linda M van den Berg, Roberto Verado, Dipti Vijayan, Ilya E Vorontsov, Wyeth W Wasserman, Shoko Watanabe, Christine A Wells, Louise N Winteringham, Ernst Wolvetang, Emily J Wood, Yoko Yamaguchi, Masayuki Yamamoto, Misako Yoneda, Yohei Yonekura, Shigehiro Yoshida, Susan E Zabierowski, Peter G Zhang, Xiaobei Zhao, Silvia Zucchelli, Kim M Summers, Harukazu Suzuki, Carsten O Daub, Jun Kawai, Peter Heutink, Winston Hide, Tom C Freeman, Boris Lenhard, Vladimir B Bajic, Martin S Taylor, Vsevolod J Makeev, Albin Sandelin, David A Hume, Piero Carninci, Yoshihide Hayashizaki

    Nature　507　(7493)　462-70　2014/03/27

    DOI： 10.1038/nature13182 　

    More details Close

    Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research.

  535. The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis. International-journal Peer-reviewed

    Vanja Pekovic-Vaughan, Julie Gibbs, Hikari Yoshitane, Nan Yang, Dharshika Pathiranage, Baoqiang Guo, Aya Sagami, Keiko Taguchi, David Bechtold, Andrew Loudon, Masayuki Yamamoto, Jefferson Chan, Gijsbertus T J van der Horst, Yoshitaka Fukada, Qing-Jun Meng

    Genes & development　28　(6)　548-60　2014/03/15

    DOI： 10.1101/gad.237081.113 　

    ISSN： 0890-9369

    eISSN： 1549-5477

  536. Does Nrf2 Gene Transfer Facilitate Recovery After Contusion Spinal Cord Injury? Peer-reviewed

    Yuriy Pomeshchik, Iurii Kidin, Ekaterina Savchenko, Taisia Rolova, Masayuki Yamamoto, Anna-Liisa Levonen, Seppo Yla-Herttuala, Tarja Malm, Katja Kanninen, Jari Koistinaho

    ANTIOXIDANTS & REDOX SIGNALING　20　(8)　1313-1323　2014/03

    DOI： 10.1089/ars.2013.5453 　

    ISSN： 1523-0864

    eISSN： 1557-7716

  537. Nrf2 Enhances Cholangiocyte Expansion in Pten-Deficient Livers Peer-reviewed

    Keiko Taguchi, Ikuo Hirano, Tohru Itoh, Minoru Tanaka, Atsushi Miyajima, Akira Suzuki, Hozumi Motohashi, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　34　(5)　900-913　2014/03

    DOI： 10.1128/MCB.01384-13 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  538. Kinetic, Thermodynamic, and Structural Characterizations of the Association between Nrf2-DLGex Degron and Keap1 Peer-reviewed

    Toshiaki Fukutomi, Kenji Takagi, Tsunehiro Mizushima, Noriaki Ohuchi, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　34　(5)　832-846　2014/03

    DOI： 10.1128/MCB.01191-13 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  539. Keap1-Nrf2 system regulates cell fate determination of hematopoietic stem cells Peer-reviewed

    Shohei Murakami, Ritsuko Shimizu, Paul-Henri Romeo, Masayuki Yamamoto, Hozumi Motohashi

    GENES TO CELLS　19　(3)　239-253　2014/03

    DOI： 10.1111/gtc.12126 　

    ISSN： 1356-9597

    eISSN： 1365-2443

  540. Hematopoietic Stem and Progenitor Cell Activation During Chronic Dermatitis Provoked by Constitutively Active Aryl-Hydrocarbon Receptor Driven by Keratin 14 Promoter Peer-reviewed

    Shohei Murakami, Masayuki Yamamoto, Hozumi Motohashi

    TOXICOLOGICAL SCIENCES　138　(1)　47-58　2014/03

    DOI： 10.1093/toxsci/kft273 　

    ISSN： 1096-6080

    eISSN： 1096-0929

  541. Notch-Nrf2 Axis: Regulation of Nrf2 Gene Expression and Cytoprotection by Notch Signaling Peer-reviewed

    Nobunao Wakabayashi, John J. Skoko, Dionysios V. Chartoumpekis, Shoko Kimura, Stephen L. Slocum, Kentaro Noda, Dushani L. Palliyaguru, Masahiro Fujimuro, Patricia A. Boley, Yugo Tanaka, Norihisa Shigemura, Shyam Biswal, Masayuki Yamamoto, Thomas W. Kensler

    MOLECULAR AND CELLULAR BIOLOGY　34　(4)　653-663　2014/02

    DOI： 10.1128/MCB.01408-13 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  542. Nrf2 Protects Pancreatic beta-Cells From Oxidative and Nitrosative Stress in Diabetic Model Mice Peer-reviewed

    Yoko Yagishita, Toshiaki Fukutomi, Akira Sugawara, Hiroshi Kawamura, Tetsu Takahashi, Jingbo Pi, Akira Uruno, Masayuki Yamamoto

    DIABETES　63　(2)　605-618　2014/02

    DOI： 10.2337/db13-0909 　

    ISSN： 0012-1797

    eISSN： 1939-327X

  543. 4. Tohoku Medical Megabank Project and Future Medicine

    Yamamoto Masayuki

    Nihon Naika Gakkai Kaishi　103　110c-111a　2014

    Publisher: The Japanese Society of Internal Medicine

    DOI： 10.2169/naika.103.110c 　

    ISSN： 0021-5384

  544. Possible involvement of nuclear factor erythroid 2-related factor 2 in the gene expression of Cyp2b10 and Cyp2a5 Peer-reviewed

    Takashi Ashino, Haruyo Ohkubo-Morita, Masayuki Yamamoto, Takemi Yoshida, Satoshi Numazawa

    REDOX BIOLOGY　2　284-288　2014

    DOI： 10.1016/j.redox.2013.12.025 　

    ISSN： 2213-2317

  545. Critical role of Nrf2 in oxidative stress-induced retinal ganglion cell death Peer-reviewed

    Noriko Himori, Kotaro Yamamoto, Kazuichi Maruyama, Morin Ryu, Keiko Taguchi, Masayuki Yamamoto, Toru Nakazawa

    JOURNAL OF NEUROCHEMISTRY　127　(5)　669-680　2013/12

    DOI： 10.1111/jnc.12325 　

    ISSN： 0022-3042

    eISSN： 1471-4159

  546. KEAP1-NRF2 complex in ischemia-induced hepatocellular damage of mouse liver transplants Peer-reviewed

    Bibo Ke, Xiu-Da Shen, Yu Zhang, Haofeng Ji, Feng Gao, Shi Yue, Naoko Kamo, Yuan Zhai, Masayuki Yamamoto, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski

    JOURNAL OF HEPATOLOGY　59　(6)　1200-1207　2013/12

    DOI： 10.1016/j.jhep.2013.07.016 　

    ISSN： 0168-8278

    eISSN： 1600-0641

  547. Erythropoietin production in neuroepithelial and neural crest cells during primitive erythropoiesis Peer-reviewed

    Norio Suzuki, Ikuo Hirano, Xiaoqing Pan, Naoko Minegishi, Masayuki Yamamoto

    NATURE COMMUNICATIONS　4　2902-2902　2013/12

    DOI： 10.1038/ncomms3902 　

    ISSN： 2041-1723

  548. The Gata1 5' region harbors distinct cis-regulatory modules that direct gene activation in erythroid cells and gene inactivation in HSCs. International-journal Peer-reviewed

    Takai J, Moriguchi T, Suzuki M, Yu L, Ohneda K, Yamamoto M

    Blood　122　(20)　3450-3460　2013/11/14

    DOI： 10.1182/blood-2013-01-476911 　

    ISSN： 0006-4971

  549. Verification of the in vivo activity of three distinct cis-acting elements within the Gata1 gene promoter-proximal enhancer in mice. Peer-reviewed

    Shimizu, Ritsuko Hasegawa, Atsushi Ottolenghi, Sergio Ronchi, Antonella Yamamoto, Masayuki

    Genes Cells　18　(11)　1032-1041　2013/11

    DOI： 10.1111/gtc.12096 　

  550. Loss of a Rho-regulated actin nucleator, mDia2, impairs cytokinesis during mouse fetal erythropoiesis. Peer-reviewed

    Watanabe S, De Zan T, Ishizaki T, Yasuda S, Kamijo H, Yamada D, Aoki T, Kiyonari H, Kaneko H, Shimizu R, Yamamoto M, Goshima G, Narumiya S

    Cell reports　5　(4)　926-932　2013/11

    DOI： 10.1016/j.celrep.2013.10.021 　

    ISSN： 2211-1247

  551. GATA factor switching from GATA2 to GATA1 contributes to erythroid differentiation. Peer-reviewed

    Suzuki M, Kobayashi-Osaki M, Tsutsumi S, Pan X, Ohmori S, Takai J, Moriguchi T, Ohneda O, Ohneda K, Shimizu R, Kanki Y, Kodama T, Aburatani H, Yamamoto M

    Genes to cells : devoted to molecular & cellular mechanisms　18　(11)　921-933　2013/11

    DOI： 10.1111/gtc.12086 　

    ISSN： 1356-9597

  552. 抗酸化ストレス蛋白質Nrf2を恒常的に活性化するKeap1ノックダウンマウスは、著明な肺発癌抑制能を示す(Nrf2-constitutive activation in Keap1 knockdown mice dramatically attenuated urethane-induced lung carcinogenesis)

    佐藤 大希, 森口 尚, 海老名 雅仁, 山本 雅之

    日本癌学会総会記事　72回　512-512　2013/10

    Publisher: (一社)日本癌学会

    ISSN： 0546-0476

  553. Establishment of erythroleukemic GAK14 cells and characterization of GATA1 N-terminal domain. Peer-reviewed

    Mukai, Harumi Y Suzuki, Mikiko Nagano, Masumi Ohmori, Shin'ya Otsuki, Akihito Tsuchida, Kouhei Moriguchi, Takashi Ohneda, Kinuko Shimizu, Ritsuko Ohneda, Osamu Yamamoto, Masayuki

    Genes Cells　18　(10)　886-898　2013/10

    DOI： 10.1111/gtc.12084 　

  554. Plasticity of renal erythropoietin-producing cells governs fibrosis. Peer-reviewed

    Souma, Tomokazu Yamazaki, Shun Moriguchi, Takashi Suzuki, Norio Hirano, Ikuo Pan, Xiaoqing Minegishi, Naoko Abe, Michiaki Kiyomoto, Hideyasu Ito, Sadayoshi Yamamoto, Masayuki

    J Am Soc Nephrol　24　(10)　1599-1616　2013/10

    DOI： 10.1681/ASN.2013010030 　

  555. Nrf2 deficiency leads to behavioral, neurochemical and transcriptional changes in mice Peer-reviewed

    Hiroyuki Muramatsu, Fumiki Katsuoka, Katsuo Toide, Yusuke Shimizu, Shoji Furusako, Masayuki Yamamoto

    GENES TO CELLS　18　(10)　899-908　2013/10

    DOI： 10.1111/gtc.12083 　

    ISSN： 1356-9597

  556. 肝毒性物質による肝肥大におけるNrf2の貢献

    田口 恵子, 本橋 ほづみ, 伊藤 暢, 田中 稔, 宮島 篤, 山本 雅之

    日本生化学会大会プログラム・講演要旨集　86回　2P-246　2013/09

    Publisher: (公社)日本生化学会

  557. GATA2はマスト細胞の分化形質の維持に必須である

    大森 慎也, 石嶋 康史, 森口 尚, 山本 雅之, 大根田 絹子

    日本生化学会大会プログラム・講演要旨集　86回　1T14a-08　2013/09

    Publisher: (公社)日本生化学会

  558. 肝臓エリスロポエチン産生を制御する低酸素誘導経路の個体レベル解析 Peer-reviewed

    東條 裕, 宮田 敏男, 山本 雅之, 鈴木 教郎

    日本生化学会大会プログラム・講演要旨集　86回　2P-333　2013/09

    Publisher: (公社)日本生化学会

  559. HIF-3αによるエリスロポエチン遺伝子発現の抑制的制御 Peer-reviewed

    牧野 塁, 潘 小青, 山嵜 瞬, 平野 育生, 山本 雅之, 鈴木 教郎

    日本生化学会大会プログラム・講演要旨集　86回　2P-337　2013/09

    Publisher: (公社)日本生化学会

  560. Nrf2制御系とAdh3の協調作用による生体防御機構の解析 Peer-reviewed

    後藤 まき, 長谷場 健, 鈴木 教郎, 山本 雅之, 山本 照子, 本橋 ほづみ

    日本生化学会大会プログラム・講演要旨集　86回　3P-182　2013/09

    Publisher: (公社)日本生化学会

  561. Phosphorylation of p62 Activates the Keap1-Nrf2 Pathway during Selective Autophagy Peer-reviewed

    Yoshinobu Ichimura, Satoshi Waguri, Yu-shin Sou, Shun Kageyama, Jun Hasegawa, Ryosuke Ishimura, Tetsuya Saito, Yinjie Yang, Tsuguka Kouno, Toshiaki Fukutomi, Takayuki Hoshii, Atsushi Hirao, Kenji Takagi, Tsunehiro Mizushima, Hozumi Motohashi, Myung-Shik Lee, Tamotsu Yoshimori, Keiji Tanaka, Masayuki Yamamoto, Masaaki Komatsu

    MOLECULAR CELL　51　(5)　618-631　2013/09

    DOI： 10.1016/j.molcel.2013.08.003 　

    ISSN： 1097-2765

    eISSN： 1097-4164

  562. 生体防御におけるNrf2制御系とAdh3の協調作用の重要性 Peer-reviewed

    後藤 まき, 長谷場 健, 鈴木 教郎, 山本 照子, 山本 雅之, 橋本 ほづみ

    生化学　85　(8)　720-720　2013/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  563. 低酸素応答系を介した腫瘍免疫抑制機構への影響 Peer-reviewed

    東條 裕, 山本 雅之, 一ノ瀬 正和, 鈴木 教郎

    生化学　85　(8)　721-721　2013/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  564. Keap1 knockdown increases markers of metabolic syndrome after long-term high fat diet feeding Peer-reviewed

    Vijay R. More, Jialin Xu, Prajakta C. Shimpi, Clyde Belgrave, James P. Luyendyk, Masayuki Yamamoto, Angela L. Slitt

    FREE RADICAL BIOLOGY AND MEDICINE　61　85-94　2013/08

    DOI： 10.1016/j.freeradbiomed.2013.03.007 　

    ISSN： 0891-5849

  565. The Keap1-Nrf2 System Prevents Onset of Diabetes Mellitus Peer-reviewed

    Akira Uruno, Yuki Furusawa, Yoko Yagishita, Toshiaki Fukutomi, Hiroyuki Muramatsu, Takaaki Negishi, Akira Sugawara, Thomas W. Kensler, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　33　(15)　2996-3010　2013/08

    DOI： 10.1128/MCB.00225-13 　

    ISSN： 0270-7306

  566. The nuclear factor erythroid 2-related factor 2 activator oltipraz attenuates chronic hypoxia-induced cardiopulmonary alterations in mice Peer-reviewed

    Shunsuke Eba, Yasushi Hoshikawa, Takashi Moriguchi, Yoichiro Mitsuishi, Hironori Satoh, Kazuyuki Ishida, Tatsuaki Watanabe, Toru Shimizu, Hiroaki Shimokawa, Yoshinori Okada, Masayuki Yamamoto, Takashi Kondo

    American Journal of Respiratory Cell and Molecular Biology　49　(2)　324-333　2013/08

    DOI： 10.1165/rcmb.2011-0396OC 　

    ISSN： 1044-1549 1535-4989

  567. Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration Peer-reviewed

    Kira M. Holmstrom, Liam Baird, Ying Zhang, Iain Hargreaves, Annapurna Chalasani, John M. Land, Lee Stanyer, Masayuki Yamamoto, Albena T. Dinkova-Kostova, Andrey Y. Abramov

    BIOLOGY OPEN　2　(8)　761-770　2013/08

    DOI： 10.1242/bio.20134853 　

    ISSN： 2046-6390

  568. Erythropoietin contributes to slow oxidative muscle fiber specification via PGC-1 alpha and AMPK activation Peer-reviewed

    Li Wang, Yi Jia, Heather Rogers, Norio Suzuki, Max Gassmann, Qian Wang, Alexandra C. McPherron, Jeffery B. Kopp, Masayuki Yamamoto, Constance Tom Noguchi

    INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY　45　(7)　1155-1164　2013/07

    DOI： 10.1016/j.biocel.2013.03.007 　

    ISSN： 1357-2725

  569. 4-Hydroxy Hexenal Derived from Docosahexaenoic Acid Protects Endothelial Cells via Nrf2 Activation Peer-reviewed

    Atsushi Ishikado, Katsutaro Morino, Yoshihiko Nishio, Fumiyuki Nakagawa, Atsushi Mukose, Yoko Sono, Nagisa Yoshioka, Keiko Kondo, Osamu Sekine, Takeshi Yoshizaki, Satoshi Ugi, Takashi Uzu, Hiromichi Kawai, Taketoshi Makino, Tomio Okamura, Masayuki Yamamoto, Atsunori Kashiwagi, Hiroshi Maegawa

    PLOS ONE　8　(7)　e69415-e69415　2013/07

    DOI： 10.1371/journal.pone.0069415 　

    ISSN： 1932-6203

  570. Nf-e2 p45 is important for establishing normal function of platelets Peer-reviewed

    Rie Fujita, Mariko Takayama-Tsujimoto, Hironori Satoh, Masayuki Yamamoto, Laura Gutiérrez, Hiroyuki Aburatani, Satoshi Fujii, Akinori Sarai, Bresnick Emery, Hozumi Motohashi

    Molecular and Cellular Biology　33　(14)　2659-2670　2013/07

    DOI： 10.1128/MCB.01274-12 　

    ISSN： 0270-7306 1098-5549

    eISSN： 1098-5549

  571. Nrf2 Prevents Initiation but Accelerates Progression through the Kras Signaling Pathway during Lung Carcinogenesis Peer-reviewed

    Hironori Satoh, Takashi Moriguchi, Jun Takai, Masahito Ebina, Masayuki Yamamoto

    CANCER RESEARCH　73　(13)　4158-4168　2013/07

    DOI： 10.1158/0008-5472.CAN-12-4499 　

    ISSN： 0008-5472

  572. Transforming Growth Factor-beta Induces Transcription Factors MafK and Bach1 to Suppress Expression of the Heme Oxygenase-1 Gene Peer-reviewed

    Yukari Okita, Atsushi Kamoshida, Hiroyuki Suzuki, Ken Itoh, Hozumi Motohashi, Kazuhiko Igarashi, Masayuki Yamamoto, Tomohiro Ogami, Daizo Koinuma, Mitsuyasu Kato

    JOURNAL OF BIOLOGICAL CHEMISTRY　288　(28)　20658-20667　2013/07

    DOI： 10.1074/jbc.M113.450478 　

    ISSN： 0021-9258

  573. Toward clinical application of the Keap1-Nrf2 pathway Peer-reviewed

    Takafumi Suzuki, Hozumi Motohashi, Masayuki Yamamoto

    Trends in Pharmacological Sciences　34　(6)　340-346　2013/06

    DOI： 10.1016/j.tips.2013.04.005 　

    ISSN： 0165-6147 1873-3735

  574. Regulatory Nexus of Synthesis and Degradation Deciphers Cellular Nrf2 Expression Levels Peer-reviewed

    Takafumi Suzuki, Tatsuhiro Shibata, Kai Takaya, Kouya Shiraishi, Takashi Kohno, Hideo Kunitoh, Koji Tsuta, Koh Furuta, Koichi Goto, Fumie Hosoda, Hiromi Sakamoto, Hozumi Motohashi, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　33　(12)　2402-2412　2013/06

    DOI： 10.1128/MCB.00065-13 　

    ISSN： 0270-7306

  575. A mouse model of adult-onset anaemia due to erythropoietin deficiency Peer-reviewed

    Shun Yamazaki, Tomokazu Souma, Ikuo Hirano, Xiaoqing Pan, Naoko Minegishi, Norio Suzuki, Masayuki Yamamoto

    NATURE COMMUNICATIONS　4　1950-1950　2013/06

    DOI： 10.1038/ncomms2950 　

    ISSN： 2041-1723

  576. Deletion of Nrf2 leads to rapid progression of steatohepatitis in mice fed atherogenic plus high-fat diet Peer-reviewed

    Kosuke Okada, Eiji Warabi, Hirokazu Sugimoto, Masaki Horie, Naohiro Gotoh, Katsutoshi Tokushige, Etsuko Hashimoto, Hirotoshi Utsunomiya, Hiroshi Takahashi, Tetsuro Ishii, Masayuki Yamamoto, Junichi Shoda

    Journal of Gastroenterology　48　(5)　620-632　2013/05

    DOI： 10.1007/s00535-012-0659-z 　

    ISSN： 0944-1174 1435-5922

  577. Naturally occurring oncogenic GATA1 mutants with internal deletions in transient abnormal myelopoiesis in Down syndrome Peer-reviewed

    Toki Tsutomu, Kanezaki Rika, Kobayashi Eri, Kaneko Hiroshi, Suzuki Mikiko, Wang RuNan, Terui Kiminori, Kanegane Hirokazu, Maeda Miho, Endo Mikiya, Mizuochi Tatsuki, Adachi Souichi, Hayashi Yasuhide, Yamamoto Masayuki, Shimizu Ritsuko, Ito Etsuro

    BLOOD　121　(16)　3181-3184　2013/04/18

    DOI： 10.1182/blood-2012-01-405746 　

    ISSN： 0006-4971

  578. Disruption of the Hbs1L-Myb locus causes hereditary persistence of fetal hemoglobin in a mouse model Peer-reviewed

    Mikiko Suzuki, Hiromi Yamazaki, Harumi Y. Mukai, Hozumi Motohashi, Lihong Shi, Osamu Tanabe, James Douglas Engel, Masayuki Yamamoto

    Molecular and Cellular Biology　33　(8)　1687-1695　2013/04

    DOI： 10.1128/MCB.01617-12 　

    ISSN： 0270-7306 1098-5549

  579. Redox-sensitive transcription factor Nrf2 regulates vascular smooth muscle cell migration and neointimal hyperplasia Peer-reviewed

    Takashi Ashino, Masayuki Yamamoto, Takemi Yoshida, Satoshi Numazawa

    Arteriosclerosis, Thrombosis, and Vascular Biology　33　(4)　760-768　2013/04

    DOI： 10.1161/ATVBAHA.112.300614 　

    ISSN： 1079-5642 1524-4636

  580. The absence of macrophage Nrf2 promotes early atherogenesis Peer-reviewed

    Anna-Kaisa Ruotsalainen, Matias Inkala, Mervi E. Partanen, Jari P. Lappalainen, Emilia Kansanen, Petri I. Makinen, Suvi E. Heinonen, Heidi M. Laitinen, Janne Heikkila, Tero Vatanen, Sohvi Horkko, Masayuki Yamamoto, Seppo Yla-Herttuala, Matti Jauhiainen, Anna-Liisa Levonen

    CARDIOVASCULAR RESEARCH　98　(1)　107-115　2013/04

    DOI： 10.1093/cvr/cvt008 　

    ISSN： 0008-6363

  581. Adipose Deficiency of Nrf2 in ob/ob Mice Results in Severe Metabolic Syndrome Peer-reviewed

    Peng Xue, Yongyong Hou, Yanyan Chen, Bei Yang, Jingqi Fu, Hongzhi Zheng, Kathy Yarborough, Courtney G. Woods, Dianxin Liu, Masayuki Yamamoto, Qiang Zhang, Melvin E. Andersen, Jingbo Pi

    DIABETES　62　(3)　845-854　2013/03

    DOI： 10.2337/db12-0584 　

    ISSN： 0012-1797

  582. 【酸化ストレスとその防御】表皮の酸化ストレスとその防御機構

    小林 枝里, 日高 高徳, 山本 雅之

    FRAGRANCE JOURNAL　41　(2)　16-20　2013/02

    Publisher: フレグランスジャーナル社

    ISSN： 0288-9803

  583. Roles of keap1-Nrf2 system in upper aerodigestive tract carcinogenesis Peer-reviewed

    Akira Ohkoshi, Takafumi Suzuki, Masao Ono, Toshimitsu Kobayashi, Masayuki Yamamoto

    Cancer Prevention Research　6　(2)　149-159　2013/02

    DOI： 10.1158/1940-6207.CAPR-12-0401-T 　

    ISSN： 1940-6207 1940-6215

    eISSN： 1940-6215

  584. Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling. Peer-reviewed

    Guiu Jordi, Shimizu Ritsuko, D'Altri Teresa, Fraser Stuart T, Hatakeyama Jun, Bresnick Emery H, Kageyama Ryoichiro, Dzierzak Elaine, Yamamoto Masayuki, Espinosa Lluis, Bigas Anna

    J Exp Med　210　(1)　71-84　2013/01/14

    DOI： 10.1084/jem.20120993 　

  585. Targeting nrf2-mediated gene transcription by extremely potent synthetic triterpenoids attenuate dopaminergic neurotoxicity in the MPTP mouse model of parkinson's disease Peer-reviewed

    Navneet Ammal Kaidery, Rebecca Banerjee, Lichuan Yang, Natalya A. Smirnova, Dmitry M. Hushpulian, Karen T. Liby, Charlotte R. Williams, Masayuki Yamamoto, Thomas W. Kensler, Rajiv R. Ratan, Michael B. Sporn, M. Flint Beal, Irina G. Gazaryan, Bobby Thomas

    Antioxidants and Redox Signaling　18　(2)　139-157　2013/01/10

    DOI： 10.1089/ars.2011.4491 　

    ISSN： 1523-0864 1557-7716

  586. Clinical nephrology 尿細管・間質障害 エリスロポイエチン遺伝子の転写制御機構 Peer-reviewed

    相馬 友和, 鈴木 教郎, 山本 雅之

    Annual Review腎臓　2013　204-211　2013/01

    Publisher: (株)中外医学社

  587. The performance of Tohoku University on the innovation of academically driven drug discovery using chemical library Peer-reviewed

    Sugawara Akira, Aoki Junken, Dan Takashi, Shimizu Ritsuko, Suzuki Norio, Kano Kuniyuki, Okudaira Shinichi, Hakoda Akiko, Kaneko Hiroshi, Uchida Takafurni, Nakazawa Toru, Doi Takayuki, Miyata Toshio, Oshima Yoshiteru, Yamamoto Masayuki

    JOURNAL OF PHARMACOLOGICAL SCIENCES　121　50P　2013

    ISSN： 1347-8613

  588. Blood pressure measured in the clinic and at home during pregnancy among nulliparous and multiparous women: the BOSHI study. Peer-reviewed

    Ishikuro M, Obara T, Metoki H, Ohkubo T, Yamamoto M, Akutsu K, Sakurai K, Iwama N, Katagiri M, Yagihashi K, Yaegashi N, Mori S, Suzuki M, Kuriyama S, Imai Y

    American journal of hypertension　26　(1)　141-148　2013/01

    DOI： 10.1093/ajh/hps002 　

    ISSN： 0895-7061

  589. Roles nrf2 plays in myeloid cells and related disorders. International-journal Peer-reviewed

    Eri Kobayashi, Takafumi Suzuki, Masayuki Yamamoto

    Oxidative medicine and cellular longevity　2013　529219-529219　2013

    DOI： 10.1155/2013/529219 　

    More details Close

    The Keap1-Nrf2 system protects animals from oxidative and electrophilic stresses. Nrf2 is a transcription factor that induces the expression of genes essential for detoxifying reactive oxygen species (ROS) and cytotoxic electrophiles. Keap1 is a stress sensor protein that binds to and ubiquitinates Nrf2 under unstressed conditions, leading to the rapid proteasomal degradation of Nrf2. Upon exposure to stress, Keap1 is modified and inactivated, which allows Nrf2 to accumulate and activate the transcription of a battery of cytoprotective genes. Antioxidative and detoxification activities are important for many types of cells to avoid DNA damage and cell death. Accumulating lines of recent evidence suggest that Nrf2 is also required for the primary functions of myeloid cells, which include phagocytosis, inflammation regulation, and ROS generation for bactericidal activities. In fact, results from several mouse models have shown that Nrf2 expression in myeloid cells is required for the proper regulation of inflammation, antitumor immunity, and atherosclerosis. Moreover, several molecules generated upon inflammation activate Nrf2. Although ROS detoxification mediated by Nrf2 is assumed to be required for anti-inflammation, the entire picture of the Nrf2-mediated regulation of myeloid cell primary functions has yet to be elucidated. In this review, we describe the Nrf2 inducers characteristic of myeloid cells and the contributions of Nrf2 to diseases.

  590. Exacerbated Airway Toxicity of Environmental Oxidant Ozone in Mice Deficient in Nrf2 Peer-reviewed

    Hye-Youn Cho, Wesley Gladwell, Masayuki Yamamoto, Steven R. Kleeberger

    OXIDATIVE MEDICINE AND CELLULAR LONGEVITY　2013　254069-254069　2013

    DOI： 10.1155/2013/254069 　

    ISSN： 1942-0900

  591. The role of the Nrf2-mediated defense system in corneal epithelial wound healing Peer-reviewed

    Ryuhei Hayashi, Noriko Himori, Keiko Taguchi, Yuki Ishikawa, Kohji Uesugi, Miyuki Ito, Thomas Duncan, Motokazu Tsujikawa, Toru Nakazawa, Masayuki Yamamoto, Kohji Nishida

    Free Radical Biology and Medicine　61　333-342　2013

    DOI： 10.1016/j.freeradbiomed.2013.04.008 　

    ISSN： 0891-5849 1873-4596

  592. Regulation of GATA factor expression is distinct between erythroid and mast cell lineages. Peer-reviewed

    Ohmori S, Takai J, Ishijima Y, Suzuki M, Moriguchi T, Philipsen S, Yamamoto M, Ohneda K

    Molecular and cellular biology　32　(23)　4742-4755　2012/12

    DOI： 10.1128/MCB.00718-12 　

    ISSN： 0270-7306

  593. Metabolic stress response implicated in diabetic retinopathy: The role of calpain, and the therapeutic impact of calpain inhibitor Peer-reviewed

    Ahmed Y. Shanab, Toru Nakazawa, Morin Ryu, Yuji Tanaka, Noriko Himori, Keiko Taguchi, Masayuki Yasuda, Ryo Watanabe, Jiro Takano, Takaomi Saido, Naoko Minegishi, Toshio Miyata, Toshiaki Abe, Masayuki Yamamoto

    NEUROBIOLOGY OF DISEASE　48　(3)　556-567　2012/12

    DOI： 10.1016/j.nbd.2012.07.025 　

    ISSN： 0969-9961

    eISSN： 1095-953X

  594. Contribution of GATA1 dysfunction to multi-step leukemogenesis Peer-reviewed

    Ritsuko Shimizu, Masayuki Yamamoto

    CANCER SCIENCE　103　(12)　2039-2044　2012/12

    DOI： 10.1111/cas.12007 　

    ISSN： 1347-9032

  595. Nrf2 in bone marrow-derived cells positively contributes to the advanced stage of atherosclerotic plaque formation Peer-reviewed

    Nobuhiko Harada, Koichi Ito, Tomonori Hosoya, Junsei Mimura, Atsushi Maruyama, Noriko Noguchi, Ken-ichi Yagami, Naoki Morito, Satoru Takahashi, Jon M. Maher, Masayuki Yamamoto, Ken Itoh

    FREE RADICAL BIOLOGY AND MEDICINE　53　(12)　2256-2262　2012/12

    DOI： 10.1016/j.freeradbiomed.2012.10.001 　

    ISSN： 0891-5849

  596. ユビキチンーピロテアソーム系によるKeap1-Nrf2経路の制御機構 (医学のあゆみ)

    鈴木隆史, 山本雅之

    医学のあゆみ　243　525　2012/11/10

  597. Heme and heme biosynthesis intermediates induce heme oxygenase-1 and cytochrome P450 2A5, enzymes with putative sequential roles in heme and bilirubin metabolism: Different requirement for transcription factor nuclear factor erythroid- derived 2-like 2 Peer-reviewed

    Virpi Lämsä, Anna-Liisa Levonen, Raija Sormunen, Masayuki Yamamoto, Jukka Hakkola

    Toxicological Sciences　130　(1)　132-144　2012/11

    DOI： 10.1093/toxsci/kfs237 　

    ISSN： 1096-6080 1096-0929

  598. Genetic Evidence of an Evolutionarily Conserved Role for Nrf2 in the Protection against Oxidative Stress Peer-reviewed

    Katsuki Mukaigasa, Linh T. P. Nguyen, Li Li, Hitomi Nakajima, Masayuki Yamamoto, Makoto Kobayashi

    MOLECULAR AND CELLULAR BIOLOGY　32　(21)　4455-4461　2012/11

    DOI： 10.1128/MCB.00481-12 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  599. Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks Peer-reviewed

    Yosuke Hirotsu, Fumiki Katsuoka, Ryo Funayama, Takeshi Nagashima, Yuichiro Nishida, Keiko Nakayama, James Douglas Engel, Masayuki Yamamoto

    NUCLEIC ACIDS RESEARCH　40　(20)　10228-10239　2012/11

    DOI： 10.1093/nar/gks827 　

    ISSN： 0305-1048

    eISSN： 1362-4962

  600. Conditional Gata2 inactivation results in HSC loss and lymphatic mispatterning Peer-reviewed

    Kim-Chew Lim, Tomonori Hosoya, William Brandt, Chia-Jui Ku, Sakie Hosoya-Ohmura, Sally A. Camper, Masayuki Yamamoto, James Douglas Engel

    Journal of Clinical Investigation　122　(10)　3705-3717　2012/10/01

    DOI： 10.1172/JCI61619 　

    ISSN： 0021-9738 1558-8238

  601. Mitochondrial SKN-1/Nrf Mediates a Conserved Starvation Response Peer-reviewed

    Jennifer Paek, Jacqueline Y. Lo, Sri Devi Narasimhan, Tammy N. Nguyen, Kira Glover-Cutter, Stacey Robida-Stubbs, Takafumi Suzuki, Masayuki Yamamoto, T. Keith Blackwell, Sean P. Curran

    CELL METABOLISM　16　(4)　526-537　2012/10

    DOI： 10.1016/j.cmet.2012.09.007 　

    ISSN： 1550-4131

  602. Epigenetic regulation of hypoxia-dependent erythropoietin gene expression Peer-reviewed

    Suzuki Norio, Pan Xiaoqing, Tojo Yutaka, Dan Takashi, Miyata Toshio, Poellinger Lorenz, Yamamoto Masayuki

    AMERICAN JOURNAL OF HEMATOLOGY　87　(10)　E99　2012/10

    ISSN： 0361-8609

  603. Targeted Deletion of Nrf2 Impairs Lung Development and Oxidant Injury in Neonatal Mice Peer-reviewed

    Hye-Youn Cho, Bennett van Houten, Xuting Wang, Laura Miller-DeGraff, Jennifer Fostel, Wesley Gladwell, Ligon Perrow, Vijayalakshmi Panduri, Lester Kobzik, Masayuki Yamamoto, Douglas A. Bell, Steven R. Kleeberger

    ANTIOXIDANTS & REDOX SIGNALING　17　(8)　1066-1082　2012/10

    DOI： 10.1089/ars.2011.4288 　

    ISSN： 1523-0864

    eISSN： 1557-7716

  604. Nrf2 inhibits hepatic iron accumulation and counteracts oxidative stress-induced liver injury in nutritional steatohepatitis Peer-reviewed

    Kosuke Okada, Eiji Warabi, Hirokazu Sugimoto, Masaki Horie, Katsutoshi Tokushige, Tetsuya Ueda, Nobuhiko Harada, Keiko Taguchi, Etsuko Hashimoto, Ken Itoh, Tetsuro Ishii, Hirotoshi Utsunomiya, Masayuki Yamamoto, Junichi Shoda

    JOURNAL OF GASTROENTEROLOGY　47　(8)　924-935　2012/08

    DOI： 10.1007/s00535-012-0552-9 　

    ISSN： 0944-1174

  605. Validation of the multiple sensor mechanism of the Keap1-Nrf2 system Peer-reviewed

    Kai Takaya, Takafumi Suzuki, Hozumi Motohashi, Ko Onodera, Susumu Satomi, Thomas W. Kensler, Masayuki Yamamoto

    FREE RADICAL BIOLOGY AND MEDICINE　53　(4)　817-827　2012/08

    DOI： 10.1016/j.freeradbiomed.2012.06.023 　

    ISSN： 0891-5849

  606. Keap1 degradation by autophagy for the maintenance of redox homeostasis Peer-reviewed

    Keiko Taguchi, Nanako Fujikawa, Masaaki Komatsu, Tetsuro Ishii, Michiaki Unno, Takaaki Akaike, Hozumi Motohashi, Masayuki Yamamoto

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　109　(34)　13561-13566　2012/08

    DOI： 10.1073/pnas.1121572109 　

    ISSN： 0027-8424

  607. Endogenous erythropoietin signaling facilitates skeletal muscle repair and recovery following pharmacologically induced damage. Peer-reviewed

    Jia Y, Suzuki N, Yamamoto M, Gassmann M, Noguchi CT

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology　26　(7)　2847-2858　2012/07

    DOI： 10.1096/fj.11-196618 　

    ISSN： 0892-6638

  608. Hydrogen sulfide anion regulates redox signaling via electrophile sulfhydration. Peer-reviewed

    Nishida Motohiro, Sawa Tomohiro, Kitajima Naoyuki, Ono Katsuhiko, Inoue Hirofumi, Ihara Hideshi, Motohashi Hozumi, Yamamoto Masayuki, Suematsu Makoto, Kurose Hitoshi, van der Vliet Albert, Freeman Bruce A, Shibata Takahiro, Uchida Koji, Kumagai Yoshito, Akaike Takaaki

    Nat Chem Biol　8　(8)　714-724　2012/07/01

    DOI： 10.1038/nchembio.1018 　

  609. NF-E2-Related Factor 1 (Nrf1) Serves as a Novel Regulator of Hepatic Lipid Metabolism through Regulation of the Lipin1 and PGC-1 beta Genes Peer-reviewed

    Yosuke Hirotsu, Nami Hataya, Fumiki Katsuoka, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　32　(14)　2760-2770　2012/07

    DOI： 10.1128/MCB.06706-11 　

    ISSN： 0270-7306

  610. Highly Potent Activation of Nrf2 by Topical Tricyclic Bis(Cyano Enone): Implications for Protection against UV Radiation during Thiopurine Therapy Peer-reviewed

    Sukirti Kalra, Elena V. Knatko, Ying Zhang, Tadashi Honda, Masayuki Yamamoto, Albena T. Dinkova-Kostova

    CANCER PREVENTION RESEARCH　5　(7)　973-981　2012/07

    DOI： 10.1158/1940-6207.CAPR-12-0041 　

    ISSN： 1940-6207

  611. Nrf2 Redirects Glucose and Glutamine into Anabolic Pathways in Metabolic Reprogramming Peer-reviewed

    Yoichiro Mitsuishi, Keiko Taguchi, Yukie Kawatani, Tatsuhiro Shibata, Toshihiro Nukiwa, Hiroyuki Aburatani, Masayuki Yamamoto, Hozumi Motohashi

    CANCER CELL　22　(1)　66-79　2012/07

    DOI： 10.1016/j.ccr.2012.05.016 　

    ISSN： 1535-6108

  612. UG4 Enhancer-Driven GATA-2 and Bone Morphogenetic Protein 4 Complementation Remedies the CAKUT Phenotype in Gata2 Hypomorphic Mutant Mice Peer-reviewed

    Keiko Ainoya, Takashi Moriguchi, Shin'ya Ohmori, Tomokazu Souma, Jun Takai, Masanobu Morita, Kelly J. Chandler, Douglas P. Mortlock, Ritsuko Shimizu, James Douglas Engel, Kim-Chew Lim, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　32　(12)　2312-2322　2012/06

    DOI： 10.1128/MCB.06699-11 　

    ISSN： 0270-7306

  613. N- and C-terminal Transactivation Domains of GATA1 Protein Coordinate Hematopoietic Program Peer-reviewed

    Hiroshi Kaneko, Eri Kobayashi, Masayuki Yamamoto, Ritsuko Shimizu

    JOURNAL OF BIOLOGICAL CHEMISTRY　287　(25)　21439-21449　2012/06

    DOI： 10.1074/jbc.M112.370437 　

    ISSN： 0021-9258

  614. Transcript Profiling Identifies Dynamic Gene Expression Patterns and an Important Role for Nrf2/Keap1 Pathway in the Developing Mouse Esophagus Peer-reviewed

    Hao Chen, Jianying Li, Haiyan Li, Yuhui Hu, Whitney Tevebaugh, Masayuki Yamamoto, Jianwen Que, Xiaoxin Chen

    PLOS ONE　7　(5)　e36504-e36504　2012/05

    DOI： 10.1371/journal.pone.0036504 　

    ISSN： 1932-6203

  615. Nrf2 deficiency in myeloid cells is not sufficient to protect mice from high-fat diet-induced adipose tissue inflammation and insulin resistance Peer-reviewed

    Akshaya K. Meher, Poonam R. Sharma, Vitor A. Lira, Masayuki Yamamoto, Thomas W. Kensler, Zhen Yan, Norbert Leitinger

    FREE RADICAL BIOLOGY AND MEDICINE　52　(9)　1708-1715　2012/05

    DOI： 10.1016/j.freeradbiomed.2012.02.022 　

    ISSN： 0891-5849

  616. Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma Peer-reviewed

    Inoue Daisuke, Suzuki Takashi, Mitsuishi Yoichiro, Miki Yasuhiro, Suzuki Satoshi, Sugawara Shunichi, Watanabe Mika, Sakurada Akira, Endo Chiaki, Uruno Akira, Sasano Hironobu, Nakagawa Takayuki, Satoh Kennichi, Tanaka Nobuyuki, Kubo Hiroshi, Motohashi Hozumi, Yamamoto Masayuki

    CANCER SCIENCE　103　(4)　760-766　2012/04

    DOI： 10.1111/j.1349-7006.2012.02216.x 　

    ISSN： 1349-7006

  617. Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma Peer-reviewed

    Daisuke Inoue, Takashi Suzuki, Yoichiro Mitsuishi, Yasuhiro Miki, Satoshi Suzuki, Shunichi Sugawara, Mika Watanabe, Akira Sakurada, Chiaki Endo, Akira Uruno, Hironobu Sasano, Takayuki Nakagawa, Kennichi Satoh, Nobuyuki Tanaka, Hiroshi Kubo, Hozumi Motohashi, Masayuki Yamamoto

    CANCER SCIENCE　103　(4)　760-766　2012/04

    DOI： 10.1111/j.1349-7006.2012.02216.x 　

    ISSN： 1347-9032

    eISSN： 1349-7006

  618. Fumarates Promote Cytoprotection of Central Nervous System Cells against Oxidative Stress via the Nuclear Factor (Erythroid-Derived 2)-Like 2 Pathway Peer-reviewed

    Robert H. Scannevin, Sowmya Chollate, Mi-young Jung, Melanie Shackett, Hiral Patel, Pradeep Bista, Weike Zeng, Sarah Ryan, Masayuki Yamamoto, Matvey Lukashev, Kenneth J. Rhodes

    JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS　341　(1)　274-284　2012/04

    DOI： 10.1124/jpet.111.190132 　

    ISSN： 0022-3565

    eISSN： 1521-0103

  619. Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation Peer-reviewed

    Mingzhan Xue, Naila Rabbani, Hiroshi Momiji, Precious Imbasi, M. Maqsud Anwar, Neil Kitteringham, B. Kevin Park, Tomokazu Souma, Takashi Moriguchi, Masayuki Yamamoto, Paul J. Thornalley

    BIOCHEMICAL JOURNAL　443　(1)　213-222　2012/04

    DOI： 10.1042/BJ201116418 　

    ISSN： 0264-6021

  620. Mature erythrocyte membrane homeostasis is compromised by loss of the GATA1-FOG1 interaction Peer-reviewed

    Atsushi Hasegawa, Ritsuko Shimizu, Narla Mohandas, Masayuki Yamamoto

    BLOOD　119　(11)　2615-2623　2012/03

    DOI： 10.1182/blood-2011-09-382473 　

    ISSN： 0006-4971

  621. Embryonic Lethality and Fetal Liver Apoptosis in Mice Lacking All Three Small Maf Proteins Peer-reviewed

    Hiromi Yamazaki, Fumiki Katsuoka, Hozumi Motohashi, James Douglas Engel, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　32　(4)　808-816　2012/02

    DOI： 10.1128/MCB.06543-11 　

    ISSN： 0270-7306

  622. Molecular basis of Keap1-Nrf2 system function

    YAMAMOTO Masayuki, TAGUCHI Keiko, SUZUKI Takafumi, MOTOHASHI Hozumi

    Annual Meeting of the Japanese Society of Toxicology　39　SL3　2012

    Publisher: The Japanese Society of Toxicology

    DOI： 10.14869/toxpt.39.2.0.SL3.0 　

    More details Close

    Our bodies must counteract insults originating from the environment. Toxic chemicals (electrophiles) and reactive oxygen species (ROS) activate expression of detoxifying and antioxidant genes through antioxidant responsive element (ARE). Transcription factor Nrf2 is essential for the coordinated induction of cellular defense enzymes through ARE. This notion is best demonstrated in animal models, showing that Nrf2-null mice are sensitive to a wide variety of electrophiles and ROS. Keap1 is identified as a negative regulator of Nrf2. Electrophiles liberate Nrf2 from the repression by Keap1 and provoke nuclear accumulation of Nrf2. Keap1 possesses multiple reactive cysteine residues that covalently bound with electrophiles, indicating that Keap1 acts as a sensor for xenobiotic stresses and we refer this system to as the Cysteine Code. Mouse and zebrafish models demonstrate that multiple sensor functions reside within Keap1. The hinge and latch model proposed for the Keap1-Nrf2 system describes the regulation of nuclear accumulation of Nrf2 by a Cul3- Keap1 E3 ubiquitin ligase-dependent mechanism. We have verified this model through structure biology, mouse/zebrafish genetics and human cancer analyses. In human cancers, missense mutations have been identified in KEAP1 and NRF2 genes. These mutations disrupt the KEAP1-NRF2 complex and result in constitutive activation of NRF2. Elevated expression of NRF2 target genes confers advantages on cancer cells. Transgenic mouse models provide evidence that mutated form of Keap1 analogous to cancer genotypes lose the ability to repress Nrf2 in vivo. Thus, the Keap1-Nrf2 system opens a new avenue to the understanding of the signal transduction and regulatory processes underlying the stress response and cancer progression.

  623. Keap1-Nrf2 system for maintenance of redox homeostasis

    TAGUCHI Keiko, FUJIKAWA Nanako, MOTOHASHI Hozumi, YAMAMOTO Masayuki

    Annual Meeting of the Japanese Society of Toxicology　39　AS3-4　2012

    Publisher: The Japanese Society of Toxicology

    DOI： 10.14869/toxpt.39.2.0.AS3-4.0 　

    More details Close

    The Keap1-Nrf2 system plays a central role in cytoprotection against oxidative and electrophilic insults. Under normal conditions Keap1 serves as a substrate adaptor for Cullin3-based ubiquitin E3 ligase and promotes proteasomal degradation of Nrf2. Keap1 is inactivated upon the exposure to environmental stimuli such as electrophiles, and in this situation Nrf2 is stabilized and activates transcription of cytoprotective genes. Nrf2 knockout mouse (Nrf2–/–) is very sensitive to toxicants like acetaminophen. On the other hand, Keap1 knockdown mouse (Keap1flox/flox) in which Nrf2 is activated is resistant to toxicants. Whereas the turnover of Nrf2 has been well analyzed, little is known about the Keap1 turnover or recovery of the Keap1 activity after the electrophilic insults. We found that Keap1 is accumulated when autophagy is impaired in the liver of mice. Treatment of cells with an autophagy inhibitor or inducer markedly increased or decreased the Keap1 level, respectively. The Keap1 degradation was accelerated upon the exposure to certain type of electrophiles, implying that inactivated Keap1 after modification with electrophiles becomes a preferred substrate of autophagy. We also found that the electrophilic challenge enhances the transcription of Keap1 gene, suggesting that the Keap1 activity is recovered by de novo synthesis of Keap1. Consequently, Keap1 protein was kept in constant level even in the presence of electrophiles. These results thus demonstrate that Keap1 is degraded through autophagy and that this degradation machinery in concert with the de novo synthesis of Keap1 maintains the active Keap1 level and the redox homeostasis regulated by Nrf2.

  624. Transcriptional regulation of megakaryopoiesis and thrombopoiesis

    FUJITA Rie, MOTOHASHI Hozumi, YAMAMOTO Masayuki

    Blood & Vessel　23　(6)　539-543　2012

    Publisher: The Japanese Society on Thrombosis and Hemostasis

    DOI： 10.2491/jjsth.23.539 　

    ISSN： 0915-7441

  625. Daily serial hemodynamic data during pregnancy and seasonal variation: the BOSHI study. Peer-reviewed

    Metoki H, Ohkubo T, Obara T, Akutsu K, Yamamoto M, Ishikuro M, Sakurai K, Iwama N, Katagiri M, Sugawara J, Hirose T, Sato M, Kikuya M, Yagihashi K, Matsubara Y, Yaegashi N, Mori S, Suzuki M, Imai Y, BOSHI Study Group

    Clinical and experimental hypertension (New York, N.Y. : 1993)　34　(4)　290-296　2012

    DOI： 10.3109/10641963.2012.681086 　

    ISSN： 1064-1963

  626. The Keap1-Nrf2 system in cancers: stress response and anabolic metabolism. Peer-reviewed

    Mitsuishi, Yoichiro Motohashi, Hozumi Yamamoto, Masayuki

    Front Oncol　2　200-200　2012

    DOI： 10.3389/fonc.2012.00200 　

  627. Pathophysiological regulation of cellular stress response by Keapl-Nrf2 system Peer-reviewed

    Masayuki Yamamoto

    Clinical Neurology　52　(11)　861-861　2012

    DOI： 10.5692/clinicalneurol.52.861 　

    ISSN： 0009-918X

  628. Correction: tissue-restricted expression of nrf2 and its target genes in zebrafish with gene-specific variations in the induction profiles. Peer-reviewed

    Nakajima, Hitomi Nakajima-Takagi, Yaeko Tsujita, Tadayuki Akiyama, Shin-Ichi Wakasa, Takeshi Mukaigasa, Katsuki Kaneko, Hiroshi Tamaru, Yutaka Yamamoto, Masayuki Kobayashi, Makoto

    PLoS One　7　(9)　2012

    DOI： 10.1371/annotation/50ee3aff-3010-4c42-a130-70509c88a67e 　

  629. Nuclear factor erythroid-derived factor 2-related factor 2 regulates transcription of CCAAT/enhancer-binding protein beta during adipogenesis Peer-reviewed

    Yongyong Hou, Peng Xue, Yushi Bai, Dianxin Liu, Courtney G. Woods, Kathy Yarborough, Jingqi Fu, Qiang Zhang, Guifan Sun, Sheila Collins, Jefferson Y. Chan, Masayuki Yamamoto, Melvin E. Andersen, Jingbo Pi

    FREE RADICAL BIOLOGY AND MEDICINE　52　(2)　462-472　2012/01

    DOI： 10.1016/j.freeradbiomed.2011.10.453 　

    ISSN： 0891-5849

    eISSN： 1873-4596

  630. Selective isotope labeling of recombinant proteins in escherichia coli Peer-reviewed

    Kit I. Tong, Masayuki Yamamoto, Toshiyuki Tanaka

    Methods in Molecular Biology　896　439-448　2012

    DOI： 10.1007/978-1-4614-3704-8_30 　

    ISSN： 1064-3745

  631. Analysis of the role of Nrf2 in the expression of liver proteins in mice using two-dimensional gel-based proteomics Peer-reviewed

    Azman Abdullah, Neil R. Kitteringham, Rosalind E. Jenkins, Christopher Goldring, Larry Higgins, Masayuki Yamamoto, John Hayes, B. Kevin Park

    Pharmacological Reports　64　(3)　680-697　2012

    Publisher: Elsevier B.V.

    DOI： 10.1016/S1734-1140(12)70863-0 　

    ISSN： 1734-1140

  632. Metabolism and Tissue Distribution of Sulforaphane in Nrf2 Knockout and Wild-Type Mice Peer-reviewed

    John D. Clarke, Anna Hsu, David E. Williams, Roderick H. Dashwood, Jan F. Stevens, Masayuki Yamamoto, Emily Ho

    PHARMACEUTICAL RESEARCH　28　(12)　3171-3179　2011/12

    DOI： 10.1007/s11095-011-0500-z 　

    ISSN： 0724-8741

  633. Disrupted erythropoietin signalling promotes obesity and alters hypothalamus proopiomelanocortin production Peer-reviewed

    Ruifeng Teng, Oksana Gavrilova, Norio Suzuki, Tatyana Chanturiya, Daniel Schimel, Lynne Hugendubler, Selin Mammen, Dena R. Yver, Samuel W. Cushman, Elisabetta Mueller, Masayuki Yamamoto, Lewis L. Hsu, Constance Tom Noguchi

    NATURE COMMUNICATIONS　2　520　2011/11

    DOI： 10.1038/ncomms1526 　

    ISSN： 2041-1723

  634. Dual regulation of the transcriptional activity of Nrf1 by β-TrCP- and Hrd1-dependent degradation mechanisms. Peer-reviewed

    Tsuchiya Y, Morita T, Kim M, Iemura S, Natsume T, Yamamoto M, Kobayashi A

    Molecular and cellular biology　31　(22)　4500-4512　2011/11

    DOI： 10.1128/MCB.05663-11 　

    ISSN： 0270-7306

  635. Association of Keap1 and Nrf2 Genetic Mutations and Polymorphisms With Endometrioid Endometrial Adenocarcinoma Survival Peer-reviewed

    Tze Fang Wong, Kousuke Yoshinaga, Yasutake Monma, Kiyoshi Ito, Hitoshi Niikura, Satoru Nagase, Masayuki Yamamoto, Nobuo Yaegashi

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER　21　(8)　1428-1435　2011/11

    DOI： 10.1097/IGC.0b013e31822d0eb2 　

    ISSN： 1048-891X

  636. Protective role of Nrf2 in age-related hearing loss and gentamicin ototoxicity Peer-reviewed

    Tomofumi Hoshino, Keiji Tabuchi, Bungo Nishimura, Shuho Tanaka, Masahiro Nakayama, Tetsuro Ishii, Eiji Warabi, Toru Yanagawa, Ritsuku Shimizu, Masayuki Yamamoto, Akira Hara

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　415　(1)　94-98　2011/11

    DOI： 10.1016/j.bbrc.2011.10.019 　

    ISSN： 0006-291X

  637. Tissue-Restricted Expression of Nrf2 and Its Target Genes in Zebrafish with Gene-Specific Variations in the Induction Profiles Peer-reviewed

    Hitomi Nakajima, Yaeko Nakajima-Takagi, Tadayuki Tsujita, Shin-Ichi Akiyama, Takeshi Wakasa, Katsuki Mukaigasa, Hiroshi Kaneko, Yutaka Tamaru, Masayuki Yamamoto, Makoto Kobayashi

    PLOS ONE　6　(10)　e26884-e26884　2011/10

    DOI： 10.1371/journal.pone.0026884 　

    ISSN： 1932-6203

  638. Targeted Deletion of Nrf2 Reduces Urethane-Induced Lung Tumor Development in Mice Peer-reviewed

    Alison K. Bauer, Hye-Youn Cho, Laura Miller-DeGraff, Christopher Walker, Katherine Helms, Jennifer Fostel, Masayuki Yamamoto, Steven R. Kleeberger

    PLOS ONE　6　(10)　e26590-e26590　2011/10

    DOI： 10.1371/journal.pone.0026590 　

    ISSN： 1932-6203

  639. Isolation and Characterization of Renal Erythropoietin-Producing Cells from Genetically Produced Anemia Mice Peer-reviewed

    Xiaoqing Pan, Norio Suzuki, Ikuo Hirano, Shun Yamazaki, Naoko Minegishi, Masayuki Yamamoto

    PLOS ONE　6　(10)　e25839-e25839　2011/10

    DOI： 10.1371/journal.pone.0025839 　

    ISSN： 1932-6203

  640. Oral Azathioprine Leads to Higher Incorporation of 6-Thioguanine in DNA of Skin than Liver: The Protective Role of the Keap1/Nrf2/ARE Pathway Peer-reviewed

    Sukirti Kalra, Ying Zhang, Elena V. Knatko, Stewart Finlayson, Masayuki Yamamoto, Albena T. Dinkova-Kostova

    CANCER PREVENTION RESEARCH　4　(10)　1665-1674　2011/10

    DOI： 10.1158/1940-6207.CAPR-11-0137 　

    ISSN： 1940-6207

  641. Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice Peer-reviewed

    Nariaki Asada, Masayuki Takase, Jin Nakamura, Akiko Oguchi, Misako Asada, Norio Suzuki, Ken-ichi Yamarnura, Narihito Nagoshi, Shinsuke Shibata, Tata Nageswara Rao, Hans Joerg Fehling, Atsushi Fukatsu, Naoko Minegishi, Toru Kita, Takeshi Kimura, Hideyuki Okano, Masayuki Yamamoto, Motoko Yanagita

    JOURNAL OF CLINICAL INVESTIGATION　121　(10)　3981-3990　2011/10

    DOI： 10.1172/JCI57301 　

    ISSN： 0021-9738

    eISSN： 1558-8238

  642. Specific Contribution of the Erythropoietin Gene 3 &apos; Enhancer to Hepatic Erythropoiesis after Late Embryonic Stages Peer-reviewed

    Norio Suzuki, Naoshi Obara, Xiaoqing Pan, Miho Watanabe, Kou-Ichi Jishage, Naoko Minegishi, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　31　(18)　3896-3905　2011/09

    DOI： 10.1128/MCB.05463-11 　

    ISSN： 0270-7306

  643. NRF2 Mutation Confers Malignant Potential and Resistance to Chemoradiation Therapy in Advanced Esophageal Squamous Cancer Peer-reviewed

    Tatsuhiro Shibata, Akiko Kokubu, Shigeru Saito, Mako Narisawa-Saito, Hiroki Sasaki, Kazuhiko Aoyagi, Yuki Yoshimatsu, Yuji Tachimori, Ryoji Kushima, Tohru Kiyono, Masayuki Yamamoto

    NEOPLASIA　13　(9)　864-U133　2011/09

    DOI： 10.1593/neo.11750 　

    ISSN： 1522-8002

  644. Constitutive Activation of Nuclear Factor-E2-Related Factor 2 Induces Biotransformation Enzyme and Transporter Expression in Livers of Mice with Hepatocyte-Specific Deletion of Kelch-Like ECH-Associated Protein 1 Peer-reviewed

    Qiuqiong Cheng, Keiko Taguchi, Lauren M. Aleksunes, Jose E. Manautou, Nathan J. Cherrington, Masayuki Yamamoto, Angela L. Slitt

    JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY　25　(5)　320-329　2011/09

    DOI： 10.1002/jbt.20392 　

    ISSN： 1095-6670

  645. 【腎臓と貧血】EPO遺伝子の発現制御と産生細胞の同定 Peer-reviewed

    鈴木 教郎, 山本 雅之

    腎と透析　71　(2)　183-191　2011/08

    Publisher: (株)東京医学社

    ISSN： 0385-2156

  646. Nrf2 regulates NGF mRNA induction by carnosic acid in T98G glioblastoma cells and normal human astrocytes Peer-reviewed

    Junsei Mimura, Kunio Kosaka, Atsushi Maruyama, Takumi Satoh, Nobuhiko Harada, Hidemi Yoshida, Kei Satoh, Masayuki Yamamoto, Ken Itoh

    JOURNAL OF BIOCHEMISTRY　150　(2)　209-217　2011/08

    DOI： 10.1093/jb/mvr065 　

    ISSN： 0021-924X

  647. Acceleration of UVB-induced photoageing in nrf2 gene-deficient mice Peer-reviewed

    Ayako Hirota, Yasuhiro Kawachi, Masayuki Yamamoto, Tsutomu Koga, Kazuhiko Hamada, Fujio Otsuka

    EXPERIMENTAL DERMATOLOGY　20　(8)　664-668　2011/08

    DOI： 10.1111/j.1600-0625.2011.01292.x 　

    ISSN： 0906-6705

  648. Isothiocyanates Reduce Mercury Accumulation via an Nrf2-Dependent Mechanism during Exposure of Mice to Methylmercury Peer-reviewed

    Takashi Toyama, Yasuhiro Shinkai, Akira Yasutake, Koji Uchida, Masayuki Yamamoto, Yoshito Kumagai

    ENVIRONMENTAL HEALTH PERSPECTIVES　119　(8)　1117-1122　2011/08

    DOI： 10.1289/ehp.1003123 　

    ISSN： 0091-6765

  649. Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis Peer-reviewed

    Stefan Freigang, Franziska Ampenberger, Gunther Spohn, Sebastian Heer, Abdijapar T. Shamshiev, Jan Kisielow, Martin Hersberger, Masayuki Yamamoto, Martin F. Bachmann, Manfred Kopf

    EUROPEAN JOURNAL OF IMMUNOLOGY　41　(7)　2040-2051　2011/07

    DOI： 10.1002/eji.201041316 　

    ISSN： 0014-2980

    eISSN： 1521-4141

  650. Central nervous system-specific deletion of transcription factor Nrf1 causes progressive motor neuronal dysfunction Peer-reviewed

    Akira Kobayashi, Takako Tsukide, Tomohiro Miyasaka, Tomoko Morita, Tatsuya Mizoroki, Yoshiro Saito, Yasuo Ihara, Akihiko Takashima, Noriko Noguchi, Akiyoshi Fukamizu, Yosuke Hirotsu, Makiko Ohtsuji, Fumiki Katsuoka, Masayuki Yamamoto

    GENES TO CELLS　16　(6)　692-703　2011/06

    DOI： 10.1111/j.1365-2443.2011.01522.x 　

    ISSN： 1356-9597

  651. The novel Nrf2-interacting factor KAP1 regulates susceptibility to oxidative stress by promoting the Nrf2-mediated cytoprotective response Peer-reviewed

    Atsushi Maruyama, Keizo Nishikawa, Yukie Kawatani, Junsei Mimura, Tomonori Hosoya, Nobuhiko Harada, Masayuki Yamamato, Ken Itoh

    BIOCHEMICAL JOURNAL　436　(2)　387-397　2011/06

    DOI： 10.1042/BJ20101748 　

    ISSN： 0264-6021

  652. Keap1抑制による糸球体硬化症の軽減

    清水 昭博, 宮田 敏男, 田口 恵子, 山本 雅之, 細谷 龍男, 市川 家國, 深川 雅史, 松阪 泰二

    日本腎臓学会誌　53　(3)　385-385　2011/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  653. Role of Nrf2 in Host Defense against Influenza Virus in Cigarette Smoke-Exposed Mice Peer-reviewed

    Yuichi Yageta, Yukio Ishii, Yuko Morishima, Hironori Masuko, Satoshi Ano, Tadahiro Yamadori, Ken Itoh, Kaoru Takeuchi, Masayuki Yamamoto, Nobuyuki Hizawa

    JOURNAL OF VIROLOGY　85　(10)　4679-4690　2011/05

    DOI： 10.1128/JVI.02456-10 　

    ISSN： 0022-538X

  654. Acute erythropoietin cardioprotection is mediated by endothelial response Peer-reviewed

    Ruifeng Teng, John W. Calvert, Nathawut Sibmooh, Barbora Piknova, Norio Suzuki, Junhui Sun, Kevin Martinez, Masayuki Yamamoto, Alan N. Schechter, David J. Lefer, Constance Tom Noguchi

    BASIC RESEARCH IN CARDIOLOGY　106　(3)　343-354　2011/05

    DOI： 10.1007/s00395-011-0158-z 　

    ISSN： 0300-8428

  655. Up-regulation of p27(kip1) contributes to Nrf2-mediated protection against angiotensin II-induced cardiac hypertrophy Peer-reviewed

    Jinqing Li, Cheng Zhang, Yifan Xing, Joseph S. Janicki, Masayuki Yamamoto, Xing Li Wang, Dong-Qi Tang, Taixing Cui

    CARDIOVASCULAR RESEARCH　90　(2)　315-324　2011/05

    DOI： 10.1093/cvr/cvr010 　

    ISSN： 0008-6363

  656. Antioxidant signaling via Nrf2 counteracts lipopolysaccharide-mediated inflammatory responses in foam cell macrophages Peer-reviewed

    Anne-Marie Kuhn, Nico Tzieply, Martina Victoria Schmidt, Andreas von Knethen, Dmitry Namgaladze, Masayuki Yamamoto, Bernhard Bruene

    FREE RADICAL BIOLOGY AND MEDICINE　50　(10)　1382-1391　2011/05

    DOI： 10.1016/j.freeradbiomed.2011.02.036 　

    ISSN： 0891-5849

  657. Heme regulates B-cell differentiation, antibody class switch, and heme oxygenase-1 expression in B cells as a ligand of Bach2 Peer-reviewed

    Miki Watanabe-Matsui, Akihiko Muto, Toshitaka Matsui, Ari Itoh-Nakadai, Osamu Nakajima, Kazutaka Murayama, Masayuki Yamamoto, Masao Ikeda-Saito, Kazuhiko Igarashi

    BLOOD　117　(20)　5438-5448　2011/05

    DOI： 10.1182/blood-2010-07-296483 　

    ISSN： 0006-4971

  658. Nrf2 degron-fused reporter system: a new tool for specific evaluation of Nrf2 inducers Peer-reviewed

    Yosuke Hirotsu, Fumiki Katsuoka, Ken Itoh, Masayuki Yamamoto

    GENES TO CELLS　16　(4)　406-415　2011/04

    DOI： 10.1111/j.1365-2443.2011.01496.x 　

    ISSN： 1356-9597

  659. Luminal Alkalinization Attenuates Proteinuria-Induced Oxidative Damage in Proximal Tubular Cells Peer-reviewed

    Tomokazu Souma, Michiaki Abe, Takashi Moriguchi, Jun Takai, Noriko Yanagisawa-Miyazawa, Eisuke Shibata, Yasutoshi Akiyama, Takafumi Toyohara, Takehiro Suzuki, Masayuki Tanemoto, Takaaki Abe, Hiroshi Sato, Masayuki Yamamoto, Sadayoshi Ito

    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY　22　(4)　635-648　2011/04

    DOI： 10.1681/ASN.2009111130 　

    ISSN： 1046-6673

    eISSN： 1533-3450

  660. Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts lipopolysaccharide-induced ferroportin 1 mRNA suppression in macrophages Peer-reviewed

    Nobuhiko Harada, Masaya Kanayama, Atsushi Maruyama, Aruto Yoshida, Kyoko Tazumi, Tomonori Hosoya, Junsei Mimura, Tsutomu Toki, Jonathan M. Maher, Masayuki Yamamoto, Ken Itoh

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS　508　(1)　101-109　2011/04

    DOI： 10.1016/j.abb.2011.02.001 　

    ISSN： 0003-9861

  661. Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells Peer-reviewed

    Yoshihiro Inami, Satoshi Waguri, Ayako Sakamoto, Tsuguka Kouno, Kazuto Nakada, Okio Hino, Sumio Watanabe, Jin Ando, Manabu Iwadate, Masayuki Yamamoto, Myung-Shik Lee, Keiji Tanaka, Masaaki Komatsu

    JOURNAL OF CELL BIOLOGY　193　(2)　275-284　2011/04

    DOI： 10.1083/jcb.201102031 　

    ISSN： 0021-9525

  662. Initial Response and Cellular Protection through the Keap1/Nrf2 System during the Exposure of Primary Mouse Hepatocytes to 1,2-Naphthoquinone Peer-reviewed

    Takashi Miura, Yasuhiro Shinkai, Hai-Yan Jiang, Noriko Iwamoto, Daigo Sumi, Keiko Taguchi, Masayuki Yamamoto, Hideto Jinno, Toshiko Tanaka-Kagawa, Arthur K. Cho, Yoshito Kumagai

    CHEMICAL RESEARCH IN TOXICOLOGY　24　(4)　559-567　2011/04

    DOI： 10.1021/tx100427p 　

    ISSN： 0893-228X

    eISSN： 1520-5010

  663. Electrophilic Nitro-fatty Acids Activate NRF2 by a KEAP1 Cysteine 151-independent Mechanism Peer-reviewed

    Emilia Kansanen, Gustavo Bonacci, Francisco J. Schopfer, Suvi M. Kuosmanen, Kit I. Tong, Hanna Leinonen, Steven R. Woodcock, Masayuki Yamamoto, Carsten Carlberg, Seppo Yla-Herttuala, Bruce A. Freeman, Anna-Liisa Levonen

    JOURNAL OF BIOLOGICAL CHEMISTRY　286　(16)　14019-14027　2011/04

    DOI： 10.1074/jbc.M110.190710 　

    ISSN： 0021-9258

  664. Select Heterozygous Keap1 Mutations Have a Dominant-Negative Effect on Wild-Type Keap1 In Vivo Peer-reviewed

    Takafumi Suzuki, Jonathan Maher, Masayuki Yamamoto

    CANCER RESEARCH　71　(5)　1700-1709　2011/03

    DOI： 10.1158/0008-5472.CAN-10-2939 　

    ISSN： 0008-5472

  665. Transcription factor Nrf2 maintains the basal expression of Mdm2: An implication of the regulation of p53 signaling by Nrf2 Peer-reviewed

    Aram You, Chang-won Nam, Nobunao Wakabayashi, Masayuki Yamamoto, Thomas W. Kensler, Mi-Kyoung Kwak

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS　507　(2)　356-364　2011/03

    DOI： 10.1016/j.abb.2010.12.034 　

    ISSN： 0003-9861

  666. Transcriptional regulation by GATA1 and GATA2 during erythropoiesis Peer-reviewed

    Mikiko Suzuki, Ritsuko Shimizu, Masayuki Yamamoto

    INTERNATIONAL JOURNAL OF HEMATOLOGY　93　(2)　150-155　2011/02

    DOI： 10.1007/s12185-011-0770-6 　

    ISSN： 0925-5710

  667. Inducible disruption of autophagy in the lung causes airway hyper-responsiveness Peer-reviewed

    Daisuke Inoue, Hiroshi Kubo, Keiko Taguchi, Takashi Suzuki, Masaaki Komatsu, Hozumi Motohashi, Masayuki Yamamoto

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　405　(1)　13-18　2011/02

    DOI： 10.1016/j.bbrc.2010.12.092 　

    ISSN： 0006-291X

  668. The Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice Peer-reviewed

    Kanako Tatsumi, Harumi Yamamoto-Mukai, Ritsuko Shimizu, Satoshi Waguri, Yu-Shin Sou, Ayako Sakamoto, Choji Taya, Hiroshi Shitara, Takahiko Hara, Chin Ha Chung, Keiji Tanaka, Masayuki Yamamoto, Masaaki Komatsu

    NATURE COMMUNICATIONS　2　181-181　2011/02

    DOI： 10.1038/ncomms1182 　

    ISSN： 2041-1723

  669. Molecular Determinants for Small Maf Protein Control of Platelet Production Peer-reviewed

    Hozumi Motohashi, Rie Fujita, Mariko Takayama, Ai Inoue, Fumiki Katsuoka, Emery H. Bresnick, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　31　(1)　151-162　2011/01

    DOI： 10.1128/MCB.00798-10 　

    ISSN： 0270-7306

  670. Nitro-fatty acids and cyclopentenone prostaglandins share strategies to activate the Keap1-Nrf2 system: a study using green fluorescent protein transgenic zebrafish Peer-reviewed

    Tadayuki Tsujita, Li Li, Hitomi Nakajima, Noriko Iwamoto, Yaeko Nakajima-Takagi, Ken Ohashi, Koichi Kawakami, Yoshito Kumagai, Bruce A. Freeman, Masayuki Yamamoto, Makoto Kobayashi

    GENES TO CELLS　16　(1)　46-57　2011/01

    DOI： 10.1111/j.1365-2443.2010.01466.x 　

    ISSN： 1356-9597

  671. Possible Involvement of Oxidative Stress in 5-Fluorouracil-Mediated Myelosuppression in Mice Peer-reviewed

    Satoshi Numazawa, Kazuko Sugihara, Shota Miyake, Hirono Tomiyama, Ayako Hida, Misato Hatsuno, Masayuki Yamamoto, Takemi Yoshida

    BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY　108　(1)　40-45　2011/01

    DOI： 10.1111/j.1742-7843.2010.00621.x 　

    ISSN： 1742-7835

  672. Nrf2 and selenoproteins are essential for maintaining oxidative homeostasis in erythrocytes and protecting against hemolytic anemia Peer-reviewed

    Yukie Kawatani, Takafumi Suzuki, Ritsuko Shimizu, Vincent P. Kelly, Masayuki Yamamoto

    BLOOD　117　(3)　986-996　2011/01

    DOI： 10.1182/blood-2010-05-285817 　

    ISSN： 0006-4971

  673. Differential Modulation of Keratin Expression by Sulforaphane Occurs via Nrf2-dependent and -independent Pathways in Skin Epithelia Peer-reviewed

    Michelle Kerns, Daryle DePianto, Masayuki Yamamoto, Pierre A. Coulombe

    MOLECULAR BIOLOGY OF THE CELL　21　(23)　4068-4075　2010/12

    DOI： 10.1091/mbc.E10-02-0153 　

    ISSN： 1059-1524

  674. The flavanol (-)-epicatechin prevents stroke damage through the Nrf2/HO1 pathway Peer-reviewed

    Zahoor A. Shah, Rung-chi Li, Abdullah S. Ahmad, Thomas W. Kensler, Masayuki Yamamoto, Shyam Biswal, Sylvain Dore

    JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM　30　(12)　1951-1961　2010/12

    DOI： 10.1038/jcbfm.2010.53 　

    ISSN： 0271-678X

  675. HEMATOPOIESIS - CYTOKINES, SIGNAL TRANSDUCTION, APOPTOSIS AND CELL CYCLE REGULATION POSTER I

    Pan, Xiaoqing, Suzuki, Norio, Hirano, Ikuo, Yamazaki, Shun, Yamashita, Toshiharu, Ohneda, Osamu, Minegishi, Naoko, Yamamoto, Masayuki

    BLOOD　116　(21)　656-656　2010/11

    Publisher: AMER SOC HEMATOLOGY

    ISSN： 0006-4971

  676. Isolation and Characterization of Renal Erythropoietin-Producing Cells: Contribution of HIF3 alpha In Vivo

    Pan, Xiaoqing, Suzuki, Norio, Hirano, Ikuo, Yamazaki, Shun, Yamashita, Toshiharu, Ohneda, Osamu, Minegishi, Naoko, Yamamoto, Masayuki

    BLOOD　116　(21)　656-656　2010/11

    Publisher: AMER SOC HEMATOLOGY

    ISSN： 0006-4971

  677. CD36 participates in a signaling pathway that regulates ROS formation in murine VSMCs Peer-reviewed

    Wei Li, Maria Febbraio, Sekhar P. Reddy, Dae-Yeul Yu, Masayuki Yamamoto, Roy L. Silverstein

    JOURNAL OF CLINICAL INVESTIGATION　120　(11)　3996-4006　2010/11

    DOI： 10.1172/JCI42823 　

    ISSN： 0021-9738

  678. Nrf2 is closely related to allergic airway inflammatory responses induced by low-dose diesel exhaust particles in mice Peer-reviewed

    Ying Ji Li, Hajime Takizawa, Arata Azuma, Tadashi Kohyama, Yasuhiro Yamauchi, Satoru Takahashi, Masayuki Yamamoto, Tomoyuki Kawada, Shoji Kudoh, Isamu Sugawara

    CLINICAL IMMUNOLOGY　137　(2)　234-241　2010/11

    DOI： 10.1016/j.clim.2010.07.014 　

    ISSN： 1521-6616

  679. Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection Peer-reviewed

    Brigit E. Riley, Stephen E. Kaiser, Thomas A. Shaler, Aylwin C. Y. Ng, Taichi Hara, Mark S. Hipp, Kasper Lage, Ramnik J. Xavier, Kwon Yul Ryu, Keiko Taguchi, Masayuki Yamamoto, Keiji Tanaka, Noboru Mizushima, Masaaki Komatsu, Ron R. Kopito

    JOURNAL OF CELL BIOLOGY　191　(3)　537-552　2010/11

    DOI： 10.1083/jcb.201005012 　

    ISSN： 0021-9525

  680. Global Downstream Pathway Analysis Reveals a Dependence of Oncogenic NF-E2-Related Factor 2 Mutation on the mTOR Growth Signaling Pathway Peer-reviewed

    Tatsuhiro Shibata, Shigeru Saito, Akiko Kokubu, Takafumi Suzuki, Masayuki Yamamoto, Setsuo Hirohashi

    CANCER RESEARCH　70　(22)　9095-9105　2010/11

    DOI： 10.1158/0008-5472.CAN-10-0384 　

    ISSN： 0008-5472

  681. Aggressive mammary carcinoma progression in Nrf2 knockout mice treated with 7,12-dimethylbenz[a]anthracene Peer-reviewed

    Lisa Becks, Misty Prince, Hannah Burson, Christopher Christophe, Mason Broadway, Ken Itoh, Masayuki Yamamoto, Michael Mathis, Elysse Orchard, Runhua Shi, Jerry McLarty, Kevin Pruitt, Songlin Zhang, Heather E. Kleiner-Hancock

    BMC CANCER　10　540-540　2010/10

    DOI： 10.1186/1471-2407-10-540 　

    ISSN： 1471-2407

  682. Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung Peer-reviewed

    Hironori Satoh, Takashi Moriguchi, Keiko Taguchi, Jun Takai, Jonathan M. Maher, Takafumi Suzuki, Paul T. Winnard, Venu Raman, Masahito Ebina, Toshihiro Nukiwa, Masayuki Yamamoto

    CARCINOGENESIS　31　(10)　1833-1843　2010/10

    DOI： 10.1093/carcin/bgq105 　

    ISSN： 0143-3334

  683. Dual-Color Luciferase Mouse Directly Demonstrates Coupled Expression of Two Clock Genes Peer-reviewed

    Takako Noguchi, Tomoko Michihata, Wataru Nakamura, Toru Takumi, Ritsuko Shimizu, Masayuki Yamamoto, Masaaki Ikeda, Yoshihiro Ohmiya, Yoshihiro Nakajima

    BIOCHEMISTRY　49　(37)　8053-8061　2010/09

    DOI： 10.1021/bi100545h 　

    ISSN： 0006-2960

  684. Suppression of SLC11A2 Expression Is Essential to Maintain Duodenal Integrity During Dietary Iron Overload Peer-reviewed

    Tomoyuki Shirase, Kiyoshi Mori, Yasumasa Okazaki, Ken Itoh, Masayuki Yamamoto, Mitsuaki Tabuchi, Fumio Kishi, Li Jiang, Shinya Akatsuka, Kazuwa Nakao, Shinya Toyokuni

    AMERICAN JOURNAL OF PATHOLOGY　177　(2)　677-685　2010/08

    DOI： 10.2353/ajpath.2010.090823 　

    ISSN： 0002-9440

  685. Ablation of the transcription factor Nrf2 promotes ischemia-induced neovascularization by enhancing the inflammatory response. International-journal Peer-reviewed

    Sahoko Ichihara, Yoshiji Yamada, Fang Liu, Toyoaki Murohara, Ken Itoh, Masayuki Yamamoto, Gaku Ichihara

    Arteriosclerosis, thrombosis, and vascular biology　30　(8)　1553-61　2010/08

    DOI： 10.1161/ATVBAHA.110.204123 　

    More details Close

    OBJECTIVE: To investigate the potential role of nuclear factor-erythroid 2-related factor 2 (Nrf2) in neovascularization with a murine surgical model of ischemia. METHODS AND RESULTS: The transcription factor Nrf2 protects against oxidative stress by increasing the transcription of genes, including those for several antioxidant enzymes that contain an antioxidant response element. Ischemia was induced by femoral artery ligation in Nrf2-deficient (Nrf2(-/-)) and wild-type mice. Ischemia-induced neovascularization was enhanced in Nrf2(-/-) mice compared with that in wild-type mice. The expression of Nrf2 target genes for heme oxygenase 1 and thioredoxin 1 and the concentration of total glutathione in the ischemic hindlimb were reduced for Nrf2(-/-) mice compared with wild-type mice. The infiltration of inflammatory cells and the abundance of adhesion molecule mRNA were greater in the ischemic hindlimb of Nrf2(-/-) mice than in wild-type mice. The expression of monocyte chemoattractant protein-1, tumor necrosis factor-alpha, cyclooxygenase 2, and angiogenic factors in the ischemic hindlimb was also greater for Nrf2(-/-) mice than for wild-type mice. CONCLUSIONS: The ablation of Nrf2 promoted ischemia-induced neovascularization. This effect likely resulted from impaired antioxidant defense and increased accumulation of reactive oxygen species in endothelial cells; consequently, there was an enhanced inflammatory response.

  686. Regulation of Notch1 Signaling by Nrf2: Implications for Tissue Regeneration Peer-reviewed

    Nobunao Wakabayashi, Soona Shin, Stephen L. Slocum, Elin S. Agoston, Junko Wakabayashi, Mi-Kyoung Kwak, Vikas Misra, Shyam Biswal, Masayuki Yamamoto, Thomas W. Kensler

    SCIENCE SIGNALING　3　(130)　ra52-ra52　2010/07

    DOI： 10.1126/scisignal.2000762 　

    ISSN： 1937-9145

  687. The anemia of the newborn induces erythropoietin expression in the developing mouse retina Peer-reviewed

    N. Scheerer, N. Duenker, S. Imagawa, M. Yamamoto, N. Suzuki, J. Fandrey

    AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY　299　(1)　R111-R118　2010/07

    DOI： 10.1152/ajpregu.00108.2010 　

    ISSN： 0363-6119

  688. The Critical Role of Nitric Oxide Signaling, via Protein S-Guanylation and Nitrated Cyclic GMP, in the Antioxidant Adaptive Response Peer-reviewed

    Shigemoto Fujii, Tomohiro Sawa, Hideshi Ihara, Kit I. Tong, Tomoaki Ida, Tatsuya Okamoto, Ahmed Khandaker Ahtesham, Yu Ishima, Hozumi Motohashi, Masayuki Yamamoto, Takaaki Akaike

    JOURNAL OF BIOLOGICAL CHEMISTRY　285　(31)　23970-23984　2010/07

    DOI： 10.1074/jbc.M110.145441 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  689. Role of Keap1 S-guanylation in the antioxidant adaptive response in C6 glioma cells Peer-reviewed

    Fujii Shigemoto, Sawa Tomohiro, Ihara Hideshi, Ida Tomoaki, Okamoto Tatsuya, Motohashi Hozumi, Yamamoto Masayuki, Akaike Takaaki

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S58　2010/06

    DOI： 10.1016/j.niox.2010.05.168 　

    ISSN： 1089-8603

  690. Genetic Analysis of Cytoprotective Functions Supported by Graded Expression of Keap1 Peer-reviewed

    Keiko Taguchi, Jonathan M. Maher, Takafumi Suzuki, Yukie Kawatani, Hozumi Motohashi, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　30　(12)　3016-3026　2010/06

    DOI： 10.1128/MCB.01591-09 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  691. Genetic Analysis of Hierarchical Regulation for Gata1 and NF-E2 p45 Gene Expression in Megakaryopoiesis Peer-reviewed

    Mariko Takayama, Rie Fujita, Mikiko Suzuki, Ryuhei Okuyama, Setsuya Aiba, Hozumi Motohashi, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　30　(11)　2668-2680　2010/06

    DOI： 10.1128/MCB.01304-09 　

    ISSN： 0270-7306

  692. Increased susceptibility of Nrf2-null mice to 1-bromopropane-induced hepatotoxicity. International-journal Peer-reviewed

    Fang Liu, Sahoko Ichihara, William M Valentine, Ken Itoh, Masayuki Yamamoto, Sahabudeen Sheik Mohideen, Junzoh Kitoh, Gaku Ichihara

    Toxicological sciences : an official journal of the Society of Toxicology　115　(2)　596-606　2010/06

    DOI： 10.1093/toxsci/kfq075 　

    More details Close

    1-Bromopropane (1-BP) was introduced as an alternative to ozone-depleting solvents. However, it was found to exhibit neurotoxicity, reproductive toxicity, and hepatotoxicity in rodents and neurotoxicity in human. However, the mechanisms underlying the toxicities of 1-BP remain elusive. The present study investigated the role of oxidative stress in 1-BP-induced hepatotoxicity using nuclear factor erythroid 2-related factor 2 (Nrf2)-null mice. Groups of 24 male Nrf2-null mice and 24 male wild-type (WT) C57BL/6J mice were each divided into three groups of eight and exposed to 1-BP at 0, 100, or 300 ppm for 8 h/day for 28 days by inhalation. Liver histopathology showed significantly larger area of necrosis in Nrf2-null mice relative to WT mice at the same exposure level. Nrf2-null mice also had greater malondialdehyde (MDA) levels, higher ratio of oxidized glutathione/reduced form of glutathione, and lower total glutathione content. The constitutive level and the increase in ratio per exposure level of glutathione S-transferase (GST) activity were lower in the liver of Nrf2-null mice than WT mice. Exposure to 1-BP at 300 ppm increased the messenger RNA levels of heme oxygenase-1 (HO-1), glutamate-cysteine ligase modifier subunit (GcLm), glutamate-cysteine synthetase (GcLc), glutathione reductase, and NAD(P)H: quinone oxidoreductase 1 (NQO1) in WT mice but not in Nrf2-null mice except for GST Yc2. Nrf2-null mice were more susceptible to 1-BP-induced hepatotoxicity. That oxidative stress plays a role in 1-BP hepatotoxicity is deduced from the low expression levels and activities of antioxidant enzymes and high MDA levels in Nrf2-null mice.

  693. Proteomic analysis of Nrf2 deficient transgenic mice reveals cellular defence and lipid metabolism as primary Nrf2-dependent pathways in the liver Peer-reviewed

    Neil R. Kitteringham, Azman Abdullah, Joanne Walsh, Laura Randle, Rosalind E. Jenkins, Rowena Sison, Christopher E. P. Goldring, Helen Powell, Christopher Sanderson, Samantha Williams, Larry Higgins, Masayuki Yamamoto, John Hayes, B. Kevin Park

    JOURNAL OF PROTEOMICS　73　(8)　1612-1631　2010/06

    DOI： 10.1016/j.jprot.2010.03.018 　

    ISSN： 1874-3919

    eISSN： 1876-7737

  694. GATA factor switching during erythroid differentiation Invited Peer-reviewed

    Kaneko Hiroshi, Shimizu Ritsuko, Yamamoto Masayuki

    CURRENT OPINION IN HEMATOLOGY　17　(3)　163-168　2010/05

    DOI： 10.1097/MOH.0b013e32833800b8 　

    ISSN： 1065-6251

  695. The Transcriptome of Nrf2(-/-) Mice Provides Evidence for Impaired Cell Cycle Progression in the Development of Cigarette Smoke-Induced Emphysematous Changes Peer-reviewed

    Stephan Gebel, Svenja Diehl, Jan Pype, Baerbel Friedrichs, Horst Weiler, Jutta Schueller, Haiyan Xu, Keiko Taguchi, Masayuki Yamamoto, Thomas Mueller

    TOXICOLOGICAL SCIENCES　115　(1)　238-252　2010/05

    DOI： 10.1093/toxsci/kfq039 　

    ISSN： 1096-6080

  696. Cytochrome P450 2A5 Constitutive Expression and Induction by Heavy Metals Is Dependent on Redox-Sensitive Transcription Factor Nrf2 in Liver Peer-reviewed

    Virpi Lamsa, Anna-Liisa Levonen, Hanna Leinonen, Seppo Yla-Herttuala, Masayuki Yamamoto, Jukka Hakkola

    CHEMICAL RESEARCH IN TOXICOLOGY　23　(5)　977-985　2010/05

    DOI： 10.1021/tx100084c 　

    ISSN： 0893-228X

    eISSN： 1520-5010

  697. Significant reduction of granulomas in nrf2-deficient mice infected with Mycobacterium tuberculosis Peer-reviewed

    S. Mizuno, M. Yamamoto, I. Sugawara

    Indian Journal of Tuberculosis　57　(2)　108-113　2010/04

    ISSN： 0019-5707

  698. Role of Nrf2 in retinal vascular development and the vaso-obliterative phase of oxygen-induced retinopathy Peer-reviewed

    Koichi Uno, Tarl W. Prow, Imran A. Bhutto, Adi Yerrapureddy, D. Scott McLeod, Masayuki Yamamoto, Sekhar P. Reddy, Gerard A. Lutty

    EXPERIMENTAL EYE RESEARCH　90　(4)　493-500　2010/04

    DOI： 10.1016/j.exer.2009.12.012 　

    ISSN： 0014-4835

  699. Nrf2 Regulates Microglial Dynamics and Neuroinflammation in Experimental Parkinson&apos;s Disease Peer-reviewed

    Ana I. Rojo, Nadia G. Innamorato, Ana M. Martin-Moreno, Maria L. De Ceballos, Masayuki Yamamoto, Antonio Cuadrado

    GLIA　58　(5)　588-598　2010/04

    DOI： 10.1002/glia.20947 　

    ISSN： 0894-1491

  700. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1 Peer-reviewed

    Masaaki Komatsu, Hirofumi Kurokawa, Satoshi Waguri, Keiko Taguchi, Akira Kobayashi, Yoshinobu Ichimura, Yu-Shin Sou, Izumi Ueno, Ayako Sakamoto, Kit I. Tong, Mihee Kim, Yasumasa Nishito, Shun-ichiro Iemura, Tohru Natsume, Takashi Ueno, Eiki Kominami, Hozumi Motohashi, Keiji Tanaka, Masayuki Yamamoto

    NATURE CELL BIOLOGY　12　(3)　213-U17　2010/03

    DOI： 10.1038/ncb2021 　

    ISSN： 1465-7392

    eISSN： 1476-4679

  701. Suppression of AhR signaling pathway is associated with the down-regulation of UDP-glucuronosyltransferases during BBN-induced urinary bladder carcinogenesis in mice Peer-reviewed

    Katsuyuki Iida, Junsei Mimura, Ken Itoh, Chikara Ohyama, Yoshiaki Fujii-Kuriyama, Toru Shimazui, Hideyuki Akaza, Masayuki Yamamoto

    JOURNAL OF BIOCHEMISTRY　147　(3)　353-360　2010/03

    DOI： 10.1093/jb/mvp169 　

    ISSN： 0021-924X

    eISSN： 1756-2651

  702. Nrf2 protects against pulmonary fibrosis by regulating the lung oxidant level and Th1/Th2 balance Peer-reviewed

    Norihiro Kikuchi, Yukio Ishii, Yuko Morishima, Yuichi Yageta, Norihiro Haraguchi, Ken Itoh, Masayuki Yamamoto, Nobuyuki Hizawa

    RESPIRATORY RESEARCH　11　31-31　2010/03

    DOI： 10.1186/1465-9921-11-31 　

    ISSN： 1465-9921

  703. Efficient transient rescue of hematopoietic mutant phenotypes in zebrafish using Tol2-mediated transgenesis Peer-reviewed

    Miki Takeuchi, Hiroshi Kaneko, Keizo Nishikawa, Koichi Kawakami, Masayuki Yamamoto, Makoto Kobayashi

    DEVELOPMENT GROWTH & DIFFERENTIATION　52　(2)　245-250　2010/02

    DOI： 10.1111/j.1440-169X.2010.01168.x 　

    ISSN： 0012-1592

  704. Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice Peer-reviewed

    Hirokazu Sugimoto, Kosuke Okada, Junichi Shoda, Eiji Warabi, Kazunori Ishige, Tetsuya Ueda, Keiko Taguchi, Toru Yanagawa, Akira Nakahara, Ichinosuke Hyodo, Tetsuro Ishii, Masayuki Yamamoto

    AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY　298　(2)　G283-G294　2010/02

    DOI： 10.1152/ajpgi.00296.2009 　

    ISSN： 0193-1857

  705. Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains Peer-reviewed

    Toshihiko Ogura, Kit I. Tong, Kazuhiro Mio, Yuusuke Maruyama, Hirofumi Kurokawa, Chikara Sato, Masayuki Yamamoto

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　107　(7)　2842-2847　2010/02

    DOI： 10.1073/pnas.0914036107 　

    ISSN： 0027-8424

  706. A Novel Type of E3 Ligase for the Ufm1 Conjugation System Peer-reviewed

    Kanako Tatsumi, Yu-shin Sou, Norihiro Tada, Eri Nakamura, Shun-ichiro Iemura, Tohru Natsume, Sung Hwan Kang, Chin Ha Chung, Masanori Kasahara, Eiki Kominami, Masayuki Yamamoto, Keiji Tanaka, Masaaki Komatsu

    JOURNAL OF BIOLOGICAL CHEMISTRY　285　(8)　5417-5427　2010/02

    DOI： 10.1074/jbc.M109.036814 　

    ISSN： 0021-9258

  707. Fractionation of Mature Eosinophils in GATA-Reporter Transgenic Mice Peer-reviewed

    Kibom Kim, Norio Suzuki, Kinuko Ohneda, Naoko Minegishi, Masayuki Yamamoto

    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE　220　(2)　127-138　2010/02

    DOI： 10.1620/tjem.220.127 　

    ISSN： 0040-8727

    eISSN： 1349-3329

  708. NF-E2-related factor 2 regulates the stress response to UVA-1-oxidized phospholipids in skin cells Peer-reviewed

    Florian Gruber, Herbert Mayer, Barbara Lengauer, Veronika Mlitz, John M. Sanders, Alexandra Kadl, Martin Bilban, Rainer de Martin, Oswald Wagner, Thomas W. Kensler, Masayuki Yamamoto, Norbert Leitinger, Erwin Tschachler

    FASEB JOURNAL　24　(1)　39-48　2010/01

    DOI： 10.1096/fj.09-133520 　

    ISSN： 0892-6638

    eISSN： 1530-6860

  709. Role of Nrf2 and p62/ZIP in the neurite outgrowth by carnosic acid in PC12h cells Peer-reviewed

    Kunio Kosaka, Junsei Mimura, Ken Itoh, Takumi Satoh, Yosuke Shimojo, Chieko Kitajima, Atsushi Maruyama, Masayuki Yamamoto, Takuji Shirasawa

    JOURNAL OF BIOCHEMISTRY　147　(1)　73-81　2010/01

    DOI： 10.1093/jb/mvp149 　

    ISSN： 0021-924X

  710. Indispensable function for embryogenesis, expression and regulation of the nonspecific form of the 5-aminolevulinate synthase gene in mouse Peer-reviewed

    Satoshi Okano, Lingyun Zhou, Toshimasa Kusaka, Kazuhide Shibata, Kazuhiro Shimizu, Xu Gao, Yuko Kikuchi, Yoshiyuki Togashi, Tomonori Hosoya, Satoru Takahashi, Osamu Nakajima, Masayuki Yamamoto

    GENES TO CELLS　15　(1)　77-89　2010/01

    DOI： 10.1111/j.1365-2443.2009.01366.x 　

    ISSN： 1356-9597

  711. Loss of the Gata1 Gene IE Exon Leads to Variant Transcript Expression and the Production of a GATA1 Protein Lacking the N-terminal Domain Peer-reviewed

    Eri Kobayashi, Ritsuko Shimizu, Yuko Kikuchi, Satoru Takahashi, Masayuki Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　285　(1)　773-783　2010/01

    DOI： 10.1074/jbc.M109.030726 　

    ISSN： 0021-9258

  712. NF-E2 domination over Nrf2 promotes ROS accumulation and megakaryocytic maturation Peer-reviewed

    Hozumi Motohashi, Momoko Kimura, Rie Fujita, Ai Inoue, Xiaoqing Pan, Mariko Takayama, Fumiki Katsuoka, Hiroyuki Aburatani, Emery H. Bresnick, Masayuki Yamamoto

    BLOOD　115　(3)　677-686　2010/01

    DOI： 10.1182/blood-2009-05-223107 　

    ISSN： 0006-4971

  713. Structural Basis of Alternative DNA Recognition by Maf Transcription Factors Peer-reviewed

    Hirofumi Kurokawa, Hozumi Motohashi, Shinji Sueno, Momoko Kimura, Hiroaki Takagawa, Yousuke Kanno, Masayuki Yamamoto, Toshiyuki Tanaka

    MOLECULAR AND CELLULAR BIOLOGY　29　(23)　6232-6244　2009/12

    DOI： 10.1128/MCB.00708-09 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  714. Loss of the Gata1 Gene IE Exon Leads to Variant Transcript Expression and the Production of GATA1 Protein Lacking the N-Terminal Domain Peer-reviewed

    Kobayashi, Eri, Shimizu, Ritsuko, Kikuchi, Yuko, Takahashi, Satoru, Yamamoto, Masayuki

    BLOOD　114　(22)　1407-1407　2009/11

    Publisher: AMER SOC HEMATOLOGY

    ISSN： 0006-4971

  715. Runx1 is involved in the fusion of the primary and the secondary palatal shelves (vol 326, pg 392, 2009) Peer-reviewed

    Charoenchaikorn, Kesinee, Yokomizo, Tomomasa, Rice, David P, Honjo, Tadashi, Matsuzaki, Kiyomi, Shintaku, Yuko, Imai, Yuichi, Wakamatsu, Asami, Takahashi, Satoru, Ito, Yoshiaki, Takano-Yamamoto, Teruko, Thesleff, Irma, Yamamoto, Masayuki, Yamashiro, Takashi

    DEVELOPMENTAL BIOLOGY　335　(2)　464-464　2009/11

    Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE

    DOI： 10.1016/j.ydbio.2009.09.017 　

    ISSN： 0012-1606

  716. Nrf2 Protects Against Maladaptive Cardiac Responses to Hemodynamic Stress Peer-reviewed

    Jinqing Li, Tomonaga Ichikawa, Luis Villacorta, Joseph S. Janicki, Gregory L. Brower, Masayuki Yamamoto, Taixing Cui

    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY　29　(11)　1843-U324　2009/11

    DOI： 10.1161/ATVBAHA.109.189480 　

    ISSN： 1079-5642

  717. The Triterpenoid CDDO-Imidazolide Confers Potent Protection against Hyperoxic Acute Lung Injury in Mice Peer-reviewed

    Narsa M. Reddy, Vegiraju Suryanaraya, Melinda S. Yates, Steven R. Kleeberger, Paul M. Hassoun, Masayuki Yamamoto, Karen T. Liby, Michael B. Sporn, Thomas W. Kensler, Sekhar P. Reddy

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE　180　(9)　867-874　2009/11

    DOI： 10.1164/rccm.200905-0670OC 　

    ISSN： 1073-449X

  718. Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems Peer-reviewed

    Kosuke Okada, Junichi Shoda, Keiko Taguchi, Jonathan M. Maher, Kaoru Ishizaki, Yoshimi Inoue, Makio Ohtsuki, Nobuharu Goto, Hirokazu Sugimoto, Hirotoshi Utsunomiya, Koji Oda, Eiji Warabi, Tetsuro Ishii, Masayuki Yamamoto

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　389　(3)　431-436　2009/11

    DOI： 10.1016/j.bbrc.2009.08.156 　

    ISSN： 0006-291X

  719. Characterization of a Functional ZBP-89 Binding Site That Mediates Gata1 Gene Expression during Hematopoietic Development Peer-reviewed

    Kinuko Ohneda, Shin&apos;ya Ohmori, Yasushi Ishijima, Mayu Nakano, Masayuki Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　284　(44)　30187-30199　2009/10

    DOI： 10.1074/jbc.M109.026948 　

    ISSN： 0021-9258

  720. Lansoprazole, a Proton Pump Inhibitor, Mediates Anti-Inflammatory Effect in Gastric Mucosal Cells through the Induction of Heme Oxygenase-1 via Activation of NF-E2-Related Factor 2 and Oxidation of Kelch-Like ECH-Associating Protein 1 Peer-reviewed

    Tomohisa Takagi, Yuji Naito, Hitomi Okada, Takeshi Ishii, Katsura Mizushima, Satomi Akagiri, Satoko Adachi, Osamu Handa, Satoshi Kokura, Hiroshi Ichikawa, Ken Itoh, Masayuki Yamamoto, Hirofumi Matsui, Toshikazu Yoshikawa

    JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS　331　(1)　255-264　2009/10

    DOI： 10.1124/jpet.109.152702 　

    ISSN： 0022-3565

  721. 1-Cyano-2,3-epithiopropane is a novel plant-derived chemopreventive agent which induces cytoprotective genes that afford resistance against the genotoxic alpha,beta-unsaturated aldehyde acrolein Peer-reviewed

    Michael O. Kelleher, Michael McMahon, Ian M. Eggleston, Mark J. Dixon, Keiko Taguchi, Masayuki Yamamoto, John D. Hayes

    CARCINOGENESIS　30　(10)　1754-1762　2009/10

    DOI： 10.1093/carcin/bgp182 　

    ISSN： 0143-3334

  722. Innate Immunity against Bacterial Infection following Hyperoxia Exposure Is Impaired in NRF2-Deficient Mice Peer-reviewed

    Narsal M. Reddy, Vegiraju Suryanarayana, Dhananjaya V. Kalvakolanu, Masayuki Yamamoto, Thomas W. Kensler, Paul M. Hassoun, Steven R. Kleeberger, Sekhar P. Reddy

    JOURNAL OF IMMUNOLOGY　183　(7)　4601-4608　2009/10

    DOI： 10.4049/jimmunol.0901754 　

    ISSN： 0022-1767

  723. Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-Imidazolide Peer-reviewed

    Soona Shin, Junko Wakabayashi, Melinda S. Yates, Nobunao Wakabayashi, Patrick M. Dolan, Susan Aja, Karen T. Liby, Michael B. Sporn, Masayuki Yamamoto, Thomas W. Kensler

    EUROPEAN JOURNAL OF PHARMACOLOGY　620　(1-3)　138-144　2009/10

    DOI： 10.1016/j.ejphar.2009.08.022 　

    ISSN： 0014-2999

  724. Induction of hyperproliferative fetal megakaryopoiesis by an N-terminally truncated GATA1 mutant Peer-reviewed

    Ritsuko Shimizu, Eri Kobayashi, James Douglas Engel, Masayuki Yamamoto

    GENES TO CELLS　14　(9)　1119-1131　2009/09

    DOI： 10.1111/j.1365-2443.2009.01338.x 　

    ISSN： 1356-9597

  725. Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice Peer-reviewed

    Manchang Liu, Dmitry N. Grigoryev, Michael T. Crow, Mark Haas, Masayuki Yamamoto, Sekhar P. Reddy, Hamid Rabb

    KIDNEY INTERNATIONAL　76　(3)　277-285　2009/08

    DOI： 10.1038/ki.2009.157 　

    ISSN： 0085-2538

  726. Neither MafA/L-Maf nor MafB is essential for lens development in mice Peer-reviewed

    Takashi Takeuchi, Takashi Kudo, Kiyohito Ogata, Michito Hamada, Megumi Nakamura, Katsumi Kito, Yasuhito Abe, Norifumi Ueda, Masayuki Yamamoto, James Douglas Engel, Satoru Takahashi

    GENES TO CELLS　14　(8)　941-947　2009/08

    DOI： 10.1111/j.1365-2443.2009.01321.x 　

    ISSN： 1356-9597

  727. Constitutively active aryl hydrocarbon receptor expressed in T cells increases immunization-induced IFN-gamma production in mice but does not suppress T(h)2-cytokine production or antibody production Peer-reviewed

    Keiko Nohara, Takehiro Suzuki, Kana Ao, Hikari Murai, Yoshimi Miyamoto, Kaoru Inouye, Xiaoqing Pan, Hozumi Motohashi, Yoshiaki Fujii-Kuriyama, Masayuki Yamamoto, Chiharu Tohyama

    INTERNATIONAL IMMUNOLOGY　21　(7)　769-777　2009/07

    DOI： 10.1093/intimm/dxp045 　

    ISSN： 0953-8178

  728. Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice Peer-reviewed

    Melinda S. Yates, Quynh T. Tran, Patrick M. Dolan, William O. Osburn, Soona Shin, Colin C. McCulloch, Jay B. Silkworth, Keiko Taguchi, Masayuki Yamamoto, Charlotte R. Williams, Karen T. Liby, Michael B. Sporn, Thomas R. Sutter, Thomas W. Kensler

    CARCINOGENESIS　30　(6)　1024-1031　2009/06

    DOI： 10.1093/carcin/bgp100 　

    ISSN： 0143-3334

  729. Disruption of Nrf2 Impairs the Resolution of Hyperoxia-Induced Acute Lung Injury and Inflammation in Mice Peer-reviewed

    Narsa M. Reddy, Steven R. Kleeberger, Thomas W. Kensler, Masayuki Yamamoto, Paul M. Hassoun, Sekhar P. Reddy

    JOURNAL OF IMMUNOLOGY　182　(11)　7264-7271　2009/06

    DOI： 10.4049/jimmunol.0804248 　

    ISSN： 0022-1767

  730. Direct Binding of pRb/E2F-2 to GATA-1 Regulates Maturation and Terminal Cell Division during Erythropoiesis Peer-reviewed

    Zahra Kadri, Ritsuko Shimizu, Osamu Ohneda, Leila Maouche-Chretien, Sylvie Gisselbrecht, Masayuki Yamamoto, Paul-Henri Romeo, Philippe Leboulch, Stany Chretien

    PLOS BIOLOGY　7　(6)　e1000123-e1000123　2009/06

    DOI： 10.1371/journal.pbio.1000123 　

    ISSN： 1544-9173

  731. Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents Peer-reviewed

    Larry G. Higgins, Michael O. Kelleher, Ian M. Eggleston, Ken Itoh, Masayuki Yamamoto, John D. Hayes

    TOXICOLOGY AND APPLIED PHARMACOLOGY　237　(3)　267-280　2009/06

    DOI： 10.1016/j.taap.2009.03.005 　

    ISSN： 0041-008X

  732. GATA2-dependent and region-specific regulation of Gata2 transcription in the mouse midbrain Peer-reviewed

    Daisuke Nozawa, Norio Suzuki, Maki Kobayashi-Osaki, Xiaoqing Pan, James Douglas Engel, Masayuki Yamamoto

    GENES TO CELLS　14　(5)　569-582　2009/05

    DOI： 10.1111/j.1365-2443.2009.01289.x 　

    ISSN： 1356-9597

  733. Nrf2 Enhances Cell Proliferation and Resistance to Anticancer Drugs in Human Lung Cancer Peer-reviewed

    Shinsuke Homma, Yukio Ishii, Yuko Morishima, Tadahiro Yamadori, Yosuke Matsuno, Norihiro Haraguchi, Norihiro Kikuchi, Hiroaki Satoh, Tohru Sakamoto, Nobuyuki Hizawa, Ken Itoh, Masayuki Yamamoto

    CLINICAL CANCER RESEARCH　15　(10)　3423-3432　2009/05

    DOI： 10.1158/1078-0432.CCR-08-2822 　

    ISSN： 1078-0432

  734. Stem cells of GATA1-related leukemia undergo pernicious changes after 5-fluorouracil treatment Peer-reviewed

    Kanako Abe, Ritsuko Shimizu, Xiaoqing Pan, Hiromi Hamada, Hiroyuki Yoshikawa, Masayuki Yamamoto

    EXPERIMENTAL HEMATOLOGY　37　(4)　435-445　2009/04

    DOI： 10.1016/j.exphem.2008.12.004 　

    ISSN： 0301-472X

  735. Leukemia-related transcription factor TEL/ETV6 expands erythroid precursors and stimulates hemoglobin synthesis Peer-reviewed

    Minenori Eguchi-Ishimae, Mariko Eguchi, Kazuhiro Maki, Catherine Porcher, Ritsuko Shimizu, Masayuki Yamamoto, Kinuko Mitani

    CANCER SCIENCE　100　(4)　689-697　2009/04

    DOI： 10.1111/j.1349-7006.2009.01097.x 　

    ISSN： 1347-9032

  736. Dietary Sulforaphane-Rich Broccoli Sprouts Reduce Colonization and Attenuate Gastritis in Helicobacter pylori-Infected Mice and Humans Peer-reviewed

    Akinori Yanaka, Jed W. Fahey, Atsushi Fukumoto, Mari Nakayama, Souta Inoue, Songhua Zhang, Masafumi Tauchi, Hideo Suzuki, Ichinosuke Hyodo, Masayuki Yamamoto

    CANCER PREVENTION RESEARCH　2　(4)　353-360　2009/04

    DOI： 10.1158/1940-6207.CAPR-08-0192 　

    ISSN： 1940-6207

  737. Differential Contribution of the Gata1 Gene Hematopoietic Enhancer to Erythroid Differentiation Peer-reviewed

    Suzuki, Mikiko, Moriguchi, Takashi, Ohneda, Kinuko, Yamamoto, Masayuki

    MOLECULAR AND CELLULAR BIOLOGY　29　(5)　1163-1175　2009/03

    DOI： 10.1128/MCB.01572-08 　

    ISSN： 0270-7306

  738. Keap1/Nrf2 system regulates neuronal survival as revealed through study of keap1 gene-knockout mice Peer-reviewed

    Takumi Satoh, Nobuhiko Harada, Tomonori Hosoya, Koujiro Tohyama, Masayuki Yamamoto, Ken Itoh

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　380　(2)　298-302　2009/03

    DOI： 10.1016/j.bbrc.2009.01.063 　

    ISSN： 0006-291X

  739. Comparison of citrus coumarins on carcinogen-detoxifying enzymes in Nrf2 knockout mice Peer-reviewed

    Misty Prince, Yan Li, Asper Childers, Ken Ltoh, Masayuki Yamamoto, Heather E. Kleiner

    TOXICOLOGY LETTERS　185　(3)　180-186　2009/03

    DOI： 10.1016/j.toxlet.2008.12.014 　

    ISSN： 0378-4274

    eISSN： 1879-3169

  740. Nrf2-dependent sulfiredoxin-1 expression protects against cigarette smoke-induced oxidative stress in lungs Peer-reviewed

    Anju Singh, Guoyu Ling, Avvaru N. Suhasini, Ping Zhang, Masayuki Yamamoto, Ana Navas-Acien, Gregory Cosgrove, Rubin M. Tuder, Thomas W. Kensler, Walter H. Watson, Shyam Biswal

    Free Radical Biology and Medicine　46　(3)　376-386　2009/02/01

    DOI： 10.1016/j.freeradbiomed.2008.10.026 　

    ISSN： 0891-5849

  741. Identification of the multi sensing mechanism in the Nrf2 system Peer-reviewed

    Kobayashi;M, Li;L, Iwamoto;N, Nakajima-Takagi;Y, Kaneko;H, Nakayama;Y, Eguchi;M, Wada;Y, Kumagai;Y, Yamamoto;M, 小林, 麻己人

    International symposium on “Molecular mechanism of environmental response to food and oxygen III”　2009/02

  742. Nrf2 activation by genetically induced endoplasmic reticulum stress in zebrafish Peer-reviewed

    Mukaigasa;K, Tsujita;T, Li;L, Kobayashi;M, Yamamoto;M, 小林, 麻己人

    International symposium on “Molecular mechanism of environmental response to food and oxygen III”　2009/02

  743. Runx1 is involved in the fusion of the primary and the secondary palatal shelves Peer-reviewed

    Kesinee Charoenchaikorn, Tomomasa Yokomizo, David P. Rice, Tadashi Honjo, Kiyomi Matsuzaki, Yuko Shintaku, Yuichi Imai, Asami Wakamatsu, Satoru Takahashi, Yoshiaki Ito, Teruko Takano-Yamamoto, Irma Thesleff, Masayuki Yamamoto, Takashi Yamashiro

    DEVELOPMENTAL BIOLOGY　326　(2)　392-402　2009/02

    DOI： 10.1016/j.ydbio.2008.10.018 　

    ISSN： 0012-1606

  744. Increased Nrf2 activation in livers from keap1-knockdown mice Increases expression of cytoprotective genes that detoxify electrophiles more than those that detoxify reactive oxygen species Peer-reviewed

    Scott A. Reisman, Ronnie L. Yeager, Masayuki Yamamoto, Curtis D. Klaassen

    Toxicological Sciences　108　(1)　35-47　2009

    DOI： 10.1093/toxsci/kfn267 　

    ISSN： 1096-6080 1096-0929

  745. Nrf2 Counteracts Cholestatic Liver Injury via Stimulation of Hepatic Defense Systems. Peer-reviewed

    Okada, K, Shoda, J, Taguchi, K, Maher, J.M, Ishizaki, K, Inoue, Y, Ohtsuki, M, Goto, N, Sugimoto, H, Utsunomiya, H, Oda, K, Warabi, E, Ishii, T, Yamamoto, M

    Biochem Biophys Res Commun　389　(3)　431-436　2009/01

    DOI： 10.1016/j.bbrc.2009.08.156 　

    ISSN： 1090-2104

    More details Close

    The transcription factor Nrf2 is a key regulator for hepatic induction of detoxifying enzymes, antioxidative stress genes and Mrp efflux transporters. We aimed to investigate whether Nrf2 activation counteracts liver injury associated with cholestasis. The role of Nrf2 activation in counteracting cholestatic liver injury was studied using a bile duct-ligation (BDL) model of Keap1 gene-knockdown (Keap1-kd) mice that represent the sustained activation of Nrf2 in the liver. Upon Nrf2 activation, Keap1-kd mice showed large increases in Mrp efflux transporters, detoxifying enzymes and antioxidative stress genes in the livers. After BDL, the number of hepatic parenchymal necrosis and the reactive oxygen species content were significantly smaller in the livers of the Keap1-kd mice than in those of the WT mice. Moreover, the increase in serum bilirubin levels was attenuated in the Keap1-kd mice. In conclusion, the results suggest a hepatoprotective role of sustained Nrf2 activation against liver injury associated with cholestasis.

  746. The Antioxidant Defense System Keap1-Nrf2 Comprises a Multiple Sensing Mechanism for Responding to a Wide Range of Chemical Compounds Peer-reviewed

    Kobayashi, Makoto, Li, Li, Iwamoto, Noriko, Nakajima-Takagi, Yaeko, Kaneko, Hiroshi, Nakayama, Yuko, Eguchi, Masami, Wada, Yoshiko, Kumagai, Yoshito, Yamamoto, Masayuki

    MOLECULAR AND CELLULAR BIOLOGY　29　(2)　493-502　2009/01

    Publisher: AMER SOC MICROBIOLOGY

    DOI： 10.1128/MCB.01080-08 　

    ISSN： 0270-7306

  747. Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice Peer-reviewed

    Thomas E. Sussan, Tirumalai Rangasamy, David J. Blake, Deepti Malhotra, Hazim El-Haddad, Djahida Bedja, Melinda S. Yates, Ponvijay Kombairaju, Masayuki Yamamoto, Karen T. Liby, Michael B. Sporn, Kathleen L. Gabrielson, Hunter C. Champion, Rubin M. Tuder, Thomas W. Kensler, Shyam Biswal

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　106　(1)　250-255　2009/01

    DOI： 10.1073/pnas.0804333106 　

    ISSN： 0027-8424

  748. Antiviral Activity of Nrf2 in a Murine Model of Respiratory Syncytial Virus Disease Peer-reviewed

    Hye-Youn Cho, Farhad Imani, Laura Miller-DeGraff, Dianne Walters, Guillermina A. Melendi, Masayuki Yamamoto, Fernando P. Polack, Steven R. Kleeberger

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE　179　(2)　138-150　2009/01

    DOI： 10.1164/rccm.200804-535OC 　

    ISSN： 1073-449X

  749. The Nrf3 Transcription Factor Is a Membrane-bound Glycoprotein Targeted to the Endoplasmic Reticulum through Its N-terminal Homology Box 1 Sequence Peer-reviewed

    Yiguo Zhang, Akira Kobayashi, Masayuki Yamamoto, John D. Hayes

    JOURNAL OF BIOLOGICAL CHEMISTRY　284　(5)　3195-3210　2009/01

    DOI： 10.1074/jbc.M805337200 　

    ISSN： 0021-9258

  750. Expression of constitutively-active aryl hydrocarbon receptor in T-cells enhances the down-regulation of CD62L, but does not alter expression of CD25 or suppress the allogeneic CTL response Peer-reviewed

    Castle J. Funatake, Kana Ao, Takehiro Suzuki, Hikari Murai, Masayuki Yamamoto, Yoshiaki Fujii-Kuriyama, Nancy I. Kerkvliet, Keiko Nohara

    JOURNAL OF IMMUNOTOXICOLOGY　6　(3)　194-203　2009

    DOI： 10.1080/15476910903124454 　

    ISSN： 1547-691X

  751. A physiological study of ER stress using zebrafish mutants Peer-reviewed

    Mukaigasa;K, Tsujita;T, Li;L, Kobayashi;M, Yamamoto;M, 小林, 麻己人

    JSPS-DST Asian Academic Seminar 2008　2008/12

  752. Hepatocyte-specific deletion of heme oxygenase-1 disrupts redox homeostasis in basal and oxidative environments. Peer-reviewed

    Mamiya T, Katsuoka F, Hirayama A, Nakajima O, Kobayashi A, Maher JM, Matsui H, Hyodo I, Yamamoto M, Hosoya T

    The Tohoku journal of experimental medicine　216　(4)　331-339　2008/12

    DOI： 10.1620/tjem.216.331 　

    ISSN： 0040-8727

    eISSN： 1349-3329

  753. A Combination of HNF-4 and Foxo1 Is Required for Reciprocal Transcriptional Regulation of Glucokinase and Glucose-6-phosphatase Genes in Response to Fasting and Feeding Peer-reviewed

    Hirota, Keiko, Sakamaki, Jun-ichi, Ishida, Junji, Shimamoto, Yoko, Nishihara, Shigeki, Kodama, Norio, Ohta, Kazuhide, Yamamoto, Masayuki, Tanimoto, Keiji, Fukamizu, Akiyoshi

    JOURNAL OF BIOLOGICAL CHEMISTRY　283　(47)　32432-32441　2008/11

    Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

    DOI： 10.1074/jbc.M806179200 　

    ISSN： 0021-9258

  754. Kruppel-like factor 5 Is Essential for Blastocyst Development and the Normal Self-Renewal of Mouse ESCs Peer-reviewed

    Ema, Masatsugu, Mori, Daisuke, Niwa, Hitoshi, Hasegawa, Yoshikazu, Yamanaka, Yojiro, Hitoshi, Seiji, Mimura, Junsei, Kawabe, Yoh-ichi, Hosoya, Tomohiro, Morita, Masanobu, Shimosato, Daisuke, Uchida, Kazuhiko, Suzuki, Norio, Yanagisawa, Jun, Sogawa, Kazuhiro, Rossant, Janet, Yamamoto, Masayuki, Takahashi, Satoru, Fujii-Kuriyama, Yoshiaki

    CELL STEM CELL　3　(5)　555-567　2008/11

    Publisher: CELL PRESS

    DOI： 10.1016/j.stem.2008.09.003 　

    ISSN： 1934-5909

  755. Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient mice. Peer-reviewed

    Yoh K, Hirayama A, Ishizaki K, Yamada A, Takeuchi M, Yamagishi S, Morito N, Nakano T, Ojima M, Shimohata H, Itoh K, Takahashi S, Yamamoto M

    Genes to cells : devoted to molecular & cellular mechanisms　13　1159-1170　2008/11

    Publisher: 11

    DOI： 10.1111/j.1365-2443.2008.01234.x 　

    ISSN： 1356-9597

  756. Nrf1 and Nrf2 Play Distinct Roles in Activation of Antioxidant Response Element-dependent Genes. Peer-reviewed

    Ohtsuji M, Katsuoka F, Kobayashi A, Aburatani H, Hayes JD, Yamamoto M

    J. Biol. Chem.　283　(48)　33554-33562　2008/11

    DOI： 10.1074/jbc.M804597200 　

    ISSN： 0021-9258

  757. Disruption of the transcription factor Nrf2 promotes pro-oxidative dendritic cells that stimulate Th2-like immunoresponsiveness upon activation by ambient particulate matter Peer-reviewed

    Marc A. Williams, Tirumalai Rangasamy, Stephen M. Bauer, Smruti Killedar, Matthew Karp, Thomas W. Kensler, Masayuki Yamamoto, Patrick Breysse, Shyam Biswal, Steve N. Georas

    Journal of Immunology　181　(7)　4545-4559　2008/10/01

    Publisher: American Association of Immunologists

    DOI： 10.4049/jimmunol.181.7.4545 　

    ISSN： 1550-6606 0022-1767

  758. Ursodeoxycholic acid stimulates Nrf2-mediated hepatocellular transport, detoxification, and antioxidative stress systems in mice. Peer-reviewed

    Okada K, Shoda J, Taguchi K, Maher JM, Ishizaki K, Inoue Y, Ohtsuki M, Goto N, Takeda K, Utsunomiya H, Oda K, Warabi E, Ishii T, Osaka K, Hyodo I, Yamamoto M

    American journal of physiology. Gastrointestinal and liver physiology　295　(4)　G735-47　2008/10

    DOI： 10.1152/ajpgi.90321.2008 　

    ISSN： 0193-1857

  759. Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer. Peer-reviewed

    Shibata T, Kokubu A, Gotoh M, Ojima H, Ohta T, Yamamoto M, Hirohashi S

    Gastroenterology　135　(4)　1358-1368, 1368.e1　2008/10

    DOI： 10.1053/j.gastro.2008.06.082 　

    ISSN： 0016-5085

  760. A simple method for amino acid selective isotope labeling of recombinant proteins in E-coli Peer-reviewed

    Tong, Kit I, Yamamoto, Masayuki, Tanaka, Toshiyuki

    JOURNAL OF BIOMOLECULAR NMR　42　(1)　59-67　2008/09

    Publisher: SPRINGER

    DOI： 10.1007/s10858-008-9264-0 　

    ISSN： 0925-2738

  761. Nrf2 regulates the alternative first exons of CD36 in macrophages through specific antioxidant response elements. Peer-reviewed

    Maruyama A, Tsukamoto S, Nishikawa K, Yoshida A, Harada N, Motojima K, Ishii T, Nakane A, Yamamoto M, Itoh K

    Archives of biochemistry and biophysics　477　(1)　139-145　2008/09

    DOI： 10.1016/j.abb.2008.06.004 　

    ISSN： 0003-9861

  762. Disruption of Nrf2 enhances susceptibility to airway inflammatory responses induced by low-dose diesel exhaust particles in mice. Peer-reviewed

    Li YJ, Takizawa H, Azuma A, Kohyama T, Yamauchi Y, Takahashi S, Yamamoto M, Kawada T, Kudoh S, Sugawara I

    Clinical immunology (Orlando, Fla.)　128　366-373　2008/09

    Publisher: 3

    DOI： 10.1016/j.clim.2008.05.005 　

    ISSN： 1521-6616

  763. Genetic evidence of PEBP2beta-independent activation of Runx1 in the murine embryo. Peer-reviewed

    Yokomizo T, Yanagida M, Huang G, Osato M, Honda C, Ema M, Takahashi S, Yamamoto M, Ito Y

    International journal of hematology　88　(2)　134-138　2008/09

    DOI： 10.1007/s12185-008-0121-4 　

    ISSN： 0925-5710

  764. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Peer-reviewed

    Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, Hirohashi S

    Proceedings of the National Academy of Sciences of the United States of America　105　(36)　13568-13573　2008/09

    DOI： 10.1073/pnas.0806268105 　

    ISSN： 0027-8424

  765. Nrf2 regulates antioxidant gene expression evoked by oxidized phospholipids in endothelial cells and murine arteries in vivo Peer-reviewed

    Henna-Kaisa Jyrkkänen, Emilia Kansanen, Matias Inkala, Annukka M. Kivela, Hanna Hurttila, Suvi E. Heinonen, Gundars Goldsteins, Suvi Jauhiainen, Satu Tiainen, Harri Makkonen, Olga Oskolkova, Taras Afonyushkin, Jari Koistinaho, Masayuki Yamamoto, Valery N. Bochkov, Seppo Ylä-Herttuala, Anna-Liisa Levonen

    Circulation Research　103　(1)　e1-e9　2008/07/03

    DOI： 10.1161/CIRCRESAHA.108.176883 　

    ISSN： 0009-7330 1524-4571

  766. The transcription factor Nrf2 is a therapeutic target against brain inflammation Peer-reviewed

    Nadia G. Innamorato, Ana I. Rojo, Angel J. Garcia-Yaguee, Masayuki Yamamoto, Maria L. de Ceballos, Antonio Cuadrado

    JOURNAL OF IMMUNOLOGY　181　(1)　680-689　2008/07

    ISSN： 0022-1767

  767. Hypoxia-inducible transcription factor-2 alpha in endothelial cells regulates tumor neovascularization through activation of ephrin A1 Peer-reviewed

    Yamashita, Toshiharu, Ohneda, Kinuko, Nagano, Masumi, Miyoshi, Chika, Kaneko, Naomi, Miwa, Yoshihiro, Yamamoto, Masayuki, Ohneda, Osamu, Fujii-Kuriyama, Yoshiaki

    JOURNAL OF BIOLOGICAL CHEMISTRY　283　(27)　18926-18936　2008/07

    Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

    DOI： 10.1074/jbc.M709133200 　

    ISSN： 0021-9258

  768. Attenuation of UVB-induced sunburn reaction and oxidative DNA damage with no alterations in UVB-induced skin carcinogenesis in nrf2 gene-deficient mice Peer-reviewed

    Yasuhiro Kawachi, Xuezhu Xu, Shiroma Taguchi, Hideko Sakurai, Yasuhiro Nakamura, Yoshiyuki Ishii, Yasuhiro Fujisawa, Junichi Furuta, Takenori Takahashi, Ken Itoh, Masayuki Yamamoto, Fumikazu Yamazaki, Fujio Otsuka

    JOURNAL OF INVESTIGATIVE DERMATOLOGY　128　(7)　1773-1779　2008/07

    DOI： 10.1038/sj.jid.5701245 　

    ISSN： 0022-202X

  769. Genetic or pharmacologic amplification of Nrf2 signaling inhibits acute inflammatory liver injury in mice Peer-reviewed

    William O. Osburn, Melinda S. Yates, Patrick D. Dolan, Sining Chen, Karen T. Liby, Michael B. Sporn, Keiko Taguchi, Masayuki Yamamoto, Thomas W. Kensler

    TOXICOLOGICAL SCIENCES　104　(1)　218-227　2008/07

    DOI： 10.1093/toxsci/kfn079 　

    ISSN： 1096-6080

  770. Activation of Nrf2 defense system relieves fatal ER stress caused by a genetic mutation in zebrafish Peer-reviewed

    Tsujita;T, Li;L, Mukaigasa;K, Kobayashi;M, Yamamoto;M, 小林, 麻己人

    8th International Conference on Zebrafish Development & Genetics　2008/06

  771. Mutation of histone demethylase Lsd1 in zebrafish leads to specific defects in hematopoiesis Peer-reviewed

    Kobayashi;M, Takeuchi;M, Kaneko;H, Yamamoto;M, 小林, 麻己人

    The 21st NAITO conference on Nuclear Dynamics and RNA [I]　2008/06

  772. Keap1 regulates the constitutive expression of GST A1 during differentiation of Caco-2 cells. Peer-reviewed

    Kusano Y, Horie S, Shibata T, Satsu H, Shimizu M, Hitomi E, Nishida M, Kurose H, Itoh K, Kobayashi A, Yamamoto M, Uchida K

    Biochemistry　47　(23)　6169-6177　2008/06

    DOI： 10.1021/bi800199z 　

    ISSN： 0006-2960

  773. Repression via the GATA box is essential for tissue-specific erythropoietin gene expression Peer-reviewed

    Naoshi Obara, Norio Suzuki, Kibom Kim, Toshiro Nagasawa, Shigehiko Imagawa, Masayuki Yamamoto

    BLOOD　111　(10)　5223-5232　2008/05

    DOI： 10.1182/blood-2007-10-115857 　

    ISSN： 0006-4971

    eISSN： 1528-0020

  774. Ephrin-A1 promotes the malignant progression of intestinal tumors in Apc(min/+) mice Peer-reviewed

    L. Shi, F. Itoh, S. Itoh, S. Takahashi, M. Yamamoto, M. Kato

    ONCOGENE　27　(23)　3265-3273　2008/05

    DOI： 10.1038/sj.onc.1210992 　

    ISSN： 0950-9232

  775. Structural insights into the similar modes of Nrf2 transcription factor recognition by the cytoplasmic repressor Keap1 Peer-reviewed

    Balasundaram Padmanabhan, Kit I. Tong, Akira Kobayashi, Masayuki Yamamoto, Shigeyuki Yokoyama

    JOURNAL OF SYNCHROTRON RADIATION　15　(Pt 3)　273-276　2008/05

    DOI： 10.1107/S090904950705114X 　

    ISSN： 0909-0495

  776. GATA1 - related leukaemias Invited Peer-reviewed

    Shimizu Ritsuko, Engel James Douglas, Yamamoto Masayuki

    NATURE REVIEWS CANCER　8　(4)　279-287　2008/04

    DOI： 10.1038/nrc2348 　

    ISSN： 1474-175X

  777. Negative feedback regulation of lipopolysaccharide-induced inducible nitric oxide synthase gene expression by heme oxygenase-1 induction in macrophages Peer-reviewed

    Takashi Ashino, Rieko Yamanaka, Masayuki Yamamoto, Hiroaki Shimokawa, Kenji Sekikawa, Yoichiro Iwakura, Seiji Shioda, Satoshi Numazawa, Takemi Yoshida

    MOLECULAR IMMUNOLOGY　45　(7)　2106-2115　2008/04

    DOI： 10.1016/j.molimm.2007.10.011 　

    ISSN： 0161-5890

  778. Physiological significance of reactive cysteine residues of keap1 in determining Nrf2 activity Invited Peer-reviewed

    Tae Yamamoto, Takafumi Suzuki, Akira Kobayashi, Junko Wakabayashi, Jon Maher, Hozumi Motohashi, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　28　(8)　2758-2770　2008/04

    DOI： 10.1128/MCB.01704-07 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  779. Antioxidants and phase 2 enzymes in macrophages: Regulation by Nrf2 signaling and protection against oxidative and electrophilic stress Peer-reviewed

    Hong Zhu, Zhenquan Jia, Li Zhang, Masayuki Yamamoto, Hara P. Misra, Michael A. Trush, Yunbo Li

    EXPERIMENTAL BIOLOGY AND MEDICINE　233　(4)　463-474　2008/04

    DOI： 10.3181/0711-RM-304 　

    ISSN： 1535-3702

  780. Notch signaling is necessary for GATA3 function in the initiation of T cell development Peer-reviewed

    Katsuto Hozumi, Naoko Negishi, Izumi Tsuchiya, Natsumi Abe, Ken-Ichi Hirano, Daisuke Suzuki, Masayuki Yamamoto, James D. Engel, Sonoko Habu

    EUROPEAN JOURNAL OF IMMUNOLOGY　38　(4)　977-985　2008/04

    DOI： 10.1002/eji.200737688 　

    ISSN： 0014-2980

  781. Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury Peer-reviewed

    Jutta Lamle, Silke Marhenke, Juergen Borlak, Reinhard Von Wasielewski, C. J. Peter Eriksson, Robert Geffers, Michael P. Manns, Masayuki Yamamoto, Arndt Vogel

    GASTROENTEROLOGY　134　(4)　1159-1168　2008/04

    DOI： 10.1053/j.gastro.2008.01.011 　

    ISSN： 0016-5085

  782. Defining the functional boundaries of the Gata2 locus by rescue with a linked bacterial artificial chromosome transgene Peer-reviewed

    William Brandt, Melin Khandekar, Norio Suzuki, Masayuki Yamamoto, Kim-Chew Lim, James Douglas Engel

    JOURNAL OF BIOLOGICAL CHEMISTRY　283　(14)　8976-8983　2008/04

    DOI： 10.1074/jbc.M709364200 　

    ISSN： 0021-9258

  783. Runx1 is involved in primitive erythropoiesis in the mouse Peer-reviewed

    Tomomasa Yokomizo, Kazuteru Hasegawa, Hiroyuki Ishitobi, Motomi Osato, Masatsugu Erna, Yoshiaki Lto, Masayuki Yamamoto, Satoru Takahashi

    BLOOD　111　(8)　4075-4080　2008/04

    DOI： 10.1182/blood-2007-05-091637 　

    ISSN： 0006-4971

  784. Ablation of Gata1 in adult mice results in aplastic crisis, revealing its essential role in steady-state and stress erythropolesis Peer-reviewed

    Laura Gutierrez, Saho Tsukamoto, Mikiko Suzuki, Harumi Yamamoto-Mukai, Masayuki Yamamoto, Sjaak Philipsen, Kinuko Ohneda

    BLOOD　111　(8)　4375-4385　2008/04

    DOI： 10.1182/blood-2007-09-115121 　

    ISSN： 0006-4971

  785. Redox cycling of 9,10-phenanthraquinone to cause oxidative stress is terminated through its monoglucuronide conjugation in human pulmonary epithelial A549 cells Peer-reviewed

    Keiko Taguchi, Megumi Shimada, Sayako Fujii, Daigo Sumi, Xiaoqing Pan, Shigeru Yamano, Takahito Nishiyama, Akira Hiratsuka, Masayuki Yamamoto, Arthur K. Cho, John R. Froines, Yoshito Kumagai

    FREE RADICAL BIOLOGY AND MEDICINE　44　(8)　1645-1655　2008/04

    DOI： 10.1016/j.freeradbiomed.2008.01.024 　

    ISSN： 0891-5849

    eISSN： 1873-4596

  786. Nrf2ノックアウトマウスにおける低濃度ディーゼル排気粒子曝露の気道炎症反応への影響 Peer-reviewed

    李, 英姫, 滝澤, 始, 吾妻安, 良太, 管原, 勇, 幸山, 正, 山内, 康宏, 高橋, 智, 山本, 雅之, 川田, 智之, 工藤, 翔二

    日本衞生學雜誌　63　(2)　586　2008/03

    ISSN： 0021-5082

  787. Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth Peer-reviewed

    Tsutonm Ohta, Kumiko Iijima, Mamiko Miyamoto, Izumi Nakahara, Hiroshi Tanaka, Makiko Ohtsuji, Takafumi Suzuki, Akira Kobayashi, Jun Yokota, Tokuki Sakiyama, Tatsuhiro Shibata, Masayuki Yamamoto, Setsuo Hirohashi

    CANCER RESEARCH　68　(5)　1303-1309　2008/03

    DOI： 10.1158/0008-5472.CAN-07-5003 　

    ISSN： 0008-5472

  788. Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1 Peer-reviewed

    Takumi Satoh, Kunio Kosaka, Ken Itoh, Akira Kobayashi, Masayuki Yamamoto, Yosuke Shimojo, Chieko Kitajima, Jiankun Cui, Joshua Kamins, Shu-ichi Okamoto, Masanori Izumi, Takuji Shirasawa, Stuart A. Lipton

    JOURNAL OF NEUROCHEMISTRY　104　(4)　1116-1131　2008/02

    DOI： 10.1111/j.1471-4159.2007.05039.x 　

    ISSN： 0022-3042

  789. Reduced BMP4 abundance in Gata2 hypomorphic mutant mice result in uropathies resembling human CAKUT Peer-reviewed

    Tomofumi Hoshino, Ritsuko Shimizu, Shinya Ohmori, Masumi Nagano, Xiaoqing Pan, Osamu Ohneda, Melin Khandekar, Masayuki Yamamoto, Kim-Chew Lim, James Douglas Engel

    GENES TO CELLS　13　(2)　159-170　2008/02

    DOI： 10.1111/j.1365-2443.2007.01158.x 　

    ISSN： 1356-9597

  790. Abnormal heart development and lung remodeling in mice lacking the hypoxia-inducible factor-related basic helix-loop-helix PAS protein NEPAS Peer-reviewed

    Toshiharu Yamashita, Osamu Ohneda, Masumi Nagano, Motoyuki Iemitsu, Yuichi Makino, Hirotoshi Tanaka, Takashi Miyauchi, Katsutoshi Goto, Kinuko Ohneda, Yoshiaki Fujii-Kuriyama, Lorenz Poellinger, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　28　(4)　1285-1297　2008/02

    DOI： 10.1128/MCB.01332-07 　

    ISSN： 0270-7306

  791. Impairment of erythroid and megakaryocytic differentiation by a leukemia-associated and t(9;9)-derived fusion gene product, SET/TAF-I beta-CAN/NUp214 Peer-reviewed

    Shoko Saito, Kaoru Nouno, Ritsuko Shimizu, Masayuki Yamamoto, Kyosuke Nagata

    JOURNAL OF CELLULAR PHYSIOLOGY　214　(2)　322-333　2008/02

    DOI： 10.1002/jcp.21199 　

    ISSN： 0021-9541

  792. Induction of cancer chemopreventive enzymes by coffee is mediated by transcription factor Nrf2. Evidence that the coffee-specific diterpenes cafestol and kahweol confer protection against acrolein Peer-reviewed

    Larry G. Higgins, Christophe Cavin, Ken Toh, Masayuki Yamamoto, John D. Hayes

    TOXICOLOGY AND APPLIED PHARMACOLOGY　226　(3)　328-337　2008/02

    DOI： 10.1016/j.taap.2007.09.018 　

    ISSN： 0041-008X

  793. Molecular evolution of Keap1 - Two Keap1 molecules with distinctive intervening region structures are conserved among fish Peer-reviewed

    Li Li, Makoto Kobayashi, Hiroshi Kaneko, Yaeko Nakajima-Takagi, Yuko Nakayama, Masayuki Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　283　(6)　3248-3255　2008/02

    DOI： 10.1074/jbc.M708702200 　

    ISSN： 0021-9258

  794. Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction Peer-reviewed

    Kevin J. Pearson, Kaitlyn N. Lewis, Nathan L. Price, Joy W. Chang, Evelyn Perez, Maria Victoria Cascajo, Kellie L. Tamashiro, Suresh Poosala, Anna Csiszar, Zoltan Ungvari, Thomas W. Kensler, Masayuki Yamamoto, Josephine M. Egan, Dan L. Longo, Donald K. Ingram, Placido Navas, Rafael de Cabo

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　105　(7)　2325-2330　2008/02

    DOI： 10.1073/pnas.0712162105 　

    ISSN： 0027-8424

  795. A Possible Role of Nrf2 in Prevention of Renal Oxidative Damage by Ferric Nitrilotriacetate Peer-reviewed

    Keita Kanki, Takashi Umemura, Yasuki Kitamura, Yuji Ishii, Yuichi Kuroiwa, Yukio Kodama, Ken Itoh, Masayuki Yamamoto, Akiyoshi Nishikawa, Masao Hirose

    TOXICOLOGIC PATHOLOGY　36　(2)　353-361　2008/02

    DOI： 10.1177/0192623307311401 　

    ISSN： 0192-6233

  796. Ursodeoxycholic acid exerts Nrf2-mediated stimulation of hepatobiliary transport, detoxification and antioxidative stress systems. Peer-reviewed

    Okada;K, Shoda;J, Taguchi;K, Goto;N, Takeda;K, Utsunomiya;H, Oda;K, Warabi;E, Ishii;T, Osaka;K, Yamamoto;M, 正田, 純一

    Am J Physiol　295　G735-G747　2008/01

  797. Physiological role of Keap1 S-guanylation by 8-nitroguanosine 3',5'-cyclic monophosphate formed in C6 glioma cells Peer-reviewed

    Fujii Shigemoto, Sawa Tomohiro, Okamoto Tatsuya, Ihara Hideshi, Motohashi Hozumi, Yamamoto Masayuki, Akaike Takaaki

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　19　S35-S36　2008

    DOI： 10.1016/j.niox.2008.06.069 　

    ISSN： 1089-8603

  798. Nitric oxide-dependent sulfhydryl modification of Keap1 by 8-nitroguanosine 3 ',5 '-cyclic monophosphate Peer-reviewed

    Sawa Tomohiro, Fujii Shigemoto, Irie Atsushi, Okamoto Tatsuya, Motohashi Hozumi, Yamamoto Masayuki, Akaike Takaaki

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　19　S61　2008

    DOI： 10.1016/j.niox.2008.06.176 　

    ISSN： 1089-8603

  799. Inducibility of cytochrome P450 1A1 and chemical carcinogenesis by benzo[a]pyrene in AhR repressor-deficient mice Peer-reviewed

    Tomonori Hosoya, Nobuhiko Harada, Junsei Mimura, Hozumi Motohashi, Satoru Takahashi, Osamu Nakajima, Masanobu Morita, Shimako Kawauchi, Masayuki Yamamoto, Yoshiaki Fujii-Kuriyama

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　365　(3)　562-567　2008/01

    DOI： 10.1016/j.bbrc.2007.11.016 　

    ISSN： 0006-291X

  800. Deletion of the selenocysteine tRNA gene in macrophages and liver results in compensatory gene induction of cytoprotective enzymes by Nrf2 Peer-reviewed

    Takafumi Suzuki, Vincent P. Kelly, Hozumi Motohashi, Osamu Nakajima, Satoru Takahashi, Susumu Nishimura, Masayuki Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　283　(4)　2021-2030　2008/01

    DOI： 10.1074/jbc.M708352200 　

    ISSN： 0021-9258

  801. Differential roles for Nrf2 and AP-1 in upregulation of HO-1 expression by arsenite in murine embryonic fibroblasts Peer-reviewed

    Harumi Harada, Rika Sugimoto, Ayaka Watanabe, Shigeru Taketani, Kosuke Okada, Eiji Warabi, Richard Siow, Ken Itoh, Masayuki Yamamoto, Tetsuro Ishii

    FREE RADICAL RESEARCH　42　(4)　297-304　2008

    DOI： 10.1080/10715760801975735 　

    ISSN： 1071-5762

  802. A novel class of prolyl hydroxylase inhibitors induces angiogenesis and exerts organ protection against ischemia Peer-reviewed

    Masaomi Nangaku, Yuko Izuhara, Shunya Takizawa, Toshiharu Yamashita, Yoshiaki Fujii-Kuriyama, Osamu Ohneda, Masayuki Yamamoto, Charles van Ypersele de Strihou, Noriaki Hirayama, Toshio Miyata

    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY　27　(12)　2548-2554　2007/12

    DOI： 10.1161/ATVBAHA.107.148551 　

    ISSN： 1079-5642

  803. The NHB1 (N-terminal homology box 1) sequence in transcription factor Nrf1 is required to anchor it to the endoplasmic reticulum and also to enable its asparagine-glycosylation Peer-reviewed

    Yiguo Zhang, John M. Lucocq, Masayuki Yamamoto, John D. Hayes

    BIOCHEMICAL JOURNAL　408　(2)　161-172　2007/12

    DOI： 10.1042/BJ20070761 　

    ISSN： 0264-6021

  804. Molecular mechanism of transcriptional repression of AhR repressor involving ANKRA2, HDAC4, and HDAC5 Peer-reviewed

    Motohiko Oshima, Junsei Mimura, Masayuki Yamamoto, Yoshiaki Fujii-Kuriyama

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　364　(2)　276-282　2007/12

    DOI： 10.1016/j.bbrc.2007.09.131 　

    ISSN： 0006-291X

  805. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice Peer-reviewed

    Masaaki Komatsu, Satoshi Waguri, Masato Koike, Yu-shin Sou, Takashi Ueno, Taichi Hara, Noboru Mizushima, Jun-ichi Iwata, Junji Ezaki, Shigeo Murata, Jun Hamazaki, Yasumasa Nishito, Shun-ichiro Iemura, Tohru Natsume, Toru Yanagawa, Junya Uwayama, Eiji Warabi, Hiroshi Yoshida, Tetsuro Ishii, Akira Kobayashi, Masayuki Yamamoto, Zhenyu Yue, Yasuo Uchiyama, Eiki Kominami, Keiji Tanaka

    CELL　131　(6)　1149-1163　2007/12

    DOI： 10.1016/j.cell.2007.10.035 　

    ISSN： 0092-8674

  806. Genetic and pharmacologic evidence links oxidative stress to ventilator-induced lung injury in mice Peer-reviewed

    Srinivas Papaiahgari, Adi Yerrapureddy, Swetha R. Reddy, Narsa M. Reddy, Jeffery M. Dodd-O, Michael T. Crow, Dimitry N. Grigoryev, Kathleen Barnes, Rubin M. Tuder, Masayuki Yamamoto, Thomas W. Kensler, Shyam Biswal, Wayne Mitzner, Paul M. Hassoun, Sekhar P. Reddy

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE　176　(12)　1222-1235　2007/12

    DOI： 10.1164/rccm.200701-060OC 　

    ISSN： 1073-449X

  807. Genetic dissection of the Nrf2-dependent redox signaling-regulated transcriptional programs of cell proliferation and cytoprotection Peer-reviewed

    Narsa M. Reddy, Steven R. Kleeberger, Masayuki Yamamoto, Thomas W. Kensler, Catherine Scollick, Shyam Biswal, Sekhar P. Reddy

    PHYSIOLOGICAL GENOMICS　32　(1)　74-81　2007/12

    DOI： 10.1152/physiolgenomics.00126.2007 　

    ISSN： 1094-8341

    eISSN： 1531-2267

  808. Dysfunction of Nrf2 decreases KBrO3-induced oxidative DNA damage in Ogg1-null mice Peer-reviewed

    Pawel Jaloszynski, Soichiro Murata, Yasuhiro Shinkai, Satoru Takahashi, Yoshito Kumagai, Susumu Nishimura, Masayuki Yamamoto

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　364　(4)　966-971　2007/12

    DOI： 10.1016/j.bbrc.2007.10.123 　

    ISSN： 0006-291X

  809. Detection of hypoxia-inducible gene manipulation Peer-reviewed

    Imagawa Shigehiko, Horie Masaki, Matsumoto Ken, Hirano Ikuo, Suzuki Norio, Yamamoto Masayuki

    BLOOD　110　(11)　1069A　2007/11/16

    ISSN： 0006-4971

  810. c-Myb regulates CD9 gene expression during megakaryopoiesis. Peer-reviewed

    Mukai Harumi Y, Kono Tomoko, Motohashi Hozumi, Yamamoto Masayuki, Kojima Hiroshima

    BLOOD　110　(11)　376A　2007/11/16

    ISSN： 0006-4971

  811. Different electrostatic Potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response Invited Peer-reviewed

    Kit I. Tong, Balasundaram Padmanabhan, Akira Kobayashi, Chengwei Shang, Yosuke Hirotsu, Shigeyuki Yokoyama, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　27　(21)　7511-7521　2007/11

    DOI： 10.1128/MCB.00753-07 　

    ISSN： 0270-7306

  812. Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway Peer-reviewed

    Jonathan M. Maher, Matthew Z. Dieter, Lauren M. Aleksunes, Angela L. Slitt, Grace Guo, Yuji Tanaka, George L. Scheffer, Jefferson Y. Chan, Jose E. Manautou, Ying Chen, Timothy P. Dalton, Masayuki Yamamoto, Curtis D. Klaassen

    HEPATOLOGY　46　(5)　1597-1610　2007/11

    DOI： 10.1002/hep.21831 　

    ISSN： 0270-9139

  813. Nrf2 and p53 cooperatively protect against BBN-induced urinary bladder carcinogenesis Peer-reviewed

    Katsuyuki Iida, Ken Itoh, Jonathan M. Maher, Yoshito Kumagai, Ryoichi Oyasu, Yukio Mori, Toru Shimazui, Hideyuki Akaza, Masayuki Yamamoto

    CARCINOGENESIS　28　(11)　2398-2403　2007/11

    DOI： 10.1093/carcin/bgm146 　

    ISSN： 0143-3334

  814. Protein S-guanylation by the biological signal 8-nitroguanosine 3 &apos;,5 &apos;-cyclic monophosphate Peer-reviewed

    Tomohiro Sawa, Mohammad Hasan Zaki, Tatsuya Okamoto, Teruo Akuta, Yoshiko Tokutomi, Shokei Kim-Mitsuyama, Hideshi Ihara, Akira Kobayashi, Masayuki Yamamoto, Shigemoto Fujii, Hirokazu Arimoto, Takaaki Akaike

    NATURE CHEMICAL BIOLOGY　3　(11)　727-735　2007/11

    DOI： 10.1038/nchembio.2007.33 　

    ISSN： 1552-4450

    eISSN： 1552-4469

  815. Does K-11706 enhance performance and why? Peer-reviewed

    S. Imagawa, K. Matsumoto, M. Horie, N. Ohkoshi, T. Nagasawa, T. Doi, N. Suzuki, M. Yamamoto

    INTERNATIONAL JOURNAL OF SPORTS MEDICINE　28　(11)　928-933　2007/11

    DOI： 10.1055/s-2007-964988 　

    ISSN： 0172-4622

  816. Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2-deficient mice upon dextran sulfate treatment Invited Peer-reviewed

    William O. Osburn, Baktiar Karim, Patrick M. Dolan, Guosheng Liu, Masayuki Yamamoto, David L. Huso, Thomas W. Kensler

    INTERNATIONAL JOURNAL OF CANCER　121　(9)　1883-1891　2007/11

    DOI： 10.1002/ijc.22943 　

    ISSN： 0020-7136

  817. The TR2 and TR4 orphan nuclear receptors repress Gata1 transcription Peer-reviewed

    Osamu Tanabe, Yannan Shen, Qinghui Liu, Andrew D. Campbell, Takashi Kuroha, Masayuki Yamamoto, James Douglas Engel

    GENES & DEVELOPMENT　21　(21)　2832-2844　2007/11

    DOI： 10.1101/gad.1593307 　

    ISSN： 0890-9369

  818. In vivo promoter analysis on refeeding response of hepatic sterol regulatory element-binding protein-1c expression Peer-reviewed

    Yoshinori Takeuchi, Naoya Yahagi, Yoshimi Nakagawa, Takashi Matsuzaka, Ritsuko Shimizu, Motohiro Sekiya, Yoko Iizuka, Ken Ohashi, Takanari Gotoda, Masayuki Yamamoto, Ryozo Nagai, Takashi Kadowaki, Nobuhiro Yamada, Jun-ichi Osuga, Hitoshi Shimano

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　363　(2)　329-335　2007/11

    DOI： 10.1016/j.bbrc.2007.08.165 　

    ISSN： 0006-291X

    eISSN： 1090-2104

  819. Molecular basis distinguishing the DNA binding profile of Nrf2-Maf heterodimer from that of maf homodimer Peer-reviewed

    Momoko Kimura, Tae Yamamoto, Jianyong Zhang, Ken Itoh, Motoki Kyo, Terue Kamiya, Hiroyuki Aburatani, Fumiki Katsuoka, Hirofumi Kurokawa, Toshiyuki Tanaka, Hozumi Motohashi, Masayuki Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　282　(46)　33681-33690　2007/11

    DOI： 10.1074/jbc.M706863200 　

    ISSN： 0021-9258

  820. Cytoprotective role of Nrf2/Keap1 system in methylmercury toxicity Peer-reviewed

    Takashi Toyama, Daigo Sumi, Yasuhiro Shinkai, Akira Yasutake, Keiko Taguchi, Kit I. Tong, Masayuki Yamamoto, Yoshito Kumagai

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　363　(3)　645-650　2007/11

    DOI： 10.1016/j.bbrc.2007.09.017 　

    ISSN： 0006-291X

  821. Subcellular localization and cytoplasmic complex status of endogenous Keap1 Peer-reviewed

    Yoriko Watai, Akira Kobayashi, Hiroko Nagase, Mio Mizukami, Justina McEvoy, Jeffrey D. Singer, Ken Itoh, Masayuki Yamamoto

    GENES TO CELLS　12　(10)　1163-1178　2007/10

    DOI： 10.1111/j.1365-2443.2007.01118.x 　

    ISSN： 1356-9597

    eISSN： 1365-2443

  822. NRF2 modulates aryl hydrocarbon receptor signaling: Influence on adipogenesis Invited Peer-reviewed

    Soona Shin, Nobunao Wakabayashi, Vikas Misra, Shyam Biswal, Gum Hwa Lee, Elin S. Agoston, Masayuki Yamamoto, Thomas W. Kensler

    MOLECULAR AND CELLULAR BIOLOGY　27　(20)　7188-7197　2007/10

    DOI： 10.1128/MCB.00915-07 　

    ISSN： 0270-7306

  823. 新規HIF阻害剤2-オキソグルタル酸投与による腫瘍血管新生抑制効果 Peer-reviewed

    松本 健, 今川 重彦, 小原 直, 鈴木 教郎, 長澤 俊郎, 山本 雅之

    臨床血液　48　(9)　879-879　2007/09

    Publisher: (一社)日本血液学会-東京事務局

    ISSN： 0485-1439

    eISSN： 1882-0824

  824. Role of Nrf2 in protection against intracerebral hemorrhage injury in mice Invited Peer-reviewed

    Jian Wang, Jocelyn Fields, Chunying Zhao, John Langer, Rajesh K. Thimmulappa, Thomas W. Kensler, Masayuki Yamamoto, Shyam Biswal, Sylvain Dore

    FREE RADICAL BIOLOGY AND MEDICINE　43　(3)　408-414　2007/08

    DOI： 10.1016/j.freeradbiomed.2007.04.020 　

    ISSN： 0891-5849

  825. Deficiency in Nrf2-GSH signaling impairs type II cell growth and enhances sensitivity to oxidants Invited Peer-reviewed

    Narsa M. Reddy, Steven R. Kleeberger, Hye-Youn Cho, Masayuki Yamamoto, Thomas W. Kensler, Shyam Biswal, Sekhar P. Reddy

    AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY　37　(1)　3-8　2007/07

    DOI： 10.1165/rcmb.2007-0004RC 　

    ISSN： 1044-1549

  826. Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury Invited Peer-reviewed

    Jacqui M. Marzec, Jason D. Christie, Sekhar P. Reddy, Anne E. Jedlicka, Hue Vuong, Paul N. Lanken, Richard Aplenc, Tae Yamamoto, Masayuki Yamamoto, Hye-Youn Cho, Steven R. Kleeberger

    FASEB JOURNAL　21　(9)　2237-2246　2007/07

    DOI： 10.1096/fj.06-7759com 　

    ISSN： 0892-6638

  827. Regulation of GATA1 gene expression Peer-reviewed

    Makoto Kobayashi, Masayuki Yamamoto

    JOURNAL OF BIOCHEMISTRY　142　(1)　1-10　2007/07

    DOI： 10.1093/jb/mvm122 　

    ISSN： 0021-924X

  828. Enhanced spontaneous and benzo(a)pyrene-induced mutations in the lung of Nrf2-deficient gpt delta mice Invited Peer-reviewed

    Yasunobu Aoki, Akiko H. Hashimoto, Kimiko Amanuma, Michi Matsumoto, Kyoko Hiyoshi, Hirohisa Takano, Ken-ichi Masumura, Ken Itoh, Takehiko Nohmi, Masayuki Yamamoto

    CANCER RESEARCH　67　(12)　5643-5648　2007/06

    DOI： 10.1158/0008-5472.CAN-06-3355 　

    ISSN： 0008-5472

  829. Role of reactive oxygen species in modulation of Nrf2 following ischemic reperfusion injury Invited Peer-reviewed

    Z. A. Shah, R.-C. Li, R. K. Thimmulappa, T. W. Kensler, M. Yamamoto, S. Biswal, S. Dore

    NEUROSCIENCE　147　(1)　53-59　2007/06

    DOI： 10.1016/j.neuroscience.2007.02.066 　

    ISSN： 0306-4522

  830. Dynamic regulation of Gata factor levels is more important than their identity Invited Peer-reviewed

    Rita Ferreira, Albert Wai, Ritsuko Shimizu, Nynke Gillemans, Robbert Rottier, Marieke von Lindern, Kinuko Ohneda, Frank Grosveld, Masayuki Yamamoto, Sjaak Philipsen

    BLOOD　109　(12)　5481-5490　2007/06

    DOI： 10.1182/blood-2006-11-060491 　

    ISSN： 0006-4971

    eISSN： 1528-0020

  831. Nrf2 Neh5 domain is differentially utilized in the transactivation of cytoprotective genes Invited Peer-reviewed

    Jianyong Zhang, Tomonori Hosoya, Atsushi Maruyama, Keizo Nishikawa, Jonathan M. Maher, Tsutomu Ohta, Hozumi Motohashi, Akiyoshi Fukamizu, Shigeki Shibahara, Ken Itoh, Masayuki Yamamoto

    BIOCHEMICAL JOURNAL　404　(3)　459-466　2007/06

    DOI： 10.1042/BJ20061611 　

    ISSN： 0264-6021

  832. Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells (vol 280, pg 27244, 2005) Peer-reviewed

    Hosoya Tomonori, Maruyama Atsushi, Kang Moon-Il, Kawatani Yukie, Shibata Takahiro, Uchida Koji, Itoh Ken, Yamamoto Masayuki

    JOURNAL OF BIOLOGICAL CHEMISTRY　282　(20)　15312　2007/05/18

    ISSN： 0021-9258

  833. A Gata2 intronic enhancer confers its pan-endothelia-specific regulation Invited Peer-reviewed

    Melin Khandekar, William Brandt, Yinghui Zhou, Susan Dagenais, Thomas W. Glover, Norio Suzuki, Ritsuko Shimizu, Masayuki Yamamoto, Kim-Chew Lim, James Douglas Engel

    DEVELOPMENT　134　(9)　1703-1712　2007/05

    DOI： 10.1242/dev.001297 　

    ISSN： 0950-1991

  834. Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers Invited Peer-reviewed

    Kosuke Okada, Junichi Shoda, Masahito Kano, Sachiko Suzuki, Nobuhiro Ohtake, Masahiro Yamamoto, Hiroshi Takahashi, Hirotoshi Utsunomiya, Koji Oda, Kimi Sato, Ayaka Watanabe, Tetsuro Ishii, Ken Itoh, Masayuki Yamamoto, Tsuyoshi Yokoi, Katsutoshi Yoshizato, Yuichi Sugiyama, Hiroshi Suzuki

    AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY　292　(5)　G1450-G1463　2007/05

    DOI： 10.1152/ajpgi.00302.2006 　

    ISSN： 0193-1857

  835. Concurrent transcriptional deregulation of AML1/RUNX1 and GATA factors by the AML1-TRPS1 chimeric gene in t(8;21)(q24;q22) acute myeloid leukemia Invited Peer-reviewed

    Norio Asou, Masatoshi Yanagida, Liqun Huang, Masayuki Yamamoto, Katsuya Shigesada, Hiroaki Mitsuya, Yoshiaki Ito, Motomi Osato

    BLOOD　109　(9)　4023-4027　2007/05

    DOI： 10.1182/blood-2006-01-031781 　

    ISSN： 0006-4971

  836. Embryonic and fetal beta-globin gene repression by the orphan nuclear receptors, TR2 and TR4 Invited Peer-reviewed

    Osamu Tanabe, David McPhee, Shoko Kobayashi, Yannan Shen, William Brandt, Xia Jiang, Andrew D. Campbell, Yei-Tsung Chen, Chawn shang Chang, Masayuki Yamamoto, Keiji Tanimoto, James Douglas Engel

    EMBO JOURNAL　26　(9)　2295-2306　2007/05

    DOI： 10.1038/sj.emboj.7601676 　

    ISSN： 0261-4189

  837. Cell-cycle-dependent oscillation of GATA2 expression in hematopoietic cells Invited Peer-reviewed

    Shinichiro Koga, Nobuhiro Yamaguchi, Tomoko Abe, Masayoshi Minegishi, Shigeru Tsuchiya, Masayuki Yamamoto, Naoko Minegishi

    BLOOD　109　(10)　4200-4208　2007/05

    DOI： 10.1182/blood-2006-08-044149 　

    ISSN： 0006-4971

    eISSN： 1528-0020

  838. GATA-1 self-association controls erythroid development in vivo Invited Peer-reviewed

    Ritsuko Shimizu, Cecelia D. Trainor, Keizo Nishikawa, Makoto Kobayashi, Kinuko Ohneda, Masayuki Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　282　(21)　15862-15871　2007/05

    DOI： 10.1074/jbc.M701936200 　

    ISSN： 0021-9258

  839. Stage-specific, gene-selective regulation of the embryonic and fetal beta-type globin genes by the orphan nuclear receptors TR2 and TR4 Peer-reviewed

    Tanabe Osamu, Kobayashi Shoko, Shen Yannan, McPhee David, Campbell Andrew D, Yamamoto Masayuki, Tanimoto Keiji, Engel Doug

    BLOOD CELLS MOLECULES AND DISEASES　38　(2)　180　2007/03

    DOI： 10.1016/j.bcmd.2006.10.136 　

    ISSN： 1079-9796

  840. A genetic screen for mutations affecting induction of cancer preventive phase 2 enzymes in zebrafish Peer-reviewed

    Kobayashi;M, Tsujita;T, Takagi;Y, Li;L, Nakayama;Y, Eguchi;M, Wada;Y, Yamamoto;M, 小林, 麻己人

    Second strategic conference of zebrafish investigators　2007/02

  841. Carcinogenesis and transcriptional regulation through Maf recognition elements Peer-reviewed

    Hozumi Motohashi, Masayuki Yamamoto

    CANCER SCIENCE　98　(2)　135-139　2007/02

    DOI： 10.1111/j.1349-7006.2006.00358.x 　

    ISSN： 1347-9032

  842. CLARA-CELL SPECIFIC KEAP1 CONDITIONAL KNOCKOUT MICE HAVE STRONG NRF2 ACTIVATION BUT ARE SENSITIVE TO BLEOMYCIN-INDUCED LUNG INJURY

    Maher, Jonathan M, Suzuki, Takafumi, Teguchi, Keiko, Kawatani, Yukie, Kimura, Momoko, Motohashi, Hozumi, Ishii, Yukio, Yamamoto, Masayuki

    DRUG METABOLISM REVIEWS　39　(Suppl. 1)　537-0　2007/01

    Publisher: TAYLOR & FRANCIS INC

    ISSN： 0360-2532

  843. Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes Invited Peer-reviewed

    Melinda S. Yates, Masafumi Tauchi, Fumiki Katsuoka, Kathleen C. Flanders, Karen T. Liby, Tadashi Honda, Gordon W. Gribble, Delinda A. Johnson, Jeffrey A. Johnson, Neal C. Burton, Tomas R. Guilarte, Masayuki Yamamoto, Michael B. Sporn, Thomas W. Kensler

    MOLECULAR CANCER THERAPEUTICS　6　(1)　154-162　2007/01

    DOI： 10.1158/1535-7163.MCT-06-0516 　

    ISSN： 1535-7163

  844. Increased susceptibility to hepatocarcinogenicity of Nrf2-deficient mice exposed to 2-amino-3-methylimidazo[4,5-f]quinoline Invited Peer-reviewed

    Yasuki Kitamura, Takashi Umemura, Keita Kanki, Yukio Kodama, Sachiko Kitamoto, Koichi Saito, Ken Itoh, Masayuki Yamamoto, Toshiaki Masegi, Akiyoshi Nishikawa, Masao Hirose

    CANCER SCIENCE　98　(1)　19-24　2007/01

    DOI： 10.1111/j.1349-7006.2006.00352.x 　

    ISSN： 1347-9032

  845. Characterization of GATA-1(+) hemangioblastic cells in the mouse embryo Invited Peer-reviewed

    Tomomasa Yokomizo, Satoru Takahashi, Naomi Mochizuki, Takashi Kuroha, Masatsugu Ema, Asami Wakamatsu, Ritsuko Shimizu, Osamu Ohneda, Motomi Osato, Hitoshi Okada, Toshihisa Komori, Minetaro Ogawa, Shin-Ichi Nishikawa, Yoshiaki Ito, Masayuki Yamamoto

    EMBO JOURNAL　26　(1)　184-196　2007/01

    DOI： 10.1038/sj.emboj.7601480 　

    ISSN： 0261-4189

    eISSN： 1460-2075

  846. Shear stress stabilizes NF-E2-related factor 2 and induces antioxidant genes in endothelial cells: Role of reactive oxygen/nitrogen species Invited Peer-reviewed

    Eiji Warabi, Wakako Takabe, Takashi Minami, Kenji Inoue, Ken Itoh, Masayuki Yamamoto, Tetsuro Ishii, Tatsuhiko Kodama, Noriko Noguchi

    FREE RADICAL BIOLOGY AND MEDICINE　42　(2)　260-269　2007/01

    DOI： 10.1016/j.freeradbiomed.2006.10.043 　

    ISSN： 0891-5849

  847. Use of gene-manipulated mice in the study of Erythropoietin gene expression Peer-reviewed

    Norio Suzuki, Naoshi Obara, Masayuki Yamamoto

    OXYGEN BIOLOGY AND HYPOXIA　435　157-+　2007

    DOI： 10.1016/S0076-6879(07)35009-X 　

    ISSN： 0076-6879

  848. Glutathione peroxidase 2, the major cigarette smoke-inducible isoform of GPX in lungs, is regulated by Nrf2 Invited Peer-reviewed

    Anju Singh, Tirumalai Rangasamy, Rajesh K. Thimmulappa, Hannah Lee, William O. Osburn, Regina Brigelius-Flohe, Thomas W. Kensler, Masayuki Yamamoto, Shyam Biswal

    AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY　35　(6)　639-650　2006/12

    DOI： 10.1165/rcmb.2005-03225OC 　

    ISSN： 1044-1549

  849. Unique and overlapping transcriptional roles of arylhydrocarbon receptor nuclear translocator (Arnt) and Arnt2 in xenobiotic and hypoxic responses Invited Peer-reviewed

    Hiroki Sekine, Junsei Mimura, Masayuki Yamamoto, Yoshiaki Fujii-Kuriyama

    JOURNAL OF BIOLOGICAL CHEMISTRY　281　(49)　37507-37516　2006/12

    DOI： 10.1074/jbc.M606910200 　

    ISSN： 0021-9258

  850. Primitive erythropoiesis from mesodermal precursors expressing VE-cadherin, PECAM-1, Tie2, endoglin, and CD34 in the mouse embryo Invited Peer-reviewed

    Masatsugu Ema, Tomomasa Yokomizo, Asami Wakamatsu, Tsumoru Terunuma, Masayuki Yamamoto, Satoru Takahashi

    BLOOD　108　(13)　4018-4024　2006/12

    DOI： 10.1182/blood-2006-03-012872 　

    ISSN： 0006-4971

  851. Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-imidazolide Invited Peer-reviewed

    Rajesh K. Thimmulappa, Catherine Scollick, Kassim Traore, Melinda Yates, Michael A. Trush, Karen T. Liby, Michael B. Sporn, Masayuki Yamamoto, Thomas W. Kensler, Shyam Biswal

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　351　(4)　883-889　2006/12

    DOI： 10.1016/j.bbrc.2006.10.102 　

    ISSN： 0006-291X

  852. Ebselen, a Seleno-organic Antioxidant, as an Electrophile Volume 19, Number 9, September 2006, pp 1196−1204 Peer-reviewed

    Toyo Sakurai, Masaya Kanayama, Takahiro Shibata, Ken Itoh, Akira Kobayashi, Masayuki Yamamoto, Koji Uchida

    Chemical Research in Toxicology　19　(11)　1557　2006/11/20

    DOI： 10.1021/tx600268h 　

    ISSN： 0893-228X

  853. Transgene insertion into the proximity of the c-myb gene disrupts erythroid-megakaryocytic lineage bifurcation. Peer-reviewed

    Mukai Harumi Yamamoto, Motohashi Hozumi, Nagasawa Toshiro, Yamamoto Masayuki

    BLOOD　108　(11)　346A　2006/11/16

    ISSN： 0006-4971

  854. 2-Oxoglutarate downregulates expression of vascular endothelial growth factor and erythropoietin through decreasing hypoxia-inducible factor-1 alpha and inhibits angiogenesis Invited Peer-reviewed

    Ken Matsumoto, Shigehiko Imagawa, Naoshi Obara, Norio Suzuki, Satoru Takahashi, Toshiro Nagasawa, Masayuki Yamamoto

    JOURNAL OF CELLULAR PHYSIOLOGY　209　(2)　333-340　2006/11

    DOI： 10.1002/jcp.20733 　

    ISSN： 0021-9541

  855. BRG1 interacts with Nrf2 to selectively mediate HO-1 induction in response to oxidative stress Invited Peer-reviewed

    Jianyong Zhang, Tsutomu Ohta, Atsushi Maruyama, Tomonori Hosoya, Keizo Nishikawa, Jonathan A. Maher, Shigeki Shibahara, Ken Itoh, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　26　(21)　7942-7952　2006/11

    DOI： 10.1128/MCB.00700-06 　

    ISSN： 0270-7306

  856. Transgene insertion in proximity to the c-myb gene disrupts erythroid-megakaryocytic lineage bifurcation Invited Peer-reviewed

    Harumi Y. Mukai, Hozumi Motohashi, Osamu Ohneda, Norio Suzuki, Masumi Nagano, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　26　(21)　7953-7965　2006/11

    DOI： 10.1128/MCB.00718-06 　

    ISSN： 0270-7306

  857. Negative regulation of the Nrf1 transcription factor by its N-terminal domain is independent of Keap1: Nrf1, but not Nrf2, is targeted to the endoplasmic reticulum Invited Peer-reviewed

    Yiguo Zhang, Dorothy H. Crouch, Masayuki Yamamoto, John D. Hayes

    BIOCHEMICAL JOURNAL　399　(3)　373-385　2006/11

    DOI： 10.1042/BJ20060725 　

    ISSN： 0264-6021

  858. Wilms&apos; tumor 1-associating protein regulates G(2)/M transition through stabilization of cyclin A2 mRNA Invited Peer-reviewed

    Keiko Horiuchi, Michihisa Umetani, Takashi Minami, Hiroto Okayama, Shinji Takada, Masayuki Yamamoto, Hiroyuki Aburatani, Patrick C. Reid, David E. Housman, Takao Hamakubo, Tatsuhiko Kodama

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　103　(46)　17278-17283　2006/11

    DOI： 10.1073/pnas.0608357103 　

    ISSN： 0027-8424

  859. 2-オキソグルタル酸投与による腫瘍血管新生の抑制 Peer-reviewed

    松本 健, 今川 重彦, 小原 直, 鈴木 教郎, 長澤 俊郎, 山本 雅之

    日本血栓止血学会誌　17　(5)　584-584　2006/10

    Publisher: (一社)日本血栓止血学会

    ISSN： 0915-7441

    eISSN： 1880-8808

  860. Keap1-Nrf2システムによるレドックスシグナル応答メカニズム (実験医学) Invited

    鈴木隆史, 山本雅之

    実験医学　24　1737　2006/10

  861. Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. Peer-reviewed

    Tong KI, Kobayashi A, Katsuoka F, Yamamoto M

    Biological chemistry　387　(10-11)　1311-1320　2006/10

    DOI： 10.1515/BC.2006.164 　

    ISSN： 1431-6730

  862. Gata3 participates in a complex transcriptional feedback network to regulate sympathoadrenal differentiation Invited Peer-reviewed

    Takashi Moriguchi, Nakano Takako, Michito Hamada, Atsuko Maeda, Yuki Fujioka, Takashi Kuroha, Reuben E. Huber, Susan L. Hasegawa, Arvind Rao, Masayuki Yamamoto, Satoru Takahashi, Kim-Chew Lim, James Douglas Engel

    DEVELOPMENT　133　(19)　3871-3881　2006/10

    DOI： 10.1242/dev.02553 　

    ISSN： 0950-1991

  863. GATA-4 incompletely substitutes for GATA-1 in promoting both primitive and definitive erythropoiesis in vivo Invited Peer-reviewed

    Sakie Hosoya-Ohmura, Naomi Mochizuki, Mikiko Suzuki, Osamu Ohneda, Kinuko Ohneda, Masayuki Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　281　(43)　32820-32830　2006/10

    DOI： 10.1074/jbc.M605735200 　

    ISSN： 0021-9258

  864. 2-オキソグルタル酸投与による腫瘍血管新生抑制効果 Peer-reviewed

    松本 健, 今川 重彦, 小原 直, 鈴木 教郎, 長澤 俊郎, 山本 雅之

    臨床血液　47　(9)　1237-1237　2006/09

    Publisher: (一社)日本血液学会-東京事務局

    ISSN： 0485-1439

    eISSN： 1882-0824

  865. Nrf2-mediated induction of cytoprotective enzymes by 15-deoxy-Delta(12,14)-prostaglandin J(2) is attenuated by alkenal/one oxidoreductase Peer-reviewed

    Xiang Yu, Patricia A. Egner, Junko Wakabayashi, Nobunao Wakabayashi, Masayuki Yamamoto, Thomas W. Kensler

    JOURNAL OF BIOLOGICAL CHEMISTRY　281　(36)　26245-26252　2006/09

    DOI： 10.1074/jbc.M604620200 　

    ISSN： 0021-9258

  866. Ebselen, a seleno-organic antioxidant, as an electrophile Invited Peer-reviewed

    Toyo Sakurai, Masaya Kanayama, Takahiro Shibata, Ken Itoh, Akira Kobayashi, Masayuki Yamamoto, Koji Uchida

    CHEMICAL RESEARCH IN TOXICOLOGY　19　(9)　1196-1204　2006/09

    DOI： 10.1021/tx0601105 　

    ISSN： 0893-228X

  867. MafB is essential for renal development and F4/80 expression in macrophages Invited Peer-reviewed

    Takashi Moriguchi, Michito Hamada, Naoki Morito, Tsumoru Terunuma, Kazuteru Hasegawa, Chuan Zhang, Tomomasa Yokomizo, Ritsuko Esaki, Etsushi Kuroda, Keigyou Yoh, Takashi Kudo, Michio Nagata, David R. Greaves, James Douglas Engel, Masayuki Yamamoto, Satoru Takahashi

    MOLECULAR AND CELLULAR BIOLOGY　26　(15)　5715-5727　2006/08

    DOI： 10.1128/MCB.00001-06 　

    ISSN： 0270-7306

  868. Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a "Tethering" mechanism - A two-site interaction model for the Nrf2-Keap1 complex Invited Peer-reviewed

    Michael McMahon, Nerys Thomas, Ken Itoh, Masayuki Yamamoto, John D. Hayes

    JOURNAL OF BIOLOGICAL CHEMISTRY　281　(34)　24756-24768　2006/08

    DOI： 10.1074/jbc.M601119200 　

    ISSN： 0021-9258

  869. Real-time monitoring of stress erythropoiesis in vivo using Gata1 and beta-globin LCR luciferase transgenic mice. Peer-reviewed

    Suzuki Mikiko, Ohneda Kinuko, Hosoya-Ohmura Sakie, Tsukamoto Saho, Ohneda Osamu, Philipsen Sjaak, Yamamoto Masayuki

    Blood　108　(2)　726-733　2006/07/15

    DOI： 10.1182/blood-2005-10-4064 　

  870. Nrf2 controls bone marrow stromal cell susceptibility to oxidative and electrophilic stress Invited Peer-reviewed

    H Zhu, L Zhang, K Itoh, M Yamamoto, D Ross, MA Trush, JL Zweier, Y Li

    FREE RADICAL BIOLOGY AND MEDICINE　41　(1)　132-143　2006/07

    DOI： 10.1016/j.freeradbiomed.2006.03.020 　

    ISSN： 0891-5849

  871. Predictive base substitution rules that determine the binding and transcriptional specificity of Maf recognition elements Invited Peer-reviewed

    T Yamamoto, M Kyo, T Kamiya, T Tanaka, JD Engel, H Motohashi, M Yamamoto

    GENES TO CELLS　11　(6)　575-591　2006/06

    DOI： 10.1111/j.1365-2443.2006.00965.x 　

    ISSN： 1356-9597

  872. Transgenic rescue of erythroid 5-aminolevulinate synthase-deficient mice results in the formation of ring sideroblasts and siderocytes Invited Peer-reviewed

    O Nakajima, S Okano, H Harada, T Kusaka, Gao, X, T Hosoya, N Suzuki, S Takahashi, M Yamamoto

    GENES TO CELLS　11　(6)　685-700　2006/06

    DOI： 10.1111/j.1365-2443.2006.00973.x 　

    ISSN： 1356-9597

  873. MafG sumoylation is required for active transcriptional repression. International-journal Invited Peer-reviewed

    Hozumi Motohashi, Fumiki Katsuoka, Chika Miyoshi, Yasuhiro Uchimura, Hisato Saitoh, Claire Francastel, James Douglas Engel, Masayuki Yamamoto

    Molecular and cellular biology　26　(12)　4652-63　2006/06

    DOI： 10.1128/MCB.02193-05 　

    ISSN： 0270-7306

    More details Close

    A straightforward mechanism for eliciting transcriptional repression would be to simply block the DNA binding site for activators. Such passive repression is often mediated by transcription factors that lack an intrinsic repressor activity. MafG is a bidirectional regulator of transcription, a repressor in its homodimeric state but an activator when heterodimerized with p45. Here, we report that MafG is conjugated to SUMO-2/3 in vivo. To clarify the possible physiological role(s) for sumoylation in regulating MafG activity, we evaluated mutant and wild-type MafG in transgenic mice and cultured cells. Whereas sumoylation-deficient MafG activated p45-dependent transcription normally and did not affect heterodimer activity, repression by the sumoylation-deficient MafG mutant was severely compromised in vivo. Furthermore, the SUMO-dependent repression activity of MafG was sensitive to histone deacetylase inhibition. Thus, repression by MafG is not achieved through simple passive repression by competing for the activator binding site but requires sumoylation, which then mediates transcriptional repression through recruitment of a repressor complex containing histone deacetylase activity.

  874. Keap1 recruits Neh2 through binding to ETGE and DLG motifs: Characterization of the two-site molecular recognition model Invited Peer-reviewed

    KI Tong, Y Katoh, H Kusunoki, K Itoh, T Tanaka, M Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　26　(8)　2887-2900　2006/04

    DOI： 10.1128/MCB.26.8.2887-2900.2006 　

    ISSN： 0270-7306

  875. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis Invited Peer-reviewed

    RK Thimmulappa, H Lee, T Rangasamy, SP Reddy, M Yamamoto, TW Kensler, S Biswal

    JOURNAL OF CLINICAL INVESTIGATION　116　(4)　984-995　2006/04

    DOI： 10.1127/JCI25790 　

    ISSN： 0021-9738

  876. A crucial role of Nrf2 in in vivo defense against oxidative damage by an environmental pollutant, pentachlorophenol Invited Peer-reviewed

    T Umemura, Y Kuroiwa, Y Kitamura, Y Ishii, K Kanki, Y Kodama, K Itoh, M Yamamoto, A Nishikawa, M Hirose

    TOXICOLOGICAL SCIENCES　90　(1)　111-119　2006/03

    DOI： 10.1093/toxsci/kfj076 　

    ISSN： 1096-6080

  877. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer Invited Peer-reviewed

    B Padmanabhan, KI Tong, T Ohta, Y Nakamura, M Scharlock, M Ohtsuji, MI Kang, A Kobayashi, S Yokoyama, M Yamamoto

    MOLECULAR CELL　21　(5)　689-700　2006/03

    DOI： 10.1016/j.molcel.2006.01.013 　

    ISSN： 1097-2765

  878. Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice Invited Peer-reviewed

    K Satoh, Y Kagaya, M Nakano, Y Ito, J Ohta, H Tada, A Karibe, N Minegishi, N Suzuki, M Yamamoto, M Ono, J Watanabe, K Shirato, N Ishii, K Sugamura, H Shimokawa

    CIRCULATION　113　(11)　1442-1450　2006/03

    DOI： 10.1161/CIRCULATIONAHA.105.583732 　

    ISSN： 0009-7322

  879. Constitutive activation of the aryl hydrocarbon receptor in T-lineage cells induces thymus involution independently of the Fas/Fas ligand signaling pathway Invited Peer-reviewed

    H Nagai, M Kubo, R Abe, M Yamamoto, K Nohara

    INTERNATIONAL IMMUNOPHARMACOLOGY　6　(2)　279-286　2006/02

    DOI： 10.1016/j.intimp.2005.08.015 　

    ISSN： 1567-5769

  880. Differential gene expression profiling between wild-type and ALAS2-null erythroblasts: Identification of novel heme-regulated genes Invited Peer-reviewed

    T Fujiwara, H Harigae, S Takahashi, K Furuyama, O Nakajima, JY Sun, K Igarashi, M Yamamoto, S Sassa, M Kaku, T Sasaki

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　340　(1)　105-110　2006/02

    DOI： 10.1016/j.bbrc.2005.11.163 　

    ISSN： 0006-291X

  881. Combinatorial Gata2 and Sca1 expression defines hematopoietic stem cells in the bone marrow niche Invited Peer-reviewed

    N Suzuki, O Ohneda, N Minegishi, M Nishikawa, T Ohta, S Takahashi, JD Engel, M Yamamoto

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　103　(7)　2202-2207　2006/02

    DOI： 10.1073/pnas.0508928103 　

    ISSN： 0027-8424

  882. Transcription factor Nrf2 regulates brain response to kainate-induced excitotoxicity Peer-reviewed

    Yukihiko Dan, Kosuke Kajitani, Noriko Yutsudo, Ken Itoh, Masayuki Yamamoto, Yusaku Nakabeppu

    NEUROSCIENCE RESEARCH　55　S137-S137　2006

    ISSN： 0168-0102

  883. Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species Peer-reviewed

    Kobayashi,M, Yamamoto,M

    Adv. Enzyme Reg.　46　113-140　2006/01

    ISSN： 0065-2571

  884. Players regulating and supporting cytoprotective function of Nrf2 Peer-reviewed

    Motohashi Hozumi, Suzuki Takafumi, Okawa Hiromi, Tong Kit, Katsuoka Fumiki, Kobayashi Akira, Yamamoto Masayuki

    DRUG METABOLISM REVIEWS　38　22　2006

    ISSN： 0360-2532

  885. Functional analysis of Keap1 in vivo as a electrophile-responsive regulator of Nrf2 Peer-reviewed

    Suzuki Takafumi, Yamamoto Tae, Kobayashi Akira, Motohashi Hozumi, Yamamoto Masayuki, Yamamoto Masayuki

    DRUG METABOLISM REVIEWS　38　123-124　2006

    ISSN： 0360-2532

  886. Oxidative and electophilic stresses activate Nrf2 through inhibition of ubiquitination activity if Keap1 Invited Peer-reviewed

    A Kobayashi, MI Kang, Y Watai, KI Tong, T Shibata, K Uchida, M Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　26　(1)　221-229　2006/01

    DOI： 10.1128/MCB.26.1.221-229.2006 　

    ISSN： 0270-7306

  887. Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity Invited Peer-reviewed

    H Okawa, H Motohashi, A Kobayashi, H Aburatani, TW Kensler, M Yamamoto

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　339　(1)　79-88　2006/01

    DOI： 10.1016/j.bbrc.2005.10.185 　

    ISSN： 0006-291X

    eISSN： 1090-2104

  888. Tissue Prx I in the protection against Fe-NTA and the reduction of nitroxyl radicals Invited Peer-reviewed

    J Uwayama, A Hirayama, T Yanagawa, E Warabi, R Sugimoto, K Itoh, M Yamamoto, H Yoshida, A Koyama, T Ishii

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　339　(1)　226-231　2006/01

    DOI： 10.1016/j.bbrc.2005.10.192 　

    ISSN： 0006-291X

  889. Overexpression of c-Maf contributes to T-cell lymphoma in both mice and human Invited Peer-reviewed

    N Morito, K Yoh, Y Fujioka, T Nakano, H Shimohata, Y Hashimoto, A Yamada, A Maeda, F Matsuno, H Hata, A Suzuki, S Imagawa, H Mitsuya, H Esumi, A Koyama, M Yamamoto, N Mori, S Takahashi

    CANCER RESEARCH　66　(2)　812-819　2006/01

    DOI： 10.1158/0008-5472.CAN-05-2154 　

    ISSN： 0008-5472

  890. Differential effects of GATA-1 on proliferation and differentiation of erythroid lineage cells Invited Peer-reviewed

    J Zheng, K Kitajima, E Sakai, T Kimura, N Minegishi, M Yamamoto, T Nakano

    BLOOD　107　(2)　520-527　2006/01

    DOI： 10.1182/blood-2005-04-1385 　

    ISSN： 0006-4971

  891. Nrf2-deficient mice are highly susceptible to cigarette smoke-induced emphysema Invited Peer-reviewed

    T Iizuka, Y Ishii, K Itoh, T Kiwamoto, T Kimura, Y Matsuno, Y Morishima, AE Hegab, S Homma, A Nomura, T Sakamoto, M Shimura, A Yoshida, M Yamamoto, K Sekizawa

    GENES TO CELLS　10　(12)　1113-1125　2005/12

    DOI： 10.1111/j.1365-2443.2005.00905.x 　

    ISSN： 1356-9597

    eISSN： 1365-2443

  892. Effects of aryl hydrocarbon receptor signaling on the modulation of Th1/Th2 balance Invited Peer-reviewed

    T Negishi, Y Kato, O Ooneda, J Mimura, T Takada, H Mochizuki, M Yamamoto, Y Fujii-Kuriyama, S Furusako

    JOURNAL OF IMMUNOLOGY　175　(11)　7348-7356　2005/12

    ISSN： 0022-1767

  893. Erratum: GATA motifs regulate early hematopoietic lineage-specific expression of the Gata2 gene (Molecular and Cellular Biology (2005) 25, 16 (7005-7020)) Peer-reviewed

    Maki Kobayashi-Osaki, Osamu Ohneda, Norio Suzuki, Naoko Minegishi, Tomomasa Yokomizo, Satoru Takahashi, Kim-Chew Lim, James Douglas Engel, Masayuki Yamamoto

    Molecular and Cellular Biology　25　(22)　10202　2005/11

    DOI： 10.1128/MCB.25.22.10202.2005 　

    ISSN： 0270-7306

  894. Inchinko-to - Agent for liver fibrosis, choleretic agent, hepatoprotectant

    Yamamoto, M, Shoda, J

    DRUGS OF THE FUTURE　30　(11)　1092-1101　2005/11

    Publisher: PROUS SCIENCE, SA

    DOI： 10.1358/dof.2005.030.11.944555 　

    ISSN： 0377-8282

  895. Constitutive expression of aryl hydrocarbon receptor in keratinocytes causes inflammatory skin lesions Invited Peer-reviewed

    M Tauchi, A Hida, T Negishi, F Katsuoka, S Noda, J Mimura, T Hosoya, A Yanaka, H Aburatani, Y Fujii-Kuriyama, H Motohashi, M Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　25　(21)　9360-9368　2005/11

    DOI： 10.1128/MCB.25.21.9360-9368.2005 　

    ISSN： 0270-7306

  896. Intrinsic function of the aryl hydrocarbon (Dioxin) receptor as a key factor in female reproduction Invited Peer-reviewed

    T Baba, J Mimura, N Nakamura, N Harada, M Yamamoto, K Morohashi, Y Fujii-Kuriyama

    MOLECULAR AND CELLULAR BIOLOGY　25　(22)　10040-10051　2005/11

    DOI： 10.1128/MCB.25.22.10040-10051.2005 　

    ISSN： 0270-7306

  897. Transcription factor Nrf2 plays a pivotal role in protection against elastase-induced and emphysema Invited Peer-reviewed

    Y Ishii, K Itoh, Y Morishima, T Kimura, T Kiwamoto, T Ilzuka, AE Hegab, T Hosoya, A Nomura, T Sakamoto, M Yamamoto, K Sekizawa

    JOURNAL OF IMMUNOLOGY　175　(10)　6968-6975　2005/11

    ISSN： 0022-1767

  898. 2-oxoglutarateによる血管形成抑制 Peer-reviewed

    松本 健, 今川 重彦, 小原 直, 鈴木 教郎, 長澤 俊郎, 山本 雅之

    医学のあゆみ　215　(2)　158-159　2005/10

    Publisher: 医歯薬出版(株)

    ISSN： 0039-2359

  899. Enhanced erythropoiesis mediated by activation of the renin-angiotensin system via angiotensin II type 1a receptor Invited Peer-reviewed

    H Kato, J Ishida, S Imagawa, T Saito, N Suzuki, T Matsuoka, T Sugaya, K Tanimoto, T Yokoo, O Ohneda, F Sugiyama, K Yagami, T Fujita, M Yamamoto, M Nangaku, A Fukamizu

    FASEB JOURNAL　19　(12)　2023-+　2005/10

    DOI： 10.1096/fj.05-3820fje 　

    ISSN： 0892-6638

  900. 転写因子c-Mybによる巨核球系造血制御機構の解明 Peer-reviewed

    向井 陽美, 本橋 ほづみ, 鈴木 教郎, 長澤 俊郎, 山本 雅之

    日本血液学会・日本臨床血液学会総会プログラム・抄録集　67回・47回　745-745　2005/09

    Publisher: 日本臨床血液学会

  901. 2-oxoglutarate投与による抗腫瘍血管新生療法への試み Peer-reviewed

    松本 健, 今川 重彦, 小原 直, 鈴木 教郎, 長澤 俊郎, 山本 雅之

    日本血液学会・日本臨床血液学会総会プログラム・抄録集　67回・47回　840-840　2005/09

    Publisher: 日本臨床血液学会

  902. GATA阻害・HIF-1活性薬(K-11706)による持久力増強効果 Peer-reviewed

    今川 重彦, 松本 健, 小原 直, 鈴木 教郎, 長澤 俊郎, 山本 雅之

    日本臨床スポーツ医学会誌　13　(4)　S97-S97　2005/09

    Publisher: (一社)日本臨床スポーツ医学会

    ISSN： 1346-4159

  903. Genetic evidence that small Maf proteins are essential for the activation of antioxidant response element-dependent genes Invited Peer-reviewed

    F Katsuoka, H Motohashi, T Ishii, H Aburatani, JD Engel, M Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　25　(18)　8044-8051　2005/09

    DOI： 10.1128/MCB.25.18.8044-8051.2005 　

    ISSN： 0270-7306

  904. GATA motifs regulate early hematopoietic lineage-specific expression of the Gata2 gene Invited Peer-reviewed

    M Kobayashi-Osaki, O Ohneda, N Suzuki, N Minegishi, T Yokomizo, S Takahashi, KC Lim, JD Engel, M Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　25　(16)　7005-7020　2005/08

    DOI： 10.1128/MCB.25.16.7005-7020.2005 　

    ISSN： 0270-7306

  905. Rapid turnover of GATA-2 via ubiquitin-proteasome protein degradation pathway Invited Peer-reviewed

    N Minegishi, N Suzuki, Y Kawatani, R Shimizu, M Yamamoto

    GENES TO CELLS　10　(7)　693-704　2005/07

    DOI： 10.1111/j.1365-2443.2005.00864.x 　

    ISSN： 1356-9597

  906. GATA-1 is required for expression of Fc epsilon RI on mast cells: analysis of mast cells derived from GATA-1 knockdown mouse bone marrow Invited Peer-reviewed

    C Nishiyama, T Ito, M Nishiyama, S Masaki, K Maeda, N Nakano, W Ng, K Fukuyama, M Yamamoto, K Okumura, H Ogawa

    INTERNATIONAL IMMUNOLOGY　17　(7)　847-856　2005/07

    DOI： 10.1093/intimm/dxh278 　

    ISSN： 0953-8178

  907. Selective induction of the tumor marker glutathione S-transferase P1 by proteasome inhibitors Invited Peer-reviewed

    H Usami, Y Kusano, T Kumagai, S Osada, K Itoh, A Kobayashi, M Yamamoto, K Uchida

    JOURNAL OF BIOLOGICAL CHEMISTRY　280　(26)　25267-25276　2005/07

    DOI： 10.1074/jbc.M501014200 　

    ISSN： 0021-9258

  908. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice Invited Peer-reviewed

    T Rangasamy, J Guo, WA Mitzner, J Roman, A Singh, AD Fryer, M Yamamoto, TW Kensler, RM Tuder, SN Georas, S Biswal

    JOURNAL OF EXPERIMENTAL MEDICINE　202　(1)　47-59　2005/07

    DOI： 10.1084/jem.20050538 　

    ISSN： 0022-1007

  909. Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells Invited Peer-reviewed

    T Hosoya, A Maruyama, MI Kang, Y Kawatani, T Shibata, K Uchida, K Itoh, M Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　280　(29)　27244-27250　2005/07

    DOI： 10.1074/jbc.M502551200 　

    ISSN： 0021-9258

  910. Role Of Peroxynitrite-hydroxyl Radical Pathway In Early Stage Renal Damage Of Streptozotocin Induced Diabetes--In Vivo Non-invasive Identification Using Electron Spin Resonance Peer-reviewed

    Hirayama Aki, Keigyou Yoh, Nagase Sohji, Shimizu Yoshio, Hirayama Kouichi, Koyama Akio, Ueda Atsushi, Itoh Ken, Yamamoto Masayuki, Takahashi Satoru

    Nephrology　10　A17　2005/06

    ISSN： 1320-5358

  911. MafA is a key regulator of glucose-stimulated insulin secretion Invited Peer-reviewed

    C Zhang, T Moriguchi, M Kajihara, R Esaki, A Harada, H Shimohata, H Oishi, M Hamada, N Morito, K Hasegawa, T Kudo, JD Engel, M Yamamoto, S Takahashi

    MOLECULAR AND CELLULAR BIOLOGY　25　(12)　4969-4976　2005/06

    DOI： 10.1128/MCB.25.12.4969-4976.2005 　

    ISSN： 0270-7306

  912. Role of 15-deoxy Delta(12,14) prostaglandin J(2) and Nrf2 pathways in protection against acute lung injury Invited Peer-reviewed

    M Mochizuki, Y Ishii, K Itoh, T Iizuka, Y Morishima, T Kimura, T Kiwamoto, Y Matsuno, AE Hegab, A Nomura, T Sakamoto, K Uchida, M Yamamoto, K Sekizawa

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE　171　(11)　1260-1266　2005/06

    DOI： 10.1164/rccm.200406-755OC 　

    ISSN： 1073-449X

  913. Role of Nrf2 signaling in regulation of antioxidants and phase 2 enzymes in cardiac fibroblasts: Protection against reactive oxygen and nitrogen species-induced cell injury Invited Peer-reviewed

    H Zhu, K Itoh, M Yamamoto, JL Zweier, YB Li

    FEBS LETTERS　579　(14)　3029-3036　2005/06

    DOI： 10.1016/j.febslet.2005.04.058 　

    ISSN： 0014-5793

  914. Graded levels of GATA-1 expression modulate survival, proliferation, and differentiation of erythroid progenitors Invited Peer-reviewed

    XQ Pan, O Ohnedal, K Ohneda, F Lindeboom, F Iwata, R Shimizu, M Nagano, N Suwabe, S Philipsen, KC Lim, JD Engel, M Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　280　(23)　22385-22394　2005/06

    DOI： 10.1074/jbc.M500081200 　

    ISSN： 0021-9258

  915. Increased dosage of Runx1/AML1 acts as a positive modulator of myeloid leukemogenesis in BXH2 mice Invited Peer-reviewed

    M Yanagida, M Osato, N Yamashita, LQ Huang, B Jacob, F Wu, XM Cao, T Nakamura, T Yokomizo, S Takahashi, M Yamamoto, K Shigesada, Y Ito

    ONCOGENE　24　(28)　4477-4485　2005/06

    DOI： 10.1038/sj.onc.1208675 　

    ISSN： 0950-9232

  916. [Flies, fishes and frogs turn the tide of hematopoietic research]. Peer-reviewed

    Kinuko Ohneda, Masayuki Yamamoto

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme　50　(6 Suppl)　633-7　2005/05

    ISSN： 0039-9450

  917. The distal sequence element of the selenocysteine tRNA gene is a tissue-dependent enhancer essential for mouse embryogenesis Invited Peer-reviewed

    VP Kelly, T Suzuki, O Nakajima, T Arai, Y Tamai, S Takahashi, S Nishimura, M Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　25　(9)　3658-3669　2005/05

    DOI： 10.1128/MCB.25.9.3658-3669.2005 　

    ISSN： 0270-7306

  918. Novel serpinopathy in rat kidney and pancreas induced by overexpression of megsin Invited Peer-reviewed

    R Inagi, M Nangaku, N Usuda, A Shimizu, H Onogi, Y Izuhara, K Nakazato, Y Ueda, H Oishi, S Takahashi, M Yamamoto, D Suzuki, K Kurokawa, CVY de Strihou, T Miyata

    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY　16　(5)　1339-1349　2005/05

    DOI： 10.1681/ASN.2004070600 　

    ISSN： 1046-6673

  919. Pi class glutathione S-transferase genes are regulated by Nrf2 through an evolutionarily conserved regulatory element in zebrafish Invited Peer-reviewed

    T Suzuki, Y Takagi, H Osanai, L Li, M Takeuchi, Y Katoh, M Kobayashi, M Yamamoto

    BIOCHEMICAL JOURNAL　388　(Pt 1)　65-73　2005/05

    DOI： 10.1042/BJ20041860 　

    ISSN： 0264-6021

  920. Ultraviolet A irradiation induces NF-E2-related factor 2 activation in dermal fibroblasts: Protective role in UVA-induced apoptosis Invited Peer-reviewed

    A Hirota, Y Kawachi, K Itoh, Y Nakamura, XZ Xu, T Banno, T Takahashi, M Yamamoto, F Otsuka

    JOURNAL OF INVESTIGATIVE DERMATOLOGY　124　(4)　825-832　2005/04

    DOI： 10.1111/j.0022-202X.2005.23670.x 　

    ISSN： 0022-202X

  921. GATA transcription factors inhibit cytokine-dependent growth and survival of a hematopoietic cell line through the inhibition of STAT3 activity Invited Peer-reviewed

    S Ezoe, Matsumura, I, K Gale, Y Satoh, J Ishikawa, M Mizuki, S Takahashi, N Minegishi, K Nakajima, M Yamamoto, T Enver, Y Kanakura

    JOURNAL OF BIOLOGICAL CHEMISTRY　280　(13)　13163-13170　2005/04

    DOI： 10.1074/jbc.M413461200 　

    ISSN： 0021-9258

  922. Transgenic expression of BACH1 transcription factor results in megakaryocytic impairment Invited Peer-reviewed

    T Toki, F Katsuoka, F Kanezaki, G Xu, H Kurotaki, JY Sun, T Kamio, S Watanabe, S Tandai, K Terui, S Yagihashi, N Komatsu, K Igarashi, M Yamamoto, E Ito

    BLOOD　105　(8)　3100-3108　2005/04

    DOI： 10.1182/blood-2004-07-2826 　

    ISSN： 0006-4971

  923. Selective positive and negative regulation of mouse embryonic beta-type globin genes by the orphan nuclear receptors, TR2 and TR4. Peer-reviewed

    Tanabe O, Liu Q, Shen Y, McPhee D, Kobayashi S, Campbell AD, Yamamoto M, Tanimoto K, Engel JD

    BLOOD CELLS MOLECULES AND DISEASES　34　(2)　125　2005/03

    ISSN： 1079-9796

  924. Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation Peer-reviewed

    Kobayashi,M, Yamamoto,M

    ANTIOXIDANTS & REDOX SIGNALING　7　(3-4)　385-394　2005/03

    Publisher: MARY ANN LIEBERT INC

    ISSN： 1523-0864

  925. Constitutively active aryl hydrocarbon receptor expressed specifically in T-lineage cells causes thymus involution and suppresses the immunization-induced increase in splenocytes Invited Peer-reviewed

    K Nohara, XQ Pan, S Tsukumo, A Hida, T Ito, H Nagai, K Inouye, H Motohashi, M Yamamoto, Y Fujii-Kuriyama, C Tohyama

    JOURNAL OF IMMUNOLOGY　174　(5)　2770-2777　2005/03

    ISSN： 0022-1767

  926. Essential role of synoviolin in embryogenesis Invited Peer-reviewed

    N Yagishita, K Ohneda, T Amano, S Yamasaki, A Sugiura, K Tsuchimochi, H Shin, K Kawahara, O Ohneda, T Ohta, S Tanaka, M Yamamoto, Maruyama, I, K Nishioka, A Fukamizu, T Nakajima

    JOURNAL OF BIOLOGICAL CHEMISTRY　280　(9)　7909-7916　2005/03

    DOI： 10.1074/jbc.M410863200 　

    ISSN： 0021-9258

  927. Molecular determinants of NOTCH4 transcription in vascular endothelium Peer-reviewed

    Jing Wu, Fumiko Iwata, Jeffrey A. Grass, Cameron S. Osborne, Laura Elnitski, Peter Fraser, Osamu Ohneda, Masayuki Yamamoto, Emery H. Bresnick

    Molecular and Cellular Biology　25　(4)　1458-1474　2005/02

    DOI： 10.1128/MCB.25.4.1458-1474.2005 　

    ISSN： 0270-7306

  928. Gene expression regulation and domain function of hematopoietic GATA factors. Invited Peer-reviewed

    Shimizu R, Yamamoto M

    Seminars in cell & developmental biology　16　(1)　129-136　2005/02

    DOI： 10.1016/j.semcdb.2004.11.001 　

    ISSN： 1084-9521

  929. Gene expression profiling of NRF2-mediated protection against oxidative injury Invited Peer-reviewed

    HY Cho, SP Reddy, A DeBiase, M Yamamoto, Kleeberger, SR

    FREE RADICAL BIOLOGY AND MEDICINE　38　(3)　325-343　2005/02

    DOI： 10.1016/j.freeradbiomed.2004.10.013 　

    ISSN： 0891-5849

  930. Nrf2 transcriptionally activates the mafG gene through an antioxidant response element Invited Peer-reviewed

    F Katsuoka, L Motohashi, JD Engel, M Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　280　(6)　4483-4490　2005/02

    DOI： 10.1074/jbc.M411451200 　

    ISSN： 0021-9258

  931. Effects of sulforaphane-rich broccoli sprouts on H. pylori-infected gastric mucosa

    Akinori Yanaka, Masafumi Tauchi, Masayuki Yamamoto

    Nippon rinsho. Japanese journal of clinical medicine　63　582-586　2005

    ISSN： 0047-1852

  932. Transgenic over-expression of GATA-1 mutant lacking N-finger domain causes hemolytic syndrome in mouse erythroid cells Invited Peer-reviewed

    M Nakano, K Ohneda, H Yamamoto-Mukai, R Shimizu, O Ohneda, S Ohmura, M Suzuki, S Tsukamoto, T Yanagawa, H Yoshida, Y Takakuwa, M Yamamoto

    GENES TO CELLS　10　(1)　47-62　2005/01

    DOI： 10.1111/j.1365-2443.2005.00814.x 　

    ISSN： 1356-9597

  933. Purification, crystallization and preliminary X-ray diffraction analysis of the Kelch-like motif region of mouse Keap1 Invited Peer-reviewed

    B Padmanabhan, M Scharlock, KI Tong, Y Nakamura, MI Kang, A Kobayashi, T Matsumoto, A Tanaka, M Yamamoto, S Yokoyama

    ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY AND CRYSTALLIZATION COMMUNICATIONS　61　(Pt 1)　153-155　2005/01

    DOI： 10.1107/S1744309104032506 　

    ISSN： 1744-3091

  934. Evolutionary conserved N-terminal domain of Nrf2 is essential for the Keap1-mediated degradation of the protein by proteasome Invited Peer-reviewed

    Y Katoh, K Iida, MI Kang, A Kobayashi, M Mizukami, KI Tong, M McMahon, JD Hayes, K Itoh, M Yamamoto

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS　433　(2)　342-350　2005/01

    DOI： 10.1016/j.abb.2004.10.012 　

    ISSN： 0003-9861

  935. Role of the nrf-2 gene in protection and repair of gastric mucosa against oxidative stress Invited Peer-reviewed

    A. Yanaka, S. Zhang, M. Tauchi, H. Suzuki, T. Shibahara, H. Matsui, A. Nakahara, N. Tanaka, M. Yamamoto

    Inflammopharmacology　13　(1-3)　83-90　2005

    DOI： 10.1163/156856005774423863 　

    ISSN： 0925-4692

  936. Multiple, distant Gata2 enhancers specify temporally and tissue-specific patterning in the developing urogenital system Peer-reviewed

    M Khandekar, N Suzuki, J Lewton, M Yamamoto, JD Engel

    MOLECULAR AND CELLULAR BIOLOGY　24　(23)　10263-10276　2004/12

    DOI： 10.1128/MCB.24.23.10263-10276.2004 　

    ISSN： 0270-7306

  937. Transcription factor nrf2 is essential for induction of NAD(P)H : quinone oxidoreductase 1, glutathione S-transferases, and glutamate cysteine ligase by broccoli seeds and isothiocyanates Invited Peer-reviewed

    GK McWalter, LG Higgins, LI McLellan, CJ Henderson, LJ Song, PJ Thornalley, K Itoh, M Yamamoto, JD Hayes

    JOURNAL OF NUTRITION　134　(12)　3499S-3506S　2004/12

    ISSN： 0022-3166

  938. Leukemogenesis caused by incapacitated GATA-1 function Invited Peer-reviewed

    R Shimizu, T Kuroha, O Ohneda, XQ Pan, K Ohneda, S Takahashi, S Philipsen, M Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　24　(24)　10814-10825　2004/12

    DOI： 10.1128/MCB.24.24.10814-10825.2004 　

    ISSN： 0270-7306

  939. Oral administration of K-11706 inhibits GATA binding activity, enhances hypoxia-inducible factor 1 binding activity, and restores indicators in an in vivo mouse model of anemia of chronic disease Invited Peer-reviewed

    Y Nakano, S Imagawa, K Matsumoto, C Stockmann, N Obara, N Suzuki, T Doi, T Kodama, S Takahashi, T Nagasawa, M Yamamoto

    BLOOD　104　(13)　4300-4307　2004/12

    DOI： 10.1182/blood-2004-04-1631 　

    ISSN： 0006-4971

  940. 2-oxoglutarateによるhypoxia inducible factor-1結合活性および蛋白抑制 Peer-reviewed

    松本 健, 今川 重彦, 小原 直, 鈴木 教郎, 長澤 俊郎, 山本 雅之

    医学のあゆみ　211　(7)　785-786　2004/11

    Publisher: 医歯薬出版(株)

    ISSN： 0039-2359

  941. Transgenic expression of BACH1 transcription factor results in down-regulation of the p45 target genes in megakaryocytic lineage cells. Peer-reviewed

    T Toki, F Katsuoka, R Kanezaki, S Watanabe, T Kamio, S Tandai, H Kurotaki, S Yagihashi, JY Sun, N Komatsu, K Igarashi, M Yamamoto, E Ito

    BLOOD　104　(11)　447A-447A　2004/11

    ISSN： 0006-4971

  942. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice Invited Peer-reviewed

    T Rangasamy, CY Cho, RK Thimmulappa, LJ Zhen, SS Srisuma, TW Kensler, M Yamamoto, Petrache, I, RM Tuder, S Biswal

    JOURNAL OF CLINICAL INVESTIGATION　114　(9)　1248-1259　2004/11

    DOI： 10.1172/JCI200421146 　

    ISSN： 0021-9738

  943. Do beta-globin, GATA-1, or EpoR regulatory domains specifically mark erythroid progenitors in transgenic reporter mice? Invited Peer-reviewed

    N Suzuki, S Imagawa, CT Noguchi, M Yamamoto

    BLOOD　104　(9)　2988-2988　2004/11

    DOI： 10.1182/blood-2004-06-2081 　

    ISSN： 0006-4971

  944. 2-oxoglutarateによるvascular endothelial growth factorおよびerythropoetin産生抑制 Peer-reviewed

    今川 重彦, 松本 健, 小原 直, 鈴木 教郎, 長澤 俊郎, 山本 雅之

    医学のあゆみ　211　(4)　347-348　2004/10

    Publisher: 医歯薬出版(株)

    ISSN： 0039-2359

  945. Transcription factor regulation of drug metabolizing enzymes and antioxidant proteins(the symposium 1 "Molecular Mechanism of biological responses toward environmental pollutants" at the 32nd JEMS annual meeting, 2003.)

    Yamamoto Masayuki

    Environmental Mutagen Research　26　(2)　100-100　2004/09/30

    Publisher: The Environmental Mutagen Society of Japan

    DOI： 10.3123/jems.26.100 　

    ISSN： 0910-0865

  946. GATA結合活性阻害・HIF-1結合活性亢進薬(K-11706)の経口投与による慢性貧血改善の試み Peer-reviewed

    今川 重彦, 松本 健, 小原 直, 鈴木 教郎, 高橋 智, 長澤 俊郎, 山本 雅之

    日本血液学会・日本臨床血液学会総会プログラム・抄録集　66回・46回　874-874　2004/09

    Publisher: 日本臨床血液学会

  947. Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis Invited Peer-reviewed

    K Iida, K Itoh, Y Kumagai, R Oyasu, K Hattori, K Kawai, T Shimazui, H Akaza, M Yamamoto

    CANCER RESEARCH　64　(18)　6424-6431　2004/09

    DOI： 10.1158/0008-5472.CAN-04-1906 　

    ISSN： 0008-5472

  948. The transcription factor NRF2 protects against pulmonary fibrosis Invited Peer-reviewed

    Hye-Youn Cho, Sekhar P. M. Reddy, Masayuki Yamamoto, Steven R. Kleeberger

    FASEB Journal　18　(11)　1258-1260　2004/08

    DOI： 10.1096/fj.03-1127fje 　

    ISSN： 0892-6638

  949. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate for proteasomal degradation of Nrf2 Invited Peer-reviewed

    A Kobayashi, MI Kang, H Okawa, M Ohtsuji, Y Zenke, T Chiba, K Igarashi, M Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　24　(16)　7130-7139　2004/08

    DOI： 10.1128/MCB.24.16.7130-7139.2004 　

    ISSN： 0270-7306

  950. Identification of polymorphisms in the promoter region of the human NRF2 gene Invited Peer-reviewed

    T Yamamoto, K Yoh, A Kobayashi, Y Ishii, S Kure, A Koyama, T Sakamoto, K Sekizawa, H Motohashi, M Yamamoto

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　321　(1)　72-79　2004/08

    DOI： 10.1016/j.bbrc.2004.06.112 　

    ISSN： 0006-291X

  951. Nrf2 deficiency causes tooth decolourization due to iron transport disorder in enamel organ Invited Peer-reviewed

    T Yanagawa, K Itoh, J Uwayama, Y Shibata, A Yamaguchi, T Sano, T Ishii, H Yoshida, M Yamamoto

    GENES TO CELLS　9　(7)　641-651　2004/07

    DOI： 10.1111/j.1365-2443.2004.00753.x 　

    ISSN： 1356-9597

  952. MafT, a new member of the small Maf protein family in zebrafish Invited Peer-reviewed

    Y Takagi, M Kobayashi, L Li, T Suzuki, K Nishikawa, M Yamamoto

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　320　(1)　62-69　2004/07

    DOI： 10.1016/j.bbrc.2004.05.131 　

    ISSN： 0006-291X

  953. Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron Invited Peer-reviewed

    M McMahon, N Thomas, K Itoh, M Yamamoto, JD Hayes

    JOURNAL OF BIOLOGICAL CHEMISTRY　279　(30)　31556-31567　2004/07

    DOI： 10.1074/jbc.M403061200 　

    ISSN： 0021-9258

  954. The transcriptional programme of antibody class switching involves the repressor Bach2 Invited Peer-reviewed

    A Muto, S Tashiro, O Nakajima, H Hoshino, S Takahashi, E Sakoda, D Ikebe, M Yamamoto, K Igarashi

    NATURE　429　(6991)　566-571　2004/06

    DOI： 10.1038/nature02596 　

    ISSN： 0028-0836

  955. A constitutively active arylhydrocarbon receptor induces growth inhibition of Jurkat T cells through changes in the expression of genes related to apoptosis and cell cycle arrest Invited Peer-reviewed

    T Ito, S Tsukumo, N Suzuki, H Motohashi, M Yamamoto, Y Fujii-Kuriyama, J Mimura, TM Lin, RE Peterson, C Tohyama, K Nohara

    JOURNAL OF BIOLOGICAL CHEMISTRY　279　(24)　25204-25210　2004/06

    DOI： 10.1074/jbc.M402143200 　

    ISSN： 0021-9258

  956. ROLE OF NRF-2 GENE IN PROTECTION AND REPAIR OF GASTRIC MUCOSA DURING OXIDATIVE STRESS IN VITRO Peer-reviewed

    YANAKA,Akinori, ZHANG,Shouka, TAUCHI,Masashi, SUZUKI,Hideo, SHIBAHARA,Takeshi, MATSUI,Hiroshi, YAMAMOTO,Masayuki

    実験潰瘍 = ULCER RESEARCH　31　(1)　1-5　2004/05

    ISSN： 0916-3301

  957. Unique function of the Nrf2-Keap1 pathway in the inducible expression of antioxidant and detoxifying enzymes. Peer-reviewed

    Kobayashi A, Ohta T, Yamamoto M

    Methods Enzymol.　378　273-286　2004/05

    DOI： 10.1016/S0076-6879(04)78021-0 　

    ISSN： 0076-6879

  958. Nrf2 deficiency improves autoimmune nephritis caused by the fas mutation lpr Invited Peer-reviewed

    N Morito, K Yoh, A Hirayama, K Itoh, M Nose, A Koyama, M Yamamoto, S Takahashi

    KIDNEY INTERNATIONAL　65　(5)　1703-1713　2004/05

    DOI： 10.1111/j.1523-1755.2004.00565.x 　

    ISSN： 0085-2538

  959. Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice Invited Peer-reviewed

    CEP Goldring, NR Kitteringham, R Elsby, LE Randle, YN Clement, DP Williams, M McMahon, JD Hayes, K Itoh, M Yamamoto, BK Park

    HEPATOLOGY　39　(5)　1267-1276　2004/05

    DOI： 10.1002/hep.20183 　

    ISSN： 0270-9139

  960. Neurogenin3 delineates the earliest stages of spermatogenesis in the mouse testis Invited Peer-reviewed

    S Yoshida, A Takakura, K Ohbo, K Abe, J Wakabayashi, M Yamamoto, T Suda, Y Nabeshima

    DEVELOPMENTAL BIOLOGY　269　(2)　447-458　2004/05

    DOI： 10.1016/j.ydbio.2004.01.036 　

    ISSN： 0012-1606

  961. Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway. Peer-reviewed

    Motohashi Hozumi, Katsuoka Fumiki, Engel James Douglas, Yamamoto Masayuki

    Proc Natl Acad Sci U S A　101　(17)　6379-6384　2004/04/27

    DOI： 10.1073/pnas.0305902101 　

  962. Transgenic rescue of GATA-1-deficient mice with GATA-1 lacking a FOG-1 association site phenocopies patients with X-linked thrombocytopenia Invited Peer-reviewed

    R Shimizu, K Ohneda, JD Engel, CD Trainor, M Yamamoto

    BLOOD　103　(7)　2560-2567　2004/04

    DOI： 10.1182/blood-2003-07-2514 　

    ISSN： 0006-4971

  963. Role of Nrf2 in the regulation of CD36 and stress protein expression in murine macrophages - Activation by oxidatively modified LDL and 4-hydroxynonenal Invited Peer-reviewed

    T Ishii, K Itoh, E Ruiz, DS Leake, H Unoki, M Yamamoto, GE Mann

    CIRCULATION RESEARCH　94　(5)　609-616　2004/03

    DOI： 10.1161/01.RES.0000119171.44657.45 　

    ISSN： 0009-7330

  964. Heme positively regulates the expression of beta-globin at the locus control region via the transcriptional factor Bach1 in erythroid cells Peer-reviewed

    T Tahara, JY Sun, K Nakanishi, M Yamamoto, H Mori, T Saito, H Fujita, K Igarashi, S Taketani

    JOURNAL OF BIOLOGICAL CHEMISTRY　279　(7)　5480-5487　2004/02

    DOI： 10.1074/jbc.M302733200 　

    ISSN： 0021-9258

  965. Evaluation of MafG interaction with Maf recognition element arrays by surface plasmon resonance imaging technique Invited Peer-reviewed

    M Kyo, T Yamamoto, H Motohashi, T Kamiya, T Kuroita, T Tanaka, JD Engel, B Kawakami, M Yamamoto

    GENES TO CELLS　9　(2)　153-164　2004/02

    DOI： 10.1111/j.1365-2443.2004.00711.x 　

    ISSN： 1356-9597

  966. In vivo and in vitro constant expression of GATA-4 in mouse postnatal Sertoli cells Invited Peer-reviewed

    T Imai, Y Kawai, Y Tadokoro, M Yamamoto, Y Nishimune, K Yomogida

    MOLECULAR AND CELLULAR ENDOCRINOLOGY　214　(1-2)　107-115　2004/02

    DOI： 10.1016/j.mce.2003.10.065 　

    ISSN： 0303-7207

  967. Protection against electrophile and oxidant stress by induction of the phase 2 response: Fate of cysteines of the Keap1 sensor modified by inducers Invited Peer-reviewed

    N Wakabayashi, AT Dinkova-Kostova, WD Holtzclaw, MI Kang, A Kobayashi, M Yamamoto, TW Kensler, P Talalay

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　101　(7)　2040-2045　2004/02

    DOI： 10.1073/pnas.0307301101 　

    ISSN： 0027-8424

  968. Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes Invited Peer-reviewed

    MI Kang, A Kobayashi, N Wakabayashi, SG Kim, M Yamamoto

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　101　(7)　2046-2051　2004/02

    DOI： 10.1073/pnas.0308347100 　

    ISSN： 0027-8424

  969. 新規GATA阻害薬の経口投与による慢性貧血治療の試み Peer-reviewed

    中野 陽子, 今川 重彦, 小原 直, 鈴木 教郎, 長澤 俊郎, 山本 雅之

    医学のあゆみ　208　(3)　177-178　2004/01

    Publisher: 医歯薬出版(株)

    ISSN： 0039-2359

  970. Nrf2 deficiency intensifies early phase renal damage in streptozotocin-induced diabetic mice Peer-reviewed

    Hirayama Aki, Yoh Keigyou, Ueda Atsushi, Nagase Sohji, Itoh Ken, Oteki Takaaki, Ishizaki Kazusa, Yamada Akiko, Yamamoto Masayuki, Takahashi Satoru, o

    Free Radical Biology and Medicine　37　S134　2004

  971. Enhancement of NO and O-2 (-) production in streptozotocin treated NRF2-deficient mice Peer-reviewed

    Hirayama A, Yoh K, Ueda A, Nagase S, Ishizaki K, Yamada A, Itoh K, Takahashi S, Yamamoto M, Koyama A

    11　(1)　52　2004

  972. Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-Delta(12),(14)-prostaglandin J(2) Invited Peer-reviewed

    K Itoh, M Mochizuki, Y Ishii, T Ishii, T Shibata, Y Kawamoto, Kelly, V, K Sekizawa, K Uchida, M Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　24　(1)　36-45　2004/01

    DOI： 10.1128/MCB.24.1.36-45.2004 　

    ISSN： 0270-7306

  973. Characterization of the pufferfish Otx2 cis-regulators reveals evolutionarily conserved genetic mechanisms for vertebrate head specification Invited Peer-reviewed

    C Kimura-Yoshida, K Kitajima, Oda-Ishii, I, E Tian, M Suzuki, M Yamamoto, T Suzuki, M Kobayashi, S Aizawa, Matsuo, I

    DEVELOPMENT　131　(1)　57-71　2004/01

    DOI： 10.1242/dev.00877 　

    ISSN： 0950-1991

  974. Interleukin-6 and tumor necrosis factor-alpha in patients with obstructive sleep apnea-hypopnea syndrome Invited Peer-reviewed

    S Imagawa, Y Yamaguchi, K Ogawa, N Obara, N Suzuki, M Yamamoto, T Nagasawa

    RESPIRATION　71　(1)　24-29　2004

    DOI： 10.1159/000075645 　

    ISSN： 0025-7931

  975. Hematological aspects of a novel 9-aminoanthracycline, amrubicin Invited Peer-reviewed

    N Obara, S Imagawa, Y Nakano, M Yamamoto, T Noguchi, T Nagasawa

    CANCER SCIENCE　94　(12)　1104-1106　2003/12

    DOI： 10.1111/j.1349-7006.2003.tb01407.x 　

    ISSN： 1347-9032

  976. Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway Invited Peer-reviewed

    MK Kwak, N Wakabayashi, JL Greenlaw, M Yamamoto, TW Kensler

    MOLECULAR AND CELLULAR BIOLOGY　23　(23)　8786-8794　2003/12

    DOI： 10.1128/MCB.23.23.8786-8794.2003 　

    ISSN： 0270-7306

  977. Nrf2 regulates the sensitivity of death receptor signals by affecting intracellular glutathione levels Invited Peer-reviewed

    N Morito, K Yoh, K Itoh, A Hirayama, A Koyama, M Yamamoto, S Takahashi

    ONCOGENE　22　(58)　9275-9281　2003/12

    DOI： 10.1038/sj.onc.1207024 　

    ISSN： 0950-9232

  978. Self-association of Gata1 enhances transcriptional activity in vivo in zebra fish embryos Invited Peer-reviewed

    K Nishikawa, M Kobayashi, A Masumi, SE Lyons, BM Weinstein, PP Liu, M Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　23　(22)　8295-8305　2003/11

    DOI： 10.1128/MCB.23.22.8295-8305.2003 　

    ISSN： 0270-7306

  979. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation Invited Peer-reviewed

    N Wakabayashi, K Itoh, J Wakabayashi, H Motohashi, S Noda, S Takahashi, S Imakado, T Kotsuji, F Otsuka, DR Roop, T Harada, JD Engel, M Yamamoto

    NATURE GENETICS　35　(3)　238-245　2003/11

    DOI： 10.1038/ng1248 　

    ISSN： 1061-4036

    eISSN： 1546-1718

  980. Expression of the aflatoxin B-1-8,9-epoxide-metabolizing murine glutathione S-transferase A3 subunit is regulated by the Nrf2 transcription factor through an antioxidant response element Invited Peer-reviewed

    IR Jowsey, Q Jiang, K Itoh, M Yamamoto, JD Hayes

    MOLECULAR PHARMACOLOGY　64　(5)　1018-1028　2003/11

    DOI： 10.1124/mol.64.5.1018 　

    ISSN： 0026-895X

  981. Identification and characterization of 2 types of erythroid progenitors that express GATA-1 at distinct levels Invited Peer-reviewed

    N Suzuki, N Suwabe, O Ohneda, N Obara, S Imagawa, XQ Pan, H Motohashi, M Yamamoto

    BLOOD　102　(10)　3575-3583　2003/11

    DOI： 10.1182/blood-2003-04-1154 　

    ISSN： 0006-4971

  982. Transgenic overexpression of GATA-3 in T lymphocytes improves autoimmune glomerulonephritis in mice with a BXSB/MpJ-Yaa genetic background Invited Peer-reviewed

    K Yoh, K Shibuya, N Morito, T Nakano, K Ishizaki, H Shimohata, M Nose, S Izui, A Shibuya, A Koyama, JD Engel, M Yamamoto, S Takahashi

    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY　14　(10)　2494-2502　2003/10

    DOI： 10.1097/01.ASN.0000086473.23379.25 　

    ISSN： 1046-6673

  983. Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome Invited Peer-reviewed

    G Xu, M Nagano, R Kanezaki, T Toki, Y Hayashi, T Taketani, T Taki, T Mitui, K Koike, K Kato, M Imaizumi, Sekine, I, Y Ikeda, R Hanada, M Sako, K Kudo, S Kojima, O Ohneda, M Yamamoto, E Ito

    BLOOD　102　(8)　2960-2968　2003/10

    DOI： 10.1182/blood-2003-02-0390 　

    ISSN： 0006-4971

  984. Transcription factor Nrf2 is required for the constitutive and inducible expression of multidrug resistance-associated protein 1 in mouse embryo fibroblasts Invited Peer-reviewed

    A Hayashi, H Suzuki, K Itoh, M Yamamoto, Y Sugiyama

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　310　(3)　824-829　2003/10

    DOI： 10.1016/j.bbrc.2003.09.086 　

    ISSN： 0006-291X

  985. Identification of a novel Nrf2-regulated antioxidant response element (ARE) in the mouse NAD(P)H: quinone oxidoreductase 1 gene: reassessment of the ARE consensus sequence Invited Peer-reviewed

    P Nioi, M McMahon, K Itoh, M Yamamoto, JD Hayes

    BIOCHEMICAL JOURNAL　374　(Pt 2)　337-348　2003/09

    DOI： 10.1042/BJ20030754 　

    ISSN： 0264-6021

  986. 化学的二量体化物質による人工的赤血球造血制御 Peer-reviewed

    向井 陽美, 鈴木 教郎, 大根田 修, 長澤 俊郎, 山本 雅之

    臨床血液　44　(8)　714-714　2003/08

    Publisher: (一社)日本血液学会-東京事務局

    ISSN： 0485-1439

    eISSN： 1882-0824

  987. 新規GATA特異的阻害薬の経口投与による慢性貧血改善の試み Peer-reviewed

    中野 陽子, 今川 重彦, 小原 直, 鈴木 教郎, 長澤 俊郎, 山本 雅之

    臨床血液　44　(8)　714-714　2003/08

    Publisher: (一社)日本血液学会-東京事務局

    ISSN： 0485-1439

    eISSN： 1882-0824

  988. 機能的レスキュー法を用いた個体レベルでの血球系GATA因子群の分子機能比較 Peer-reviewed

    小原 直, 鈴木 教郎, 大根田 修, 高橋 智, 今川 重彦, 長澤 俊郎, 山本 雅之

    臨床血液　44　(8)　779-779　2003/08

    Publisher: (一社)日本血液学会-東京事務局

    ISSN： 0485-1439

    eISSN： 1882-0824

  989. Expression and domain-specific function of GATA-2 during differentiation of the hematopoietic precursor cells in midgestation mouse embryos Invited Peer-reviewed

    N Minegishi, N Suzuki, T Yokomizo, XQ Pan, T Fujimoto, S Takahashi, T Hara, A Miyajima, S Nishikawa, M Yamamoto

    BLOOD　102　(3)　896-905　2003/08

    DOI： 10.1182/blood-2002-12-3809 　

    ISSN： 0006-4971

  990. The dred repressor. Peer-reviewed

    Tanabe O, Katsuoka F, Campbell A, Kobayashi S, Yamamoto M, Tanimoto K, Engel D

    BLOOD CELLS MOLECULES AND DISEASES　31　(1)　139　2003/07

    ISSN： 1079-9796

  991. GATA-1 testis activation region is essential for Sertoli cell-specific expression of GATA-1 gene in transgenic mouse Invited Peer-reviewed

    J Wakabayashi, K Yomogida, O Nakajima, K Yoh, S Takahashi, JD Engel, K Ohneda, M Yamamoto

    GENES TO CELLS　8　(7)　619-630　2003/07

    DOI： 10.1046/j.1365-2443.2003.00658.x 　

    ISSN： 1356-9597

  992. A potential mechanism for the impairment of nitric oxide formation caused by prolonged oral exposure to arsenate in rabbits Invited Peer-reviewed

    JB Pi, S Horiguchi, Y Sun, M Nikaido, N Shimojo, T Hayashi, H Yamauchi, K Itoh, M Yamamoto, GF Sun, MP Waalkes, Y Kumagai

    FREE RADICAL BIOLOGY AND MEDICINE　35　(1)　102-113　2003/07

    DOI： 10.1016/S0891-5849(03)00269-7 　

    ISSN： 0891-5849

  993. A GATA-specific inhibitor (K-7174) rescues anemia induced by IL-1 beta, TNF-alpha, or L-NMMA Invited Peer-reviewed

    S Imagawa, Y Nakano, N Obara, N Suzuki, T Doi, T Kodama, T Nagasawa, M Yamamoto

    FASEB JOURNAL　17　(10)　1742-+　2003/07

    DOI： 10.1096/fj.02-1134fje 　

    ISSN： 0892-6638

  994. Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression Invited Peer-reviewed

    M McMahon, K Itoh, M Yamamoto, JD Hayes

    JOURNAL OF BIOLOGICAL CHEMISTRY　278　(24)　21592-21600　2003/06

    DOI： 10.1074/jbc.M300931200 　

    ISSN： 0021-9258

  995. Distinct response to dioxin in an arylhydrocarbon receptor (AHR)-humanized mouse. Peer-reviewed

    Moriguchi Takashi, Motohashi Hozumi, Hosoya Tomonori, Nakajima Osamu, Takahashi Satoru, Ohsako Seiichiroh, Aoki Yasunobu, Nishimura Noriko, Tohyama Chiharu, Fujii-Kuriyama Yoshiaki, Yamamoto Masayuki

    Proc Natl Acad Sci U S A　100　(10)　5652-5657　2003/05/13

    DOI： 10.1073/pnas.1037886100 　

  996. Suppression of erythropoietin gene expression by cadmium depends on inhibition of HIF-1, not stimulation of GATA-2 Invited Peer-reviewed

    N Obara, S Imagawa, Y Nakano, N Suzuki, M Yamamoto, T Nagasawa

    ARCHIVES OF TOXICOLOGY　77　(5)　267-273　2003/05

    DOI： 10.1007/s00204-003-0444-0 　

    ISSN： 0340-5761

  997. EPR imaging of reducing activity in Nrf2 transcriptional factor-deficient mice Invited Peer-reviewed

    A Hirayama, K Yoh, S Nagase, A Ueda, K Itoh, N Morito, K Hirayama, S Takahashi, M Yamamoto, A Koyama

    FREE RADICAL BIOLOGY AND MEDICINE　34　(10)　1236-1242　2003/05

    DOI： 10.1016/S0891-5849(03)00073-X 　

    ISSN： 0891-5849

  998. Activation of Nrf2 and accumulation of ubiquitinated A170 by arsenic in osteoblasts Invited Peer-reviewed

    J Aono, T Yanagawa, K Itoh, BJ Li, H Yoshida, Y Kumagai, M Yamamoto, T Ishii

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　305　(2)　271-277　2003/05

    DOI： 10.1016/S0006-291X(03)00728-9 　

    ISSN： 0006-291X

  999. Functional analysis of basic transcription element binding protein by gene targeting technology Invited Peer-reviewed

    M Morita, A Kobayashi, T Yamashita, T Shimanuki, O Nakajima, S Takahashi, S Ikegami, K Inokuchi, K Yamashita, M Yamamoto, Y Fujii-Kuriyama

    MOLECULAR AND CELLULAR BIOLOGY　23　(7)　2489-2500　2003/04

    DOI： 10.1128/MCB.23.7.2489-2500.2003 　

    ISSN： 0270-7306

  1000. Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles Invited Peer-reviewed

    K Itoh, N Wakabayashi, Y Katoh, T Ishii, T O'Connor, M Yamamoto

    GENES TO CELLS　8　(4)　379-391　2003/04

    DOI： 10.1046/j.1365-2443.2003.00640.x 　

    ISSN： 1356-9597

  1001. 二次性貧血に対する新規治療薬の開発 Peer-reviewed

    今川 重彦, 中野 陽子, 小原 直, 鈴木 教郎, 土肥 武, 児玉 龍彦, 長澤 俊郎, 山本 雅之

    医学のあゆみ　204　(12)　903-904　2003/03

    Publisher: 医歯薬出版(株)

    ISSN： 0039-2359

  1002. Interactive effects of nrf2 genotype and oltipraz on benzo[a]pyrene-DNA adducts and tumor yield in mice Invited Peer-reviewed

    M Ramos-Gomez, PM Dolan, K Itoh, M Yamamoto, TW Kensler

    CARCINOGENESIS　24　(3)　461-467　2003/03

    DOI： 10.1093/carcin/24.3.461 　

    ISSN： 0143-3334

  1003. HLF/HIF-2 alpha is a key factor in retinopathy of prematurity in association with erythropoietin Invited Peer-reviewed

    M Morita, O Ohneda, T Yamashita, S Takahashi, N Suzuki, O Nakajima, S Kawauchi, M Ema, S Shibahara, T Udono, K Tomita, M Tamai, K Sogawa, M Yamamoto, Y Fujii-Kuriyama

    EMBO JOURNAL　22　(5)　1134-1146　2003/03

    DOI： 10.1093/emboj/cdg117 　

    ISSN： 0261-4189

  1004. Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway - Identification of novel gene clusters for cell survival Invited Peer-reviewed

    MK Kwak, N Wakabayashi, K Itoh, H Motohashi, M Yamamoto, TW Kensler

    JOURNAL OF BIOLOGICAL CHEMISTRY　278　(10)　8135-8145　2003/03

    DOI： 10.1074/jbc.M211898200 　

    ISSN： 0021-9258

  1005. Gene expression of detoxifying enzymes in AhR and Nrf2 compound null mutant mouse Invited Peer-reviewed

    S Noda, N Harada, A Hida, Y Fujii-Kuriyama, H Motohashi, M Yamamoto

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　303　(1)　105-111　2003/03

    DOI： 10.1016/S0006-291X(03)00306-1 　

    ISSN： 0006-291X

  1006. Regulation of YB-1 gene expression by GATA transcription factors Invited Peer-reviewed

    H Yokoyama, H Harigae, S Takahashi, S Takahashi, K Furuyama, M Kaku, M Yamamoto, T Sasaki

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　303　(1)　140-145　2003/03

    DOI： 10.1016/S0006-291X(03)00296-1 　

    ISSN： 0006-291X

  1007. Small Maf compound mutants display central nervous system neuronal degeneration, aberrant transcription, and Bach protein mislocalization coincident with myoclonus and abnormal startle response Invited Peer-reviewed

    F Katsuoka, H Motohashi, Y Tamagawa, S Kure, K Igarashi, JD Engel, M Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　23　(4)　1163-1174　2003/02

    DOI： 10.1128/MCB.23.4.1163-1174.2003 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  1008. Hemogenic and nonhemogenic endothelium can be distinguished by the activity of fetal liver kinase (Flk)-1 promoter/enhancer during mouse embryogenesis Invited Peer-reviewed

    H Hirai, M Ogawa, N Suzuki, M Yamamoto, G Breier, O Mazda, J Imanishi, S Nishikawa

    BLOOD　101　(3)　886-893　2003/02

    DOI： 10.1182/blood-2002-02-0655 　

    ISSN： 0006-4971

  1009. Aberrant iron accumulation and oxidized status of erythroid-specific delta-aminolevulinate synthase (ALAS2)-deficient definitive erythroblasts Invited Peer-reviewed

    H Harigae, O Nakajima, N Suwabe, H Yokoyama, K Furuyama, T Sasaki, M Kaku, M Yamamoto, S Sassa

    BLOOD　101　(3)　1188-1193　2003/02

    DOI： 10.1182/blood-2002-01-0309 　

    ISSN： 0006-4971

  1010. 新規エリスロポエチン発現促進剤(K-7174) 腎性貧血への試み Peer-reviewed

    今川 重彦, 中野 陽子, 小原 直, 鈴木 教郎, 土肥 武, 児玉 龍彦, 長澤 俊郎, 山本 雅之

    医学のあゆみ　204　(4)　291-292　2003/01

    Publisher: 医歯薬出版(株)

    ISSN： 0039-2359

  1011. A minigene containing four discrete cis elements recapitulates GATA-1 gene expression in vivo Peer-reviewed

    K Ohneda, R Shimizu, S Nishimura, Y Muraosa, S Takahashi, JD Engel, M Yamamoto

    GENES TO CELLS　7　(12)　1243-1254　2002/12

    DOI： 10.1046/j.1365-2443.2002.00595.x 　

    ISSN： 1356-9597

  1012. Transgenic expression of BACH1 results in megakaryocytic linage impairement. Peer-reviewed

    T Toki, F Katsuoka, R Kanezaki, T Kamio, S Tandai, H Kurotaki, S Yagihashi, K Igarashi, M Yamamoto, E Ito

    BLOOD　100　(11)　721A-721A　2002/11

    ISSN： 0006-4971

  1013. GATA-2/estrogen receptor chimera regulates cytokine-dependent growth of hematopoietic cells through accumulation of p21(WAF1) and p27(Kip1) proteins Peer-reviewed

    S Ezoe, Matsumura, I, S Nakata, K Gale, K Ishihara, N Minegishi, T Machii, T Kitamura, M Yamamoto, T Enver, Y Kanakura

    BLOOD　100　(10)　3512-3520　2002/11

    DOI： 10.1182/blood-2002-04-1177 　

    ISSN： 0006-4971

  1014. Electrophile response element-mediated induction of the cystine/glutamate exchange transporter gene expression Peer-reviewed

    H Sasaki, H Sato, K Kuriyama-Matsumura, K Sato, K Maebara, HY Wang, M Tamba, K Itoh, M Yamamoto, S Bannai

    JOURNAL OF BIOLOGICAL CHEMISTRY　277　(47)　44765-44771　2002/11

    DOI： 10.1074/jbc.M208704200 　

    ISSN： 0021-9258

  1015. Erythroid-specific expression of the erythropoietin receptor rescued its null mutant mice from lethality Peer-reviewed

    N Suzuki, O Ohneda, S Takahashi, M Higuchi, HY Mukai, T Nakahata, S Imagawa, M Yamamoto

    BLOOD　100　(7)　2279-2288　2002/10

    DOI： 10.1182/blood-2002-01-0124 　

    ISSN： 0006-4971

  1016. Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene Peer-reviewed

    JY Sun, H Hoshino, K Takaku, O Nakajima, A Muto, H Suzuki, S Tashiro, S Takahashi, S Shibahara, J Alam, MM Taketo, M Yamamoto, K Igarashi

    EMBO JOURNAL　21　(19)　5216-5224　2002/10

    DOI： 10.1093/emboj/cdf516 　

    ISSN： 0261-4189

  1017. Isolation and characterization of zebrafish NFE2 Peer-reviewed

    SJ Pratt, A Drejer, H Foott, B Barut, A Brownlie, J Postlethwait, Y Kato, M Yamamoto, LI Zon

    PHYSIOLOGICAL GENOMICS　11　(2)　91-98　2002/10

    DOI： 10.1152/physiolgenomics.00112.2001 　

    ISSN： 1094-8341

  1018. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants Peer-reviewed

    AT Dinkova-Kostova, WD Holtzclaw, RN Cole, K Itoh, N Wakabayashi, Y Katoh, M Yamamoto, P Talalay

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　99　(18)　11908-11913　2002/09

    DOI： 10.1073/pnas.172398899 　

    ISSN： 0027-8424

  1019. Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray Peer-reviewed

    RK Thimmulappa, KH Mai, S Srisuma, TW Kensler, M Yamamato, S Biswal

    CANCER RESEARCH　62　(18)　5196-5203　2002/09

    ISSN： 0008-5472

  1020. GATA転写因子による多機能蛋白YB-1の発現調節

    横山 寿行, 張替 秀郎, 高橋 伸一郎, 山田 実名美, 佐々木 治, 石澤 賢一, 宮村 耕一, 亀岡 淳一, 高橋 智, 山本 雅之, 佐々木 毅

    臨床血液　43　(8)　183-183　2002/08

    Publisher: (一社)日本血液学会-東京事務局

    ISSN： 0485-1439

    eISSN： 1882-0824

  1021. ヘム結合性転写因子Bach1によるヘムオキシゲナーゼ-1遺伝子制御機構の解析

    孫 継英, 中島 修, 鈴木 洋, 武藤 哲彦, 田代 聡, 柴原 茂樹, 武藤 誠, 山本 雅之, 五十嵐 和彦

    生化学　74　(8)　1002-1002　2002/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  1022. GATA-1-GFPトランスジェニックマウスを用いた赤芽球前駆細胞の解析 Peer-reviewed

    鈴木 教郎, 諏訪部 徳芳, 小原 直, 潘 小青, 高橋 智, 大根田 修, 山本 雅之

    生化学　74　(8)　805-805　2002/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

    eISSN： 2189-0544

  1023. 新規エリスロポエチン発現促進薬(K-7174) 腎性貧血への試み Peer-reviewed

    今川 重彦, 土肥 武, 小原 直, 中野 陽子, 樋口 正人, 鈴木 教郎, 山本 雅之, 長澤 俊郎

    臨床血液　43　(8)　88-88　2002/08

    Publisher: (一社)日本血液学会-東京事務局

    ISSN： 0485-1439

    eISSN： 1882-0824

  1024. カドミウムによるエリスロポエチン遺伝子発現抑制機序 Peer-reviewed

    小原 直, 今川 重彦, 中野 陽子, 樋口 正人, 鈴木 教郎, 山本 雅之, 長澤 俊郎

    臨床血液　43　(8)　175-175　2002/08

    Publisher: (一社)日本血液学会-東京事務局

    ISSN： 0485-1439

    eISSN： 1882-0824

  1025. 2-oxoglutarateによるVEGF・Epo産生抑制作用 Peer-reviewed

    中野 陽子, 今川 重彦, 小原 直, 樋口 正人, 鈴木 教郎, 山本 雅之, 長澤 俊郎

    臨床血液　43　(8)　175-175　2002/08

    Publisher: (一社)日本血液学会-東京事務局

    ISSN： 0485-1439

    eISSN： 1882-0824

  1026. Identification of the interactive interface and phylogenic conservation of the Nrf2-Keap1 system Peer-reviewed

    M Kobayashi, K Itoh, T Suzuki, H Osanai, K Nishikawa, Y Katoh, Y Takagi, M Yamamoto

    GENES TO CELLS　7　(8)　807-820　2002/08

    DOI： 10.1046/j.1365-2443.2002.00561.x 　

    ISSN： 1356-9597

  1027. Elimination of Pasteurella pneumotropica from a contaminated mouse colony by oral administration of enrofloxacin Peer-reviewed

    Y Ueno, R Shimizu, R Nozu, S Takahashi, M Yamamoto, F Sugiyama, A Takakura, T Itoh, K Yagami

    EXPERIMENTAL ANIMALS　51　(4)　401-405　2002/07

    DOI： 10.1538/expanim.51.401 　

    ISSN： 1341-1357

  1028. An embryonic/fetal beta-type globin gene repressor contains a nuclear receptor TR2/TR4 heterodimer Peer-reviewed

    O Tanabe, F Katsuoka, AD Campbell, WM Song, M Yamamoto, K Tanimoto, JD Engel

    EMBO JOURNAL　21　(13)　3434-3442　2002/07

    DOI： 10.1093/emboj/cdf340 　

    ISSN： 0261-4189

  1029. Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female mice Peer-reviewed

    SA Chanas, Q Jiang, M McMahon, GK McWalter, LI McLellan, CR Elcombe, CJ Henderson, CR Wolf, GJ Moffat, K Itoh, M Yamamoto, JD Hayes

    BIOCHEMICAL JOURNAL　365　(Pt 2)　405-416　2002/07

    DOI： 10.1042/BJ2002/0320 　

    ISSN： 0264-6021

  1030. Essential and instructive roles of GATA factors in eosinophil development Peer-reviewed

    R Hirasawa, R Shimizu, S Takahashi, M Osawa, S Takayanagi, Y Kato, M Onodera, N Minegishi, M Yamamoto, K Fukao, H Taniguchi, H Nakauchi, A Iwama

    JOURNAL OF EXPERIMENTAL MEDICINE　195　(11)　1379-1386　2002/06

    DOI： 10.1084/jem.20020170 　

    ISSN： 0022-1007

  1031. Activation of Maf/AP-1 repressor Bach2 by oxidative stress promotes apoptosis and its interaction with promyelocytic leukemia nuclear bodies Peer-reviewed

    A Muto, S Tashiro, H Tsuchiya, A Kume, M Kanno, E Ito, M Yamamoto, K Igarashi

    JOURNAL OF BIOLOGICAL CHEMISTRY　277　(23)　20724-20733　2002/06

    DOI： 10.1074/jbc.M112003200 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  1032. Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: Role of antioxidant response element-like sequences in the nrf2 promoter Peer-reviewed

    MK Kwak, K Itoh, M Yamamoto, TW Kensler

    MOLECULAR AND CELLULAR BIOLOGY　22　(9)　2883-2892　2002/05

    DOI： 10.1128/MCB.22.9.2883-2892.2002 　

    ISSN： 0270-7306

  1033. GATA suppresses erythropoietin gene expression through GATA site in mouse erythropoietin gene promoter Peer-reviewed

    S Imagawa, N Suzuki, K Ohmine, N Obara, HY Mukai, K Ozawa, M Yamamoto, T Nagasawa

    INTERNATIONAL JOURNAL OF HEMATOLOGY　75　(4)　376-381　2002/05

    DOI： 10.1007/BF02982127 　

    ISSN： 0925-5710

  1034. A functional role of Stat3 in in vivo megakaryopoiesis Peer-reviewed

    K Kirito, M Osawa, H Morita, R Shimizu, M Yamamoto, A Oda, H Fujita, M Tanaka, K Nakajima, Y Miura, K Ozawa, N Komatsu

    BLOOD　99　(9)　3220-3227　2002/05

    DOI： 10.1182/blood.V99.9.3220 　

    ISSN： 0006-4971

  1035. The human prepro-orexin gene regulatory region that activates gene expression in the lateral region and represses it in the medial regions of the hypothalamus Peer-reviewed

    T Moriguchi, T Sakurai, S Takahashi, K Goto, M Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　277　(19)　16985-16992　2002/05

    DOI： 10.1074/jbc.M107962200 　

    ISSN： 0021-9258

  1036. Solution structure of the DNA-binding domain of MafG Peer-reviewed

    H Kusunoki, H Motohashi, F Katsuoka, A Morohashi, M Yamamoto, T Tanaka

    NATURE STRUCTURAL BIOLOGY　9　(4)　252-256　2002/04

    DOI： 10.1038/nsb771 　

    ISSN： 1072-8368

  1037. Effect of growth factors on ex vivo bone marrow cell expansion using three-dimensional matrix support Peer-reviewed

    T Tun, H Miyoshi, T Aung, S Takahashi, R Shimizu, T Kuroha, M Yamamoto, N Ohshima

    ARTIFICIAL ORGANS　26　(4)　333-339　2002/04

    DOI： 10.1046/j.1525-1594.2002.06842.x 　

    ISSN： 0160-564X

  1038. Nrf2 transactivator-independent GSTP1-1 expression in 'GSTP1-1 positive' single cells inducible in female mouse liver by DEN: a preneoplastic character of possible initiated cells Peer-reviewed

    K Satoh, K Itoh, M Yamamoto, M Tanaka, M Hayakari, K Ookawa, T Yamazaki, T Sato, S Tsuchida, Hatayama, I

    CARCINOGENESIS　23　(3)　457-462　2002/03

    ISSN： 0143-3334

  1039. L-arginine rescues decreased erythropoietin gene expression by stimulating GATA-2 with L-NMMA Peer-reviewed

    S Imagawa, T Tarumoto, N Suzuki, HY Mukai, Y Hasegawa, M Higuchi, T Neichi, K Ozawa, M Yamamoto, T Nagasawa

    KIDNEY INTERNATIONAL　61　(2)　396-404　2002/02

    DOI： 10.1046/j.1523-1755.2002.00152.x 　

    ISSN： 0085-2538

  1040. Role of NRF2 in protection against hyperoxic lung injury in mice Peer-reviewed

    HY Cho, AE Jedlicka, SP Reddy, TW Kensler, M Yamamoto, LY Zhang, Kleeberger, SR

    AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY　26　(2)　175-182　2002/02

    ISSN： 1044-1549

  1041. A sulforaphane analogue that potently activates the Nrf2-dependent detoxification pathway Peer-reviewed

    Y Morimitsu, Y Nakagawa, K Hayashi, H Fujii, T Kumagai, Y Nakamura, T Osawa, F Horio, K Itoh, K Iida, M Yamamoto, K Uchida

    JOURNAL OF BIOLOGICAL CHEMISTRY　277　(5)　3456-3463　2002/02

    DOI： 10.1074/jbc.M110244200 　

    ISSN： 0021-9258

  1042. Roles of hematopoietic transcription factors GATA-1 and GATA-2 in the development of red blood cell lineage Peer-reviewed

    K Ohneda, M Yamamoto

    ACTA HAEMATOLOGICA　108　(4)　237-245　2002

    DOI： 10.1159/000065660 　

    ISSN： 0001-5792

  1043. Roles of Nrf2 in activation of antioxidant enzyme genes via antioxidant responsive elements Peer-reviewed

    Tetsuro Ishii, Ken Itoh, Masayuki Yamamoto

    Methods in Enzymology　348　182-190　2002

    Publisher: Academic Press Inc.

    DOI： 10.1016/S0076-6879(02)48637-5 　

    ISSN： 0076-6879

  1044. Deterioration Of Organ Redox Status At The Onset Of Lupus-like Glomerulonephritis In Nrf2-deficient Mice Peer-reviewed

    Hirayama Aki, Yoh Keigyou, Nagase Sohji, Ueda Atsushi, Itoh Ken, Oteki Takaaki, Aoyagi Kazumasa, Yamamoto Masayuki, Takahashi Satoru, Koyama Akio

    Nephrology Dialysis Transplantation　17　77　2002

  1045. Transgenic over-expression proliferation and function of MafK suppresses T cell in vivo Peer-reviewed

    K Yoh, T Sugawara, H Motohashi, Y Takahama, A Koyama, M Yamamoto, S Takahashi

    GENES TO CELLS　6　(12)　1055-1066　2001/12

    DOI： 10.1046/j.1365-2443.2001.00489.x 　

    ISSN： 1356-9597

  1046. Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription Peer-reviewed

    Y Katoh, K Itoh, E Yoshida, M Miyagishi, A Fukamizu, M Yamamoto

    GENES TO CELLS　6　(10)　857-868　2001/10

    DOI： 10.1046/j.1365-2443.2001.00469.x 　

    ISSN： 1356-9597

  1047. Nrf2-deficient female mice develop lupus-like autoimmune nephritis Peer-reviewed

    K Yoh, K Itoh, A Enomoto, A Hirayama, N Yamaguchi, M Kobayashi, N Morito, A Koyama, M Yamamoto, S Takahashi

    KIDNEY INTERNATIONAL　60　(4)　1343-1353　2001/10

    DOI： 10.1046/j.1523-1755.2001.00939.x 　

    ISSN： 0085-2538

  1048. Role of phase 2 enzyme induction in chemoprotection by dithiolethiones Peer-reviewed

    Mi-Kyoung Kwak, Patricia A. Egner, Patrick M. Dolan, Minerva Ramos-Gomez, John D. Groopman, Ken Itoh, Masayuki Yamamoto, Thomas W. Kensler

    Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis　480-481　305-315　2001/09/01

    Publisher: Elsevier

    DOI： 10.1016/S0027-5107(01)00190-7 　

    ISSN： 0027-5107

  1049. マウスGATA-2によるマウスエリスロポエチン遺伝子の発現抑制 Peer-reviewed

    今川 重彦, 鈴木 教郎, 大嶺 謙, 小原 直, 向井 陽美, 長谷川 雄一, 山本 雅之, 長澤 俊郎

    医学のあゆみ　198　(10)　731-732　2001/09

    Publisher: 医歯薬出版(株)

    ISSN： 0039-2359

  1050. The Promoter of Mouse Transcription Repressor bach1 Is Regulated by Sp1 and Trans-Activated by Bach1 Peer-reviewed

    J Biochem (Tokyo)　130　385-392　2001/09

    DOI： 10.1093/oxfordjournals.jbchem.a002997 　

  1051. In vivo requirements for GATA-1 functional domains during primitive and definitive erythropoiesis Peer-reviewed

    R Shimizu, S Takahashi, K Ohneda, JD Engel, M Yamamoto

    EMBO JOURNAL　20　(18)　5250-5260　2001/09

    DOI： 10.1093/emboj/20.18.5250 　

    ISSN： 0261-4189

  1052. Levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea-hypopnea syndrome Peer-reviewed

    S Imagawa, Y Yamaguchi, M Higuchi, T Neichi, Y Hasegawa, HY Mukai, N Suzuki, M Yamamoto, T Nagasawa

    BLOOD　98　(4)　1255-1257　2001/08

    DOI： 10.1182/blood.V98.4.1255 　

    ISSN： 0006-4971

  1053. Hematopoietic regulatory domain of gata1 gene is positively regulated by GATA1 protein in zebrafish embryos Peer-reviewed

    M Kobayashi, K Nishikawa, M Yamamoto

    DEVELOPMENT　128　(12)　2341-2350　2001/06

    ISSN： 0950-1991

  1054. Accelerated DNA adduct formation in the lung of the Nrf2 knockout mouse exposed to diesel exhaust Peer-reviewed

    Y Aoki, H Sato, N Nishimura, S Takahashi, K Itoh, M Yamamoto

    TOXICOLOGY AND APPLIED PHARMACOLOGY　173　(3)　154-160　2001/06

    DOI： 10.1006/taap.2001.9176 　

    ISSN： 0041-008X

  1055. The cap 'n' collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes Peer-reviewed

    Michael McMahon, Ken Itoh, Masayuki Yamamoto, Simon A. Chanas, Colin J. Henderson, Lesley I. McLellan, C. Roland Wolf, Christophe Cavin, John D. Hayes

    Cancer Research　61　(8)　3299-3307　2001/04/15

    ISSN： 0008-5472

  1056. Defective development of secretory neurons in the hypothalamus of Arnt2-knockout mice. Peer-reviewed

    Hosoya, T, Oda, Y, Takahashi, S, Morita, M, Kawauchi, S, Ema, M, Yamamoto, M, Fujii-Kuriyama, Y

    Genes Cells　6　(4)　361 374　2001/04

  1057. The homeobox protein Six3 interacts with the Groucho corepressor and acts as a transcriptional repressor in eye and forebrain formation Peer-reviewed

    M Kobayashi, K Nishikawa, T Suzuki, M Yamamoto

    DEVELOPMENTAL BIOLOGY　232　(2)　315-326　2001/04

    DOI： 10.1006/dbio.2001.0185 　

    ISSN： 0012-1606

  1058. Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice Peer-reviewed

    Minerva Ramos-Gomez, Mi-Kyoung Kwak, Patrick M. Dolan, Ken Itoh, Masayuki Yamamoto, Paul Talalay, Thomas W. Kensler

    Proceedings of the National Academy of Sciences of the United States of America　98　(6)　3410-3415　2001/03/13

    DOI： 10.1073/pnas.051618798 　

    ISSN： 0027-8424

  1059. Transcription factor BACH1 is recruited to the nucleus by its novel alternative spliced isoform Peer-reviewed

    Kanezaki R, Toki T, Yokoyama M, Yomogida K, Sugiyama K, Yamamoto M, Igarashi K, Ito E

    JOURNAL OF BIOLOGICAL CHEMISTRY　276　(10)　7278-7284　2001/03/09

    DOI： 10.1074/jbc.M004227200 　

    ISSN： 0021-9258

  1060. 転写因子Bach2を介した酸化ストレス情報伝達経路の機能

    星野 英人, 吉田 稔, 武藤 哲彦, 伊藤 悦朗, 山本 雅之, 五十嵐 和彦

    生化学　73　(2)　143-143　2001/02

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

    eISSN： 2189-0544

  1061. Stimulation of GATA-2 as a mechanism of hydrogen peroxide suppression in hypoxia-induced erythropoietin gene expression. Peer-reviewed

    Tabata M, Tarumoto T, Ohmine K, Furukawa Y, Hatake K, Ozawa K, Hasegawa Y, Mukai H, Yamamoto M, Imagawa S

    Journal of cellular physiology　2001/02

    DOI： 10.1002/1097-4652(200002)186:2<260::aid-jcp1025>3.0.co;2-k 　

  1062. Hemin-induced activation of the thioredoxin gene by Nrf2: A differential regulation of the antioxidant responsive element by a switch of its binding factors Peer-reviewed

    Yong-Chul Kim, Hiroshi Masutani, Yoshimi Yamaguchi, Ken Itoh, Masayuki Yamamoto, Junji Yodoi

    Journal of Biological Chemistry　276　(21)　18399-18406　2001/01/25

    DOI： 10.1074/jbc.M100103200 　

    ISSN： 0021-9258

  1063. Role of Transcription Factor Nrf2 in the Induction of Hepatic Phase 2 and Antioxidative Enzymes in vivo by the Cancer Chemoprotective Agent, 3H-1, 2-Dithiole-3-thione Peer-reviewed

    Mi-Kyoung Kwak, Ken Itoh, Masayuki Yamamoto, Thomas R. Sutter, Thomas W. Kensler

    Molecular Medicine　7　(2)　135-145　2001

    ISSN： 1076-1551

  1064. Step-wise divergence of primitive and definitive haematopoietic and endothelial cell lineages during embryonic stem cell differentiation Peer-reviewed

    Tetsuhiro Fujimoto, Minetaro Ogawa, Naoko Minegishi, Hisahiro Yoshida, Tomomasa Yokomizo, Masayuki Yamamoto, Shin-Ichi Nishikawa

    Genes to Cells　6　(12)　1113-1127　2001

    DOI： 10.1046/j.1365-2443.2001.00490.x 　

    ISSN： 1356-9597

  1065. High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes Peer-reviewed

    Akiko Enomoto, Ken Itoh, Eiko Nagayoshi, Junko Haruta, Toyoe Kimura, Tania O'Connor, Takanori Harada, Masayuki Yamamoto

    Toxicological Sciences　59　(1)　169-177　2001

    DOI： 10.1093/toxsci/59.1.169 　

    ISSN： 1096-6080

  1066. NG-monomethyl-L-arginine(L-NMMA)のGATA-2促進によるEpo産生低下はL-arginineにより改善する Peer-reviewed

    今川 重彦, 樽本 高寿, 向井 陽美, 長谷川 雄一, 鈴木 教郎, 樋口 正人, 今井 信雄, 山本 雅之, 長澤 俊郎

    医学のあゆみ　196　(3)　229-230　2001/01

    Publisher: 医歯薬出版(株)

    ISSN： 0039-2359

  1067. Gene regulation of the zebrafish Six4 in the cranial sensory placodes.

    Kobayashi M, Suzuki T, Yamamoto M

    Development, Growth & Differentiation.　43　S99　2001

  1068. Function of GATA transcription factors in induction of endothelial vascular cell adhesion molecule-1 by tumor necrosis factor-alpha. Peer-reviewed

    Umetani M, Mataki C, Minegishi N, Yamamoto M, Hamakubo T, Kodama T

    Arteriosclerosis, Thrombosis, and Vascular Biology　21　917-922　2001

  1069. A novel cis-acting element regulates HES-1 gene expression in P19 embryonal carcinoma cells treated with retinoic acid Peer-reviewed

    N Wakabayashi, R Kageyama, T Habu, T Doi, T Morita, M Nozaki, M Yamamoto, Y Nishimune

    JOURNAL OF BIOCHEMISTRY　128　(6)　1087-1095　2000/12

    ISSN： 0021-924X

  1070. Positive or negative MARE-dependent transcriptional regulation is by the abundance of small Maf proteins Peer-reviewed

    H Motohashi, F Katsuoka, JA Shavit, JD Engel, M Yamamoto

    CELL　103　(6)　865-875　2000/12

    DOI： 10.1016/S0092-8674(00)00190-2 　

    ISSN： 0092-8674

    eISSN： 1097-4172

  1071. Gene regulation of zebrafish Gata1

    Kobayashi;M, Nishikawa;K, Yamamoto;M, 小林, 麻己人

    The 2nd International Symposium on GATA Transcription Factors: GATA Factor Functions in Development　2000/11

  1072. Expression of three zebrafish Six4 genes in the cranial sensory placodes and the developing somites Peer-reviewed

    M Kobayashi, H Osanai, K Kawakami, M Yamamoto

    MECHANISMS OF DEVELOPMENT　98　(1-2)　151-155　2000/11

    DOI： 10.1016/S0925-4773(00)00451-2 　

    ISSN： 0925-4773

  1073. Functional characterization of the two alternative promoters of human p45 NF-E2 gene Peer-reviewed

    T Toki, K Arai, K Terui, N Komatsu, M Yokoyama, F Katsuoka, M Yamamoto, E Ito

    EXPERIMENTAL HEMATOLOGY　28　(10)　1113-1119　2000/10

    DOI： 10.1016/S0301-472X(00)00523-3 　

    ISSN： 0301-472X

  1074. Biologic significance of GATA-1 activities in Ras-mediated megakaryocytic differentiation of hematopoietic cell lines Peer-reviewed

    Matsumura, I, A Kawasaki, H Tanaka, J Sonoyama, S Ezoe, N Minegishi, K Nakajima, M Yamamoto, Y Kanakura

    BLOOD　96　(7)　2440-2450　2000/10

    ISSN： 0006-4971

  1075. GATA2 is required for the generation of V2 interneurons Peer-reviewed

    YH Zhou, M Yamamoto, JD Engel

    DEVELOPMENT　127　(17)　3829-3838　2000/09

    ISSN： 0950-1991

  1076. N-G-monomethyl-L-arginine inhibits erythropoietin gene expression by stimulating GATA-2 Peer-reviewed

    T Tarumoto, S Imagawa, K Ohmine, T Nagai, M Higuchi, N Imai, N Suzuki, M Yamamoto, K Ozawa

    BLOOD　96　(5)　1716-1722　2000/09

    ISSN： 0006-4971

  1077. 転写因子Bach 1のヘム結合モチーフ

    小川 和宏, 五十嵐 和彦, 西谷 千明, 竹谷 茂, 中島 修, 山本 雅之, 柴原 茂樹, 林 典夫, 藤田 博美

    生化学　72　(8)　978-978　2000/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  1078. エリスロポエチン受容体欠損マウスの赤血球特異的トランスジーンレスキュー Peer-reviewed

    鈴木 教郎, 樋口 正人, 高橋 智, 山本 雅之

    生化学　72　(8)　1091-1091　2000/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  1079. Animal models for X-linked sideroblastic anemia Peer-reviewed

    M Yamamoto, O Nakajima

    INTERNATIONAL JOURNAL OF HEMATOLOGY　72　(2)　157-164　2000/08

    ISSN： 0925-5710

  1080. GATA factor transgenes under GATA-1 locus control rescue germline GATA-1 mutant deficiencies Peer-reviewed

    S Takahashi, R Shimizu, N Suwabe, T Kuroha, K Yoh, J Ohta, S Nishimura, KC Lim, JD Engel, M Yamamoto

    BLOOD　96　(3)　910-916　2000/08

    ISSN： 0006-4971

  1081. Cloning and expression of human B cell-specific transcription factor BACH2 mapped to chromosome 6q15 Peer-reviewed

    S Sasaki, E Ito, T Toki, T Maekawa, R Kanezaki, T Umenai, A Muto, H Nagai, T Kinoshita, M Yamamoto, J Inazawa, MM Taketo, T Nakahata, K Igarashi, M Yokoyama

    ONCOGENE　19　(33)　3739-3749　2000/08

    DOI： 10.1038/sj.onc.1203716 　

    ISSN： 0950-9232

  1082. Cloning of a coproporphyrinogen oxidase promoter regulatory element binding protein Peer-reviewed

    S Takahashi, K Furuyama, A Kobayashi, S Taketani, H Harigae, M Yamamoto, K Igarashi, T Sasaki, N Hayashi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　273　(2)　596-602　2000/07

    DOI： 10.1006/bbrc.2000.2991 　

    ISSN： 0006-291X

  1083. [An approach to analyze transcription factor function in vivo utilizing specific gene regulatory regions] Peer-reviewed

    Yamamoto M

    Tanpakushitsu Kakusan Koso　45　(9 Suppl)　1593-1602　2000/06

  1084. [Study of the transcription factor function in vivo: an overview] Peer-reviewed

    Yamamoto M

    Tanpakushitsu Kakusan Koso　45　(9 Suppl)　1573-1576　2000/06

  1085. One enhancer mediates mafK transcriptional activation in both hematopoietic and cardiac muscle cells Peer-reviewed

    F Katsuoka, H Motohashi, K Onodera, N Suwabe, JD Engel, M Yamamoto

    EMBO JOURNAL　19　(12)　2980-2991　2000/06

    DOI： 10.1093/emboj/19.12.2980 　

    ISSN： 0261-4189

    eISSN： 1460-2075

  1086. Oxidative stress abolishes Crm1/Exportin1-dependent nuclear export of Maf-interacting transcription repressor Bach2. Peer-reviewed

    J. Biol. Chem.　275　15370-15376　2000/05

    DOI： 10.1074/jbc.275.20.15370 　

  1087. Induction of murine intestinal and hepatic peroxiredoxin MSP23 by dietary butylated hydroxyanisole Peer-reviewed

    T Ishii, K Itoh, J Akasaka, T Yanagawa, S Takahashi, H Yoshida, S Bannai, M Yamamoto

    CARCINOGENESIS　21　(5)　1013-1016　2000/05

    DOI： 10.1093/carcin/21.5.1013 　

    ISSN： 0143-3334

  1088. Oxidative stress abolishes leptomycin B-sensitive nuclear export of transcription repressor Bach2 that counteracts activation of Maf recognition element Peer-reviewed

    H Hoshino, A Kobayashi, M Yoshida, N Kudo, T Oyake, H Motohashi, N Hayashi, M Yamamoto, K Igarashi

    JOURNAL OF BIOLOGICAL CHEMISTRY　275　(20)　15370-15376　2000/05

    DOI： 10.1074/jbc.275.20.15370 　

    ISSN： 0021-9258

  1089. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages Peer-reviewed

    T Ishii, K Itoh, S Takahashi, H Sato, T Yanagawa, Y Katoh, S Bannai, M Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　275　(21)　16023-16029　2000/05

    DOI： 10.1074/jbc.275.21.16023 　

    ISSN： 0021-9258

  1090. 酸素ストレスによる赤血球分化機序の検討

    永井 正, 大嶺 謙, 樽本 高壽, 今川 重彦, 小松 則男, 五十嵐 和彦, 山本 雅之, 佐々 茂, 小澤 敬也

    International Journal of Hematology　71　(Suppl.1)　192-192　2000/04

    Publisher: (一社)日本血液学会

    ISSN： 0925-5710

    eISSN： 1865-3774

  1091. A combinatorial code for gene expression generated by transcription factor Bach2 and MAZR (MAZ-related factor) through the BTB/POZ domain Peer-reviewed

    A Kobayashi, H Yamagiwa, H Hoshino, A Muto, K Sato, M Morita, N Hayashi, M Yamamoto, K Igarashi

    MOLECULAR AND CELLULAR BIOLOGY　20　(5)　1733-1746　2000/03

    DOI： 10.1128/MCB.20.5.1733-1746.2000 　

    ISSN： 0270-7306

  1092. Perinatal synthetic lethality and hematopoietic defects in compound mafG : mafK mutant mice Peer-reviewed

    K Onodera, JA Shavit, H Motohashi, M Yamamoto, JD Engel

    EMBO JOURNAL　19　(6)　1335-1345　2000/03

    DOI： 10.1093/emboj/19.6.1335 　

    ISSN： 0261-4189

  1093. Eosinophil-specific regulation of gp91(phox) gene expression by transcription factors GATA-1 and GATA-2 Peer-reviewed

    D Yang, S Suzuki, LJ Hao, Y Fujii, A Yamauchi, M Yamamoto, M Nakamura, A Kumatori

    JOURNAL OF BIOLOGICAL CHEMISTRY　275　(13)　9425-9432　2000/03

    DOI： 10.1074/jbc.275.13.9425 　

    ISSN： 0021-9258

  1094. The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin Peer-reviewed

    JD Hayes, SA Chanas, CJ Henderson, M McMahon, C Sun, GJ Moffat, CR Wolf, M Yamamoto

    BIOCHEMICAL SOCIETY TRANSACTIONS　28　(2)　33-41　2000/02

    ISSN： 0300-5127

  1095. GATA-1 blocks IL-6-induced macrophage differentiation and apoptosis through the sustained expression of cyclin D1 and Bcl-2 in a murine myeloid cell line M1 Peer-reviewed

    H Tanaka, Matsumura, I, K Nakajima, H Daino, J Sonoyama, H Yoshida, K Oritani, T Machii, M Yamamoto, T Hirano, Y Kanakura

    BLOOD　95　(4)　1264-1273　2000/02

    ISSN： 0006-4971

  1096. Generation of molecular probes for hematopoietic cell purification Peer-reviewed

    S Takahashi, N Minegishi, K Igarashi, M Yamamoto

    TISSUE ENGINEERING FOR THERAPEUTIC USE 4　1198　131-140　2000

    ISSN： 0531-5131

  1097. [Molecular diagnosis of hereditary sideroblastic anemia and model mouse of the disease] (Rinsho Ketsueki)

    Yamamoto M, Nakajima O, Furuyama K, Harigae H, Hayashi N

    Rinsho Ketsueki　41　(7)　540-543　2000

  1098. 遺伝性鉄芽球性貧血の分子診断とモデルマウス

    山本 雅之, 中島 修, 古山 和道, 張替 秀郎, 林 典夫

    臨床血液　41　(7)　540-543　2000

    Publisher: 一般社団法人 日本血液学会

    DOI： 10.11406/rinketsu.41.540 　

  1099. Identification of human GATA-2 gene distal IS exon and its expression in hematopoietic stem cell fractions Peer-reviewed

    XQ Pan, N Minegishi, H Harigae, H Yamagiwa, M Minegishi, Y Akine, M Yamamoto

    JOURNAL OF BIOCHEMISTRY　127　(1)　105-112　2000/01

    ISSN： 0021-924X

  1100. A GATA box in the GATA-1 gene hematopoietic enhancer is a critical element in the network of GATA factors and sites that regulate this gene Peer-reviewed

    S Nishimura, S Takahashi, T Kuroha, N Suwabe, T Nagasawa, C Trainor, M Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　20　(2)　713-723　2000/01

    DOI： 10.1128/MCB.20.2.713-723.2000 　

    ISSN： 0270-7306

  1101. Inhibitory interaction of c-Myb and GATA-1 via transcriptional co-activator CBP Peer-reviewed

    T Takahashi, N Suwabe, P Dai, M Yamamoto, S Ishii, T Nakano

    ONCOGENE　19　(1)　134-140　2000/01

    DOI： 10.1038/sj.onc.1203228 　

    ISSN： 0950-9232

  1102. [Transcriptional regulation of the phase II drug detoxifying enzyme genes] Peer-reviewed

    Itoh K, Yamamoto M

    Tanpakushitsu Kakusan Koso　44　(15 Suppl)　2370-2376　1999/11

  1103. [Transcriptional regulation of detoxication enzyme genes: overview] Peer-reviewed

    Yamamoto M

    Tanpakushitsu Kakusan Koso　44　(15 Suppl)　2368-2369　1999/11

  1104. [Present status and future aspects on study of molecular mechanisms of animal physiological adaptation to the environment] Peer-reviewed

    Yamamoto M

    Tanpakushitsu Kakusan Koso　44　(15 Suppl)　2366-2367　1999/11

  1105. Long range interaction of cis-DNA elements mediated by architectural transcription factor Bach1 Peer-reviewed

    C Yoshida, F Tokumasu, KI Hohmura, J Bungert, N Hayashi, T Nagasawa, JD Engel, M Yamamoto, K Takeyasu, K Igarashi

    GENES TO CELLS　4　(11)　643-655　1999/11

    DOI： 10.1046/j.1365-2443.1999.00291.x 　

    ISSN： 1356-9597

  1106. Heme deficiency in erythroid lineage causes differentiation arrest and cytoplasmic iron overload Peer-reviewed

    O Nakajima, S Takahashi, H Harigae, K Furuyama, N Hayashi, S Sassa, M Yamamoto

    EMBO JOURNAL　18　(22)　6282-6289　1999/11

    DOI： 10.1093/emboj/18.22.6282 　

    ISSN： 0261-4189

  1107. A novel mutation of the erythroid-specific delta-aminolevulinate synthase gene in a patient with non-inherited pyridoxine-responsive sideroblastic anemia Peer-reviewed

    H Harigae, K Furuyama, K Kudo, N Hayashi, M Yamamoto, S Sassa, T Sasaki

    AMERICAN JOURNAL OF HEMATOLOGY　62　(2)　112-114　1999/10

    DOI： 10.1002/(SICI)1096-8652(199910)62:2<112::AID-AJH9>3.0.CO;2-L 　

    ISSN： 0361-8609

  1108. ヘムによる転写因子Bach1の活性調節

    小川 和宏, 五十嵐 和彦, 竹谷 茂, 吉田 近思, 中島 修, 山本 雅之, 柴原 茂樹, 林 典夫, 藤田 博美

    生化学　71　(8)　948-948　1999/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  1109. 腎性貧血の機序解明 L-NMMAによるエリスロポエチン遺伝子発現抑制 Peer-reviewed

    樽本 高壽, 大嶺 護, 小澤 敬也, 鈴木 教郎, 山本 雅之, 樋口 正人, 今井 信雄, 今川 重彦

    生化学　71　(8)　814-814　1999/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  1110. A novel mutation of the erythroid-specific delta-aminolaevulinate synthase gene in a patient with X-linked sideroblastic anaemia Peer-reviewed

    H Harigae, K Furuyama, A Kimura, K Neriishi, N Tahara, M Kondo, N Hayashi, M Yamamoto, S Sassa, T Sasaki

    BRITISH JOURNAL OF HAEMATOLOGY　106　(1)　175-177　1999/07

    DOI： 10.1046/j.1365-2141.1999.01479.x 　

    ISSN： 0007-1048

  1111. Regulation of lens fiber cell differentiation by transcription factor c-Maf Peer-reviewed

    S Kawauchi, S Takahashi, O Nakajima, H Ogino, M Morita, M Nishizawa, K Yasuda, M Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　274　(27)　19254-19260　1999/07

    DOI： 10.1074/jbc.274.27.19254 　

    ISSN： 0021-9258

  1112. Characterization of the murine mafF gene Peer-reviewed

    K Onodera, JA Shavit, H Motohashi, F Katsuoka, JE Akasaka, JD Engel, M Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　274　(30)　21162-21169　1999/07

    DOI： 10.1074/jbc.274.30.21162 　

    ISSN： 0021-9258

  1113. The mouse GATA-2 gene is expressed in the para-aortic splanchnopleura and aorta-gonads and mesonephros region. Peer-reviewed

    Minegishi, N, Ohta, J, Yamagiwa, H, Suzuki, N, Kawauchi, S, Zhou, Y, Takahashi, S, Hayashi, N, Engel, J.D, Yamamoto, M

    Blood　93　(12)　4196 4207　1999/06

  1114. 転写調節不均衡による貧血の発生機序 Peer-reviewed

    樽本 高壽, 今川 重彦, 大嶺 謙, 永井 正, 樋口 正人, 今井 信雄, 鈴木 教郎, 山本 雅之, 小澤 敬也

    International Journal of Hematology　69　(Suppl.1)　197-197　1999/04

    Publisher: (一社)日本血液学会

    ISSN： 0925-5710

    eISSN： 1865-3774

  1115. Transcriptional regulation of cell type-specific expression of the TATA-less A subunit gene for human coagulation factor XIII Peer-reviewed

    M Kida, M Souri, M Yamamoto, H Saito, A Ichinose

    JOURNAL OF BIOLOGICAL CHEMISTRY　274　(10)　6138-6147　1999/03

    DOI： 10.1074/jbc.274.10.6138 　

    ISSN： 0021-9258

  1116. Molecular cloning and functional characterization of a new Cap'n' collar family transcription factor Nrf3 Peer-reviewed

    A Kobayashi, E Ito, T Toki, K Kogame, S Takahashi, K Igarashi, N Hayashi, M Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　274　(10)　6443-6452　1999/03

    DOI： 10.1074/jbc.274.10.6443 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  1117. R411C mutation of the ALAS2 gene encodes a pyridoxine-responsive enzyme with low activity Peer-reviewed

    K Furuyama, R Uno, A Urabe, N Hayashi, H Fujita, M Kondo, S Sassa, M Yamamoto

    BRITISH JOURNAL OF HAEMATOLOGY　103　(3)　839-841　1998/12

    DOI： 10.1046/j.1365-2141.1998.01050.x 　

    ISSN： 0007-1048

  1118. GATA-1 regulates growth and differentiation of definitive erythroid lineage cells during in vitro ES cell differentiation Peer-reviewed

    N Suwabe, S Takahashi, T Nakano, M Yamamoto

    BLOOD　92　(11)　4108-4118　1998/12

    ISSN： 0006-4971

  1119. Differential regulation of coproporphyrinogen oxidase gene between erythroid and nonerythroid cells Peer-reviewed

    S Takahashi, S Taketani, J Akasaka, A Kobayashi, N Hayashi, M Yamamoto, T Nagai

    BLOOD　92　(9)　3436-3444　1998/11

    ISSN： 0006-4971

  1120. Rescue of the embryonic lethal hematopoietic defect reveals a critical role for GATA-2 in urogenital development Peer-reviewed

    YH Zhou, KC Lim, K Onodera, S Takahashi, J Ohta, N Minegishi, FY Tsai, SH Orkin, M Yamamoto, JD Engel

    EMBO JOURNAL　17　(22)　6689-6700　1998/11

    DOI： 10.1093/emboj/17.22.6689 　

    ISSN： 0261-4189

    eISSN： 1460-2075

  1121. Reduction of DNA binding activity of the GATA-1 transcription factor in the apoptotic process induced by overexpression of PU.1 in murine erythroleukemia cells Peer-reviewed

    T Yamada, F Kihara-Negishi, H Yamamoto, M Yamamoto, Y Hashimoto, T Oikawa

    EXPERIMENTAL CELL RESEARCH　245　(1)　186-194　1998/11

    DOI： 10.1006/excr.1998.4251 　

    ISSN： 0014-4827

  1122. A core region of the mafK gene I-N promoter directs neurone-specific transcription in vivo Peer-reviewed

    H Motohashi, U Ohta, LD Engel, M Yamamoto

    GENES TO CELLS　3　(10)　671-684　1998/10

    DOI： 10.1046/j.1365-2443.1998.00222.x 　

    ISSN： 1356-9597

  1123. Identification of Bach2 as a B-cell-specific partner for small Maf proteins that negatively regulate the immunoglobulin heavy chain gene 3 ' enhancer Peer-reviewed

    A Muto, H Hoshino, L Madisen, N Yanai, M Obinata, H Karasuyama, M Hayashi, H Nakauchi, M Yamamoto, M Groudine, K Igarashi

    EMBO JOURNAL　17　(19)　5734-5743　1998/10

    DOI： 10.1093/emboj/17.19.5734 　

    ISSN： 0261-4189

    eISSN： 1460-2075

  1124. Chromatin immunoselection defines a TAL-1 target gene Peer-reviewed

    S Cohen-Kaminsky, L Maouche-Chretien, L Vitelli, MA Vinit, Blanchard, I, M Yamamoto, C Peschle, PH Romeo

    EMBO JOURNAL　17　(17)　5151-5160　1998/09

    DOI： 10.1093/emboj/17.17.5151 　

    ISSN： 0261-4189

  1125. 転写調節 L-NMMAによるエリスロポエチン遺伝子発現抑制が腎性貧血の一因である Peer-reviewed

    樽本 高寿, 大嶺 謙, 小澤 敬也, 鈴木 教郎, 山本 雅之, 樋口 正人, 今井 信雄, 今川 重彦

    生化学　70　(8)　783-783　1998/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  1126. Role of GATA-1 in proliferation and differentiation of definitive erythroid and megakaryocytic cells in vivo Peer-reviewed

    S Takahashi, T Komeno, N Suwabe, K Yoh, O Nakajima, S Nishimura, T Kuroha, T Nagasawa, M Yamamoto

    BLOOD　92　(2)　434-442　1998/07

    ISSN： 0006-4971

  1127. Impaired megakaryopoiesis and behavioral defects in mafG-null mutant mice Peer-reviewed

    JA Shavit, H Motohashi, K Onodera, J Akasaka, M Yamamoto, JD Engel

    GENES & DEVELOPMENT　12　(14)　2164-2174　1998/07

    ISSN： 0890-9369

  1128. Mechanisms of transcription in eosinophils: GATA-1, but not GATA-2, transactivates the promoter of the eosinophil granule major basic protein gene Peer-reviewed

    Y Yamaguchi, SJ Ackerman, N Minegishi, M Takiguchi, M Yamamoto, T Suda

    BLOOD　91　(9)　3447-3458　1998/05

    ISSN： 0006-4971

  1129. Multivalent DNA binding complex generated by small Maf and Bach1 as a possible biochemical basis for beta-globin locus control region complex Peer-reviewed

    K Igarashi, H Hoshino, A Muto, N Suwabe, S Nishikawa, H Nakauchi, M Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　273　(19)　11783-11790　1998/05

    DOI： 10.1074/jbc.273.19.11783 　

    ISSN： 0021-9258

  1130. Ablation of Nrf2 function does not increase the erythroid or megakaryocytic cell lineage dysfunction caused by p45 NF-E2 gene disruption Peer-reviewed

    T Kuroha, S Takahashi, T Komeno, K Itoh, T Nagasawa, M Yamamoto

    JOURNAL OF BIOCHEMISTRY　123　(3)　376-379　1998/03

    ISSN： 0021-924X

  1131. Deficient heme and globin synthesis in embryonic stem cells lacking the erythroid-specific delta-aminolevulinate synthase gene Peer-reviewed

    H Harigae, N Suwabe, PH Weinstock, M Nagai, H Fujita, M Yamamoto, S Sassa

    BLOOD　91　(3)　798-805　1998/02

    ISSN： 0006-4971

  1132. Alternative promoters regulate transcription of the mouse GATA-2 gene Peer-reviewed

    N Minegishi, J Ohta, N Suwabe, H Nakauchi, H Ishihara, N Hayashi, M Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　273　(6)　3625-3634　1998/02

    DOI： 10.1074/jbc.273.6.3625 　

    ISSN： 0021-9258

  1133. Regulation of NF-E2 activity in erythroleukemia cell differentiation Peer-reviewed

    T Nagai, K Igarashi, J Akasaka, K Furuyama, H Fujita, N Hayashi, M Yamamoto, S Sassa

    JOURNAL OF BIOLOGICAL CHEMISTRY　273　(9)　5358-5365　1998/02

    DOI： 10.1074/jbc.273.9.5358 　

    ISSN： 0021-9258

  1134. Differential roles of GATA-1 and GATA-2 in growth and differentiation of mast cells Peer-reviewed

    H Harigae, S Takahashi, N Suwabe, H Ohtsu, L Gu, ZY Yang, FY Tsai, Y Kitamura, JD Engel, M Yamamoto

    GENES TO CELLS　3　(1)　39-50　1998/01

    DOI： 10.1046/j.1365-2443.1998.00166.x 　

    ISSN： 1356-9597

  1135. Forced GATA-1 expression in the murine myeloid cell line M1: Induction of c-Mpl expression and megakaryocytic/erythroid differentiation Peer-reviewed

    Y Yamaguchi, LI Zon, SJ Ackerman, M Yamamoto, T Suda

    BLOOD　91　(2)　450-457　1998/01

    ISSN： 0006-4971

  1136. Structure and chromosome mapping of the human small mafgenes MAFG and MAFK Peer-reviewed

    T Iwata, K Kogame, T Toki, M Yokoyama, M Yamamoto, E Ito

    CYTOGENETICS AND CELL GENETICS　82　(1-2)　88-90　1998

    ISSN： 0301-0171

  1137. Cloning of human Bach1 transcription factor which regulates transcription through NF-E2 site with small Maf proteins. Peer-reviewed

    Toki T, Kanezaki R, Arai K, Yokoyama M, Igarashi K, Yamamoto M, Ito E

    BLOOD　90　(10)　196　1997/11/15

    ISSN： 0006-4971

  1138. Pyridoxine refractory X-linked sideroblastic anemia caused by a point mutation in the erythroid 5-aminolevulinate synthase gene Peer-reviewed

    K Furuyama, H Fujita, T Nagai, K Yomogida, H Munakata, M Kondo, A Kimura, A Kuramoto, N Hayashi, M Yamamoto

    BLOOD　90　(2)　822-830　1997/07

    ISSN： 0006-4971

  1139. An Nrf2 small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements Peer-reviewed

    K Itoh, T Chiba, S Takahashi, T Ishii, K Igarashi, Y Katoh, T Oyake, N Hayashi, K Satoh, Hatayama, I, M Yamamoto, Y Nabeshima

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　236　(2)　313-322　1997/07

    DOI： 10.1006/bbrc.1997.6943 　

    ISSN： 0006-291X

  1140. Arrest in primitive erythroid cell development caused by promoter-specific disruption of the GATA-1 gene Peer-reviewed

    S Takahashi, K Onodera, H Motohashi, N Suwabe, N Hayashi, N Yanai, Y Nabesima, M Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　272　(19)　12611-12615　1997/05

    DOI： 10.1074/jbc.272.19.12611 　

    ISSN： 0021-9258

  1141. Involvement of the transcriptional factor GATA-1 in regulation of expression of coproporphyrinogen oxidase in mouse erythroleukemia cells Peer-reviewed

    Atsuko Tanabe, Takako Furukawa, Yutaka Ogawa, Masayuki Yamamoto, Norio Hayashi, Rikio Tokunaga, Shigeru Taketani

    Biochemical and Biophysical Research Communications　233　(3)　729-736　1997/04/28

    Publisher: Academic Press Inc.

    DOI： 10.1006/bbrc.1997.6532 　

    ISSN： 0006-291X

  1142. Expression of GATA transcription factors in myelogenous and lymphoblastic leukemia cells Peer-reviewed

    N Minegishi, S Morita, M Minegishi, S Tsuchiya, T Konno, N Hayashi, M Yamamoto

    INTERNATIONAL JOURNAL OF HEMATOLOGY　65　(3)　239-249　1997/04

    DOI： 10.1016/S0925-5710(96)00553-1 　

    ISSN： 0925-5710

  1143. Human small Maf proteins form heterodimers with CNC family transcription factors and recognize the NF-E2 motif Peer-reviewed

    T Toki, J Itoh, J Kitazawa, K Arai, K Hatakeyama, J Akasaka, K Igarashi, N Nomura, M Yokoyama, M Yamamoto, E Ito

    ONCOGENE　14　(16)　1901-1910　1997/04

    DOI： 10.1038/sj.onc.1201024 　

    ISSN： 0950-9232

  1144. GATA-1 transcription is controlled by distinct regulatory mechanisms during primitive and definitive erythropoiesis Peer-reviewed

    K Onodera, S Takahashi, S Nishimura, J Ohta, H Motohashi, K Yomogida, N Hayashi, JD Engel, M Yamamoto

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　94　(9)　4487-4492　1997/04

    DOI： 10.1073/pnas.94.9.4487 　

    ISSN： 0027-8424

  1145. 5-aminolevulinate synthase expression and hemoglobin synthesis in a human myelogenous leukemia cell line Peer-reviewed

    T Nagai, H Harigae, K Furuyama, H Munakata, N Hayashi, K Endo, S Sassa, M Yamamoto

    JOURNAL OF BIOCHEMISTRY　121　(3)　487-495　1997/03

    DOI： 10.1093/oxfordjournals.jbchem.a021613 　

    ISSN： 0021-924X

  1146. Novel regulation of delta-aminolevulinate synthase in the rat Harderian gland Peer-reviewed

    M Nagai, T Nagai, M Yamamoto, K Goto, TR Bishop, N Hayashi, H Kondo, Y Seyama, K Kano, H Fujita, S Sassa

    BIOCHEMICAL PHARMACOLOGY　53　(5)　643-650　1997/03

    DOI： 10.1016/S0006-2952(96)00871-4 　

    ISSN： 0006-2952

  1147. Cell-cycle-dependent regulation of erythropoietin receptor gene. Peer-reviewed

    Komatsu N, Kirito K, Kashii Y, Furukawa Y, Kikuchi J, Suwabe N, Yamamoto M, Miura Y

    Blood　1997/02

  1148. Conserved structure, regulatory elements, and transcriptional regulation from the GATA-1 gene testis promoter Peer-reviewed

    K Onodera, K Yomogida, N Suwabe, S Takahashi, Y Muraosa, N Hayashi, E Ito, L Gu, M Rassoulzadegan, JD Engel, M Yamamoto

    JOURNAL OF BIOCHEMISTRY　121　(2)　251-263　1997/02

    ISSN： 0021-924X

    eISSN： 1756-2651

  1149. Negative regulation of the erythropoietin gene expression by the GATA transcription factors Peer-reviewed

    S Imagawa, M Yamamoto, Y Miura

    BLOOD　89　(4)　1430-1439　1997/02

    ISSN： 0006-4971

  1150. Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site Peer-reviewed

    T Oyake, K Itoh, H Motohashi, N Hayashi, H Hoshino, M Nishizawa, M Yamamoto, K Igarashi

    MOLECULAR AND CELLULAR BIOLOGY　16　(11)　6083-6095　1996/11

    ISSN： 0270-7306

  1151. Differentiation-dependent enhanced expression of protein phosphatase 2C beta in germ cells of mouse seminiferous tubules Peer-reviewed

    S Kato, T Kobayashi, K Kusuda, Y Nishina, Y Nishimune, K Yomogida, M Yamamoto, H Sakagami, H Kondo, M Ohnishi, N Chida, Y Yanagawa, S Tamura

    FEBS LETTERS　396　(2-3)　293-297　1996/11

    DOI： 10.1016/0014-5793(96)01119-2 　

    ISSN： 0014-5793

  1152. Histidine decarboxylase expression in mouse mast cell line P815 is induced by mouse peritoneal cavity incubation Peer-reviewed

    H Ohtsu, A Kuramasu, S Suzuki, K Igarashi, Y Ohuchi, M Sato, S Tanaka, S Nakagawa, K Shirato, M Yamamoto, A Ichikawa, T Watanabe

    JOURNAL OF BIOLOGICAL CHEMISTRY　271　(45)　28439-28444　1996/11

    DOI： 10.1074/jbc.271.45.28439 　

    ISSN： 0021-9258

  1153. Establishment and characterization of the thrombopoietin-dependent megakaryocytic cell line, UT-7/TPO Peer-reviewed

    N Komatsu, M Kunitama, M Yamada, T Hagiwara, T Kato, H Miyazaki, M Eguchi, M Yamamoto, Y Miura

    BLOOD　87　(11)　4552-4560　1996/06

    ISSN： 0006-4971

  1154. Mesodermal- vs neuronal-specific expression of MafK is elicited by different promoters Peer-reviewed

    H Motohashi, K Igarashi, K Onodera, S Takahashi, H Ohtani, M Nakafuku, M Nishizawa, JD Engel, M Yamamoto

    GENES TO CELLS　1　(2)　223-238　1996/02

    ISSN： 1356-9597

  1155. Abundant expression of transcription factor GATA-2 in proliferating but not in differentiated mast cells in tissues of mice: Demonstration by in situ hybridization Peer-reviewed

    T Jippo, H Mizuno, ZD Xu, S Nomura, M Yamamoto, Y Kitamura

    BLOOD　87　(3)　993-998　1996/02

    ISSN： 0006-4971

  1156. Abundant expression of erythroid transcription factor P45 NF-E2 mRNA in human peripheral granulocytes Peer-reviewed

    T Toki, J Itoh, K Arai, J Kitazawa, M Yokoyama, K Igarashi, M Yamamoto, E Ito

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　219　(3)　760-765　1996/02

    DOI： 10.1006/bbrc.1996.0307 　

    ISSN： 0006-291X

  1157. Aberrant progenitors common to megakaryocytic and myeloid cells in a Down's infant with transient abnormal myelopoiesis Peer-reviewed

    A Sato, M Imaizumi, T Noro, R Ichinohasama, T Saito, M Yoshinari, N Suwabe, H Suzuki, Y Koizumi, Y Cui, M Yamamoto, K Iinuma

    LEUKEMIA RESEARCH　19　(11)　811-&　1995/11

    ISSN： 0145-2126

  1158. 血球系転写因子群の協調的機能発現と血液細胞の分化制御

    五十嵐 和彦, 山本 雅之

    蛋白質・核酸・酵素　40　(11)　1721-1730　1995/08

    Publisher: 共立出版(株)

    ISSN： 0039-9450

  1159. CLONING AND CHARACTERIZATION OF A NOVEL ERYTHROID CELL-DERIVED CNC FAMILY TRANSCRIPTION FACTOR HETERODIMERIZING WITH THE SMALL MAF FAMILY PROTEINS Peer-reviewed

    K ITOH, K IGARASHI, N HAYASHI, M NISHIZAWA, M YAMAMOTO

    MOLECULAR AND CELLULAR BIOLOGY　15　(8)　4184-4193　1995/08

    ISSN： 0270-7306

    eISSN： 1098-5549

  1160. CONDITIONAL EXPRESSION OF THE UBIQUITOUS TRANSCRIPTION FACTOR MAFK INDUCES ERYTHROLEUKEMIA CELL-DIFFERENTIATION Peer-reviewed

    K IGARASHI, K ITOH, N HAYASHI, M NISHIZAWA, M YAMAMOTO

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　92　(16)　7445-7449　1995/08

    DOI： 10.1073/pnas.92.16.7445 　

    ISSN： 0027-8424

  1161. THE ROLE OF THE ERYTHROID-SPECIFIC DELTA-AMINOLEVULINATE SYNTHASE GENE-EXPRESSION IN ERYTHROID HEME-SYNTHESIS Peer-reviewed

    K MEGURO, K IGARASHI, M YAMAMOTO, H FUJITA, S SASSA

    BLOOD　86　(3)　940-948　1995/08

    ISSN： 0006-4971

  1162. EXPRESSION OF ERYTHROID-SPECIFIC GENES IN ACUTE MEGAKARYOBLASTIC LEUKEMIA AND TRANSIENT MYELOPROLIFERATIVE DISORDER IN DOWNS-SYNDROME Peer-reviewed

    E ITO, M KASAI, Y HAYASHI, T TOKI, K ARAI, S YOKOYAMA, K KATO, N TACHIBANA, M YAMAMOTO, M YOKOYAMA

    BRITISH JOURNAL OF HAEMATOLOGY　90　(3)　607-614　1995/07

    ISSN： 0007-1048

  1163. SMALL MAF PROTEINS HETERODIMERIZE WITH FOS AND MAY ACT AS COMPETITIVE REPRESSORS OF THE NF-E2 TRANSCRIPTION FACTOR Peer-reviewed

    K KATAOKA, K IGARASHI, K ITOH, KT FUJIWARA, M NODA, M YAMAMOTO, M NISHIZAWA

    MOLECULAR AND CELLULAR BIOLOGY　15　(4)　2180-2190　1995/04

    ISSN： 0270-7306

  1164. STRUCTURE AND REGULATION OF THE CHICKEN GATA-3 GENE Peer-reviewed

    H ISHIHARA, JD ENGEL, M YAMAMOTO

    JOURNAL OF BIOCHEMISTRY　117　(3)　499-508　1995/03

    ISSN： 0021-924X

  1165. ACTIVITY AND EXPRESSION OF MURINE SMALL MAF FAMILY PROTEIN MAFK Peer-reviewed

    K IGARASHI, K ITOH, H MOTOHASHI, N HAYASHI, Y MATUZAKI, H NAKAUCHI, M NISHIZAWA, M YAMAMOTO

    JOURNAL OF BIOLOGICAL CHEMISTRY　270　(13)　7615-7624　1995/03

    DOI： 10.1074/jbc.270.13.7615 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  1166. Erratum: Small Maf proteins heterodimerize with fos and may act as competitive repressors of the NF-E2 transcription factor (Molecular and Cellular Biology (1995) 15:5 (2188))

    Kataoka, K., Igarashi, K., Itoh, K., Fujiwara, K.T., Noda, M., Yamamoto, M., Nishizawa, M.

    Molecular and Cellular Biology　15　(6)　1995

  1167. Combinatorial functioning of hematopoietic transcription factors and regulation of hematopoietic cell differentiation

    Igarashi, K., Yamamoto, M.

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme　40　(11)　1995

  1168. 赤血球分化の分子生物学 NF-E2とGATA因子による赤血球特異的遺伝制御

    五十嵐 和彦, 山本 雅之

    血液・腫瘍科　30　(1)　1-9　1995/01

    Publisher: (有)科学評論社

    ISSN： 0915-8529

  1169. LOSS OF DNA-BINDING ABILITY OF THE TRANSCRIPTION FACTOR ENCODED BY THE MUTANT MI-LOCUS Peer-reviewed

    E MORII, K TAKEBAYASHI, H MOTOHASHI, M YAMAMOTO, S NOMURA, Y KITAMURA

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　205　(2)　1299-1304　1994/12

    DOI： 10.1006/bbrc.1994.2806 　

    ISSN： 0006-291X

  1170. ERYTHROPOIETIN-DEPENDENT INDUCTION OF HEMOGLOBIN-SYNTHESIS IN A CYTOKINE-DEPENDENT CELL-LINE M-TAT Peer-reviewed

    N MINEGISHI, M MINEGISHI, S TSUCHIYA, H FUJIE, T NAGAI, N HAYASHI, M YAMAMOTO, T KONNO

    JOURNAL OF BIOLOGICAL CHEMISTRY　269　(44)　27700-27704　1994/11

    ISSN： 0021-9258

  1171. DEVELOPMENTAL STAGE-SPECIFIC AND SPERMATOGENIC CYCLE-SPECIFIC EXPRESSION OF TRANSCRIPTION FACTOR GATA-1 IN MOUSE SERTOLI CELLS Peer-reviewed

    K YOMOGIDA, H OHTANI, H HARIGAE, E ITO, Y NISHIMUNE, JD ENGEL, M YAMAMOTO

    DEVELOPMENT　120　(7)　1759-1766　1994/07

    ISSN： 0950-1991

  1172. TEMPORAL AND SPATIAL CHANGES IN GATA TRANSCRIPTION FACTOR EXPRESSION ARE COINCIDENT WITH DEVELOPMENT OF THE CHICKEN OPTIC TECTUM Peer-reviewed

    JM KORNHAUSER, MW LEONARD, M YAMAMOTO, JH LAVAIL, KE MAYO, JD ENGEL

    MOLECULAR BRAIN RESEARCH　23　(1-2)　100-110　1994/04

    ISSN： 0169-328X

  1173. STRUCTURE AND REGULATION OF THE CHICKEN ERYTHROID DELTA-AMINOLEVULINATE SYNTHASE GENE Peer-reviewed

    KC LIM, H ISHIHARA, RD RIDDLE, ZY YANG, N ANDREWS, M YAMAMOTO, JD ENGEL

    NUCLEIC ACIDS RESEARCH　22　(7)　1226-1233　1994/04

    DOI： 10.1093/nar/22.7.1226 　

    ISSN： 0305-1048

  1174. HUMAN GATA-3 TRANSACTIVATION, DNA-BINDING, AND NUCLEAR-LOCALIZATION ACTIVITIES ARE ORGANIZED INTO DISTINCT STRUCTURAL DOMAINS Peer-reviewed

    ZY YANG, PH ROMEO, D BORIES, H MOTOHASHI, M YAMAMOTO, JD ENGEL, L GU

    MOLECULAR AND CELLULAR BIOLOGY　14　(3)　2201-2212　1994/03

    ISSN： 0270-7306

  1175. REGULATION OF TRANSCRIPTION BY DIMERIZATION OF ERYTHROID FACTOR NF-E2 P45 WITH SMALL MAF PROTEINS Peer-reviewed

    K IGARASHI, K KATAOKA, K ITOH, N HAYASHI, M NISHIZAWA, M YAMAMOTO

    NATURE　367　(6463)　568-572　1994/02

    DOI： 10.1038/367568a0 　

    ISSN： 0028-0836

  1176. Transcription factor GATA-2 is expressed in erythroid, early myeloid, and CD34+ Human leukemia-derived cell lines. Peer-reviewed

    Nagai T, Harigae H, Ishihara H, Motohashi H, Minegishi N, Tsuchiya S, Hayashi N, Gu L, Andres B, Engel JD, Yamamoto M

    Blood　84　1074-1084　1994

  1177. STRUCTURE OF THE L-HISTIDINE DECARBOXYLASE GENE Peer-reviewed

    K YATSUNAMI, H OHTSU, M TSUCHIKAWA, T HIGUCHI, K ISHIBASHI, A SHIDA, Y SHIMA, S NAKAGAWA, K YAMAUCHI, M YAMAMOTO, N HAYASHI, T WATANABE, A ICHIKAWA

    JOURNAL OF BIOLOGICAL CHEMISTRY　269　(2)　1554-1559　1994/01

    ISSN： 0021-9258

  1178. INDUCTION OF ERYTHROID-SPECIFIC GENE-EXPRESSION IN LYMPHOID-CELLS Peer-reviewed

    T CHIBA, Y NAGATA, A KISHI, K SAKAMAKI, A MIYAJIMA, M YAMAMOTO, JD ENGEL, K TODOKORO

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　90　(24)　11593-11597　1993/12

    DOI： 10.1073/pnas.90.24.11593 　

    ISSN： 0027-8424

  1179. マウス胸腺中のT細胞初期分化におけるGATA-3の発現

    松崎 有未, 張替 秀郎, 山本 雅之, 中内 啓光

    日本免疫学会総会・学術集会記録　23　347-347　1993/10

    Publisher: (NPO)日本免疫学会

    ISSN： 0919-1984

  1180. マウス胸腺中のT細胞初期分化におけるGATA-3の発現

    松崎 有未, 張替 秀郎, 山本 雅之, 中内 啓光

    日本免疫学会総会・学術集会記録　23　347-347　1993/10

    Publisher: (NPO)日本免疫学会

    ISSN： 0919-1984

  1181. EXPRESSION OF C-ERBB-2 IN HUMAN ESOPHAGEAL-CARCINOMA CELLS - OVEREXPRESSION CORRELATED WITH GENE AMPLIFICATION OR WITH GATA-3 TRANSCRIPTION FACTOR EXPRESSION Peer-reviewed

    K SHIGA, C SHIGA, H SASANO, S MIYAZAKI, T YAMAMOTO, M YAMAMOTO, N HAYASHI, T NISHIHIRA, S MORI

    ANTICANCER RESEARCH　13　(5A)　1293-1301　1993/09

    ISSN： 0250-7005

  1182. RECOMBINANT EXPRESSION OF RAT AND HUMAN GRO PROTEINS IN ESCHERICHIA-COLI Peer-reviewed

    K KONISHI, Y TAKATA, K WATANABE, T DATE, M YAMAMOTO, A MURASE, H YOSHIDA, T SUZUKI, S TSURUFUJI, M FUJIOKA

    CYTOKINE　5　(5)　506-511　1993/09

    DOI： 10.1016/1043-4666(93)90042-4 　

    ISSN： 1043-4666

  1183. PURIFICATION AND STRUCTURE OF RAT ERYTHROID-SPECIFIC DELTA-AMINOLEVULINATE SYNTHASE Peer-reviewed

    H MUNAKATA, T YAMAGAMI, T NAGAI, M YAMAMOTO, N HAYASHI

    JOURNAL OF BIOCHEMISTRY　114　(1)　103-111　1993/07

    ISSN： 0021-924X

  1184. ESTABLISHMENT AND CHARACTERIZATION OF AN ERYTHROPOIETIN-DEPENDENT SUBLINE, UT-7/EPO, DERIVED FROM HUMAN LEUKEMIA-CELL LINE, UT-7 Peer-reviewed

    N KOMATSU, M YAMAMOTO, H FUJITA, A MIWA, K HATAKE, T ENDO, H OKANO, T KATSUBE, Y FUKUMAKI, S SASSA, Y MIURA

    BLOOD　82　(2)　456-464　1993/07

    ISSN： 0006-4971

  1185. MOLECULAR DEFECT IN HUMAN ERYTHROPOIETIC PROTOPORPHYRIA WITH FATAL LIVER-FAILURE Peer-reviewed

    Y NAKAHASHI, H MIYAZAKI, Y KADOTA, Y NAITOH, K INOUE, M YAMAMOTO, N HAYASHI, S TAKETANI

    HUMAN GENETICS　91　(4)　303-306　1993/05

    ISSN： 0340-6717

  1186. ERYTHROID TRANSCRIPTION FACTOR GATA-1 IS ABUNDANTLY TRANSCRIBED IN MOUSE TESTIS Peer-reviewed

    E ITO, T TOKI, H ISHIHARA, H OHTANI, L GU, M YOKOYAMA, JD ENGEL, M YAMAMOTO

    NATURE　362　(6419)　466-468　1993/04

    DOI： 10.1038/362466a0 　

    ISSN： 0028-0836

  1187. STRUCTURE OF THE GENE ENCODING RAT NEUTROPHIL CHEMOATTRACTANT GRO Peer-reviewed

    K KONISHI, Y TAKATA, M YAMAMOTO, K YOMOGIDA, K WATANABE, S TSURUFUJI, M FUJIOKA

    GENE　126　(2)　285-286　1993/04

    DOI： 10.1016/0378-1119(93)90382-D 　

    ISSN： 0378-1119

  1188. STRUCTURE AND EXPRESSION OF THE GENE ENCODING RAT NONSPECIFIC FORM DELTA-AMINOLEVULINATE SYNTHASE Peer-reviewed

    K YOMOGIDA, M YAMAMOTO, T YAMAGAMI, H FUJITA, N HAYASHI

    JOURNAL OF BIOCHEMISTRY　113　(3)　364-371　1993/03

    ISSN： 0021-924X

  1189. Two chronic myelogenous leultaemia cell lines which represent different stages of erythroid differentiation Peer-reviewed

    Kazuyasu Endo, Hideo Harigae, Tadashi Nagai, Hiromi Fujie, Kuniaki Meguro, Norimichi Watanabe, Kazumichi Furuyama, Junichi Kameoka, Mitsutaka Okuda, Norio Hayashi, Masayuki Yamamoto, Keishi Abe

    British Journal of Haematology　85　(4)　653-662　1993

    DOI： 10.1111/j.1365-2141.1993.tb03205.x 　

    ISSN： 1365-2141 0007-1048

  1190. DIFFERENTIAL INDUCTION RESPONSES OF DELTA-AMINOLEVULINATE SYNTHASE MESSENGER-RNAS DURING ERYTHROID-DIFFERENTIATION - USE OF NONRADIOACTIVE INSITU HYBRIDIZATION Peer-reviewed

    K MITANI, H FUJITA, N HAYASHI, M YAMAMOTO, S SASSA

    AMERICAN JOURNAL OF HEMATOLOGY　39　(1)　63-64　1992/01

    ISSN： 0361-8609

  1191. SEQUENTIAL ACTIVATION OF GENES FOR HEME PATHWAY ENZYMES DURING ERYTHROID-DIFFERENTIATION OF MOUSE FRIEND VIRUS-TRANSFORMED ERYTHROLEUKEMIA-CELLS Peer-reviewed

    H FUJITA, M YAMAMOTO, T YAMAGAMI, N HAYASHI, TR BISHOP, H DEVERNEUIL, T YOSHINAGA, S SHIBAHARA, R MORIMOTO, S SASSA

    BIOCHIMICA ET BIOPHYSICA ACTA　1090　(3)　311-316　1991/11

    ISSN： 0006-3002

  1192. ERYTHROLEUKEMIA DIFFERENTIATION - DISTINCTIVE RESPONSES OF THE ERYTHROID-SPECIFIC AND THE NONSPECIFIC DELTA-AMINOLEVULINATE SYNTHASE MESSENGER-RNA Peer-reviewed

    H FUJITA, M YAMAMOTO, T YAMAGAMI, N HAYASHI, S SASSA

    JOURNAL OF BIOLOGICAL CHEMISTRY　266　(26)　17494-17502　1991/09

    ISSN： 0021-9258

  1193. MURINE AND HUMAN LYMPHOCYTE-T GATA-3 FACTORS MEDIATE TRANSCRIPTION THROUGH A CIS-REGULATORY ELEMENT WITHIN THE HUMAN T-CELL RECEPTOR DELTA GENE ENHANCER Peer-reviewed

    LJ KO, M YAMAMOTO, MW LEONARD, KM GEORGE, P TING, JD ENGEL

    MOLECULAR AND CELLULAR BIOLOGY　11　(5)　2778-2784　1991/05

    ISSN： 0270-7306

  1194. Cysteine proteinases in bronchoalveolar epithelial cells and lavage fluid of rat lung. Peer-reviewed

    Ishii Y, Hashizume Y, Watanabe T, Waguri S, Sato N, Yamamoto M, Hasegawa S, Kominami E, Uchiyama Y

    The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society　39　461-468　1991/04

    Publisher: 4

    ISSN： 0022-1554

  1195. ISOLATION AND SEQUENCE DETERMINATION OF CDNA-ENCODING T-PROTEIN OF THE GLYCINE CLEAVAGE SYSTEM Peer-reviewed

    K OKAMURAIKEDA, K FUJIWARA, M YAMAMOTO, K HIRAGA, Y MOTOKAWA

    JOURNAL OF BIOLOGICAL CHEMISTRY　266　(8)　4917-4921　1991/03

    ISSN： 0021-9258

  1196. THE GLYCINE CLEAVAGE SYSTEM - OCCURRENCE OF 2 TYPES OF CHICKEN H-PROTEIN MESSENGER-RNAS PRESUMABLY FORMED BY THE ALTERNATIVE USE OF THE POLYADENYLATION CONSENSUS SEQUENCES IN A SINGLE EXON Peer-reviewed

    M YAMAMOTO, H KOYATA, C MATSUI, K HIRAGA

    JOURNAL OF BIOLOGICAL CHEMISTRY　266　(5)　3317-3322　1991/02

    ISSN： 0021-9258

  1197. ACTIVITY AND TISSUE-SPECIFIC EXPRESSION OF THE TRANSCRIPTION FACTOR NF-E1 MULTIGENE FAMILY Peer-reviewed

    M YAMAMOTO, LJ KO, MW LEONARD, H BEUG, SH ORKIN, JD ENGEL

    GENES & DEVELOPMENT　4　(10)　1650-1662　1990/10

    ISSN： 0890-9369

  1198. EXPRESSION OF DELTA-AMINOLEVULINATE SYNTHASE IN AVIAN CELLS - SEPARATE GENES ENCODE ERYTHROID-SPECIFIC AND NONSPECIFIC ISOZYMES Peer-reviewed

    RD RIDDLE, M YAMAMOTO, JD ENGEL

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　86　(3)　792-796　1989/02

    DOI： 10.1073/pnas.86.3.792 　

    ISSN： 0027-8424

  1199. STRUCTURE, TURNOVER, AND HEME-MEDIATED SUPPRESSION OF THE LEVEL OF MESSENGER-RNA ENCODING RAT-LIVER DELTA-AMINOLEVULINATE SYNTHASE Peer-reviewed

    M YAMAMOTO, S KURE, JD ENGEL, K HIRAGA

    JOURNAL OF BIOLOGICAL CHEMISTRY　263　(31)　15973-15979　1988/11

    ISSN： 0021-9258

  1200. CLONING OF CDNA-ENCODING HUMAN H-PROTEIN, A CONSTITUENT OF THE GLYCINE CLEAVAGE SYSTEM Peer-reviewed

    K HIRAGA, S KURE, M YAMAMOTO, Y ISHIGURO, T SUZUKI

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　151　(2)　758-762　1988/03

    DOI： 10.1016/S0006-291X(88)80345-0 　

    ISSN： 0006-291X

  1201. CHICKEN HISTONE H3.3B CDNA SEQUENCE CONFIRMS UNUSUAL 3' UTR STRUCTURE Peer-reviewed

    JB DODGSON, M YAMAMOTO, JD ENGEL

    NUCLEIC ACIDS RESEARCH　15　(15)　6294-6294　1987/08

    ISSN： 0305-1048

  1202. AN IMMUNOCHEMICAL STUDY OF OMEGA-AMINOLEVULINATE SYNTHASE AND OMEGA-AMINOLEVULINATE DEHYDRATASE IN LIVER AND ERYTHROID-CELLS OF RAT Peer-reviewed

    M YAMAMOTO, H FUJITA, N WATANABE, N HAYASHI, G KIKUCHI

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS　245　(1)　76-83　1986/02

    DOI： 10.1016/0003-9861(86)90191-8 　

    ISSN： 0003-9861

  1203. ISOLATION OF RECOMBINANT CDNAS ENCODING CHICKEN ERYTHROID DELTA-AMINOLEVULINATE SYNTHASE Peer-reviewed

    M YAMAMOTO, NS YEW, M FEDERSPIEL, JB DODGSON, N HAYASHI, JD ENGEL

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　82　(11)　3702-3706　1985

    DOI： 10.1073/pnas.82.11.3702 　

    ISSN： 0027-8424

  1204. INHIBITION OF DELTA-AMINOLEVULINIC-ACID DEHYDRATASE BY TRICHLOROETHYLENE Peer-reviewed

    A KOIZUMI, H FUJITA, T SADAMOTO, M YAMAMOTO, M KUMAI, M IKEDA

    TOXICOLOGY　30　(2)　93-102　1984

    DOI： 10.1016/0300-483X(84)90120-3 　

    ISSN： 0300-483X

  1205. INHIBITION OF DELTA-AMINOLEVULINATE DEHYDRATASE IN TRICHLOROETHYLENE-EXPOSED RATS, AND THE EFFECTS ON HEME REGULATION Peer-reviewed

    H FUJITA, A KOIZUMI, M YAMAMOTO, M KUMAI, T SADAMOTO, M IKEDA

    BIOCHIMICA ET BIOPHYSICA ACTA　800　(1)　1-10　1984

    ISSN： 0006-3002

  1206. TRANSLATIONAL INHIBITION BY HEME OF THE SYNTHESIS OF HEPATIC DELTA-AMINOLEVULINATE SYNTHASE IN A CELL-FREE SYSTEM Peer-reviewed

    M YAMAMOTO, N HAYASHI, G KIKUCHI

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　115　(1)　225-231　1983

    DOI： 10.1016/0006-291X(83)90993-2 　

    ISSN： 0006-291X

  1207. EVIDENCE FOR THE TRANSCRIPTIONAL INHIBITION BY HEME OF THE SYNTHESIS OF DELTA-AMINOLEVULINATE SYNTHASE IN RAT-LIVER Peer-reviewed

    M YAMAMOTO, N HAYASHI, G KIKUCHI

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　105　(3)　985-990　1982

    DOI： 10.1016/0006-291X(82)91067-1 　

    ISSN： 0006-291X

  1208. REGULATION OF SYNTHESIS AND INTRACELLULAR TRANSLOCATION OF DELTA-AMINOLEVULINATE SYNTHASE BY HEME AND ITS RELATION TO THE HEME SATURATION OF TRYPTOPHAN-PYRROLASE IN RAT-LIVER Peer-reviewed

    M YAMAMOTO, N HAYASHI, G KIKUCHI

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS　209　(2)　451-459　1981

    DOI： 10.1016/0003-9861(81)90302-7 　

    ISSN： 0003-9861

Show all ︎Show first 5

Misc. 468

  1. Genome-wide association study of central corneal thickness in the cohort Study

    布施昇男, 安澤隼人, 元池育子, 櫻井美由紀, 木下賢吾, 山本雅之

    日本眼科学会雑誌　128　2024

    ISSN： 0029-0203

  2. Study on the activation of Nrf2 system in thioacetamide-induced GSTp-positive hepatocyte foci

    伊藤ゆり, 井澤武史, 濱田菜々子, 田中美有, 田口恵子, 田口恵子, 山本雅之, 桑村充

    日本毒性病理学会総会及び学術集会講演要旨集　40th　2024

  3. 食道扁平上皮癌細胞におけるNRF2とNQO1の発現とゲルダナマイシン誘導体の増殖抑制

    押切裕之, 押切裕之, 田口恵子, 谷山裕亮, 山本雅之, 亀井尚

    日本食道学会学術集会抄録集(CD-ROM)　78th　2024

  4. Metabolic profiling of plasma and urine for the daprodustat treatment mice by GC-MS/MS

    内田新菜, 中井琢, 福内友子, 山岡法子, 小柴生造, 山本雅之, 鈴木教郎, 三枝大輔, 三枝大輔

    日本薬学会年会要旨集(Web)　144th　2024

    ISSN： 0918-9823

  5. 海馬周辺の脳容積値と関連する血中メタボロームの探索

    佐藤和, 藤原和樹, 長尾健児, 今泉明, 小柴生造, 佐藤允治, 元池育子, 木下賢吾, 山本雅之

    Dementia Japan　37　(4)　2023

    ISSN： 1342-646X

  6. 血中代謝プロファイルに遺伝・環境要因が与える影響の解析

    小柴生造, 小柴生造, 元池育子, 元池育子, 菱沼英史, 菱沼英史, 青木裕一, 櫻井美由紀, 佐藤允治, 七谷圭, 七谷圭, 田高周, 木下賢吾, 木下賢吾, 木下賢吾, 山本雅之, 山本雅之, 山本雅之

    日本生化学会大会(Web)　96th　2023

  7. Role of Nrf2 antioxidative system on 5-fluorouracil-induced myelosuppression

    芦野隆, 赤池哉太, 千葉莉沙子, 山本雅之, 沼澤聡

    日本薬学会年会要旨集(Web)　143rd　2023

    ISSN： 0918-9823

  8. 含セレン抗酸化酵素合成破綻状態の恒常性維持におけるKeap1過酸化水素センサーの重要性の解明

    佐藤美羽, 矢口菜穂子, 鈴木隆史, 山本雅之

    日本酸化ストレス学会学術集会プログラム・抄録集　76th　2023

  9. 東北メディカル・メガバンク計画健康調査における眼軸長のゲノムワイド関連解析

    布施 昇男, 櫻井 美由紀, 元池 育子, 小島 要, 平良 摩紀子, 宇留野 晃, 濱中 洋平, 中村 智洋, 荻島 創一, 寳澤 篤, 栗山 進一, 呉 繁夫, 木下 賢吾, 山本 雅之

    日本眼科学会雑誌　126　(臨増)　216-216　2022/03

    Publisher: (公財)日本眼科学会

    ISSN： 0029-0203

  10. 長鎖リードシークエンス技術を用いた日本人構造多型パネルJSV1の構築

    大槻晃史, 大槻晃史, 岡村容伸, 岡村容伸, 勝岡史城, 勝岡史城, 木下賢吾, 木下賢吾, 木下賢吾, 木下賢吾, 山本雅之, 山本雅之, 山本雅之

    日本生化学会大会(Web)　95th　2022

  11. 細胞競合によるNRF2活性化細胞の排除機構

    廣瀬亘, 堀内真, 田口恵子, 谷山裕亮, 山本雅之, 亀井尚

    日本食道学会学術集会抄録集(CD-ROM)　76th　2022

  12. AhR and Atopic Dermatitis

    枝光智大, 田口恵子, 山本雅之

    Journal of Toxicological Sciences　47　(Supplement (CD-ROM))　2022

    ISSN： 0388-1350

  13. 本邦における鉄代謝異常に伴う貧血に関する包括的疫学研究

    藤原亨, 大根田絹子, 佐々木克幸, 青木裕一, 工藤久智, 勝岡史城, 熊田和貴, 萩島創一, 山本雅之, 張替秀郎, 張替秀郎

    日本鉄バイオサイエンス学会学術集会プログラム・抄録集　46th　2022

  14. ゲノムコホート研究におけるBRCA1/2病的バリアント保持者への遺伝情報回付:遺伝情報回付による心理的・社会的影響の解析

    大根田絹子, 濱中洋平, 濱中洋平, 川目裕, 川目裕, 鈴木洋一, 鈴木洋一, 長神風二, 長神風二, 布施昇男, 布施昇男, 山本雅之, 山本雅之

    日本人類遺伝学会大会プログラム・抄録集　67th (CD-ROM)　2022

  15. Exploration of BRCA1/2 gene variants in a general population cohort and return of genomic results to the participants

    徳永英樹, 安田純, 島田宗昭, 濱中洋平, 重田昌吾, 布施昇男, 勝岡史城, 荻島創一, 荻島創一, 山口由美, 寳澤篤, 川目裕, 大根田絹子, 青木洋子, 山本雅之, 八重樫伸生

    日本癌学会学術総会抄録集(Web)　81st　2022

  16. High-resolution imaging mass spectrometry of CHN compounds in meteorites: organic synthesis in the early solar system

    Furukawa Yoshihiro, Saigusa Daisuke, Kano Kuniyuki, Uruno Akira, Saito Ritsumi, Ito Motoo, Matsumoto Megumi, Aoki Jyunken, Yamamoto Masayuki, Nakamura Tomoki

    Abstracts of Annual Meeting of the Geochemical Society of Japan　69　190　2022

    Publisher: GEOCHEMICAL SOCIETY OF JAPAN

    DOI： 10.14862/geochemproc.69.0_190 　

  17. GENOME-WIDE ASSOCIATION STUDY FOR THE ONSET OF CHRONIC KIDNEY DISEASE IN JAPANESE POPULATION

    Yuka Sugawara, Yosuke Hirakawa, Hajime Nagasu, Akira Narita, Jun Wada, Takashi Wada, Toshiaki Nakano, Motoko Yanagita, Ichiei Narita, Seizo Koshiba, Gen Tamiya, Masaomi Nangaku, Masayuki Yamamoto, Naoki Kashihara

    NEPHROLOGY　26　7-8　2021/08

    ISSN： 1320-5358

    eISSN： 1440-1797

  18. MARTAオランザピン誘発酸化ストレスへの応答性には性差がある

    服部 夏実, 光本 明日香[貝崎], 芦野 隆, 山本 雅之, 沼澤 聡

    日本薬学会年会要旨集　141年会　28P02-171　2021/03

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  19. Protein Scientists Meet Genome Science:東北メディカル・メガバンク計画におけるタンパク質科学

    山本雅之, 木下賢吾

    日本蛋白質科学会年会プログラム・要旨集　21st　2021

  20. Molecular Mechanism of Environmental Response and Adaptation

    田口恵子, 田口恵子, 田口恵子, 山本雅之, 山本雅之, 山本雅之

    日本体質医学会雑誌　83　(1)　2021

    ISSN： 1347-7137

  21. ゲノムコホート研究参加者へのBRCA1/2遺伝情報回付の取り組み

    大根田絹子, 濱中洋平, 濱中洋平, 川目裕, 川目裕, 鈴木洋一, 鈴木洋一, 長神風二, 布施昇男, 布施昇男, 山本雅之, 山本雅之

    日本人類遺伝学会大会プログラム・抄録集　66th (CD-ROM)　2021

  22. 代謝プロファイルに影響を与える遺伝要因の網羅的解析

    小柴生造, 小柴生造, 小柴生造, 元池育子, 元池育子, 三枝大輔, 三枝大輔, 井上仁, 井上仁, 井上仁, 菱沼英史, 青木裕一, 青木裕一, 田高周, 田高周, 城田松之, 城田松之, 城田松之, 木下賢吾, 木下賢吾, 木下賢吾, 山本雅之, 山本雅之, 山本雅之

    日本生化学会大会(Web)　94th　2021

  23. Development of high-throughput analysis using GC-MS/MS in a large-cohort study

    松川直美, 菱沼英史, 三枝大輔, 小柴生造, 山本雅之

    JSBMS Letters　46　(Supplement)　2021

    ISSN： 1881-5464

  24. 子宮体癌における血漿メタボローム解析によるバイオマーカーの探索

    辻圭太, 島田宗昭, 菱沼英史, 重田昌吾, 李賓, 宮原周子, 土岐麻実, 工藤敬, 徳永英樹, 小柴生造, 木下賢吾, 山本雅之, 八重樫伸生

    日本婦人科腫瘍学会雑誌　39　(1)　2021

    ISSN： 1347-8559

  25. がん代謝を標的とした卵巣癌におけるバイオマーカーの探索

    工藤敬, 島田宗昭, 菱沼英史, 重田昌吾, 李賓, 宮原周子, 土岐麻実, 辻圭太, 徳永英樹, 小柴生造, 木下賢吾, 山本雅之, 八重樫伸生

    日本婦人科腫瘍学会雑誌　39　(1)　2021

    ISSN： 1347-8559

  26. ESTABLISHMENT OF A COMPREHENSIVE NATIONWIDE BIOBANK FOR KIDNEY DISEASES WITH DEEP GENETIC DATA, DETAILED CLINICAL INFORMATION AND BIOSPECIMENS

    Yosuke Hirakawa, Hajime Nagasu, Yuka Sugawara, Seizo Koshiba, Ichiei Narita, Takashi Wada, Motoko Yanagita, Jun Wada, Shoichi Maruyama, Toshiaki Nakano, Masayuki Yamamoto, Masaomi Nangaku, Naoki Kashihara

    NEPHROLOGY　25　70-70　2020/10

    ISSN： 1320-5358

    eISSN： 1440-1797

  27. Body mass index and colorectal cancer risk in Japanese populations: a Mendelian randomization study

    Shiori Suzuki, Atsushi Goto, Masahiro Nakatochi, Akira Narita, Taiki Yamaji, Norie Sawada, Ryoko Katagiri, Tsuyoshi Hachiya, Yoichi Sutoh, Isao Oze, Yuriko Koyanagi, Yumiko Kasugai, Hidemi Ito, Hiroaki Ikezaki, Keitaro Tanaka, Takashi Tamura, Haruo Mikami, Toshiro Takezaki, Sadao Suzuki, Nagato Kuriyama, Kiyonori Kuriki, Yoshikuni Kita, Kokichi Arisawa, Kenji Takeuchi, Kozo Tanno, Atsushi Shimizu, Gen Tamiya, Atsushi Hozawa, Kengo Kinoshita, Kenji Wakai, Makoto Sasaki, Masayuki Yamamoto, Keitaro Matsuo, Shoichiro Tsugane, Motoki Iwasaki

    CANCER RESEARCH　80　(16)　2020/08

    DOI： 10.1158/1538-7445.AM2020-3486 　

    ISSN： 0008-5472

    eISSN： 1538-7445

  28. Deletion of Nrf2 enhances susceptibility to neurotoxic effects of acrylamide in mice

    EKUBAN Frederick Adams, ZONG Cai, TAKIKAWA Madoka, MORIKAWA Kouta, SAKURAI Toshihiro, ICHIHARA Sahoko, ITOH Ken, YAMAMOTO Masayuki, OHSAKO Seiichiroh, ICHIHARA Gaku

    Annual Meeting of the Japanese Society of Toxicology　47.1　(Supplement)　P-28E　2020

    Publisher: The Japanese Society of Toxicology

    DOI： 10.14869/toxpt.47.1.0_p-28e 　

    ISSN： 0388-1350

    More details Close

    Acrylamide (ACR) is an electrophile which has been used extensively in industry and is also formed unintentionally in food substances cooked or processed at high temperatures, such as potato chips or coffee through Maillard reaction. Acrylamide has been recognized as a potent neurotoxin which is known to cause neuropathy or encephalopathy in humans and experimental animals. As a measure of protection against neurotoxicity, the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has been identified to be a master regulator of the cellular defense system which activates antioxidant and cytoprotective genes. However, knowledge about mechanistic roles of Nrf2 in acrylamide-induced neurotoxicity remains poorly understood. This study therefore sought to investigate and clarify the roles of Nrf2 in ACR-induced neurotoxicity. Forty-eight male Nrf2-knockout (Nrf2-KO) mice from the C57BL/6JJcl background, aged 10-weeks together with their age and sex-matched wild-type (WT) counterparts were each divided into four groups of twelve and daily exposed to ACR at 0, 67, 110 or 200 ppm in drinking water for 28 days. Following exposure of mice to ACR, Landing Foot spread test, an assessment of motor function and a major endpoint marker of neurotoxicity as well as immunohistochemistry for noradrenaline transporter (NAT) and serotonin transporter (SERT) antibody in the dorsal and ventral medial prefrontal cortex were performed. Nrf2-KO mice showed exacerbated impairment of motor functions evidenced by the increased hindlimb splay relative to WT mice at the same exposure levels. Immunohistochemistry results showed severe degeneration of both noradrenergic and serotonergic axons characterized by a dose-dependent decrease in the density of immunoreactive axons in Nrf2-KO mice relative to WT mice. Moreover, body weight, whole brain weight and cerebellum weight were significantly reduced in Nrf2-KO mice compared to the WT mice. The results suggest increased susceptibility to ACR-induced neurotoxicity in mice lacking the Nrf2 gene. In conclusion, Nrf2 is able to attenuate the effects of ACR-induced neurotoxicity in mice and thus remains a crucial target for the preventive modulation of neurotoxicity.

  29. Keap1-Nrf2 system and liver toxicology

    田口恵子, 山本雅之

    Journal of Toxicological Sciences　45　(Supplement)　2020

    ISSN： 0388-1350

  30. ラット腹膜中皮細胞におけるNrf2-Keap1システムの意義

    矢花郁子, 高橋知香, 廣瀬卓男, 田口恵子, 山本雅之, 森建文

    日本透析医学会雑誌　53　(Supplement 1)　2020

    ISSN： 1340-3451

  31. 東北メディカル・メガバンク計画における遺伝情報返却の課題

    濱中洋平, 濱中洋平, 大根田絹子, 布施昇男, 川目裕, 川目裕, 長神風二, 鈴木吉也, 鈴木洋一, 鈴木洋一, 佐藤政文, 平塚真弘, 櫻井美佳, 宇留野晃, 山口由美, 平良摩紀子, 山本雅之, 濱中洋平, 濱中洋平

    日本人類遺伝学会大会プログラム・抄録集　65th (CD-ROM)　2020

  32. ゲノムコホート調査参加者に対するゲノム薬理学(PGx)遺伝情報の返却(回付)-PGxの知識・理解に関する調査票解析

    大根田絹子, 布施昇男, 川目裕, 川目裕, 長神風二, 鈴木吉也, 鈴木洋一, 鈴木洋一, 佐藤政文, 櫻井美佳, 宇留野晃, 濱中洋平, 平良摩紀子, 平塚真弘, 山本雅之, 山本雅之

    日本人類遺伝学会大会プログラム・抄録集　65th (CD-ROM)　2020

  33. The correlation between birth weight and %FEV1 in people in their 20s; exploring the factors influencing lung function based on Tohoku Medical Megabank Organization community health survey

    大江崇, 山田充啓, 杉浦久敏, 布施昇男, 寳澤篤, 中村智洋, 山本雅之, 一ノ瀬正和

    日本呼吸器学会誌(Web)　9　2020

    ISSN： 2186-5884

  34. ヘム欠乏マウスは、AMPKシグナル低下を介して、骨格筋でのグリコーゲン合成異常が惹起され、インスリン抵抗性を発症する

    斉藤 真一, ヴァンピーク・クン, 木村 朋寛, 尾崎 司, 岡野 聡, 山本 雅之, 浅尾 裕信, Kelly Vincent P., 高橋 究, 田中 徹, 中島 元夫, 中島 修

    日本生化学会大会プログラム・講演要旨集　92回　[2P-295]　2019/09

    Publisher: (公社)日本生化学会

  35. ヘム欠乏マウスは、AMPKシグナル低下を介して、骨格筋でのグリコーゲン合成異常が惹起され、インスリン抵抗性を発症する

    斉藤 真一, ヴァンピーク・クン, 木村 朋寛, 尾崎 司, 岡野 聡, 山本 雅之, 浅尾 裕信, Kelly Vincent P., 高橋 究, 田中 徹, 中島 元夫, 中島 修

    日本生化学会大会プログラム・講演要旨集　92回　[2P-295]　2019/09

    Publisher: (公社)日本生化学会

  36. GATA2ハプロ不全はEVI1誘導性白血病の発症を促進する

    片山 紗乙莉, 鈴木 未来子, 笹原 洋二, 呉 繁夫, 山本 雅之

    日本小児血液・がん学会雑誌　56　(2)　159-162　2019/09

    Publisher: (一社)日本小児血液・がん学会

    ISSN： 2187-011X

    eISSN： 2189-5384

  37. MALDI-MSI分析における導電性粘着フィルムで作製した生体組織切片の有用性について

    三枝 大輔, 齋藤 律水, 川本 孔明, 宇留野 晃, 可野 邦行, 青木 淳賢, 山本 雅之, 川本 忠文

    JSBMS Letters　44　(Suppl.)　122-122　2019/08

    Publisher: (一社)日本医用マススペクトル学会

    ISSN： 1881-5464

  38. 大規模ゲノムコホート調査におけるBRCA1/2遺伝子の病的バリアント保持者への遺伝情報回付に関する課題

    濱中 洋平, 石田 孝宣, 布施 昇男, 川目 裕, 山口 由美, 安田 純, 多田 寛, 宮下 穣, 原田 成美, 佐藤 章子, 青木 洋子, 長神 風二, 八重樫 伸生, 木下 賢吾, 呉 繁夫, 山本 雅之

    日本乳癌学会総会プログラム抄録集　27回　332-332　2019/07

    Publisher: (一社)日本乳癌学会

  39. 酸化ストレス防御因子Nrf2によるマクロファージおよび血管平滑筋細胞の接着、遊走制御を介した動脈硬化抑制機能

    芦野 隆, 山本 雅之, 沼澤 聡

    The Journal of Toxicological Sciences　44　(Suppl.)　S347-S347　2019/06

    Publisher: (一社)日本毒性学会

    ISSN： 0388-1350

    eISSN： 1880-3989

  40. 生体内のヘム欠乏は,ATP代謝障害によるグリコーゲン合成異常のため,耐糖能異常・インスリン抵抗性を発症させる

    中島 修, 斉藤 真一, 尾崎 司, van Wijk Koen, 木村 朋寛, 浅尾 裕信, 山本 雅之, 高橋 究, 田中 徹, 中島 元夫

    糖尿病　62　(Suppl.1)　S-316　2019/04

    Publisher: (一社)日本糖尿病学会

    ISSN： 0021-437X

  41. 大規模ゲノム解析による28の新規2型糖尿病感受性領域および日本人と欧米人に特徴的な2型糖尿病の生物学的パスウェイの同定

    鈴木 顕, 秋山 雅人, 石垣 和慶, 金井 仁弘, 細江 隼, 庄嶋 伸浩, 岩田 仲生, 池田 匡志, 池川 志郎, 前田 士郎, 村上 善則, 若井 建志, 津金 昌一郎, 佐々木 真理, 山本 雅之, 岡田 随象, 久保 充明, 鎌谷 洋一郎, 堀越 桃子, 山内 敏正, 門脇 孝

    糖尿病　62　(Suppl.1)　S-108　2019/04

    Publisher: (一社)日本糖尿病学会

    ISSN： 0021-437X

    eISSN： 1881-588X

  42. Nrf2欠損はマウス急性膵炎モデルにおいて炎症を増悪させるか

    鍋島 立秀, 濱田 晋, 田口 恵子, 田中 裕, 松本 諒太郎, 山本 雅之, 正宗 淳

    日本消化器病学会雑誌　116　(臨増総会)　A263-A263　2019/03

    Publisher: (一財)日本消化器病学会

    ISSN： 0446-6586

  43. 【卵巣がん征圧へのマイルストーン】JGOG-ToMMoバイオバンキング事業

    島田 宗昭, 峯岸 直子, 八重樫 伸生, 山本 雅之, 榎本 隆之, 杉山 徹

    産婦人科の実際　68　(3)　267-271　2019/03

    Publisher: 金原出版(株)

    ISSN： 0558-4728

  44. ディーゼル排気ガス曝露による気道炎症病態におけるIL-17の発現

    李 英姫, 清水 孝子, 小林 麻衣子, 加藤 活人, 武田 健, 山本 雅之, 川田 智之

    日本衛生学雑誌　74　(Suppl.)　S165-S165　2019/02

    Publisher: (一社)日本衛生学会

    ISSN： 0021-5082

    eISSN： 1882-6482

  45. Nrf2欠損はマウス急性膵炎モデルにおいて炎症を増悪させるか

    鍋島立秀, 濱田晋, 田口恵子, 田中裕, 松本諒太郎, 山本雅之, 正宗淳

    日本消化器病学会雑誌(Web)　116　2019

    ISSN： 1349-7693

  46. Bag-1はGSH合成阻害剤BSO存在下における細胞増殖と細胞内GSHレベルの低下に寄与する

    猪瀬(丸山)敦史, 猪瀬(丸山)敦史, 田口恵子, 守田匡伸, 山本雅之, 久下周佐

    日本生化学会大会(Web)　92nd　2019

  47. ミトコンドリアComplex I阻害によるマウス網膜グリア細胞変化の検討

    柳町真希, 檜森紀子, 佐藤孝太, 山本雅之, 中澤徹

    日本緑内障学会抄録集　30th　2019

  48. 日本人1070人の全ゲノム解析で同定された21種のDihydropyrimidine dehydrogenaseレアバリアント活性変化

    菱沼英史, 菱沼英史, 菱沼英史, 成田瑶子, 齋藤さかえ, 前川正充, 赤井文香, 中西悠悦, 安田純, 長崎正朗, 山本雅之, 山本雅之, 山口浩明, 眞野成康, 平澤典保, 平澤典保, 平塚真弘, 平塚真弘, 平塚真弘, 平塚真弘

    医薬品毒性機序研究会要旨(Web)　1st　2019

  49. In vivo imaging of inflammatory status in GATA2 heterozygous mice

    高井淳, 島田昂志, 上村聡志, 山本雅之, 山本雅之, 森口尚

    日本生化学会大会(Web)　92nd　2019

  50. 大規模ゲノム解析による28の新規2型糖尿病感受性領域および日本人と欧米人に特徴的な2型糖尿病の生物学的パスウェイの同定

    鈴木顕, 鈴木顕, 鈴木顕, 秋山雅人, 石垣和慶, 金井仁弘, 細江隼, 庄嶋伸浩, 岩田伸生, 池田匡志, 池川志郎, 前田士郎, 村上善則, 若井建志, 津金昌一郎, 佐々木真理, 山本雅之, 岡田随象, 久保充明, 鎌谷洋一郎, 堀越桃子, 山内敏正, 門脇孝

    糖尿病(Web)　62　(Suppl)　2019

    ISSN： 1881-588X

  51. ROLE OF NRF2 IN LUNG INJURY INDUCED BY DIESEL EXHAUST

    Ying-Ji Li, Takako Shimizu, Maiko Kobayashi, Ken Takeda, Masayuki Yamamoto, Arata Azuma, Tomoyuki Kawada

    RESPIROLOGY　23　151-151　2018/11

    ISSN： 1323-7799

    eISSN： 1440-1843

  52. 肺移植後虚血再灌流肺障害におけるNrf2活性化の効果

    東郷 威男, 星川 康, 田口 恵子, 矢吹 皓, 三友 英紀, 渡邊 龍秋, 松田 安史, 大石 久, 佐渡 哲, 野田 雅史, 舟橋 淳一, 山本 雅之, 岡田 克典

    移植　53　(総会臨時)　398-398　2018/09

    Publisher: (一社)日本移植学会

    ISSN： 0578-7947

  53. 肺移植後虚血再灌流肺障害におけるNrf2活性化の効果

    東郷 威男, 星川 康, 田口 恵子, 矢吹 皓, 三友 英紀, 渡邊 龍秋, 松田 安史, 大石 久, 佐渡 哲, 野田 雅史, 舟橋 淳一, 山本 雅之, 岡田 克典

    移植　53　(総会臨時)　398-398　2018/09

    Publisher: (一社)日本移植学会

    ISSN： 0578-7947

  54. Global metabolomicsを用いた腎癌の臨床的因子と関連代謝物の解析(The value of global metabolomics in association with clinical factors for diagnosis of renal cell carcinoma)

    佐藤 友紀, 川崎 芳英, 前川 正充, 高崎 新也, 三塚 浩二, 伊藤 明宏, 山本 雅之, 荒井 陽一

    日本癌学会総会記事　77回　1625-1625　2018/09

    Publisher: 日本癌学会

    ISSN： 0546-0476

  55. 急性巨核芽球性白血病に対するNOTCH活性化剤による新規治療(Notch activation impedes cell proliferation and survival in acute megakaryoblastic leukemia)

    大里 元美, Ong Kelly Ooi Kee, Mok Michelle Meng Huang, 横溝 智雅, 松村 貴由, 須田 年生, 麻生 範雄, Koeffler Phillip, Tenen Daniel G., 清水 律子, 山本 雅之, 伊藤 嘉明, Yeoh Allen Eng-Juh, Chng Wee Joo

    臨床血液　59　(9)　1700-1700　2018/09

    Publisher: (一社)日本血液学会-東京事務局

    ISSN： 0485-1439

    eISSN： 1882-0824

  56. 一般住民における尿中蛋白排泄量に関連するSNPの探索

    奥田 拓史, 牧野 悟士, 田邊 修, 石井 正, 伊藤 貞嘉, 寳澤 篤, 丹野 高三, 佐々木 真理, 田宮 元, 山本 雅之, 阿部 倫明

    日本高血圧学会総会プログラム・抄録集　41回　OE02-05　2018/09

    Publisher: (NPO)日本高血圧学会

  57. 内因性エリスロポエチンの腎保護作用の検討

    田中真生, 高瀬昌幸, 金子惠一, 佐藤有紀, 鈴木教郎, 山本雅之, 柳田素子

    日本腎臓学会誌　60　(3)　463　2018/04/30

    ISSN： 0385-2385

  58. Estimating frequency of pathogenic variants in a Japanese population by using the whole-genome reference panel of ToMMo

    Yumi Yamaguchi-Kabata, Jun Yasuda, Osamu Tanabe, Yoichi Suzuki, Hiroshi Kawame, Nobuo Fuse, Masao Nagasaki, Yosuke Kawai, Kaname Kojima, Fumiki Katsuoka, Sakae Saito, Inaho Danjoh, Ikuko N. Motoike, Riu Yamashita, Seizo Koshiba, Daisuke Saigusa, Gen Tamiya, Shigeo Kure, Nobuo Yaegashi, Yoshio Kawaguchi, Fuji Nagami, Shinichi Kuriyama, Junichi Sugawara, Naoko Minegishi, Atsushi Hozawa, Soichi Ogishima, Hideyasu Kiyomoto, Takako Takai-Igarashi, Kengo Kinoshita, Masayuki Yamamoto

    HUMAN GENOMICS　12　2018/03

    ISSN： 1473-9542

    eISSN： 1479-7364

  59. ディーゼル排気ガス曝露による気道炎症病態におけるNrf2の役割

    李 英姫, 清水 孝子, 小林 麻衣子, 加藤 活人, 武田 健, 山本 雅之, 川田 智之

    日本衛生学雑誌　73　(Suppl.)　S232-S232　2018/03

    Publisher: (一社)日本衛生学会

    ISSN： 0021-5082

    eISSN： 1882-6482

  60. 東北メディカル・メガバンク地域住民コホート調査に基づく、日本人呼気一酸化窒素濃度の分布と影響因子の解析(中間報告)

    山田 充啓, 杉浦 久敏, 布施 昇男, 寳澤 篤, 高井 貴子, 土屋 奈歩, 光根 歩, 栗山 進一, 山本 雅之, 一ノ瀬 正和

    日本呼吸器学会誌　7　(増刊)　213-213　2018/03

    Publisher: (一社)日本呼吸器学会

    ISSN： 2186-5876

  61. AhRによる神経栄養因子アルテミンの発現誘導が惹起するアトピー性皮膚炎の痒み過敏

    枝光智大, 枝光智大, 田口恵子, 小林枝里, 奥山隆平, 山本雅之

    日本生化学会大会(Web)　91st　2018

  62. 活性酸素種センサーBag-1遺伝子エキソン5領域欠失のマウス個体におよぼす影響解析

    猪瀬(丸山)敦史, 田口恵子, 守田匡伸, 山本雅之, 久下周佐

    日本生化学会大会(Web)　91st　2018

  63. Nrf2およびCSEは環境中親電子物質によるマウス肝細胞毒性の抑制に必須である

    鵜木隆光, 秋山雅博, 新開泰弘, 石井功, 山本雅之, 赤池孝章, 熊谷嘉人

    衛生薬学・環境トキシコロジー講演要旨集　2018　2018

    ISSN： 0919-2115

  64. Nrf2とCSEはメチル水銀中毒症状を抑制する鍵分子である

    秋山雅博, 鵜木隆光, 新開泰弘, 石井功, 山本雅之, 赤池孝章, 熊谷嘉人

    衛生薬学・環境トキシコロジー講演要旨集　2018　2018

    ISSN： 0919-2115

  65. 視神経挫滅モデル網膜のメタボローム解析

    佐藤孝太, 三枝大輔, 元池育子, 齋藤律水, 藤岡周, 山本雅之, 中澤徹

    日本緑内障学会抄録集　29th　2018

  66. ゲノム情報と連携した日本人多層オミックス参照パネルの意義

    小柴生造, 小柴生造, 元池育子, 元池育子, 三枝大輔, 三枝大輔, 井上仁, 井上仁, 城田松之, 城田松之, 青木裕一, 青木裕一, 田高周, 田高周, 斎藤智, 木下賢吾, 木下賢吾, 山本雅之, 山本雅之

    糖尿病(Web)　61　(Suppl)　2018

    ISSN： 1881-588X

  67. KEAP1‐NRF2制御系の活性化はアルツハイマー病様病態を改善する

    松丸大輔, 領家梨恵, 齋藤律水, 三枝大輔, 齊藤貴志, 西道隆臣, 川島隆太, 山本雅之, 山本雅之, 宇留野晃, 宇留野晃, 本橋ほづみ

    日本生化学会大会(Web)　91st　ROMBUNNO.3P‐285 (WEB ONLY)　2018

  68. 感音聴責任遺伝子Gata3の内耳特異的発現制御領域の解析

    森口尚, 星野朝文, 星野朝文, 高井淳, 上村聡志, 伊勢和枝, 中村保宏, 山本雅之, 山本雅之, ENGEL James Douglas

    日本分子生物学会年会プログラム・要旨集(Web)　41st　ROMBUNNO.1LBA‐066 (WEB ONLY)　2018

  69. メタボローム解析による血液検体保管条件の検討

    井上仁, 三枝大輔, 工藤久智, 峯岸直子, 峯岸直子, 小柴生造, 山本雅之, 山本雅之

    日本生化学会大会(Web)　90th　ROMBUNNO.2P‐0981 (WEB ONLY)-0981]　2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  70. オートファジーの異常は転写調節を介して代謝再編成を引き起こす

    齊藤哲也, 一村義信, 田口恵子, 藤村務, 上野隆, 本橋ほづみ, 和栗聡, 曽我朋義, 山本雅之, 田中啓二, 小松雅明

    がんと代謝研究会プログラム&amp;抄録集　5th　60　2017/07

  71. エリスロポエチン欠損は腎臓における慢性的代償機能を破綻させる(Erythropoietin maintains long-term compensatory renal hypertrophy)

    中野 大介, 管 う, 鈴木 教郎, 山本 雅之, 西山 成

    The Journal of Toxicological Sciences　42　(Suppl.)　S205-S205　2017/06

    Publisher: (一社)日本毒性学会

    ISSN： 0388-1350

  72. Identification of six new genetic loci associated with atrial fibrillation in the Japanese population Peer-reviewed

    Low S-K, Takahashi A, Ebana Y, Ozaki K, Christophersen I E, Ellinor P T, Consortium A F, Ogishima S, Yamamoto M, Satoh M, Sasaki M, Yamaji T, Iwasaki M, Tsugane S, Tanaka K, Naito M, Wakai K, Tanaka H, Furukawa T, Kubo M, Ito K, Kamatani Y, Tanaka T

    Nat Genet　49　(6)　953-958　2017/06

    DOI： 10.1038/ng.3842 　

    ISSN： 1546-1718

  73. オートファジーによる細胞死の制御 オートファジーとKeap1-Nrf2システム

    田口 恵子, 小松 雅明, 山本 雅之

    The Journal of Toxicological Sciences　42　(Suppl.)　S143-S143　2017/06

    Publisher: (一社)日本毒性学会

    ISSN： 0388-1350

  74. 一般集団への家族性高コレステロール血症(FH)の遺伝情報回付パイロット研究における事前アンケートについて

    沼田 早苗, 相澤 弥生, 山本 佳世乃, 徳富 智明, 石垣 泰, 遠藤 龍人, 丹野 高三, 佐藤 衛, 小林 朋子, 清水 厚志, 川目 裕, 福島 明宗, 山本 雅之, 佐々木 真理

    日本遺伝カウンセリング学会誌　38　(2)　97-97　2017/05

    Publisher: 日本遺伝カウンセリング学会

    ISSN： 1347-9628

  75. 遺伝と遺伝性疾患に関する講習会 ゲノムコホート研究における個人への遺伝情報の回付に関するパイロット研究参加者への試み

    徳富 智明, 清水 厚志, 福島 明宗, 山本 佳世乃, 石垣 泰, 川目 裕, 長神 風二, 小林 朋子, 相澤 弥生, 沼田 早苗, 鈴木 洋一, 布施 昇男, 菅原 敦子, 中山 文予, 山本 雅之, 佐々木 真理

    日本遺伝カウンセリング学会誌　38　(2)　144-144　2017/05

    Publisher: 日本遺伝カウンセリング学会

    ISSN： 1347-9628

  76. エリスロポエチンはネフロンロスに対する長期腎代償性機構に必須である

    中野大介, GUAN Yu, 鈴木教郎, 山本雅之, 西山成

    日本腎臓学会誌　59　(3)　263　2017/04/25

    ISSN： 0385-2385

  77. SIMULTANEOUS ACTIVATION OF K-RAS AND NRF2 INDUCE PANCREATIC ATROPHY

    Shin Hamada, Atsushi Masamune, Keiko Taguchi, Masayuki Yamamoto, Tooru Shimosegawa

    GASTROENTEROLOGY　152　(5)　S894-S894　2017/04

    ISSN： 0016-5085

    eISSN： 1528-0012

  78. Nrf2欠損マウスにおけるペントバルビタールの薬効延長とCYP2B遺伝子発現低下

    芦野 隆, 山本 雅之, 沼澤 聡

    日本薬学会年会要旨集　137年会　(3)　180-180　2017/03

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  79. 早発型発達緑内障における原因遺伝子の探索

    布施 昇男, 木村 雅恵, 清水 愛, 河合 洋介, 小島 要, 長崎 正朗, 濱中 輝彦, 石田 誠夫, 中村 誠, 酒井 寛, 池田 陽子, 森 和彦, 中澤 徹, 勝岡 史城, 安田 純, 山本 雅之

    日本眼科学会雑誌　121　(臨増)　227-227　2017/03

    Publisher: (公財)日本眼科学会

    ISSN： 0029-0203

  80. Nrf2欠損マウスにおけるディーゼル排ガス吸入曝露のブレオマイシン肺障害病態への影響

    李 英姫, 清水 孝子, 新海 雄介, 平田 幸代, 稲垣 弘文, 武田 健, 吾妻 安良太, 山本 雅之, 川田 智之

    日本衛生学雑誌　72　(Suppl.)　S210-S210　2017/03

    Publisher: 日本衛生学会

    ISSN： 0021-5082

  81. 大気汚染がアトピー性皮膚炎を引き起こす分子メカニズム

    枝光智大, 田口恵子, 山本雅之

    感染・炎症・免疫　47　(3)　2017

    ISSN： 0387-1010

  82. Pten欠失肝臓がんにおけるNrf2活性獲得の意義

    田口恵子, 一戸理沙, 山本雅之

    がんと代謝研究会プログラム&抄録集　5th　2017

  83. マウス一過性中大脳動脈閉塞モデルにおけるimaging mass spectrometryによるメタボローム解析

    阿部考貢, 新妻邦泰, 鹿毛淳史, 藤村幹, 三枝大輔, 宇留野晃, 山本雅之, 冨永悌二

    日本分子脳神経外科学会プログラム・抄録集　18th　2017

  84. Role of transcription factor Nrf2 in the metabolism of pentobarbital and the gene expression of cytochrome P450s

    ASHINO Takashi, YAMAMOTO Masayuki, NUMAZAWA Satoshi

    Annual Meeting of the Japanese Society of Toxicology　44　(0)　P-213　2017

    Publisher: The Japanese Society of Toxicology

  85. 「遺伝の仕組み」と「多様性」を学ぶための小児を対象とした遺伝教育ツール開発の取り組み

    小林朋子, 小林朋子, 菅原美智子, 石原利乃, 本郷一夫, 相澤弥生, 山口由美, 齋藤さかえ, 田中由佳里, 栗木美穂, 長神風二, 安田純, 櫻井美佳, 栗山進一, 川目裕, 鈴木吉也, 山本雅之, 鈴木洋一, 鈴木洋一

    日本人類遺伝学会大会プログラム・抄録集　62nd　324　2017

  86. Erythropoietin maintains long-term compensatory renal hypertrophy

    NAKANO Daisuke, GUAN Yu, SUZUKI Norio, YAMAMOTO Masayuki, NISHIYAMA Akira

    Annual Meeting of the Japanese Society of Toxicology　44　(0)　O-54　2017

    Publisher: 日本毒性学会

    More details Close

    Kidney has ability to adapt its size and function against partial nephron loss to maintain total renal function, for example, in both donor and recipient in renal transplantation. However, the factors that regulate this compensation have not been fully clarified yet. Hereby we examined the effects of erythropoietin (EPO)/anemia on the compensatory renal hypertrophy in the mice lacking EPO production. The anemic mice showed similar compensatory renal hypertrophy compared to normoxemic mice at week 1 after unilateral nephrectomy (UNX). However, the compensation was disrupted only in anemic mice at week 4 after UNX, which was accompanied by the decreased phosphorylation of ribosomal protein S6, a marker of mTOR activation. In the renal interstitium of anemic mice at week 4 of UNX, the number of cells promoting epo gene transcription (but disable to produce EPO protein in the mice) was reduced even under the anemia, and the number of α-smooth muscle actin-positive cells was increased, suggesting the transdifferentiation of EPO-producing cells into myofibroblast. These changes were restored by the supplementation of recombinant EPO. In conclusion, EPO is not essential for the onset of compensatory renal hypertrophy after UNX, but is essential to maintain the compensation persistently.

  87. Specific Deletion of Keap1 in Endothelial Cells or/and Macrophages of SCD Mice Induces Nrf2 to Protect Tissues Against Oxidative Insults

    Nadine Keleku-Lukwete, Panda Harit, Eriko Naganuma, Mikiko Suzuki, Masayuki Yamamoto

    BLOOD　128　(22)　2016/12

    ISSN： 0006-4971

    eISSN： 1528-0020

  88. 東北メディカル・メガバンク事業 地域住民コホート調査の詳細とドルーゼン解析調査

    本間 慶, 布施 昇男, 高井 貴子, 清元 秀泰, 菅原 純一, 鈴木 洋一, 菊谷 昌浩, 栗山 進一, 寳澤 篤, 八重樫 伸生, 呉 繁夫, 山本 雅之

    眼科臨床紀要　9　(11)　926-926　2016/11

    Publisher: 眼科臨床紀要会

    ISSN： 1882-5176

  89. マルチオミクスが解き明かす疾患生物学 日本人多層オミックス参照パネルの拡張

    小柴 生造, 三枝 大輔, 元池 育子, 小島 要, 城田 松之, 齋藤 智, 勝岡 史城, 河合 洋介, 山口 由美, 田邉 修, 長崎 正郎, 安田 純, 木下 賢吾, 山本 雅之

    日本生化学会大会プログラム・講演要旨集　89回　[1S05-5]　2016/09

    Publisher: (公社)日本生化学会

  90. オートファジーの破綻による肝腫瘍とKeap1-Nrf2システム

    田口 恵子, 小松 雅明, 山本 雅之

    日本生化学会大会プログラム・講演要旨集　89回　[3P-025]　2016/09

    Publisher: (公社)日本生化学会

  91. GATA2遺伝子ヘテロ欠失は3番染色体逆位を伴う白血病の発症を促進する

    片山 紗乙莉, 鈴木 未来子, 呉 繁夫, 山本 雅之

    日本生化学会大会プログラム・講演要旨集　89回　[2T07-01(2P　2016/09

    Publisher: (公社)日本生化学会

  92. Renal erythropoietin-producing cells and tubular interstitial cells in kidney development

    鈴木 教郎, 山本 雅之

    医学のあゆみ　257　(11)　1151-1155　2016/06/11

    Publisher: 医歯薬出版

    ISSN： 0039-2359

  93. オルガネラトキシコロジー NRF2依存性環境ストレス応答 内耳酸化ストレス障害の軽減に対するNRF2の貢献

    本蔵 陽平, 松尾 洋孝, 村上 昌平, 崎山 真幸, 水足 邦雄, 塩谷 彰浩, 山本 雅之, 森田 一郎, 四ノ宮 成祥, 川瀬 哲明, 香取 幸夫, 本橋 ほづみ

    The Journal of Toxicological Sciences　41　(Suppl.)　S90-S90　2016/06

    Publisher: (一社)日本毒性学会

    ISSN： 0388-1350

  94. NRF2 Knockout Suppresses Pancreatic Carcinogenesis in a Mouse Model

    Shin Hamada, Atsushi Masamune, Keiko Taguchi, Masayuki Yamamoto, Tooru Shimosegawa

    GASTROENTEROLOGY　150　(4)　S163-S163　2016/04

    ISSN： 0016-5085

    eISSN： 1528-0012

  95. Nrf2システムによる血管細胞アポトーシス調節を介した血管内膜肥厚抑制機能

    芦野 隆, 山本 雅之, 沼澤 聡

    日本薬学会年会要旨集　136年会　(3)　130-130　2016/03

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  96. 三世代コホート調査の進捗について

    目時 弘仁, 石黒 真美, 小原 拓, 佐藤 ゆき, 菊谷 昌浩, 栗山 進一, 寳澤 篤, 大隅 典子, 清元 秀泰, 菅原 準一, 鈴木 洋一, 冨永 悌二, 布施 昇男, 峯岸 直子, 辻 一郎, 呉 繁夫, 八重樫 伸生, 山本 雅之

    宮城県公衆衛生学会会誌　(48)　10-10　2016/03

    Publisher: 宮城県公衆衛生学会

    ISSN： 0912-747X

  97. 東日本大震災後の宮城県沿岸部における治療中断東北メディカル・メガバンク事業 地域住民コホート調査

    中谷 直樹, 中村 智洋, 土屋 菜歩, 成田 暁, 小暮 真奈, 中谷 純, 峯岸 直子, 布施 昇男, 鈴木 洋一, 菅原 準一, 菊谷 昌浩, 富田 博秋, 清元 秀泰, 栗山 進一, 辻 一郎, 呉 繁夫, 山本 雅之, 寳澤 篤, 丹野 高三, 佐々木 亮平, 坂田 清美

    宮城県公衆衛生学会会誌　(48)　11-11　2016/03

    Publisher: 宮城県公衆衛生学会

    ISSN： 0912-747X

  98. 東北メディカル・メガバンク事業 地域住民コホート調査における眼軸長検査

    布施 昇男, 本間 慶, 高井 貴子, 荻島 創一, 清元 秀泰, 菅原 準一, 鈴木 洋一, 菊谷 昌浩, 栗山 進一, 寳澤 篤, 八重樫 伸生, 呉 繁夫, 山本 雅之

    日本眼科学会雑誌　120　(臨増)　200-200　2016/03

    Publisher: (公財)日本眼科学会

    ISSN： 0029-0203

  99. 三世代コホート調査の進捗と子どもの父母の質問票

    目時弘仁, 石黒真美, 石黒真美, 小原拓, 小原拓, 佐藤ゆき, 水野聖士, 水野聖士, 宮下真子, 宮下真子, 菊谷昌浩, 菊谷昌浩, 栗山進一, 栗山進一, 栗山進一, 寳澤篤, 寳澤篤, 大隅典子, 大隅典子, 清元秀泰, 清元秀泰, 菅原準一, 菅原準一, 鈴木洋一, 鈴木洋一, 冨永悌二, 冨永悌二, 布施昇男, 布施昇男, 峯岸直子, 峯岸直子, 辻一郎, 辻一郎, 呉繁夫, 呉繁夫, 八重樫伸生, 八重樫伸生, 山本雅之, 山本雅之

    Journal of Epidemiology (Web)　26　(Supplement 1)　105　2016/01/21

    ISSN： 1349-9092

  100. エストロゲンはNrf2を介して逆流性食道炎を抑制する

    鳥畑勇大, 淺沼清孝, 田口恵子, 浅野直喜, 今谷晃, 山本雅之, 下瀬川徹

    日本消化器病学会大会(Web)　58th　2016

  101. Keap1欠失によるNrf2非依存的なPten発現上昇と肝病態抑制

    一戸理沙, 田口恵子, 山本雅之

    日本生化学会大会(Web)　89th　2016

  102. Nrf2はPten欠失による脂肪肝炎から肝臓がんへの進展に関与する

    一戸理沙, 田口恵子, 山本雅之

    衛生薬学・環境トキシコロジー講演要旨集　2016　2016

    ISSN： 0919-2115

  103. Nrf2はヘム合成阻害剤による肝毒性を防御する

    増井紗帆, 田口恵子, 山本雅之

    衛生薬学・環境トキシコロジー講演要旨集　2016　2016

    ISSN： 0919-2115

  104. p62/Sqstm1はNrf2依存的代謝再編成により肝細胞がんの悪性化をもたらす

    齊藤哲也, 一村義信, 田口恵子, 藤村務, 上野隆, 若井俊文, 本橋ほづみ, 和栗聡, 曽我朋義, 山本雅之, 田中啓二, 小松雅明

    がんと代謝研究会プログラム&抄録集　4th　2016

  105. p62/Sqstm1はNrf2依存的代謝再編成により肝細胞がんの悪性化をもたらす

    齊藤哲也, 一村義信, 田口恵子, 鈴木隆史, 水島恒裕, 藤村務, 上野隆, 大江知之, 増野匡彦, 若井俊文, 岡部隆義, 長野哲雄, 本橋ほづみ, 和栗聡, 曽我朋義, 山本雅之, 田中啓二, 小松雅明

    日本分子生物学会年会プログラム・要旨集(Web)　39th　2016

  106. Overview of redox regulation by Keap1–Nrf2 system in toxicology and cancer

    Mikiko Suzuki, Akihito Otsuki, Nadine Keleku-Lukwete, Masayuki Yamamoto

    Current Opinion in Toxicology　1　29-36　2016

    Publisher: Elsevier B.V.

    DOI： 10.1016/j.cotox.2016.10.001 　

    ISSN： 2468-2020

  107. Role of redox-sensitive transcription factor Nrf2 in monocyte chemotactic protein-1-induced monocyte/macrophage infiltration and migration

    ASHINO Takashi, YAMAMOTO Masayuki, NUMAZAWA Satoshi

    Annual Meeting of the Japanese Society of Toxicology　43　(0)　P-170　2016

    Publisher: The Japanese Society of Toxicology

  108. 転写因子GATA3低発現マウスはメサンギウム増殖性糸球体腎炎を呈する

    森口尚, 于磊, 大槻晃史, 山本雅之, エンゲル ジェームスダグラス

    日本生化学会大会(Web)　89th　ROMBUNNO.3P‐218 (WEB ONLY)　2016

  109. 生体防御因子Nrf2の遺伝的および薬剤誘導的活性化は多発性硬化症の症状を改善する

    林真貴子, 森口尚, 森口尚, 鈴木未来子, 鈴木未来子, 小林枝里, 山本雅之, 山本雅之

    日本生化学会大会(Web)　89th　ROMBUNNO.2T17‐06(2P‐362) (WEB ONLY)　2016

  110. マタニティログ調査:ヘルスケアデータと多層オミックスデータによる妊娠関連疾患の予防・早期発見に向けたコホート調査

    原田祐希, 越智大介, 山内隆史, 山下理宇, 高井貴子, 荻島創一, 峯岸直子, 田邉修, 田邉修, 栗山進一, 栗山進一, 布施昇男, 八重樫伸生, 八重樫伸生, 山本雅之, 山本雅之, 檜山聡, 長崎正朗, 菅原準一, 菅原準一

    日本分子生物学会年会プログラム・要旨集(Web)　39th　ROMBUNNO.3LBA‐096 (WEB ONLY)　2016

  111. Estimation of allele frequency of pathological variants based on whole-genome sequencing of 1070 Japanese individuals

    Yumi Yamaguchi-Kabata, Yosuke Kawai, Kaname Kojima, Naoki Nariai, Takahiro Mimori, Yukuto Sato, Fumiki Katsuoka, Jun Yasuda, Masayuki Yamamoto, Masao Nagasaki

    GENES & GENETIC SYSTEMS　90　(6)　379-379　2015/12

    ISSN： 1341-7568

    eISSN： 1880-5779

  112. GATA1 Changes DNA-Binding Fashion in a Binding-Site-Specific Manner and Alters Transcriptional Activity during Erythropoiesis

    Atsushi Hasegawa, Hiroshi Kaneko, Daishi Ishihara, Masahiro Nakamura, Akira Watanabe, Cecelia D. Trainor, Yamamoto Masayuki, Ritsuko Shimizu

    BLOOD　126　(23)　2015/12

    ISSN： 0006-4971

    eISSN： 1528-0020

  113. A Stress-Responsive Transcriptional Factor NRF2 Activates Hematopoietic Stem Cells

    Murakami Shohei, Masayuki Yamamoto, Hozumi Motohashi

    BLOOD　126　(23)　2015/12

    ISSN： 0006-4971

    eISSN： 1528-0020

  114. GATA-2 Regulates Dendritic Cell Differentiation

    Koichi Onodera, Tohru Fujiwara, Yasushi Onishi, Ari Itoh-Nakadai, Yoko Okitsu, Noriko Fukuhara, Kenichi Ishizawa, Ritsuko Shimizu, Masayuki Yamamoto, Hideo Harigae

    BLOOD　126　(23)　2015/12

    ISSN： 0006-4971

    eISSN： 1528-0020

  115. オートファジーの抑制は代謝および転写リプログラミングを引き起こす

    斉藤 哲也, 和栗 聡, 藤村 務, 上野 隆, 田口 恵子, 本橋 ほづみ, 山本 雅之, 曽我 朋義, 田中 啓二, 小松 雅明

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[2P0443]-[2P0443]　2015/12

    Publisher: (公社)日本生化学会

  116. SOD1H46R発現ALSマウスモデルの運動ニューロン変性はNrf2ではなく、p62/SQSTM1の機能喪失により悪化する

    三井 駿, 久保 瑞希, 潘 雷, 大友 麻子, 小池 正人, 内山 安男, 青木 正志, 山本 雅之, 石井 哲郎, 柳川 徹, Shang Hui-Fang, 吉井 文均, 秦野 伸二

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[4T15L-01(3P1231)]　2015/12

    Publisher: (公社)日本生化学会

  117. SOD1H46R発現ALSマウスモデルの運動ニューロン変性はNrf2ではなく、p62/SQSTM1の機能喪失により悪化する

    三井 駿, 久保 瑞希, 潘 雷, 大友 麻子, 小池 正人, 内山 安男, 青木 正志, 山本 雅之, 石井 哲郎, 柳川 徹, Shang Hui-Fang, 吉井 文均, 秦野 伸二

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[4T15L-01(3P1231)]　2015/12

    Publisher: (公社)日本生化学会

  118. 日本人多層オミックス参照パネルの公開

    小柴生造, 加藤恭丈, 三枝大輔, 元池育子, 城田松之, 斎藤智, 田邉修, 安田純, 木下賢吾, 山本雅之

    日本生化学会大会(Web)　88th　4T21L-07(3P0816) (WEB ONLY)-07(3P0816)]　2015/12

    Publisher: (公社)日本生化学会

  119. エリスロポエチン遺伝子の腎特異的転写制御領域の解析と腎性貧血モデルマウスの樹立

    平野育生, 鈴木教郎, 祢津昌広, 関根弘樹, 相馬友和, 峯岸直子, 清水律子, 山本雅之

    日本生化学会大会(Web)　88th　4T5L-10(3P0698) (WEB ONLY)-10(3P0698)]　2015/12

    Publisher: (公社)日本生化学会

  120. ヒトIL6遺伝子モニターマウスを用いたin vivoイメージングによる炎症状態解析システムの開発とその利用

    林 真貴子, 高井 淳, 于 磊, 本橋 ほづみ, 森口 尚, 山本 雅之

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[4T19L-02(3P0890)]　2015/12

    Publisher: (公社)日本生化学会

  121. NRF2活性化による、強大音曝露に伴う酸化ストレスからの内耳保護効果の解明

    本蔵 陽平, 村上 昌平, 山本 雅之, 川瀬 哲明, 香取 幸夫, 本橋 ほづみ

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[3P1212]-[3P1212]　2015/12

    Publisher: (公社)日本生化学会

  122. 東北メディカル・メガバンク地域住民コホート調査(宮城)における高血圧の規定要因

    寳澤 篤, 清元 秀泰, 中谷 直樹, 中村 智洋, 土屋 菜歩, 成田 暁, 小原 拓, 目時 弘仁, 丹野 高三, 中谷 純, 菊谷 昌浩, 栗山 進一, 辻 一郎, 呉 繁夫, 山本 雅之

    日本公衆衛生学会総会抄録集　74回　260-260　2015/10

    Publisher: 日本公衆衛生学会

    ISSN： 1347-8060

  123. 東北メディカル・メガバンク地域住民コホート調査(宮城)における高血圧の規定要因

    寳澤 篤, 清元 秀泰, 中谷 直樹, 中村 智洋, 土屋 菜歩, 成田 暁, 小原 拓, 目時 弘仁, 丹野 高三, 中谷 純, 菊谷 昌浩, 栗山 進一, 辻 一郎, 呉 繁夫, 山本 雅之

    日本公衆衛生学会総会抄録集　74回　260-260　2015/10

    Publisher: 日本公衆衛生学会

    ISSN： 1347-8060

  124. 東日本大震災後の高血圧の治療中断と関連する要因 地域住民コホート調査

    中谷 直樹, 中村 智洋, 土屋 菜歩, 成田 暁, 丹野 高三, 佐々木 亮平, 坂田 清美, 中谷 純, 菊谷 昌浩, 清元 秀泰, 栗山 進一, 辻 一郎, 呉 繁夫, 山本 雅之, 寳澤 篤

    日本公衆衛生学会総会抄録集　74回　261-261　2015/10

    Publisher: 日本公衆衛生学会

    ISSN： 1347-8060

  125. 東日本大震災後の宮城県における歯科受診状況と関連因子についての検討

    土屋 菜歩, 坪井 明人, 白石 成, 中谷 直樹, 中村 智洋, 成田 暁, 小暮 真奈, 鈴木 洋一, 菊谷 昌浩, 富田 博秋, 栗山 進一, 辻 一郎, 呉 繁夫, 山本 雅之, 寳澤 篤

    日本公衆衛生学会総会抄録集　74回　261-261　2015/10

    Publisher: 日本公衆衛生学会

    ISSN： 1347-8060

  126. 宮城県地域住民における心理的苦痛と喫煙行動の関連についての検討

    成田 暁, 中谷 直樹, 中村 智洋, 土屋 菜歩, 小暮 真奈, 丹野 高三, 佐々木 亮平, 坂田 清美, 富田 博秋, 栗山 進一, 辻 一郎, 呉 繁夫, 山本 雅之, 寳澤 篤

    日本公衆衛生学会総会抄録集　74回　296-296　2015/10

    Publisher: 日本公衆衛生学会

    ISSN： 1347-8060

  127. 東日本大震災後の睡眠薬服用開始に関連する規定要因の検討 地域住民コホート調査

    中村 智洋, 富田 博秋, 中谷 直樹, 土屋 菜歩, 成田 暁, 中谷 純, 菊谷 昌浩, 栗山 進一, 辻 一郎, 呉 繁夫, 山本 雅之, 寳澤 篤, 丹野 高三, 佐々木 亮平, 坂田 清美

    日本公衆衛生学会総会抄録集　74回　296-296　2015/10

    Publisher: 日本公衆衛生学会

    ISSN： 1347-8060

  128. Aryl hydrocarbon receptor activation at keratinocyte leads to atopic dermatitis-like lesion via artemin induction

    T. Hidaka, E. Ogawa, E. Kobayashi, T. Suzuki, T. Fujimura, S. Aiba, R. Okuyama, M. Yamamoto

    JOURNAL OF INVESTIGATIVE DERMATOLOGY　135　S2-S2　2015/09

    ISSN： 0022-202X

    eISSN： 1523-1747

  129. 東北メディカル・メガバンク事業-地域住民コホート調査のデザインと経過報告(眼圧検査)

    布施 昇男, 本間 慶, 高井 貴子, 清元 秀泰, 菅原 準一, 鈴木 洋一, 菊谷 昌浩, 栗山 進一, 寳澤 篤, 八重樫 伸生, 山本 雅之

    日本緑内障学会抄録集　26回　130-130　2015/09

    Publisher: 日本緑内障学会

  130. 東北メディカル・メガバンク 地域住民コホート宮城エリアにおける随時尿Na/K比の内陸部・沿岸部比較

    寳澤 篤, 中谷 直樹, 中村 智洋, 土屋 菜歩, 小暮 真奈, 丹野 高三, 佐々木 亮平, 坂田 清美, 中谷 純, 峯岸 直子, 清元 秀泰, 菅原 準一, 布施 昇男, 菊谷 昌浩, 鈴木 洋一, 富田 博秋, 栗山 進一, 辻 一郎, 呉 繁夫, 八重樫 伸生, 山本 雅之

    日本循環器病予防学会誌　50　(2)　126-126　2015/06

    Publisher: (一社)日本循環器病予防学会

    ISSN： 1346-6267

  131. 疾患レジストリーの現状と未来 東北メディカル・メガバンク機構 被災地からともに始めるゲノムコホート

    清元 秀泰, 伊藤 貞嘉, 八重樫 伸生, 山本 雅之

    日本腎臓学会誌　57　(3)　453-453　2015/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

  132. LC‐MSによる大規模コホートメタボローム解析

    三枝大輔, 加藤恭丈, 小柴生造, 元池育子, 荻島創一, 本橋ほづみ, 菅原準一, 中谷純, 寳澤篤, 峯岸直子, 木下賢吾, 田邉修, 山本雅之

    日本農芸化学会大会講演要旨集(Web)　2015　4SY19-2 (WEB ONLY)　2015/03/05

    ISSN： 2186-7976

  133. OVAアレルギー性気道炎症病態のマウス系統差におけるNrf2の役割

    李 英姫, 清水 孝子, 滝澤 始, 吾妻 安良太, 山本 雅之, 川田 智之

    日本衛生学雑誌　70　(Suppl.)　S181-S181　2015/03

    Publisher: 日本衛生学会

    ISSN： 0021-5082

  134. 東北メディカル・メガバンク事業

    八重樫 伸生, 山本 雅之

    日本消化器病学会雑誌　112　(臨増総会)　A11-A11　2015/03

    Publisher: (一財)日本消化器病学会

    ISSN： 0446-6586

  135. 動き出した創薬オープンイノベーションネットワーク アカデミック創薬 東北からの発信

    青木 淳賢, 可野 邦行, 濱 直人, 辻田 忠志, 土井 隆行, 菅原 明, 清水 律子, 大島 吉輝, 山本 雅之

    日本薬学会年会要旨集　135年会　(1)　155-155　2015/03

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  136. オートファジー障害に伴う糖,アミノ酸代謝再編成

    斉藤哲也, 斉藤哲也, 斉藤哲也, 和栗聡, 藤村務, 上野隆, 田口恵子, 本橋ほづみ, 山本雅之, 曽我朋義, 田中啓二, 小松雅明

    がんと代謝研究会プログラム&抄録集　3rd　2015

  137. Nrf2はPten欠失による脂肪肝炎から肝がんへの移行を促進する

    田口恵子, 一戸理沙, 山本雅之

    がんと代謝研究会プログラム&抄録集　3rd　2015

  138. タンパク質分解によるNrf2活性制御メカニズム

    田口恵子, 田口恵子, 本橋ほづみ, 山本雅之

    日本薬学会年会要旨集(CD-ROM)　135th　2015

  139. Nrf2はPten欠失による脂肪肝炎から肝臓がんの移行を促進する

    田口恵子, 一戸理沙, 山本雅之

    日本生化学会大会(Web)　88th　2015

  140. Role of Keap1/Nrf2 system in vascular smooth muscle cell apoptosis during neointimal expansion after vascular injury

    ASHINO Takashi, YAMAMOTO Masayuki, NUMAZAWA Satoshi

    Annual Meeting of the Japanese Society of Toxicology　42　(0)　P-187　2015

    Publisher: The Japanese Society of Toxicology

  141. Plasma proteome analysis for a large-scale population-based cohort study

    Katoh Yasutake, Koshiba Seizo, Igarashi Kazuhiko, Yamamoto Masayuki, Tanabe Osamu, Ebina Masayuki, Shirota Matsuyuki, Motoike Ikuko, Kinoshita Kengo, Kudo Hisaaki, Nobukuni Takahiro, Minegishi Naoko, Saigusa Daisuke

    Abstracts for Annual Meeting of Japanese Proteomics Society　2015　(0)　62-62　2015

    Publisher: Japanese Proteomics Society (Japan Human Proteome Organisation)

  142. Novel Role of Kelch-like ECH-associated Protein 1/NF-E2-related Factor 2 System in Vascular Smooth Muscle Cell Apoptosis Following Vascular Injury

    Takashi Ashino, Masayuki Yamamoto, Satoshi Numazawa

    CIRCULATION　130　2014/11

    ISSN： 0009-7322

    eISSN： 1524-4539

  143. Generation of Nrf2 point mutant mice by CRISPR/Cas9 system

    Masanobu Morita, Takafumi Suzuki, Hiromi Suda, Akihito Otsuki, Mikiko Suzuki, Ritsuko Shimizu, Masayuki Yamamoto

    TRANSGENIC RESEARCH　23　(5)　874-874　2014/10

    ISSN： 0962-8819

    eISSN： 1573-9368

  144. 大規模住民コホート研究のためのLC‐MS/MS血漿プロテオーム解析の標準化

    加藤恭丈, 蝦名真行, 城田松之, 木下賢吾, 五十嵐和彦, 田邉修, 山本雅之

    日本生化学会大会(Web)　87th　3P-505 (WEB ONLY)-505]　2014/10

    Publisher: (公社)日本生化学会

  145. 生体防御における転写因子Nrf2とグルタチオン依存性ホルムアルデヒド脱水素酵素Adh3による協調作用

    後藤 まき, 北村 大志, 井田 智章, 澤 智裕, 赤池 孝章, 長谷場 健, 秋元 敏雄, 山本 照子, 野, 山本 雅之, 本橋 ほづみ

    日本生化学会大会プログラム・講演要旨集　87回　[4T09p-06]　2014/10

    Publisher: (公社)日本生化学会

  146. 被災地健康調査における家庭血圧計診断に基づく高血圧症の実態

    清元 秀泰, 寳澤 篤, 田中 由香利, 奥田 拓史, 菅原 準一, 坪井 明人, 布施 昇男, 栗山 進一, 瀧 靖之, 辻 一郎, 阿部 倫明, 高井 貴子, 八重樫 伸生, 山本 雅之, 伊藤 貞嘉

    日本高血圧学会総会プログラム・抄録集　37回　442-442　2014/10

    Publisher: (NPO)日本高血圧学会

  147. ヒトIL-6遺伝子BAC(大腸菌人工染色体)レポーターマウスを用いたin vivoイメージングによる炎症状態モニターリングシステムの開発とその利用

    林 真貴子, 高井 淳, 于 磊, 本橋 ほづみ, 森口 尚, 山本 雅之

    日本生化学会大会プログラム・講演要旨集　87回　[2T15p-14]　2014/10

    Publisher: (公社)日本生化学会

  148. Nrf2 lowers risk for lung injury induced by diesel exhaust

    Ying-Ji Li, Takako Shimizu, Katsuhito Kato, Masao Sugamata, Ken Takeda, Masayuki Yamamoto, Tomoyuki Kawada

    EUROPEAN RESPIRATORY JOURNAL　44　2014/09

    ISSN： 0903-1936

    eISSN： 1399-3003

  149. LC/MSによる分離技術を基盤とした高感度メタボローム解析手法の開発と臨床応用に関する研究

    三枝大輔, 城田松之, 小柴正造, 菅原準一, 田邉修, 本橋ほづみ, 山本雅之

    BMSコンファレンス講演要旨集　41st　122-126　2014/07/07

  150. Keap1/Nrf2 Pathway Activation Represses Hepatic Gluconeogenesis and Lipogenesis

    Dionysios V. Chartoumpekis, Stephen L. Slocum, John J. Skoko, Nobunao Wakabayashi, Susan Aja, Masayuki Yamamoto, Thomas W. Kensler

    DIABETES　63　A457-A457　2014/06

    ISSN： 0012-1797

    eISSN： 1939-327X

  151. GATA2 REGULATES DIFFERENTIATION OF BONE MARROW-DERIVED MESENCHYMAL STEM CELLS

    M. Kamata, Y. Okitsu, T. Fujiwara, S. Nakajima, T. Takahashi, A. Inoue, N. Fukuhara, Y. Onishi, K. Ishizawa, R. Shimizu, M. Yamamoto, H. Harigae

    HAEMATOLOGICA　99　173-173　2014/06

    ISSN： 0390-6078

  152. EPOETIN BETA PEGOL PROMOTES IRON UTILIZATION FOR ERYTHROPOIESIS THROUGH INTENSIVE SUPPRESSION OF SERUM HEPCIDIN LEVELS IN INHERITED SUPER-ANAEMIC MICE

    Yusuke Sasaki, Shun Yamazaki, Ken Fujita, Mitsue Kurasawa, Keigo Yorozu, Yasushi Shimonaka, Norio Suzuki, Masayuki Yamamoto

    NEPHROLOGY DIALYSIS TRANSPLANTATION　29　495-496　2014/05

    ISSN： 0931-0509

    eISSN： 1460-2385

  153. Nrf2欠損マウスにおけるディーゼル排気粒子の気道・肺への影響

    李 英姫, 清水 孝子, 加藤 活人, 菅又 昌雄, 武田 健, 山本 雅之, 川田 智之

    日本衛生学雑誌　69　(Suppl.)　S210-S210　2014/05

    Publisher: (一社)日本衛生学会

    ISSN： 0021-5082

  154. 腎疾患個別化医療実現に向けた健常人ゲノムコホートの構築

    清元 秀泰, 阿部 倫昭, 奥田 拓史, 岡村 将史, 宮崎 真理子, 寳澤 篤, 栗山 進一, 高井 貴子, 長崎 正朗, 峯岸 直子, 安田 純, 森 建文, 中谷 純, 菅原 準一, 八重樫 伸生, 佐藤 博, 山本 雅之, 伊藤 貞嘉

    日本腎臓学会誌　56　(3)　352-352　2014/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

  155. PS-083-8 マウス門脈枝結紮後の代償的肝肥大におけるNrf2の役割(PS-083 肝 基礎-3,ポスターセッション,第114回日本外科学会定期学術集会)

    白崎 圭一, 藪内 伸一, 田口 恵子, 川口 桂, 唐澤 秀明, 青木 豪, 深瀬 耕二, 水間 正道, 坂田 直昭, 中川 圭, 林 洋毅, 岡田 恭穂, 森川 孝則, 吉田 寛, 元井 冬彦, 内藤 剛, 片寄 友, 江川 新一, 本橋 ほづみ, 山本 雅之, 海野 倫明

    日本外科学会雑誌　115　(2)　2014/03/05

    Publisher: 一般社団法人日本外科学会

    ISSN： 1880-1129

  156. 眼疾患と遺伝子 緑内障のゲノム解析 次世代医療・個別化医療に向けて

    布施 昇男, 清水 愛, 木村 雅恵, 高野 良真, 石 棟, 宮澤 晃子, 国松 志保, 劉 孟林, 渡邉 亮, 安田 正幸, 横山 悠, 檜森 紀子, 津田 聡, 山本 耕太郎, 中澤 徹, 安田 純, 勝岡 史城, 小島 要, 成相 直樹, 松本 光代, 元池 育子, 長崎 正朗, 木下 賢吾, 五十嵐 和彦, 山本 雅之, 新堀 哲也, 青木 洋子, 松原 洋一, 舟山 亮, 長嶋 剛史, 中山 啓子, 眞島 行彦, 船山 智代, 田中 光一, 原田 高幸, 阿部 春樹, 福地 健郎, 安田 典子, 出田 秀尚, 鄭 暁東, 白石 敦, 大橋 裕一, 石田 誠夫, 原 岳, 金森 章泰, 山田 裕子, 中村 誠, 酒井 寛, Richards Julia E

    日本眼科学会雑誌　118　(3)　216-240　2014/03

    Publisher: (公財)日本眼科学会

    ISSN： 0029-0203

  157. マウス門脈枝結紮後の代償的肝肥大におけるNrf2の役割

    白崎 圭一, 藪内 伸一, 田口 恵子, 川口 桂, 唐澤 秀明, 青木 豪, 深瀬 耕二, 水間 正道, 坂田 直昭, 中川 圭, 林 洋毅, 岡田 恭穂, 森川 孝則, 吉田 寛, 元井 冬彦, 内藤 剛, 片寄 友, 江川 新一, 橋本 ほづみ, 山本 雅之, 海野 倫明

    日本外科学会雑誌　115　(臨増2)　741-741　2014/03

    Publisher: (一社)日本外科学会

    ISSN： 0301-4894

  158. 在宅医療・遠隔医療の未来 東日本大震災被災地における地域医療支援の現況と今後の遠隔医療の重要性

    清元 秀泰, 奥田 拓史, 伊藤 大亮, 阿部 倫明, 石井 正, 鈴木 洋一, 川目 裕, 菅原 準一, 瀧 靖之, 中谷 純, 井戸端 永遠, 八重樫 伸生, 山本 雅之

    医工学治療　26　(Suppl.)　76-76　2014/03

    Publisher: (NPO)日本医工学治療学会

    ISSN： 1344-1221

  159. 東北メディカル・メガバンク事業―地域住民コホート調査に関する経過報告

    寶澤篤, 寶澤篤, 寶澤篤, 中谷直樹, 中村智洋, 土屋菜歩, 菊谷昌浩, 目時弘仁, 小原拓, 大隅典子, 清元秀泰, 菅原準一, 鈴木洋一, 中谷直樹, 中村智洋, 土屋菜歩, 菊谷昌浩, 目時弘仁, 小原拓, 大隅典子, 清元秀泰, 菅原準一, 鈴木洋一, 富田博秋, 富田博秋, 富田博秋, 冨永悌二, 中谷純, 布施昇男, 峯岸直子, 辻一郎, 八重樫伸生, 山本雅之, 冨永悌二, 中谷純, 布施昇男, 峯岸直子, 辻一郎, 八重樫伸生, 山本雅之

    J Epidemiol　24　(Supplement 1)　67　2014/01/23

    ISSN： 0917-5040

  160. オートファジー障害に伴う糖,アミノ酸代謝再編成

    斉藤哲也, 斉藤哲也, 斉藤哲也, 曽友深, 和栗聡, 藤村務, 上野隆, 田口恵子, 本橋ほづみ, 山本雅之, 田中啓二, 曽我朋義, 小松雅明

    日本分子生物学会年会プログラム・要旨集(Web)　37th　2014

  161. Nrf2の活性制御破綻がもたらす肝病態

    田口恵子, 田口恵子, 本橋ほづみ, 山本雅之

    日本生化学会大会(Web)　87th　2014

  162. GATA2がCebpaの転写を抑制することが骨髄マスト細胞の分化形質維持に必要である

    大森慎也, 登丸菜月, 石嶋康史, 森口尚, 山本雅之, 大根田絹子

    日本分子生物学会年会プログラム・要旨集(Web)　37th　3P-0588 (WEB ONLY)　2014

  163. 東北メディカル・メガバンク事業 三世代コホート調査の進捗について

    目時 弘仁, 石黒 真美, 小原 拓, 佐藤 ゆき, 菊谷 昌浩, 栗山 進一, 寳澤 篤, 大隅 典子, 清元 秀泰, 菅原 準一, 鈴木 洋一, 冨永 悌二, 布施 昇男, 峯岸 直子, 辻 一郎, 呉 繁夫, 八重樫 伸生, 山本 雅之

    DOHaD研究　3　(1)　46-46　2014

    Publisher: 日本DOHaD研究会

    ISSN： 2187-2597

    More details Close

    第3回日本DOHaD研究会学術集会 抄録集 【ポスター発表】

  164. Nrf2 Lowers Risk for Neurodegenerative Diseases Caused by Oxidative Stresses Induced by Diesel Exhaust

    Masao Sugamata, Tomomi Ihara, Miho Sugamata, Ying Ji Li, Masayuki Yamamoto, Ken Takeda

    ANNALS OF NEUROLOGY　74　S93-S93　2013/10

    ISSN： 0364-5134

    eISSN： 1531-8249

  165. ヒト乳癌におけるNRF2発現の免疫組織化学的検討(Immunolocalization of NRF2 in human breast carcinoma)

    小野寺 好明, 本橋 ほづみ, 高木 清司, 三木 康宏, 柴原 裕紀子, 渡辺 みか, 石田 孝宣, 笹野 公伸, 山本 雅之, 鈴木 貴

    日本癌学会総会記事　72回　403-403　2013/10

    Publisher: 日本癌学会

    ISSN： 0546-0476

  166. 転写因子GATA2の尿細管特異的欠損マウスは尿濃縮障害を呈する

    Lei Yu, 森口 尚, 相馬 友和, 高井 淳, 山本 雅之

    生化学　85　(8)　718-718　2013/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  167. BACトランスジェニックマウスを用いた血球分化マスター転写因子GATA1の遺伝子発現制御機構の解析

    高井 淳, 森口 尚, 鈴木 未来子, 大根田 絹子, 山本 雅之

    生化学　85　(8)　720-720　2013/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  168. Toward clinical application of the Keap1-Nrf2 pathway

    Takafumi Suzuki, Hozumi Motohashi, Masayuki Yamamoto

    Trends in Pharmacological Sciences　34　(6)　340-346　2013/06

    DOI： 10.1016/j.tips.2013.04.005 　

    ISSN： 0165-6147 1873-3735

  169. 慢性腎臓病における線維化と腎性貧血を担う細胞の同定およびその制御法の開発

    高瀬昌幸, 浅田礼光, 中村仁, 小口綾貴子, 浅田三咲子, 鈴木教郎, 山村研一, 名越慈人, 芝田晋介, RAO Tata Nageswara, FEHLING Hans Joerg, 深津敦司, 峯岸直子, 北徹, 木村剛, 岡野栄之, 山本雅之, 柳田素子

    Pharma Medica　31　(5)　90-92　2013/05/10

    Publisher: (株)メディカルレビュー社

    ISSN： 0289-5803

  170. Nrf2欠損マウスにおけるディーゼル排気粒子曝露のプレオマイシン気道炎症病態への影響

    李 英姫, 清水 孝子, 平田 幸代, 稲垣 弘文, 新海 雄介, 武田 健, 吾妻 安良太, 滝澤 始, 山本 雅之, 川田 智之, 工藤 翔二

    日本呼吸器学会誌　2　(増刊)　176-176　2013/03

    Publisher: (一社)日本呼吸器学会

    ISSN： 2186-5876

  171. Nrf2欠損マウスを用いたディーゼル排気粒子のブレオマイシン気道炎症病態への影響

    李 英姫, 清水 孝子, 平田 幸代, 稲垣 弘文, 新海 雄介, 武田 健, 吾妻 安良太, 滝澤 始, 山本 雅之, 川田 智之

    日本衛生学雑誌　68　(Suppl.)　S214-S214　2013/03

    Publisher: 日本衛生学会

    ISSN： 0021-5082

  172. エリスロポエチンノックアウトマウスを用いた網膜・視神経の組織学的検討

    安田 正幸, 劉 孟林, 田中 佑治, 檜森 紀子, 面高 宗子, 横山 悠, 雪田 昌克, 津田 聡, 丸山 和一, 山本 雅之, 中澤 徹

    日本眼科学会雑誌　117　(臨増)　311-311　2013/03

    Publisher: (公財)日本眼科学会

    ISSN： 0029-0203

  173. 肝毒性物質による肝肥大における転写因子Nrf2の役割

    田口恵子, 田口恵子, 本橋ほづみ, 伊藤暢, 田中稔, 宮島篤, 山本雅之

    衛生薬学・環境トキシコロジー講演要旨集　2013　2013

    ISSN： 0919-2115

  174. 細胞増殖におけるKeap1-Nrf2酸化ストレス応答機構の役割

    本橋ほづみ, 白崎圭一, 白崎圭一, 白崎圭一, 光石陽一郎, 光石陽一郎, 田口恵子, 田口恵子, 山本雅之

    がんと代謝研究会プログラム&抄録集　1st　2013

  175. 門脈枝結紮による代償的肝肥大におけるNrf2の役割

    白崎圭一, 白崎圭一, 白崎圭一, 田口恵子, 本橋ほづみ, 海野倫明, 山本雅之

    日本生化学会大会(Web)　86th　2013

  176. 細胞増殖におけるKeap1-Nrf2酸化ストレス応答機構の役割

    本橋ほづみ, 白崎圭一, 白崎圭一, 白崎圭一, 光石陽一郎, 光石陽一郎, 田口恵子, 田口恵子, 山本雅之

    日本分子生物学会年会プログラム・要旨集(Web)　36th　2013

  177. 角膜上皮創傷治癒におけるNrf2の役割

    林竜平, 檜森紀子, 田口恵子, 石川幸, 上杉晃司, 伊藤美由紀, DUNCAN Thomas, 中澤徹, 山本雅之, 西田幸二

    日本眼科学会雑誌　117　2013

    ISSN： 0029-0203

  178. Regulatory mechanism of neointimal formation after vascular injury by transcription factor Nrf2 via inhibiting ROS&mdash;ERK pathway

    ASHINO Takashi, YAMAMOTO Masayuki, YOSHIDA Takemi, NUMAZAWA Satoshi

    Annual Meeting of the Japanese Society of Toxicology　40　(0)　2013

    Publisher: The Japanese Society of Toxicology

  179. 肺細胞と機能・分化 抗酸化ストレス転写因子Nrf 2欠損マウス由来肺腫瘍は、Kras経路の抑制と肺腺癌特異的な遺伝子発現低下をきたす

    佐藤 大希, 森口 尚, 海老名 雅仁, 山本 雅之

    日本呼吸器学会誌　2　(増刊)　137-137　2013

  180. 腎線維化を規定する腎エリスロポイエチン産生細胞の形質転換とその可逆性

    相馬 友和, 山崎 瞬, 鈴木 教郎, 森口 尚, 阿部 倫明, 清元 秀泰, 伊藤 貞嘉, 山本 雅之

    日本腎臓学会誌　55　(3)　345-345　2013

  181. 【慢性炎症と本態-線維化・免疫・炎症の各視点から-】 環境応答破綻がもたらす炎症の慢性化機構

    森口 尚, 本橋 ほづみ, 山本 雅之

    BIO Clinica　28　(12)　1111-1115　2013

  182. トランスジェニックマウスを利用したエリスロポエチン遺伝子エンハンサーの探索

    平野育生, 鈴木教郎, 山崎瞬, 峯岸直子, 山本雅之, 清水律子

    日本分子生物学会年会プログラム・要旨集(Web)　36th　1P-0195 (WEB ONLY)　2013

  183. 環境応答破綻がもたらす炎症の慢性化機構 Invited Peer-reviewed

    森口 尚, 本橋ほづみ, 山本雅之

    Bio Clinica　28　(12)　12-23　2013

  184. Roles nrf2 plays in myeloid cells and related disorders. International-journal

    Eri Kobayashi, Takafumi Suzuki, Masayuki Yamamoto

    Oxidative medicine and cellular longevity　2013　529219-529219　2013

    DOI： 10.1155/2013/529219 　

    More details Close

    The Keap1-Nrf2 system protects animals from oxidative and electrophilic stresses. Nrf2 is a transcription factor that induces the expression of genes essential for detoxifying reactive oxygen species (ROS) and cytotoxic electrophiles. Keap1 is a stress sensor protein that binds to and ubiquitinates Nrf2 under unstressed conditions, leading to the rapid proteasomal degradation of Nrf2. Upon exposure to stress, Keap1 is modified and inactivated, which allows Nrf2 to accumulate and activate the transcription of a battery of cytoprotective genes. Antioxidative and detoxification activities are important for many types of cells to avoid DNA damage and cell death. Accumulating lines of recent evidence suggest that Nrf2 is also required for the primary functions of myeloid cells, which include phagocytosis, inflammation regulation, and ROS generation for bactericidal activities. In fact, results from several mouse models have shown that Nrf2 expression in myeloid cells is required for the proper regulation of inflammation, antitumor immunity, and atherosclerosis. Moreover, several molecules generated upon inflammation activate Nrf2. Although ROS detoxification mediated by Nrf2 is assumed to be required for anti-inflammation, the entire picture of the Nrf2-mediated regulation of myeloid cell primary functions has yet to be elucidated. In this review, we describe the Nrf2 inducers characteristic of myeloid cells and the contributions of Nrf2 to diseases.

  185. アミノ酸飢餓応答因子GCN1L1によるNrf2活性制御機構の解析

    KIMURA SHINTAROU, NISHIKAWA KEIZO, MATSUMIYA TOMOO, HARADA NOBUHIKO, YAMAMOTO MASAYUKI, ITO KEN

    日本生化学会大会(Web)　85回　3P-415　2012/12

    Publisher: (公社)日本生化学会

  186. エリスロポエチン産生細胞特異的Cre発現マウスの樹立と解析

    山嵜瞬, 峯岸直子, 鈴木教郎, 山本雅之

    日本生化学会大会(Web)　85th　3T01-01 (WEB ONLY)-01　2012/12

    Publisher: (公社)日本生化学会

  187. 神経堤細胞におけるエリスロポエチン遺伝子発現

    平野育生, 鈴木教郎, PAN Xiaoqing, 峯岸直子, 山本雅之

    日本生化学会大会(Web)　85th　3T09-04 (WEB ONLY)-04　2012/12

    Publisher: (公社)日本生化学会

  188. Contribution of GATA1 dysfunction to multi-step leukemogenesis

    Ritsuko Shimizu, Masayuki Yamamoto

    CANCER SCIENCE　103　(12)　2039-2044　2012/12

    DOI： 10.1111/cas.12007 　

    ISSN： 1347-9032

  189. Regulation of the Keap1-Nrf2 pathway by the ubiquitin proteasome system

    243　(6)　525-529　2012/11/10

    Publisher: 医歯薬出版

    ISSN： 0039-2359

  190. DNA Binding Diversity Achieved Through the Interaction of GATA1 N-Finger and GATA Motif Is Important for Embryonic Erythropoiesis

    Atsushi Hasegawa, Ritsuko Shimizu, Hirofumi Kurokawa, Masayuki Yamamoto

    BLOOD　120　(21)　2012/11

    ISSN： 0006-4971

  191. Erythropoietin production in neural crest cells

    Ikuo Hirano, Norio Suzuki, Xiaoqing Pan, Shun Yamazaki, Naoko Minegishi, Masayuki Yamamoto

    AMERICAN JOURNAL OF HEMATOLOGY　87　(10)　E100-E100　2012/10

    ISSN： 0361-8609

  192. Nrf2 is closely related to enhance bleomycin induced airway inflammatory responses caused by diesel exhaust particles in mice

    Ying-Ji Li, Tkako Shimizu, Yukiyo Hirata, Hirofumi Inagaki, Yusuke Shinkai, Ken Takeda, Arata Azuma, Hajime Takizawa, Yamamoto Masayuki, Tomoyuki Kawada, Shoji Kudoh

    EUROPEAN RESPIRATORY JOURNAL　40　2012/09

    ISSN： 0903-1936

    eISSN： 1399-3003

  193. Molecular Determinants for Small Maf Protein Control of Platelet Production (vol 31, pg 151, 2011)

    Hozumi Motohashi, Rie Fujita, Mariko Takayama, Ai Inoue, Fumiki Katsuoka, Emery H. Bresnick, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　32　(10)　2041-2041　2012/05

    DOI： 10.1128/MCB.00364-12 　

    ISSN： 0270-7306

  194. Constitutive Expression of Aryl Hydrocarbon Receptor in Keratinocytes Causes Inflammatory Skin Lesions (vol 25, pg 9360, 2005)

    Masafumi Tauchi, Azumi Hida, Takaaki Negishi, Fumiki Katsuoka, Shuhei Noda, Junsei Mimura, Tomonori Hosoya, Akinori Yanaka, Hiroyuki Aburatani, Yoshiaki Fujii-Kuriyama, Hozumi Motohashi, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　32　(9)　1759-1759　2012/05

    DOI： 10.1128/MCB.00292-12 　

    ISSN： 0270-7306

  195. 慢性腎臓病における線維化と腎性貧血を担う細胞の同定およびその制御法の開発

    高瀬昌幸, 浅田礼光, 中村仁, 小口綾貴子, 浅田三咲子, 鈴木教郎, 山村研一, 名越慈人, 芝田晋介, 深津敦司, 峯岸直子, 北徹, 木村剛, 岡野栄之, 山本雅之, 柳田素子

    日本腎臓学会誌　54　(3)　261-261　2012/04/25

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

  196. 創薬オープンイノベーションネットワークの構築 アカデミック発創薬 東北大学の試み

    青木 淳賢, 段 孝, 宮田 敏男, 土井 隆行, 根東 義則, 山本 雅之, 大島 吉輝

    日本薬学会年会要旨集　132年会　(1)　124-124　2012/03

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  197. 酸化ストレス研究における網膜神経節細胞純化回収法の確立

    檜森 紀子, 田口 恵子, 劉 孟林, 安田 正幸, 横山 悠, 相澤 奈帆子, 面高 宗子, 山本 雅之, 中澤 徹

    日本眼科学会雑誌　116　(臨増)　303-303　2012/03

    Publisher: (公財)日本眼科学会

    ISSN： 0029-0203

  198. マウス網膜神経節細胞障害時におけるHO-1

    檜森紀子, 檜森紀子, 田口恵子, 山本雅之, 中澤徹

    日本緑内障学会抄録集　23rd　2012

  199. 転写因子Nrf2はペントースリン酸経路とグルタミン代謝を制御して細胞増殖に貢献する

    光石陽一郎, 光石陽一郎, 田口恵子, 油谷浩幸, 貫和敏博, 本橋ほづみ, 山本雅之

    日本呼吸器学会誌　1　2012

    ISSN： 2186-5876

  200. シグナル伝達機構研究の最前線 7.活性酸素種や親電子性物質によるシグナル伝達

    田口恵子, 山本雅之

    実験医学　30　(5)　2012

    ISSN： 0288-5514

  201. 肝臓における2つのNrf2活性制御機構と胆管形成

    田口恵子, 本橋ほづみ, 山本雅之

    衛生薬学・環境トキシコロジー講演要旨集　2012　2012

    ISSN： 0919-2115

  202. がん細胞における酸化ストレス応答機構の役割と代謝リプログラミングへの貢献

    光石陽一郎, 光石陽一郎, 田口恵子, 山本雅之, 本橋ほづみ

    日本生化学会大会(Web)　85th　2012

  203. 肝臓における2つのNrf2活性制御機構と胆管形成

    田口恵子, 本橋ほづみ, 山本雅之

    日本生化学会大会(Web)　85th　2012

  204. マウス網膜神経節細胞障害における網膜神経節細胞純化回収法の確立

    檜森紀子, 田口恵子, 山本雅之, 中澤徹

    日本抗加齢医学会総会プログラム・抄録集　12th　2012

  205. Role of the redox-sensitive transcription factor Nrf2 in vascular smooth muscle cell migration and vascular remodeling

    ASHINO Takashi, YAMAMOTO Masayuki, YOSHIDA Takemi, NUMAZAWA Satoshi

    Annual Meeting of the Japanese Society of Toxicology　39　(0)　P-110　2012

    Publisher: The Japanese Society of Toxicology

    DOI： 10.1161/ATVBAHA.112.300614 　

  206. 肺癌 遺伝子変異、遺伝子介入 Nrf2ノックアウトマウスはウレタン肺発癌に抵抗性を示しNrf2欠損癌結節はNudeマウスへの著しい生着不全をきたす.

    佐藤 大希, 森口 尚, 海老名 雅仁, 山本 雅之

    日本呼吸器学会誌　1　(増刊)　123-123　2012

  207. 転写因子Nrf2の欠損はKras経路の抑制と肺発生関連遺伝子の発現低下を介して、ウレタン誘導性肺腺癌の悪性化を阻害する

    佐藤 大希, 森口 尚, 海老名 雅仁, 山本 雅之

    日本癌学会総会記事　71回　124-124　2012

  208. HDC-GFP TRANSGENIC MOUSE

    Ohtsu, H, Sato, A, Moriguchi, T, Takai, J, Yamamoto, M

    Inflamm. Res.　61　(2)　S77-S77　2012

  209. The Keap1-Nrf2 system in cancers: stress response and anabolic metabolism.

    Mitsuishi, Yoichiro Motohashi, Hozumi Yamamoto, Masayuki

    Front Oncol　2　200-200　2012

    DOI： 10.3389/fonc.2012.00200 　

  210. [Pathophysiological regulation of cellular stress response by Keap1-Nrf2 system].

    Yamamoto, Masayuki

    Rinsho Shinkeigaku　52　(11)　861-861　2012

    DOI： 10.5692/clinicalneurol.52.861 　

  211. Selective isotope labeling of recombinant proteins in Escherichia coli.

    Tong, Kit I Yamamoto, Masayuki Tanaka, Toshiyuki

    Methods Mol Biol　896　439-448　2012

    DOI： 10.1007/978-1-4614-3704-8_30 　

  212. GATA1 Mutants Lacking Rb-Binding Motif Observed in Transient Abnormal Myelopoiesis in Down Syndrome

    Tsutomu Toki, Eri Kobayashi, Rika Kanezaki, RuNan Wang, Kiminori Terui, Hirokazu Kanegane, Miho Maeda, Mikiya Endo, Tatsuki Mizuochi, Souichi Adachi, Yasuhide Hayashi, Ritsuko Shimizu, Masayuki Yamamoto, Etsuro Ito

    BLOOD　118　(21)　647-647　2011/11

    ISSN： 0006-4971

  213. Two Distinct Transactivation Domains of GATA1 Contribute Megakaryopoiesis

    Hiroshi Kaneko, Eri Kobayashi, Ritsuko Shimizu, Masayuki Yamamoto

    BLOOD　118　(21)　1451-1451　2011/11

    ISSN： 0006-4971

  214. 胎仔期神経細胞,神経堤細胞によるエリスロポエチン産生

    平野育生, 鈴木教郎, PAN Xiaoqing, 山崎瞬, 峯岸直子, 山本雅之

    生化学　84回　ROMBUNNO.3T14A-3-3　2011/09

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  215. エリスロポエチン欠損マウスの部分レスキューによる遺伝性超貧血マウスの樹立

    山嵜瞬, 峯岸直子, 鈴木教郎, 山本雅之

    生化学　84回　ROMBUNNO.3T16P-17-17　2011/09

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  216. Keap1 and Nrf2 genetic mutations and polymorphisms: Associations with clinical outcome in endometrial cancer

    Tze Fang Wong, Kousuke Yoshinaga, Yasutake Monma, Kiyoshi Ito, Hitoshi Niikura, Satoru Nagase, Masayuki Yamamoto, Nobuo Yaegashi

    CANCER RESEARCH　71　2011/04

    DOI： 10.1158/1538-7445.AM2011-316 　

    ISSN： 0008-5472

    eISSN： 1538-7445

  217. マウス網膜神経節細胞障害におけるNrf2の役割

    檜森 紀子, 中澤 徹, 田口 恵子, 劉 孟林, 安田 正幸, 面高 宗子, シャナブ・アフメド, 山本 雅之

    日本眼科学会雑誌　115　(臨増)　252-252　2011/04

    Publisher: (公財)日本眼科学会

    ISSN： 0029-0203

  218. 血管平滑筋遊走におけるHO-1およびその転写因子Nrf2の役割

    芦野 隆, 崔 理紗, 益本 愛子, 山本 雅之, 沼澤 聡, 吉田 武美

    日本薬学会年会要旨集　131年会　(3)　192-192　2011/03

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  219. Nrf2欠損マウスにおけるブレオマイシン肺線維症病態

    李 英姫, 清水 孝子, 平田 幸代, 稲垣 弘文, 吾妻 安良太, 滝澤 始, 高橋 智, 山本 雅之, 川田 智之, 工藤 翔二

    日本呼吸器学会雑誌　49　(増刊)　243-243　2011/03

    Publisher: (一社)日本呼吸器学会

    ISSN： 1343-3490

  220. Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Invited Peer-reviewed

    Taguchi Keiko, Motohashi Hozumi, Yamamoto Masayuki

    Genes Cells　16　(2)　123-140　2011/02

    DOI： 10.1111/j.1365-2443.2010.01473.x 　

  221. 転写因子Nrf2はペントースリン酸経路とグルタミン代謝を制御して細胞増殖に貢献する

    光石陽一郎, 田口恵子, 油谷浩幸, 貫和敏博, 本橋ほづみ, 山本雅之

    生化学　2011

    ISSN： 0037-1017

  222. 転写因子Nrf2の活性制御タンパク質Keap1の分解と合成

    田口恵子, 藤川奈々子, 本橋ほづみ, 山本雅之

    衛生薬学・環境トキシコロジー講演要旨集　2011　2011

    ISSN： 0919-2115

  223. 角膜上皮創傷治時におけるNrf2を介した酸化ストレス防御機構の役割

    林竜平, 檜森紀子, 田口惠子, 伊藤美由紀, 山本雅之, 西田幸二

    日本眼科学会雑誌　115　2011

    ISSN： 0029-0203

  224. Nrf2 activates the pentose phosphate pathway and glutamine consumption in proliferating cells

    Yoichiro Mitsuishi, Keiko Taguchi, Masayuki Yamamoto, Hozumi Motohashi

    INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE　28　S16-S16　2011

    ISSN： 1107-3756

  225. Select heterozygous Keap1 mutations have a dominant-negative effect on wild-type Keap1 in vivo

    Takafumi Suzuki, Jonathan Maher, Masayuki Yamamoto

    INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE　28　S74-S74　2011

    ISSN： 1107-3756

  226. Keap1 degradation by autophagy for the maintenance of redox homeostasis

    Nanako Fujikawa, Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto

    INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE　28　S75-S75　2011

    ISSN： 1107-3756

  227. APP-091 Caudal domain of urogenital mesenchymal GATA2 expression is essential for proper development of vesicoureteral junction(総会賞応募ポスター,第99回日本泌尿器科学会総会)

    相野谷 慶子, 森口 尚, 大森 慎也, 守田 匡伸, Lim Kim-Chew, Engel James Douglas, 山本 雅之

    日本泌尿器科学会雑誌　102　(2)　2011

    Publisher: 一般社団法人 日本泌尿器科学会

    ISSN： 0021-5287

  228. 尿細管管腔内アルカリ化は蛋白尿による近位尿細管細胞酸化ストレスをPyk2経路を介して改善させる.

    相馬 友和, 阿部 倫明, 森口 尚, 高井 淳, 秋山 泰利, 豊原 敬文, 鈴木 健弘, 種本 雅之, 阿部 高明, 山本 雅之, 伊藤 貞嘉

    血管　34　(1)　32-33　2011

  229. 泌尿生殖器間質GATA2発現の尾部ドメインは膀胱尿管移行部の適切な形成に必要である.

    相野谷 慶子, 森口 尚, 大森 慎也, 守田 匡伸, Lim Kim-Chew, Douglas Engel James, 山本 雅之

    日本泌尿器科学会雑誌　102　(2)　338-338　2011

  230. 転写因子GATA2と尿管膀胱接合部の正常な形成.

    山本 雅之, 相野谷 慶子, 森口 尚

    日本小児泌尿器科学会雑誌　20　(2)　150-150　2011

  231. 転写因子Nrf2欠損はウレタン誘導性肺発癌を減少させNrf2欠損癌組織は免疫不全マウスで著しい生着不全と増殖能低下をきたす.

    佐藤 大希, 森口 尚, 田口 恵子, 海老名 雅仁, 貫和 敏博, 山本 雅之

    日本癌学会総会記事　70回　150-150　2011

  232. 蛋白尿による近位尿細管細胞酸化ストレス蓄積における腎内酸性環境の役割.

    相馬 友和, 阿部 倫明, 森口 尚, 阿部 高明, 山本 雅之, 伊藤 貞嘉

    血管　34　(4)　167-171　2011

  233. 慢性腎臓病における線維化と腎性貧血を担う細胞の同定およびその制御法の開発

    高瀬昌幸, 浅田礼光, 中村仁, 小口綾貴子, 浅田三咲子, 鈴木教郎, 山村研一, 名越慈人, 芝田晋介, NAGESWARA Tata Rao, JOERG HansFehling, 深津敦司, 峯岸直子, 北徹, 木村剛, 岡野栄之, 山本雅之, 柳田素子

    日本分子生物学会年会プログラム・要旨集(Web)　34th　WEB ONLY 2T13A-5　2011

  234. Discovery of the Negative Regulator of Nrf2, Keap1: A Historical Overview

    Ken Itoh, Junsei Mimura, Masayuki Yamamoto

    ANTIOXIDANTS & REDOX SIGNALING　13　(11)　1665-1678　2010/12

    DOI： 10.1089/ars.2010.3222 　

    ISSN： 1523-0864

    eISSN： 1557-7716

  235. 転写因子GATA2によるG1サイクリン遺伝子発現の制御

    峯岸直子, 鈴木教郎, 鈴木未来子, 張替秀郎, 山本雅之

    生化学　83回・33回　ROMBUNNO.2T8-4-4　2010/12

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  236. 成獣における誘導的エリスロポエチン遺伝子破壊の造血に与える影響

    山嵜瞬, 峯岸直子, 鈴木教郎, 小原直, PAN Xiaoqing, 平野育生, 寺社下浩一, 本田紅里穂, 山本雅之

    生化学　83回・33回　ROMBUNNO.1P-0304-0304　2010/12

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  237. 単離腎臓Erythropoietin産生細胞を用いたErythropoietin遺伝子制御機構の解明

    平野育生, PAN Xiaoqing, 鈴木教郎, 山崎瞬, 小原直, 峯岸直子, 山本雅之

    生化学　83回・33回　ROMBUNNO.1P-0690-0690　2010/12

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  238. Gata1遺伝子発現制御機構のBACトランスジェニックマウスを用いた解析

    高井 淳, 森口 尚, 鈴木 未来子, 大根田 絹子, 山本 雅之

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　83回・33回　2P-0548　2010/12

    Publisher: (公社)日本生化学会

  239. Erythropoietin producing cells Peer-reviewed

    MINEGISHI Naoko

    The Japanese journal of clinical hematology　51　(10)　1607-1615　2010/10/30

    Publisher: 「臨床血液」編集部

    DOI： 10.11406/rinketsu.51.1607 　

    ISSN： 0485-1439 1882-0824

  240. 宿主におけるNrf2欠損はMDSCs細胞に著明な酸化ストレスの蓄積を誘導し、肺癌転移に対して有利な微小環境を創造する(Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung by MDSCs ROS accumulation)

    佐藤 大希, 森口 尚, 田口 恵子, 海老名 雅仁, 貫和 敏博, 山本 雅之

    日本癌学会総会記事　69回　137-137　2010/08

    Publisher: (一社)日本癌学会

    ISSN： 0546-0476

  241. Nitric oxide responsive transcription factor Nrf2 regulates Fpn1-mediated iron efflux and counteracts the inflammation-mediated Fpn1 mRNA suppression

    Ken Itoh, Nobuhiko Harada, Masaya Kanayama, Atsushi Maruyama, Aruto Yoshida, Masayuki Yamamoto

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S56-S56　2010/06

    DOI： 10.1016/j.niox.2010.05.160 　

    ISSN： 1089-8603

  242. Electrophiles as potential anti-platelet reagents through modulation of gene expression in megalcaryocytes

    Hozumi Motohashi, Rie Fujita, Hiroyuki Aburatani, Masayuki Yamamoto

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S14-S15　2010/06

    DOI： 10.1016/j.niox.2010.05.037 　

    ISSN： 1089-8603

  243. Role of Nrf2/antioxidant response element in mammary carcinogenesis

    Lisa Becks, Misty Prince, Hannah Burson, Christopher Christophe, Ken Itoh, Masayuki Yamamoto, Elysse Orchard, Jerry McLarty, Songlin Zhang, Heather E. Kleiner-Hancock

    FASEB JOURNAL　24　2010/04

    ISSN： 0892-6638

  244. The rise of antioxidant signaling-The evolution and hormetic actions of Nrf2

    Jonathan Maher, Masayuki Yamamoto

    Toxicology and Applied Pharmacology　244　(1)　4-15　2010/04/01

    DOI： 10.1016/j.taap.2010.01.011 　

    ISSN： 0041-008X 1096-0333

  245. Nrf2 in toxicology and pharmacology: The good, the bad and the ugly?

    Jingbo Pi, Michael L. Freeman, Masayuki Yamamoto

    TOXICOLOGY AND APPLIED PHARMACOLOGY　244　(1)　1-3　2010/04

    DOI： 10.1016/j.taap.2010.01.005 　

    ISSN： 0041-008X

  246. 上皮細胞における転写因子Nrf2の活性化

    田口恵子, 鈴木隆史, 本橋ほづみ, 山本雅之

    生化学　82　(7)　2010

    ISSN： 0037-1017

  247. 上皮細胞における転写因子Nrf2の活性化

    田口恵子, 鈴木隆史, 本橋ほづみ, 山本雅之

    衛生薬学・環境トキシコロジー講演要旨集　2010　2010

    ISSN： 0919-2115

  248. 総胆管結紮による急性胆汁うっ滞におけるKeap1-Nrf2systemの役割

    杉本浩一, 岡田浩介, 正田純一, 蕨栄治, 田口恵子, 宇都宮洋才, 小田高司, 後藤信冶, 兵頭一之介, 石井哲郎, 山本雅之

    肝臓　51　(Supplement 1)　2010

    ISSN： 0451-4203

  249. 総胆管結紮による急性胆汁うっ滞におけるKeap1-Nrf2Systemの役割

    杉本浩一, 岡田浩介, 兵頭一之介, 正田純一, 蕨栄治, 石井哲郎, 田口恵子, 山本雅之, 後藤信治

    薬理と治療　38　(Suppl.2)　2010

    ISSN： 0386-3603

  250. 転写因子Nrf2は宿主肺における癌転移抑制性因子である

    佐藤大希, 田口恵子, 森口尚, 海老名雅仁, 貫和敏博, 山本雅之

    日本呼吸器学会雑誌　48　(増刊)　151-151　2010

    Publisher: (一社)日本呼吸器学会

    ISSN： 1343-3490

  251. 【ストレスと糖尿病】 ストレスと生体反応 Nrf2-Keap1システムによるストレス応答の制御 (Diabetes Frontier)

    宇留野晃, 森口尚, 山本雅之

    Diabetes Frontier　21　(4)　412-417　2010

    Publisher: (株)メディカルレビュー社

    ISSN： 0915-6593

  252. ニトロ化環状ヌクレオチドによる蛋白質S-グアニル化を介する酸化ストレス適応応答の分子機序

    藤井重元, 澤智裕, 居原秀, TONG Kit I., 井田智章, 岡本竜哉, AHTESHAM Ahmed Khandaker, 本橋ほづみ, 山本雅之, 赤池孝章

    生化学　2010

    ISSN： 0037-1017

  253. 【ストレスと糖尿病】 ストレスと生体反応 Nrf2-Keap1システムによるストレス応答の制御.

    宇留野 晃, 森口 尚, 山本 雅之

    Diabetes Frontier　21　(4)　412-417　2010

  254. GATA1は骨髄マスト細胞(BMMCs)の増殖と生存に必要である.

    植栗 幸洋, 大森 慎也, 石嶋 康史, 平林 優奈, 森口 尚, フィリップセン・シャック, 山本 雅之, 大根田 絹子

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　83回・33回　2P-0545　2010

  255. 転写因子Nrf2は宿主肺における癌転移抑制性因子である

    佐藤大希, 田口恵子, 森口尚, 海老名雅仁, 貫和敏博, 山本雅之

    日本呼吸器学会雑誌　48　(増刊)　151-151　2010

  256. Spherocytic Hemolytic Anemia Caused by Disruption of GATA1-FOG1 Interaction

    Ritsuko Shimizu, Atsushi Hasegawa, Masayuki Yamamoto

    BLOOD　114　(22)　321-321　2009/11

    ISSN： 0006-4971

  257. Compound Deficiency of Nrf2 and Selenoproteins in Hematopoietic Cells Leads to Severe Defects in Erythroid and Lympboid Lineage Development

    Yukie Kawatani, Takafumi Suzuki, Ritsuko Shimizu, Vincent Kelly, Masayuki Yamamoto

    BLOOD　114　(22)　788-788　2009/11

    ISSN： 0006-4971

  258. Rescue of Erythropoietin-Deficient Mice From Anemia by Complementation with BAC Transgene.

    Shun Yamazaki, Norio Suzuki, Naoshi Obara, Xiaoqing Pan, Ikuo Hirano, Kou-ichi Jishage, Kurisu Honda, Naoko Minegishi, Masayuki Yamamoto

    BLOOD　114　(22)　1397-1397　2009/11

    ISSN： 0006-4971

  259. Epo遺伝子欠失マウスのレスキューと条件付きEpo遺伝子破壊マウスの樹立

    山崎瞬, 鈴木教郎, 小原直, PAN Xiaoqing, 平野育生, 峯岸直子, 山本雅之

    生化学　82回　ROMBUNNO.4T4P-11-11　2009/09/25

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  260. 転写因子GATA2によるG1サイクリン遺伝子発現の制御

    峯岸直子, 張替英郎, 山本雅之

    臨床血液　50　(9)　950-950　2009/09

    Publisher: (一社)日本血液学会-東京事務局

    ISSN： 0485-1439

  261. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy (vol 105, 13568, 2008)

    Tatsuhiro Shibata, Tsutomu Ohta, Kit I. Tong, Akiko Kokubu, Reiko Odogawa, Koji Tsuta, Hisao Asamura, Masayuki Yamamoto, Setsuo Hirohashi

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　106　(25)　10392-10393　2009/06

    DOI： 10.1073/pnas.0905305106 　

    ISSN： 0027-8424

  262. BACトランスジェニックマウスを用いたGata1遺伝子発現制御機構の解析

    森口 尚, 鈴木 未来子, 高井 淳, 山本 雅之

    生化学　81　(6)　536-536　2009/06

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  263. オートファジー選択的基質p62による転写調節機構(Discovery of novel regulation of Nrf2-Keap1 system by a selective autophagy substrate, p62)

    小松 雅明, 黒河 博文, 和栗 聡, 小林 聡, 田中 啓二, 山本 雅之

    日本細胞生物学会大会講演要旨集　61回　196-196　2009/05

    Publisher: (一社)日本細胞生物学会

  264. Analysis of erythropoietic signal using in vivo β-globin LCR luciferase transgenic mice and application to doping material detection

    HORIE M., NAKA A., MATSUMOTO K., HIRANO I., YAMAMOTO M., IMAGAWA S.

    Japanese journal of clinical sports medicine　17　(2)　239-246　2009/04/30

    Publisher: 日本臨床スポーツ医学会

    ISSN： 1346-4159

  265. 転写因子Nrf2はコリンメチオニン欠乏食(MCDD)誘発非アルコール性脂肪性肝炎(NASH)を防御する

    杉本浩一, 岡田浩介, 正田純一, 蕨栄治, 柳川徹, 田口恵子, 兵頭一之介, 石井哲郎, 山本雅之

    肝臓　50　(Supplement 2)　2009

    ISSN： 0451-4203

  266. 転写因子Nrf2はコリンメチオニン欠乏食(MCDD)誘発非アルコール性脂肪性肝炎(NASH)を防御する

    杉本浩一, 岡田浩介, 正田純一, 蕨栄治, 柳川徹, 田口恵子, 兵頭一之介, 石井哲郎, 山本雅之

    肝臓　50　(Supplement 1)　2009

    ISSN： 0451-4203

  267. 親電子性環境化学物質1,2-ナフトキノンの毒性発現におけるNrf2/Keap1システムの役割

    三浦高, 角大悟, 姜海燕, 田口恵子, 山本雅之, 熊谷嘉人, 熊谷嘉人

    日本薬学会年会要旨集　129th　(1)　2009

    ISSN： 0918-9823

  268. Gata2低発現マウスに対する泌尿器トランスジェニックレスキュー解析

    相野谷慶子, 守田匡伸, 星野朝文, 大森慎也, 森口尚, 山本雅之

    日本分子生物学会年会講演要旨集　32nd　(Vol.3)　2009

  269. An induction of heme oxygenase -1 by isothiocyanate-related compounds

    FUSHIMI Aya, SAWADA Shohei, ASHINO Takasi, NUMAZAWA Satoshi, YAMAMOTO Masayuki, YOSHIDA Takemi

    Annual Meeting of the Japanese Society of Toxicology　36　(0)　4106-4106　2009

    Publisher: The Japanese Society of Toxicology

    More details Close

    【目的】ヘムオキシゲナーゼ-1(HO-1)はヘム分解の律速酵素であり、その酵素反応の代謝物の抗酸化作用から、酸化ストレスに対する防御作用を示すことが知られている。また、HO-1は様々な物質により誘導されることが報告されている。その中には天然化合物も含まれており、イソチオシアネート関連化合物やクルクミンなどもin vitroにおいてHO-1を誘導することが報告されている。しかし、これらの化合物のin vivoにおける作用は明らかではない。そこで本研究では、HO-1の転写因子として重要な役割を担っているNrf2のノックアウト(KO)マウスを用い、in vivoにおけるイソチオシアネート関連化合物によるHO-1誘導を検討した。【方法】C57BL/6系雄性の野生型(WT)及びNrf2 KOマウスにアリルイソチオシアネート(AITC)を腹腔内投与し、経時的に肝臓を摘出した。肝臓より常法に従いmRNAを抽出し、またミクロソーム画分を調製し、HO-1のmRNAとタンパク質をそれぞれノーザンブロット法とウエスタンブロット法を用いて測定した。【結果及び考察】WT及びNrf2 KOマウスにAITC(25mg/kg, i.p.)を処置し、HO-1タンパク量を検討したところ、両マウスにおいて有意な増加が認められた。その後用量依存性について検討した結果、WTマウスにおいては、HO-1のmRNA量及びタンパク量は用量依存的に増加した。以上のことから、AITCはin vivoにおいてもHO-1を誘導することが分かった。また、AITCは、Nrf2 KOマウスにおいてもHO-1誘導を引き起こすことから、in vitroの誘導機構とされているNrf2を介する以外の経路の関与が示唆された。現在、他の類縁化合物についても検討を進めているところである。

  270. Nrf2は肺における新規転移抑制因子として働く

    佐藤大希, 田口恵子, 森口尚, 鈴木隆史, 海老名雅仁, 貫和敏博, 山本雅之

    日本癌学会総会記事　68回　248-248　2009

  271. Ufm1システムはマウス胎児における赤血球造血に必須のシステムである

    辰巳 加奈子, 向井 陽美, 田中 啓二, 山本 雅之, 小松 雅明

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　81回・31回　3T10-1　2008/11

    Publisher: (公社)日本生化学会

  272. Bidirectional Control of Transcription Factor GATA2 and Cyclin/Cdks in Hematopoietic Cells

    Naoko Minegishi, Hideo Harigae, Masayuki Yamamoto

    BLOOD　112　(11)　495-495　2008/11

    ISSN： 0006-4971

  273. Induction of Hyperproliferative Fetal Megakaryopoiesis by An N-Terminally Truncated GATA1 Mutant

    Shimizu Ritsuko, Kobayashi Eri, Engel James, Yamamoto Masayuki

    BLOOD　112　(11)　434-435　2008/11

    ISSN： 0006-4971

  274. BACトランスジェニックマウスを用いたGata1遺伝子発現制御機構の解析

    高井 淳, 森口 尚, 鈴木 美来子, 大根田 絹子, 山本 雅之

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　81回・31回　2T3-11　2008/11

    Publisher: (公社)日本生化学会

  275. GATA-1の機能異常と白血病-Leukemogenesis related to GATA-1 mutation (日本産婦人科血液学会誌)

    安倍加奈子, 清水律子, 山本雅之

    日本産婦人科血液学会誌　17　1-8　2008/11

  276. エリスロポエチン産生細胞の同定と解析 (腎臓)

    潘小青, 鈴木教郎, 山本雅之

    腎臓　31　(2)　98-103　2008/11

    Publisher: (公財)日本腎臓財団

    ISSN： 0911-9752

  277. Nrf2-Keap1制御系から望む呼吸器疾患 (呼吸)

    佐藤大希, 山本雅之

    呼吸　27　(5)　439-445　2008/05

  278. Sulforaphane ameliorates H-pylori-induced gastritis via upregulating NRF2-dependent peroxiredoxin I in mice

    Akinon Yanaka, Daisuke Sato, Takeshi Shibahara, Ken Itoh, Masayuki Yamamoto, Toru Yanagawa, Tetsuro Ishii, Ichinosuke Hyodo

    GASTROENTEROLOGY　134　(4)　A124-A125　2008/04

    ISSN： 0016-5085

  279. Erythropoietin in myoblast maintenance and muscle regeneration

    Yi Jia, Norio Suzuki, Masayuki Yamamoto, Max Gassmann, Constance Tom Noguchi

    FASEB JOURNAL　22　2008/04

    ISSN： 0892-6638

  280. 酸化ストレス応答と疾患 (日本内分泌学会雑誌)

    山本雅之

    日本内分泌学会雑誌　84　(1)　183-183　2008/04

  281. 親電子性物質・活性酸素応答の分子メカニズム (Pharma Medica)

    山本雅之

    Pharma Medica　26　(2)　187-195　2008/02

  282. 閉塞性胆汁うっ滞において転写因子Nrf2は生体防御の役割を果たす

    杉本浩一, 岡田浩介, 正田純一, 兵頭一之介, 田口恵子, 山本雅之, 蕨栄治, 石井哲郎, 武田公一, 宇都宮洋才, 小田高司, 後藤信冶

    胆汁酸研究会プログラム・抄録集　30th　2008

  283. UDCAは転写因子Nrf2を活性化し,肝細胞の輸送,解毒代謝,抗酸化ストレス応答を賦活する

    岡田浩介, 正田純一, 田口恵子, 蕨栄治, 宇都宮洋才, 小田高司, 後藤信治, 石井哲郎, 山本雅之, 兵頭一之介

    肝臓　49　(Supplement 1)　2008

    ISSN： 0451-4203

  284. SIMULTANEOUS INDUCTION OF HEME OXYGENASE-1 AND CYTOCHROME P450 IN NRF2KO MICE

    Sawada Shohei, Ashino Takashi, Yamamoto Msayuki, Numasawa Satoshi, Fushimi Aya, Yoshida Takemi

    Abstracts of JSSX meeting　23　(0)　205-205　2008

    Publisher: The Japanese Society for the Study of Xenobiotics

    DOI： 10.14896/jssxmeeting.23.0.205.0 　

  285. Gata1遺伝子発現制御領域の血球分化段階特異的な機能的貢献

    森口尚, 鈴木未来子, 高井淳, 大根田絹子, 山本雅之

    生化学　2008

    ISSN： 0037-1017

  286. Role of nrf2 in gastric mucosal protection against oxidative stress

    Akinori Yanaka, Ken Itoh, Masayuki Yamamoto

    JOURNAL OF PHARMACOLOGICAL SCIENCES　106　18P-18P　2008

    ISSN： 1347-8613

  287. Nrf2 mediated induction of Cyp2b10 gene expression

    Yoshida Takemi, Okubo Haruyo, Ashino Takashi, Yamamoto Masayuki, Numazawa Satoshi

    Annual Meeting of the Japanese Society of Toxicology　35　(0)　197-197　2008

    Publisher: The Japanese Society of Toxicology

    More details Close

    【目的】転写因子Nrf2は抗酸化タンパク質群や薬物代謝第二相酵素群など生体防御関連遺伝子発現を統合的に制御し、酸化ストレス、発がん物質、環境汚染物質などから生体を保護する。シトクロムP450（P450）は、薬物代謝第一相反応において酸化反応を触媒する酵素群であり、薬物によるP450の誘導は、PXRやCAR等の分子種特異的な転写因子の存在が明らかとなっている。本研究では生体防御という一連の観点から、Nrf2がP450の遺伝子発現調節にも関与するという仮説を立て検討を行った。【方法】C57BL/6系雄性、8週齢のwild-type（WT）および Nrf2 ノックアウト（KO）マウスにブチルヒドロキシアニソール（BHA）、ホロン、フェノバルビタール（PB）を処置し、経時的に肝臓を摘出した。Cyp2b10のmRNAとタンパク質はそれぞれノーザンブロット法とウェスタンブロット法より測定した。肝におけるPBREM転写活性化はPBREM-Lucリポーターベクターを、CARの核移行はCAR-GFP発現ベクターをトランスフェクトすることにより検討した。【結果及び考察】BHA、ホロンおよびOPZ処置によるP450各分子種のmRNA量の変動を検討したところ、特にCyp2b10 mRNAで強い増加が認められた。さらに、Nrf2 KOマウスを用いてホロンによるCyp2b10の mRNA量、タンパク量の変動を検討したところWT比較して両者とも有意に低下していた。次にNrf2活性化物質によるCyp2b10誘導が、Nrf2による制御なのか、転写因子CARによるものなのかを詳細に検討する目的でPBを用いて検討した。WTマウスと比較してNrf2 KOマウスでは、PBのCyp2b10 mRNA誘導能が有意に減弱した。さらに、BHA処置12時間後にCARの核集積が確認され、BHA処置よるCARの核移行が明らかとなった。また、PBREM転写活性がホロン処置24時間後で上昇した。しかし、Nrf2 KOマウスではこれらのことが認められなかった。以上のことから、Nrf2のCyp2bの遺伝子発現への関与が示唆された。

  288. Hepatoprotective Role of Heme Oxygenase-1 in vivo in Basal and Oxidative Environments.

    Mamiya T, Katsuoka F, Hosoya T, Hirayama A, Kobayashi A, Maher J, Matsui H, Hyodo I, Yamamoto M

    Tohoku J Exp Med.　216　(4)　331-339　2008

    DOI： 10.1620/tjem.216.331 　

  289. 「食物と酸素由来の環境ストレスを感知するセンサー系」 (細胞工学)

    大辻摩希子, 山本雅之

    細胞工学　26　(12)　1386-1390　2007/12

    Publisher: 秀潤社

    ISSN： 0287-3796

  290. 酸素に対する細胞の適応応答の分子機構 (東北医学雑誌)

    山本雅之

    東北医学雑誌　119　(2)　143-149　2007/12

    Publisher: 東北医学会

    ISSN： 0040-8700

  291. Analyses of heme-regulated genes during erythoid differentiation Peer-reviewed

    Fujiwara Tohru, Okitsu Yoko, Ikura Tsuyoshi, Takahashi Shinichiro, Furuyama Kazumichi, Igarashi Kazuhiko, Yamamoto Masayuki, Sassa Shigeru, Harigae Hideo

    BLOOD　110　(11)　782A　2007/11/16

    ISSN： 0006-4971

  292. Leukemia-related transcription factor TEL expands erythroid precursors Peer-reviewed

    Mitani Kinuko, Eguchi-Ishimae Minenori, Maki Kazuhiro, Shimizu Ritsuko, Yamamoto Masayuki, Eguchi Mariko

    BLOOD　110　(11)　108B　2007/11

    ISSN： 0006-4971

  293. Function and gene expression regulation of GATA-1 and GATA-2 transcription

    Ritsuko Shimizu, Masayuki Yamamoto

    SEIKAGAKU　79　(10)　941-952　2007/10

    ISSN： 0037-1017

  294. 新しいユビキチン様修飾システムUfm1 systemの血液学的機能解析

    辰巳 加奈子, 向井 陽美, 小松 雅明, 家村 俊一郎, 夏目 徹, 田中 啓二, 山本 雅之

    臨床血液　48　(9)　909-909　2007/09

    Publisher: (一社)日本血液学会-東京事務局

    ISSN： 0485-1439

  295. GATA-2による間葉系幹細胞から脂肪細胞への分化制御 (臨床血液)

    沖津庸子, 高橋伸一郎, 峯岸直子, 亀岡淳一, 山本雅之, 張替秀郎

    臨床血液　48　(9)　934-934　2007/09

    ISSN： 0485-1439

  296. サイクリン/Cdk依存性リン酸化を介したGATA2の細胞周期特異的発現と血液細胞生存の制御 (臨床血液)

    峯岸直子, 古賀晋一郎, 阿部朋子, 峯岸正好, 土屋滋, 山本雅之

    臨床血液　48　(9)　914-914　2007/09

    ISSN： 0485-1439

  297. マウスGATA-1関連白血病と白血病幹細胞の遺伝学的解析 (日本癌学会総会記事)

    山本雅之, 安部加奈子, 清水律子

    日本癌学会総会記事　66回　248-248　2007/08

  298. シグナル伝達研究の最新動向 細胞から個体レベルへ 親電子性物質・活性酸素応答の分子メカニズム (生化学)

    山本雅之

    生化学　79　(7)　719-719　2007/07

  299. 【転写因子による生命現象解明の最前線 クロマチン制御機構・エピジェネティクスと転写因子複合体ネットワークの包括的解明】 転写研究の古くて新しい諸問題について (実験医学)

    五十嵐和彦, 山本雅之

    実験医学　25　(10)　1418-1430　2007/06

    Publisher: (株)羊土社

    ISSN： 0288-5514

  300. ダウン症候群と一過性骨髄造血(TAM) GATA転写因子群の機能異常と白血病 (日本産婦人科・新生児血液学会誌)

    山本雅之

    日本産婦人科・新生児血液学会誌　17　(1)　S-5　2007/06

    ISSN： 0916-8796

  301. Erratum: Identification of human GATA-2 gene distal IS exon and its expression in hematopoietic stem cell fractions (Journal of Biochemistry (2000) 127, (105-112))

    Xiaoqing Pan, Naoko Minegishi, Hideo Harigae, Hironori Yamagiwa, Masayoshi Minegishi, Yasuyuki Akine, Masayuki Yamamoto

    Journal of Biochemistry　141　767　2007/05/01

    DOI： 10.1093/jb/mvm078 　

    ISSN： 0021-924X

  302. 生物環境としての太陽紫外線 生体の環境応答制御機構 (FRAGRANCE JOURNAL)

    山本雅之

    FRAGRANCE JOURNAL　35　(5)　84-84　2007/05

  303. SREBP-1c遺伝子のin vivoプロモーター解析

    武内 謙憲, 矢作 直也, 中川 嘉, 関谷 元博, 松坂 賢, 大橋 健, 位高 啓史, 片岡 一則, 山崎 力, 永井 良三, 清水 律子, 山本 雅之, 山田 信博, 大須賀 淳一, 門脇 孝, 島野 仁

    糖尿病　50　(Suppl.1)　S-278　2007/04

    Publisher: (一社)日本糖尿病学会

    ISSN： 0021-437X

  304. Dimerisation of adaptor protein Keap1 is required to correctly position Nrf2 for ubiquitylation upon the Cul3-Rbx1 holoenzyme: the 'fixed-ends' model

    Michael McMahon, Ken Itoh, Masayuki Yamamoto, John D. Hayes

    FASEB JOURNAL　21　(6)　A1020-A1020　2007/04

    ISSN： 0892-6638

  305. 酸化ストレス応答と呼吸器疾患 Oxidative Stress Response and Respiratory Diseases (日本呼吸器学会雑誌)

    山本雅之

    日本呼吸器学会雑誌　45　(増刊)　2-2　2007/04

  306. G1HE-core contributes to the stage-specific expression of the Gata1 gene during erythroid development

    Mikiko Suzuki, Kinuko Ohneda, Masayuki Yamamoto

    BLOOD CELLS MOLECULES AND DISEASES　38　(2)　180-180　2007/03

    DOI： 10.1016/j.bcmd.2006.10.135 　

    ISSN： 1079-9796

  307. Regulation of mouse Gatal gene expression in erythroid progenitors

    Yamamoto Masayuki, Suzuki Mikiko, Suzuki Norio, Shimizu Ritsuko

    BLOOD CELLS MOLECULES AND DISEASES　38　(2)　188　2007/03

    DOI： 10.1016/j.bcmd.2006.10.153 　

    ISSN： 1079-9796

  308. Developmental regulation of Gata1 gene expression through adjacent GATA boxes and CP2-binding sites

    Shimizu Ritsuko, Fujita Rie, Ohmori Shinya, Ottolenghi Sergio, Ronchi Antonella, Yamamoto Masayuki

    BLOOD CELLS MOLECULES AND DISEASES　38　(2)　177　2007/03

    DOI： 10.1016/j.bcmd.2006.10.128 　

    ISSN： 1079-9796

  309. TAL-1 and GATA-1 coupled cell proliferation and differentiation during terminal erythroid differentiation

    Kadri Zahra, Goardon Nicolas, Shimizu Ritsuko, Ohneda Osamu, Hoang Tran, Leboulch Philippe, Gisselbrecht Sylvie, Yamamoto Masayuki, Chretien Stany, Romeo Paul Henri

    BLOOD CELLS MOLECULES AND DISEASES　38　(2)　175-176　2007/03

    DOI： 10.1016/j.bcmd.2006.10.125 　

    ISSN： 1079-9796

  310. Dynamic regulation of gata factor levels is more important than their identity

    Ferreira Rita, Wai Albert, Shimizu Ritsuko, Gillemans Nynke, Rottier Robbert, von Lindern Marieke, Ohneda Kinuko, Grosveld Frank, Yamamoto Masayuki, Philipsen Sjaak

    BLOOD CELLS MOLECULES AND DISEASES　38　(2)　171-172　2007/03

    DOI： 10.1016/j.bcmd.2006.10.117 　

    ISSN： 1079-9796

  311. インチンコウ湯は転写因子Nrf2を活性化し,生体の抗酸化ストレス応答機構を賦活する

    岡田浩介, 正田純一, 兵頭一之介, 石井哲郎, 大嶽信弘, 鈴木祥子, 山本雅浩, 田口恵子, 山本雅之

    日本消化器病学会雑誌　104　2007

    ISSN： 0446-6586

  312. 恒常的なNrf2活性化によるアセトアミノフェン毒性発現の防御

    田口恵子, MAHER Jonathan M., 川谷幸恵, 鈴木隆史, 山本雅之

    Journal of Toxicological Sciences　32　(Supplement)　2007

    ISSN： 0388-1350

  313. Nrf2/Keap1システムは神経細胞においてメチル水銀の解毒を促す

    外山喬士, 角大悟, 角大悟, 新開泰弘, 田口恵子, 山本雅之, 山本雅之, 熊谷嘉人, 熊谷嘉人

    Journal of Toxicological Sciences　32　(Supplement)　2007

    ISSN： 0388-1350

  314. 1,2-ナフトキノンの解毒に関わるNrf2/Keap1システムの役割

    JIANG Hai-Yan, 角大悟, 田口恵子, TONG Kit I., 山本雅之, 熊谷嘉人, 熊谷嘉人

    衛生薬学・環境トキシコロジー講演要旨集　2007　2007

    ISSN： 0919-2115

  315. Keap1遺伝子部分破壊によるNrf2抑制破綻の表現型解析

    田口恵子, PFEIFFER Martin J., MAHER Jonathan M., 川谷幸恵, 鈴木隆史, 山本雅之

    衛生薬学・環境トキシコロジー講演要旨集　2007　2007

    ISSN： 0919-2115

  316. 胆汁うっ滞症における肝輸送蛋白の発現異常と分子標的薬物療法

    正田純一, 岡田浩介, 石井哲郎, 田口恵子, 山本雅之

    日本薬学会年会要旨集　127th　(1)　2007

    ISSN： 0918-9823

  317. ME3738によるアセトアミノフェン肝傷害時のNrf2防御機能の亢進

    川村祐司, 川村祐司, 平塚一幸, 蓮沼惠子, 伊藤富美, 庄司陽子, 今井聖子, 黒沢亨, 田口恵子, 田口恵子, 田口恵子, 芦野隆, 山本雅之, 山本雅之, 山本雅之, 吉田武美

    Journal of Toxicological Sciences　32　(Supplement)　2007

    ISSN： 0388-1350

  318. 赤血球造血におけるSUMO化GATA-1の生理的意義

    清水律子, 大森慎也, 森口尚, 山本雅之, 山本雅之

    生化学　2007

    ISSN： 0037-1017

  319. INDUCTION OF CYP2B10 AND CYP2A GENE EXPRESSIONS BY NRF2 ACTIVATORS

    Haruyo Ohkubo, Takashi Ashino, Masayuki Yamamoto, Satoshi Numazawa, Takemi Yoshida

    DRUG METABOLISM REVIEWS　39　195-196　2007

    ISSN： 0360-2532

  320. 転写因子GATA‐2とCyclin/Cdk系との双方向性制御

    峯岸直子, 古賀晋一郎, 古賀晋一郎, 阿部朋子, 峯岸正好, 土屋滋, 山本雅之

    生化学　2P-0998　2007

    ISSN： 0037-1017

  321. Regulation of adipocyte differentiation of bone marrow stromal cells by transcription factor GATA-2.

    Okitsu Yoko, Takahashi Shinichiro, Minegishi Naoko, Kameoka Junichi, Kaku Mitsuo, Yamamoto Masayuki, Sasaki Takeshi, Harigae Hideo

    Biochem Biophys Res Commun　364　(2)　383-387　2007

    DOI： 10.1016/j.bbrc.2007.10.031 　

    ISSN： 0006-291X

  322. 酸素センシングと赤血球造血シグナル (細胞39)

    今川 重彦, 小原 直, 鈴木 教郎, 山本 雅之

    細胞39　537-540　2007/01

  323. 「GATA因子スイッチングとGATA-1白血病」 (生化学 79)

    清水律子, 山本雅之

    生化学 79　941-952　2007/01

  324. 「酸化ストレス防御のための生体内センサー: Keap1-Nrf2制御システム」 (化学と生物 45)

    田口恵子, 山本雅之

    化学と生物 45　45　(12)　857-862　2007/01

    Publisher: Japan Society for Bioscience, Biotechnology, and Agrochemistry

    DOI： 10.1271/kagakutoseibutsu1962.45.857 　

    ISSN： 0453-073X

  325. Cell-cycle-dependent oscillation of GATA2 expression in hematopoietic cells.

    Shinichiro Koga, Nobuhiro Yamaguchi, Tomoko Abe, Masayoshi Minegishi, Shigeru Tsuchiya, Masayuki Yamamoto, Naoko Minegishi

    BLOOD　108　(11)　129B-129B　2006/11

    ISSN： 0006-4971

  326. Phenotypic changes of hematopoietic stem cells and stromal cells by aberrant expression of GATA-2; Possible role for the development of aplastic anemia.

    Yoko Okitsu, Hideo Harigae, Shinichiro Takahashi, Naoko Minegishi, Norio Suzuki, Junichi Kameoka, Masayuki Yamamoto, Takeshi Sasaki

    BLOOD　108　(11)　378A-378A　2006/11

    ISSN： 0006-4971

  327. 転写因子GATA-2の細胞周期特異的発現制御 P815細胞を用いた内在性発現の検討 (臨床血液)

    古賀晋一郎, 阿部朋子, 山口展寛, 土屋滋, 山本雅之, 峯岸直子

    臨床血液　47　(9)　1219-1219　2006/09

  328. Role of 15-deoxy prostaglandin j2 and NRF2 in protection of gastric mucosa against oxidative stress during H-pylori infection in mice

    Akinori Yanaka, Ken Itoh, Masafumi Truchi, Hideo Suzuki, Takeshi Shibahara, Hirofumi Matsui, Akira Nakahara, Ichmosuke Hyodo, Masayuki Yamamoto

    GASTROENTEROLOGY　130　(4)　A150-A150　2006/04

    ISSN： 0016-5085

  329. Lansoprazole protects gastric mucosa from H.pylori-induced oxidative injury by up-regulating NRF2-dependent antioxidant enzymes in mice

    Akinon Yanaka, Ken Itoh, Hirofumi Matsui, Masafumi Tauchi, Hideo Suzuki, Takeshi Shibahara, Akira Nakahara, Ichinosuke Hyodo, Masayuki Yamamoto

    GASTROENTEROLOGY　130　(4)　A407-A407　2006/04

    ISSN： 0016-5085

  330. KeaP1-Nrf2システムが担う生体防御機構 (特集 活性酸素・フリーラジカル機能と病態解明への新たなる展開 バイオスピンとシグナル伝達)

    勝岡 史城, 山本 雅之

    細胞工学　25　(2)　153-156　2006/02

    Publisher: 秀潤社

    ISSN： 0287-3796

  331. Caffeine と taurine の併用による持久力および乳酸に及ぼす効果

    今川 貴彦, 松本 健, 小原 直, 鈴木 教郎, 山本 雅之, 今川 重彦

    臨床スポーツ医学 = The journal of clinical sports medicine　23　(2)　207-210　2006/02/01

    Publisher: 文光堂

    ISSN： 0289-3339

  332. ウルソデオキシコール酸(UDCA)は転写因子Nrf2を活性化し,肝細胞の輸送,解毒代謝,抗酸化ストレス応答を賦活する

    岡田浩介, 正田純一, 兵頭一之介, 田口恵子, 山本雅之, 蕨栄治, 石井哲郎, 宇都宮洋才, 小田高司, 後藤信冶

    胆汁酸研究会プログラム・抄録集　28th　2006

  333. Integrated mechanisms for detoxification and anti-oxidant response in animals

    H Motohashi, T Suzuki, H Okawa, K Tong, M Tauchi, F Katsuoka, A Kobayashi, Y Fujii, M Yamamoto

    PLANT AND CELL PHYSIOLOGY　47　S19-S19　2006

    ISSN： 0032-0781

  334. 2-oxoglutarate down-regulates expression of vascular endothelial growth factor and erythropoietin through decreasing hypoxia inducible factor-1 alpha and inhibits angiogenesis.

    S Imagawa, K Matsumoto, N Obara, N Suzuki, T Nagasawa, M Yamamoto

    BLOOD　106　(11)　69B-69B　2005/11

    ISSN： 0006-4971

  335. GATA motif on the erythropoietin gene promoter is essential for repression of ectopic constitutive erythropoietin production.

    N Obara, N Suzuki, K Ki-Bom, S Imagawa, T Nagasawa, M Yamamoto

    BLOOD　106　(11)　878A-878A　2005/11

    ISSN： 0006-4971

  336. Essential role and regulatory mechanism of the erythropoietin gene in the liver.

    N Suzuki, N Obara, KB Kim, XQ Pan, KI Jishage, S Imagawa, M Yamamoto

    BLOOD　106　(11)　878A-878A　2005/11

    ISSN： 0006-4971

  337. mafB deficient mouse results in impaired macrophage differentiation.

    M Hamada, T Moriguchi, N Morito, C Zhang, K Hasegawa, K Yoh, E Kuroda, T Yokomizo, JD Engel, M Yamamoto, S Takahashi

    BLOOD　106　(11)　626A-627A　2005/11

    ISSN： 0006-4971

  338. The direct association of GATA-1 to rb is necessary for definitive erythropoiesis.

    Z Kadri, R Shimizu, S Gisselbrecht, O Ohneda, M Yamamoto, PH Romeo, S Chretien

    BLOOD　106　(11)　94A-94A　2005/11

    ISSN： 0006-4971

  339. 【血液疾患 state of arts】 病態生理に関する基礎的・臨床的研究 最近の進歩 病態研究 血液疾患に対する発生工学的アプローチ 転写因子GATA-1の機能破綻と血液疾患 (医学のあゆみ)

    清水律子, 山本雅之

    医学のあゆみ　別冊　(血液疾患-state of arts Ver.3)　187-190　2005/09

  340. ユビキチン・プロテアソーム経路を介したGATA-2の迅速な代謝回転 (日本血液学会・日本臨床血液学会総会プログラム・抄録集)

    峯岸直子, 鈴木教郎, 川谷幸恵, 清水律子, 山本雅之

    日本血液学会・日本臨床血液学会総会プログラム・抄録集　67回・47回　749-749　2005/09

    Publisher: 日本臨床血液学会

  341. Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells. (vol 280, pg 27244, 2005)

    T Hosoya, A Maruyama, MI Kang, Y Kawatani, T Shibata, K Uchida, E Warabi, N Noguchi, K Itoh, M Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　280　(33)　29988-29988　2005/08

    ISSN： 0021-9258

  342. GATA阻害薬・HIF-1活性薬(K-11706)による持久力増強効果

    今川 重彦, 松本 健, 長澤 俊郎, 土肥 武, 鈴木 教郎, 山本 雅之

    臨床スポーツ医学 = The journal of clinical sports medicine　22　(8)　1049-1052　2005/08/01

    Publisher: 文光堂

    ISSN： 0289-3339

  343. モデル生物が切り開く造血発生研究の新展開 (発生システムのダイナミクス) -- (組織・器官形成)

    大根田 絹子, 山本 雅之

    蛋白質核酸酵素　50　(6)　633-637,495　2005/05

    Publisher: 共立出版

    ISSN： 0039-9450

  344. Application of Modern Biotechnology and Mouse Genetics for the Study of Hematopoiesis Invited

    Yamamoto M, Shimizu R

    Education Program Book　157-163　2005/04

    Publisher: he Joint Meeting of the 67th Annual Meeting of Japanese Society of Hematology and the 47th Annual Meeting of Japanese Society of Clinical Hematology

  345. Two novel erythroid progenitor fractions expressing GATA-1.

    N Suzuki, O Ohneda, N Obara, S Imagawa, M Yamamoto

    BLOOD CELLS MOLECULES AND DISEASES　34　(2)　124-125　2005/03

    ISSN： 1079-9796

  346. Fine regulation of GATA-1 and GATA-2 gene expression in vivo hematopoiesis.

    M Yamamoto, N Suzuki, O Ohneda, S Takahashi, JD Engel

    BLOOD CELLS MOLECULES AND DISEASES　34　(2)　132-132　2005/03

    ISSN： 1079-9796

  347. Perturbation of hematopoiesis as a consequence of transgene insertion into the proximity of c-myb gene.

    HY Mukai, H Motohashi, N Suzuki, O Ohneda, T Nagasawa, M Yamamoto

    BLOOD CELLS MOLECULES AND DISEASES　34　(2)　108-108　2005/03

    ISSN： 1079-9796

  348. Self-association of GATA-1 is required for erythropoiesis in vivo.

    R Shimizu, K Ohneda, K Nishikawa, CD Trainor, M Yamamoto

    BLOOD CELLS MOLECULES AND DISEASES　34　(2)　122-122　2005/03

    ISSN： 1079-9796

  349. Identification of a novel functional domain conferring positive and negative bidirectional regulator property on MafG in megakaryocytes.

    H Motohashi, F Katsuoka, C Francastel, JD Engel, M Yamamoto

    BLOOD CELLS MOLECULES AND DISEASES　34　(2)　107-108　2005/03

    ISSN： 1079-9796

  350. Small Maf proteins are dispensable for the expression of globin genes in primitive hematopoiesis.

    F Katsuoka, H Motohashi, JD Engel, M Yamamoto

    BLOOD CELLS MOLECULES AND DISEASES　34　(2)　97-97　2005/03

    ISSN： 1079-9796

  351. GATA1 function, a paradigm for transcription factors in hematopoiesis

    Rita Ferreira, Kinuko Ohneda, Masayuki Yamamoto, Sjaak Philipsen

    Molecular and Cellular Biology　25　(4)　1215-1227　2005/02

    DOI： 10.1128/MCB.25.4.1215-1227.2005 　

    ISSN： 0270-7306

  352. Regulatory role of the COX-2 pathway in the Nrf2-mediated anti-inflammatory response

    Ken Itoh, Masayuki Yamamoto

    Journal of Clinical Biochemistry and Nutrition　37　(1)　9-18　2005

    DOI： 10.3164/jcbn.37.9 　

    ISSN： 0912-0009

  353. 赤血球系細胞分化の転写因子GATA‐1による増殖・分化調節機構

    ZHENG J, 北島健二, 仲野徹, 峯岸直子, 山本雅之

    日本分子生物学会年会プログラム・講演要旨集　27th　689　2004/11/25

  354. Ubiquitin-proteasome-dependent degradation of GATA-2 and its contribution to the UV-C-induced down-regulation

    N Minegishi, N Suzuki, Y Kawatani, M Yamamoto

    BLOOD　104　(11)　133B-133B　2004/11

    ISSN： 0006-4971

  355. Nrf2-Keap1 defines a physiologically important stress response mechanism. Invited Peer-reviewed

    Motohashi Hozumi, Yamamoto Masayuki

    Trends Mol Med　10　(11)　549-557　2004/11

    DOI： 10.1016/j.molmed.2004.09.003 　

  356. 【転写制御と疾患 温故知新】 GATA-1変異と白血病 転写因子の質的異常と量的異常 (医学のあゆみ)

    長野真澄, 清水律子, 山本雅之

    医学のあゆみ　211　(2)　159-162　2004/10

  357. RUNX1/AML1の増量投与は骨髄性白血病の発生を促進する DS-AMKL(ダウン症関連急性巨核芽球性白血病)の意味(An increased dose of RUNX1/AML1 promotes the development of myeloid leukemia: implications for DS-AMKL)

    大里 元美, 柳田 匡俊, 山下 南海子, 岩崎 正幸, 中村 卓郎, 横溝 智雅, 高橋 智, 山本 雅之, 重定 勝哉, 伊藤 嘉明

    日本癌学会総会記事　63回　409-409　2004/09

    Publisher: 日本癌学会

    ISSN： 0546-0476

  358. 造血幹細胞の発生と分化を制御する転写因子GATA‐2のドメイン特異的な機能

    峯岸直子, 川谷幸恵, 山本雅之

    臨床血液　45　(8)　873　2004/08/30

    ISSN： 0485-1439

  359. モデルマウスが教える造血制御と白血病発症 GATA-1ノックダウンマウス (Mebio)

    清水律子, 山本雅之

    Mebio　21　(8)　58-62　2004/08

  360. Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles

    Ken Itoh, Kit I. Tong, Masayuki Yamamoto

    Free Radical Biology and Medicine　36　(10)　1208-1213　2004/05/15

    DOI： 10.1016/j.freeradbiomed.2004.02.075 　

    ISSN： 0891-5849

  361. Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-D12,14-prostagiandin J2

    K Itoh, M Mochizuki, Y Ishii, T Ishii, K Sekizawa, K Uchida, M Yamamoto

    FASEB JOURNAL　18　(8)　C94-C94　2004/05

    ISSN： 0892-6638

  362. Molecular mechanism of adaptive response to electrophiles

    ITOH Ken, YAMAMOTO Masayuki

    76　(4)　339-348　2004/04/25

    Publisher: 日本生化学会

    ISSN： 0037-1017

  363. 転写因子・4 転写因子と血液疾患

    峯岸直子, 山本雅之

    臨床検査　48　(4)　473-481　2004/04/15

    DOI： 10.11477/mf.1542100484 　

    ISSN： 0485-1420

  364. Role of Nrf2 in mediating regulation of cytoprotective genes by chemopreventive agents

    JD Hayes, M McMahon, IR Jowsey, Q Jiang, P Nioi, LG Higgins, LI McLellan, CJ Henderson, K Itoh, M Yamamoto

    TOXICOLOGY　194　(3)　198-199　2004/01

    ISSN： 0300-483X

  365. プロテアソーム依存性分解系を介したGATA‐2蛋白質の迅速な代謝回転

    峯岸直子, 鈴木教郎, 川谷幸恵, 山本雅之

    日本分子生物学会年会プログラム・講演要旨集　26th　488　2003/11/25

  366. 新規GATA因子結合蛋白質WTAP(Wilms′ tumor 1‐associating protein)の相互作用および細胞内局在

    堀内恵子, 梅渓通久, 南敬, 峯岸直子, 山本雅之, 浜窪隆雄, 児玉龍彦

    日本分子生物学会年会プログラム・講演要旨集　26th　842　2003/11/25

  367. A novel GATA-specific inhibitor (GSI) rescues anemia of chronic disease by oral administration.

    S Imagawa, Y Nakano, N Obara, N Suzuki, T Nagasawa, M Yamamoto

    BLOOD　102　(11)　510A-510A　2003/11

    ISSN： 0006-4971

  368. Transcription factor regulation of drug metabolizing enzymes and antioxidant proteins

    YAMAMOTO Masayuki

    32　53-53　2003/10/31

  369. BACH1トランスジェニック・マウスにおける血小板産生抑制及び骨髄繊維化

    土岐 力, 金崎 里香, 山本 雅之, 伊藤 悦朗

    臨床血液　44　(8)　865-865　2003/08

    Publisher: (一社)日本血液学会-東京事務局

    ISSN： 0485-1439

  370. Transgenic expression of erythropoietin receptor (EPOR) under the GATA-1 gene regulatory domain rescued EPOR knockout mouse from lethality.

    N Suzuki, O Ohneda, HY Mukai, S Imagawa, S Takahashi, M Yamamoto

    BLOOD CELLS MOLECULES AND DISEASES　31　(1)　166-166　2003/07

    ISSN： 1079-9796

  371. A minigene containing four discrete cis elements recapitulates GATA-1 gene expression in vivo.

    K Ohneda, R Shimizu, S Takahashi, JD Enge, M Yamamoto

    BLOOD CELLS MOLECULES AND DISEASES　31　(1)　157-157　2003/07

    ISSN： 1079-9796

  372. Hemoprotein BACH1 regulates enhancer accessibility of heme oxygenase-1 gene.

    JY Sun, A Muto, H Suzuki, O Nakajima, M Yamamoto, K Igarashi

    BLOOD CELLS MOLECULES AND DISEASES　31　(1)　146-147　2003/07

    ISSN： 1079-9796

  373. 中胚葉におけるGata-2の発現と細胞運命

    小川 峰太郎, 山本 雅之

    日本発生生物学会大会講演要旨集　36回　124-124　2003/06

    Publisher: 日本発生生物学会

  374. Thymocyte alterations in CD2-driven constitutively active arylhydrocarbon receptor (AhR) transgenic mice.

    K Nohara, S Tsukumo, T Ito, M Yamamoto, H Motohashi, A Hida, Y Fujii-Kuriyama, K Inouye, H Nagai, C Tohyama

    TOXICOLOGICAL SCIENCES　72　362-362　2003/03

    ISSN： 1096-6080

  375. A constitutively active aryl hydrocarbon receptor induces growth inhibition by cell cycle arrest and apoptosis in Jurkat T cells.

    T Ito, S Tsukumo, M Yamamoto, H Motohashi, N Suzuki, Y Fujii-Kuriyama, J Mimura, C Tohyama, K Nohara

    TOXICOLOGICAL SCIENCES　72　367-367　2003/03

    ISSN： 1096-6080

  376. c-Maf knockoutマウスの骨・軟骨組織における表現型解析

    いそ貝真史, 梶原美和子, 川内紫真子, 浜田理人, 森口尚, 山本雅之, 高橋智

    日本分子生物学会年会プログラム・講演要旨集　26th　2003

  377. mafAノックアートマウスの解析

    ZHANG C, 森口尚, 梶原美和子, 大石久史, 浜田理人, 森戸直記, 大根田絹子, DOUGLAS ENGEL J, 山本雅之

    日本分子生物学会年会プログラム・講演要旨集　26th　2003

  378. ヒト型ダイオキシン受容体ノックインマウスの薬剤応答性

    本橋ほづみ, 森口尚, 大迫誠一郎, 青木康展, 遠山千春, 山本雅之

    衛生薬学・環境トキシコロジー講演要旨集　2003　2003

    ISSN： 0919-2115

  379. GATA-specific inhibitor (K-7174) rescues anemia induced by IL-1 beta, TNF-alpha or L-NMMA.

    S Imagawa, Y Nakano, N Obara, N Suzuki, T Doi, T Kodama, M Yamamoto, T Nagasawa

    BLOOD　100　(11)　657A-657A　2002/11

    ISSN： 0006-4971

  380. Aberrant iron accumulation and peroxidized status of erythroid-specific delta-aminolevulinate synthase (ALAS2)-deficient definitive erythroblasts.

    H Harigae, O Nakajima, K Furuyama, H Yokoyama, K Ishizawa, K Miyamura, J Kameoka, T Sasaki, M Kaku, M Yamamoto, S Sassa

    BLOOD　100　(11)　6A-6A　2002/11

    ISSN： 0006-4971

  381. The multifunctional gene YB-1 is a novel target of GATA factors in erythroid differentiation.

    H Yokoyama, H Harigae, S Takahashi, K Miyamura, J Kameoka, K Ishizawa, M Yamada, K Furuyama, M Kaku, T Sasaki, S Takahashi, M Yamamoto

    BLOOD　100　(11)　718A-718A　2002/11

    ISSN： 0006-4971

  382. GATA転写因子と造血器腫瘍 (特集 癌細胞のシグナル伝達)

    張替 秀郎, 山本 雅之

    モレキュラ-メディシン　39　(11)　1298-1303　2002/11

    Publisher: 中山書店

    ISSN： 0918-6557

  383. 赤芽球・巨核球特異的発現ベクターを用いたヒトBACH1トランスジェニック・マウスの表現型の検索

    土岐 力, 金崎 里香, 伊藤 悦朗, 山本 雅之

    臨床血液　43　(8)　126-126　2002/08

    Publisher: (一社)日本血液学会-東京事務局

    ISSN： 0485-1439

  384. 赤血球型アミノレブリン酸合成酵素欠損赤芽球における鉄代謝異常

    張替 秀郎, 中島 修, 古山 和道, 横山 寿行, 佐々木 毅, 山本 雅之, 佐々 茂

    臨床血液　43　(8)　122-122　2002/08

    Publisher: (一社)日本血液学会-東京事務局

    ISSN： 0485-1439

  385. Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors. Invited Peer-reviewed

    Motohashi Hozumi, O'Connor Tania, Katsuoka Fumiki, Engel James Douglas, Yamamoto Masayuki

    Gene　294　(1月2日)　1-12　2002/07

    DOI： 10.1016/S0378-1119(02)00788-6 　

  386. Elevation of vascular endothelial growth factor in patients with obstructive sleep apnea-hypopnea syndrome is not due to increased platelet counts - Response

    S Imagawa, Y Yamaguchi, M Higuchi, T Neichi, Y Hasegawa, H Mukai, N Suzuki, M Yamamoto, T Nagasawa

    BLOOD　99　(1)　393-394　2002/01

    ISSN： 0006-4971

  387. GATA-2 is a negative regulator of erythropoietin gene expression in mouse.

    S Imagawa, N Suzuki, K Ohmine, N Obara, M Yamamoto, T Nagasawa

    BLOOD　98　(11)　127B-127B　2001/11

    ISSN： 0006-4971

  388. 成体での血管新生におけるHLFの役割

    守田匡伸, 高橋智, 中島修, 山下年晴, 柴原茂樹, 鵜殿徹男, 富田浩史, 山本雅之, 藤井義明

    生化学　73　(8)　918　2001/08/25

    ISSN： 0037-1017

  389. 造血組織の個体発生における転写因子の発現と機能の動的解析

    峯岸直子, 鈴木教郎, 山本雅之

    Cytom Res　11　(Suppl.)　20-20　2001/06/01

    Publisher: (一社)日本サイトメトリー学会

    ISSN： 0916-6920

  390. 遺伝子改変マウスを用いた血液疾患病態の解明 (臨床血液)

    山本雅之, 清水律子

    臨床血液　42　(4)　233-236　2001/04

    Publisher: 日本臨床血液学会

    DOI： 10.11406/rinketsu.42.233 　

    ISSN： 0485-1439

  391. p45 NF-E2関連転写因子Bach1の新たなイソ・フォームの機能解析(Functional Analysis of a Novel Isoform of p45 NF-E2 Related Transcription Factor BACH1)

    土岐 力, 金崎 里香, 伊藤 悦朗, 山本 雅之

    International Journal of Hematology　73　(Suppl.1)　119-119　2001/03

    Publisher: (一社)日本血液学会

    ISSN： 0925-5710

  392. Nrf2 activation by electrophiles is mediated by the inhibition of proteasomal degradation of Nrf2 protein in activated macrophages

    K Itoh, T Ishii, N Wakabayashi, Y Katoh, M Yamamoto

    FASEB JOURNAL　15　(5)　A899-A899　2001/03

    ISSN： 0892-6638

  393. ヘム欠損成体型赤芽球の形質解析

    張替秀郎, 中島修, 古山和道, 佐々木毅, 佐々茂, 山本雅之

    International Journal of Hematology　73　(Suppl.1)　80-80　2001

  394. Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1.

    Ogawa K, Sun J, Taketani S, Nakajima O, Nishitani C, Sassa S, Hayashi N, Yamamoto M, Shibahara S, Fujita H, Igarashi K

    EMBO J　20　(11)　2835-2843　2001

    DOI： 10.1093/emboj/20.11.2835 　

  395. Runx1/AML1/PEBP2 alpha beta is involved in primitive hematopoiesis in addition to definitive hematopoiesis.

    T Yokomizo, M Osato, S Takahashi, T Kuroha, M Yamamoto, Y Ito

    BLOOD　96　(11)　283A-283A　2000/11

    ISSN： 0006-4971

  396. Non-hematopoietic expression of mouse EpoR is inessential for survival, development, and reproduction.

    N Suzuki, H Mukai, M Higuchi, S Takahashi, S Imagawa, M Yamamoto

    BLOOD　96　(11)　84A-84A　2000/11

    ISSN： 0006-4971

  397. L-arginine rescues decreased erythropoietin gene expression by stimulating GATA-2 with N-G-monomethyl L-arginine.

    S Imagawa, T Tarumoto, H Mukai, M Higuchi, N Imai, N Suzuki, M Yamamoto, K Ozawa, T Nagasawa

    BLOOD　96　(11)　132B-132B　2000/11

    ISSN： 0006-4971

  398. Differential role of the erythroid-specific delta-aminolevulinate synthase in primitive and definitive erythropoiesis.

    H Harigae, O Nakajima, N Suwabe, K Furuyama, T Sasaki, M Kaku, M Yamamoto, S Sassa

    BLOOD　96　(11)　228A-228A　2000/11

    ISSN： 0006-4971

  399. Functional role of STAT3 in vivo megakaryopoiesis.

    K Kirito, M Osawa, R Shimizu, A Oda, K Nakajima, H Morita, M Yamamoto, K Ozawa, N Komatsu

    BLOOD　96　(11)　538A-538A　2000/11

    ISSN： 0006-4971

  400. Cloning of a coproporphyrinogen oxidase promoter regulatory element binding protein.

    S Takahashi, K Furuyama, A Kobayashi, S Taketani, H Harigae, M Yamamoto, K Igarashi, H Yokoyama, Ishikawa, I, O Sasaki, J Kameoka, K Miyamura, K Meguro, N Hayashi, T Sasaki

    BLOOD　96　(11)　285A-285A　2000/11

    ISSN： 0006-4971

  401. Ring sideroblast formation in mouse partially rescued from the embryonic lethality caused by the lack of erythroid-specific 5-aminolevulinate synthase gene.

    O Nakajima, S Takahashi, M Yamamoto

    BLOOD　96　(11)　228A-228A　2000/11

    ISSN： 0006-4971

  402. Contribution of small maf transcription factors to erythropoiesis.

    D Engel, K Igarashi, F Katsuoka, H Motohashi, K Onodera, J Shavit, N Suwabe, M Yamamato

    BLOOD CELLS MOLECULES AND DISEASES　26　(5)　494-495　2000/10

    ISSN： 1079-9796

  403. Regulation of mouse GATA-1 and GATA-2 genes.

    M Yamamoto, N Minegishi, R Shimizu, N Suzuki, S Takahashi

    BLOOD CELLS MOLECULES AND DISEASES　26　(5)　507-507　2000/10

    ISSN： 1079-9796

  404. GATA factor transgenes under GATA-1 locus control rescue germ line GATA-1 mutant deficiencies.

    R Shimizu, S Takahashi, JD Engel, M Yamamoto

    BLOOD CELLS MOLECULES AND DISEASES　26　(5)　527-528　2000/10

    ISSN： 1079-9796

  405. Genetic switch for transcriptional activation through MARE composed of the balance between small Maf factors and their partner molecules.

    H Motohashi, F Katsuoka, JD Engel, M Yamamoto

    BLOOD CELLS MOLECULES AND DISEASES　26　(5)　522-522　2000/10

    ISSN： 1079-9796

  406. 転写因子GATA‐2による造血幹細胞制御と発がん

    峯岸直子, 山本雅之

    Jpn J Cancer Res　91　(Supplement (Sept))　440-440　2000/09/01

    Publisher: 日本癌学会

    ISSN： 0910-5050

  407. 赤血球・巨核球造血におけるStat3の役割 トランスジェニックマウスを用いた機能解析

    桐戸敬太, 田中勝, 大沢匡毅, 森田晴彦, 清水律子, 山本雅之, 小沢敬也, 小松則夫

    International Journal of Hematology. Supplement　71　(1)　179　2000/04

    ISSN： 0917-1258

  408. 赤血球系 1. 赤血球産生と転写因子

    峯岸直子, 山本雅之

    Annual Review 血液　2000　47-57　2000/01/20

  409. ヒトオレキシン・プロモーターの機能解析.

    森口 尚, 桜井 武, 高橋 智, 山本 雅之, 後藤 勝年

    日本臨床分子医学会記録　37　38-38　2000

  410. 造血前駆細胞におけるGATA‐2発現のGFPノックイン法を用いた解析

    鈴木教郎, 峯岸直子, 中島修, 高橋智, 山本雅之

    日本分子生物学会年会プログラム・講演要旨集　22nd　597　1999/11/22

  411. 造血幹細胞で働く転写制御機構と血液細胞の分化方向性の制御

    山本雅之, 峯岸直子, 鈴木教郎, 西村滋子, 諏訪部徳芳, 高橋智

    日本分子生物学会年会プログラム・講演要旨集　22nd　196　1999/11/22

  412. Fine tuning of the GATA-2 expression during hematopoietic cell development in aorta-gonads and mesonephros region.

    N Minegishi, N Suzuki, M Yamamoto

    BLOOD　94　(10)　470A-470A　1999/11

    ISSN： 0006-4971

  413. 医学と医療の最前線 血液細胞と転写因子 (日本内科学会雑誌) Invited

    清水律子, 山本雅之

    日本内科学会雑誌　88　(10)　2057-2063　1999/10

    DOI： 10.2169/naika.88.2057 　

  414. p45 NF-E2関連転写因子Bach1の精巣特異的アイソフォームの単離

    土岐 力, 金崎 里香, 伊藤 悦朗, 横山 碓, 五十嵐 和彦, 山本 雅之

    臨床血液　40　(9)　1033-1033　1999/09

    Publisher: (一社)日本血液学会-東京事務局

    ISSN： 0485-1439

  415. 遺伝性鉄芽球性貧血の分子診断とモデルマウス

    山本 雅之, 中島 修, 古山 和道, 張替 秀郎, 林 典夫

    臨床血液　40　(9)　851-851　1999/09

    Publisher: (一社)日本血液学会-東京事務局

    ISSN： 0485-1439

  416. Nrf2転写因子のPiクラスGSTMII発現への関与

    佐藤公彦, 伊東健, 山本雅之, 池田裕美, 酒井正春, 早狩誠, 柿崎育子, 大川恵三, 畑山一郎

    日本癌学会総会記事　58回　437-437　1999/08

    Publisher: 日本癌学会

    ISSN： 0546-0476

  417. 転写因子GATA-2の胎児造血組織における発現とその転写調節機構

    峯岸 直子, 潘 小青, 太田 潤, 山際 浩徳, 鈴木 教郎, 大崎 牧, 山本 雅之

    生化学　71　(8)　947-947　1999/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  418. GC box結合転写因子BTEB遺伝子欠損マウスの小脳機能失調 (生化学)

    守田匡伸, 中島修, 高橋智, 島貫智匡, 小林聡, 今高寛晃, 小倉博雄, 山本雅之, 藤井義明

    生化学　71　(8)　997-997　1999/08

  419. 新たなNF-E2関連因子Nrf3の単離と機能解析 (生化学)

    小林聡, 伊藤悦朗, 土岐力, 小亀圭司, 五十嵐和彦, 山本雅之, 林典夫

    生化学　71　(8)　947-947　1999/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  420. マウスbach1遺伝子の構造解析 (生化学)

    孫継英, 五十嵐和彦, 小林聡, 星野英人, 西村滋子, 山本雅之, 林典夫

    生化学　71　(8)　814-814　1999/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

    eISSN： 2189-0544

  421. クロマチン機能の制御 グロビン遺伝子LCRと抗体重鎖遺伝子LCRの結合因子群 (生化学)

    五十嵐和彦, 小林聡, 吉田近思, 武藤哲彦, 星野英人, 竹安邦夫, 山本雅之, 林典夫

    生化学　71　(8)　608-608　1999/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

    eISSN： 2189-0544

  422. GATA-1陽性中胚葉細胞の血液・血管内皮分化能

    藤本 哲広, 小川 峰太郎, 峯岸 直子, 山本 雅之, 西川 伸一

    日本発生生物学会大会講演要旨集　32回　88-88　1999/05

    Publisher: 日本発生生物学会

  423. GATA-1陽性中胚葉細胞の血液・血管内皮分化能

    藤本 哲広, 峯岸 直子, 山本 雅之, 西川 伸一

    International Journal of Hematology　69　(Suppl.1)　170-170　1999/04

    Publisher: (一社)日本血液学会

    ISSN： 0925-5710

  424. 血液前駆細胞で働くヒトGATA-2遺伝子ISプロモーターの構造と機能

    潘 小青, 峯岸 直子, 山本 雅之

    International Journal of Hematology　69　(Suppl.1)　178-178　1999/04

    Publisher: (一社)日本血液学会

    ISSN： 0925-5710

  425. GATA転写因子群と血液細胞の発生・分化

    峯岸 直子, 山本 雅之

    International Journal of Hematology　69　(Suppl.1)　35-35　1999/04

    Publisher: (一社)日本血液学会

    ISSN： 0925-5710

  426. 遺伝性鉄芽球性貧血における赤血球型δ-アミノレブリン酸合成酵素(ALAS-E)の新たな遺伝子変異の解析

    張替 秀郎, 古山 和道, 木村 昭郎, 山本 雅之, 佐々木 毅

    International Journal of Hematology　69　(Suppl.1)　195-195　1999/04

    Publisher: (一社)日本血液学会

    ISSN： 0925-5710

  427. 赤血球型5-アミノレブリン酸合成酵素の遺伝子ターゲティング

    中島 修, 高橋 智, 古山 和道, 張替 秀郎, 佐々 茂, 山本 雅之

    International Journal of Hematology　69　(Suppl.1)　195-195　1999/04

    Publisher: (一社)日本血液学会

    ISSN： 0925-5710

  428. Keap 1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain.

    ITOH K, WAKABAYASHI N, KATOH Y, ISHII T, IGARASHI K, ENGEL J D, YAMAMOTO M

    M. Gene & Dev.　13　(1)　76-86　1999

    DOI： 10.1101/gad.13.17.2328 　

    ISSN： 0890-9369

  429. Regulatory mechanism of cellular response to oxidative stress

    ITOH K, ISHII T, WAKABAYASHI N, YAMAMOTO M

    Free Rad. Res.　31　(4)　319-324　1999

    DOI： 10.1080/10715769900300881 　

    ISSN： 1071-5762

  430. Functional analyses of Bach2-associated factor FOB

    KOBAYASHI Akira, YAMAGIWA Hironori, MUTO Akihiko, MOCHITA Miyuki, HOSHINO Hideto, YAMAMOTO Masayuki, HAYASHI Norio, IGARASHI Kazuhiko

    21　406-406　1998/12/01

  431. Structure of Mouse bach2 Gene

    TAKAHASHI S., HOSHINO H., MUTO A., ITO E., YAMAMOTO M., KOBAYASHI A., IGARASHI K., HAYASHI N.

    21　405-405　1998/12/01

  432. Funetion of BTB domain of FOB, a friend of Bach

    MOCHITA Miyuki, KOBAYASHI Akira, YAMAGIWA Hironori, YAMAMOTO Masayuki, HAYASHI Norio, IGARASHI Kazuhiko

    21　406-406　1998/12/01

  433. Regulation of IgH gene expression by Bach2 and samll Maf

    MUTO A., HOSHINO H., MADISEN L., YAMAMOTO M., GROUDINE M., HAYASHI N., IGARASHI K.

    21　406-406　1998/12/01

  434. Visualization of β-globin LCR/Bach1complex by Atomic Force Microscopy

    YOSHIDA Cikashi, TOKUMASU Fuyuki, HOUMURA Kenichi, HAYASHI Norio, NAGASAWA Toshiro, YAMAMOTO Masayuki, TAKEYASU Kunio, IGARASHI Kazuhiko

    21　419-419　1998/12/01

  435. Identification of the hematopoietic regulatory element of mouse maf k gene in transgenic mouse anlysis.

    KATSUOKA F., MOTOHASHI H., YAMAMOTO M.

    21　415-415　1998/12/01

  436. Novel mechanism of the renal anemia : N^G-monomethyl L-arginine inhibits erythropoietin gene expression

    TARUMOTO Takahisa, IMAGAWA Shigehiko, OHMINE Ken, NAGAI Tadashi, SUZUKI Norio, YAMAMOTO Masayuki, HIGUCHI Masato, IMAI Nobuo, OZAWA Keiya

    日本分子生物学会年会プログラム・講演要旨集　21　1998/12/01

  437. The erythroid-specific delta-aminolevulinate synthase (eALAS) mutations in pyridoxine-responsive and -refractory sideroblastic anemias

    K Furuyama, N Hayashi, H Fujita, M Kondo, M Yamamoto, S Sassa

    BLOOD　92　(10)　327A-327A　1998/11

    ISSN： 0006-4971

  438. Structure and activity of GATA-2 gene distal (IS) promoter.

    N Minegishi, Pan, X, H Yamagiwa, J Ohta, S Kawauchi, N Suzuki, S Takahashi, M Yamamoto

    BLOOD　92　(10)　570A-570A　1998/11

    ISSN： 0006-4971

  439. 赤血球型5‐アミノレブリン酸合成酵素の遺伝子ターゲッティング

    中島修, 高橋智, 古山和道, 張替秀郎, 佐々茂, 山本雅之

    日本分子生物学会年会プログラム・講演要旨集　21st　610　1998/11

  440. 【貧血 診療に必須の最新情報】 ベーシックな知識を蓄える 造血の鍵をにぎる転写因子 研究の最前線 (内科) Invited

    清水律子, 山本雅之

    内科　82　(3)　417-421　1998/09

  441. Oxidative stress response and erythroid transcription factor

    ITOH Ken, YAMAMOTO Masayuki

    Bioscience & industry　56　(6)　17-22　1998/06/01

    Publisher: バイオインダストリ-協会

    ISSN： 0914-8981

  442. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin

    S Kudoh, A Azuma, M Yamamoto, T Izumi, M Ando

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE　157　(6)　1829-1832　1998/06

    ISSN： 1073-449X

  443. Structure and Function of Human 5-Aminolevulinate Syntase Gene Promoter.

    永井正, 古山和道, 高橋伸一郎, 林典夫, 佐々茂, 山本雅之

    日本分子生物学会年会プログラム・講演要旨集　20th　617　1997/12

  444. Transcription Factors Regulation of Hematopoietic Stem Cell Differentiation.

    MINEGISHI NAOKO, YAMAMOTO MASAYUKI

    細胞工学　16　(12)　1782-1789　1997/12

    Publisher: (株)学研メディカル秀潤社

    ISSN： 0287-3796

  445. The expression and the transcriptional regulation of mouse GATA-2 gene in vivo.

    OTA JUN, MINEGISHI NAOKO, TAKAHASHI SATOSHI, SUWABE NORIYOSHI, HAYASHI NORIO, YAMAMOTO MASAYUKI

    日本分子生物学会年会プログラム・講演要旨集　20th　395　1997/12

  446. The world according to Maf. Invited Peer-reviewed

    Motohashi H, Shavit J A, Igarashi K, Yamamoto M, Engel J D

    Nucleic Acids Res　25　(15)　2953-2959　1997/08

    DOI： 10.1093/nar/25.15.2953 　

  447. Expression and Function of GATA Family Transcription Factors

    YAMAMOTO Masayuki

    65　20-20　1997/04/01

    ISSN： 0925-5710

  448. Hemopoietic stem cell. The multipotency of stem cell clarified here. A role of transcription factor in blood cell differentiation from a hemopoietic stem cell.

    MINEGISHI NAOKO, YAMAMOTO MASAYUKI

    Mebio　14　(4)　58-65　1997/04

    ISSN： 0910-0474

  449. Upstream and downstream of erythroid transcription factor GATA-1. (Genes Cells)

    Yamamoto M, Takahashi S, Onodera K, Muraosa Y, Engel J D

    Genes Cells　2　(2)　107-115　1997/02

    DOI： 10.1046/j.1365-2443.1997.1080305.x 　

  450. Human small Maf proteins form heterodimers with CNC family transcription factors and recognize NF-E2 motif.

    E Ito, T Toki, K Arai, J Kitazawa, K Igarashi, K Hatakeyama, M Yamamoto, M Yokoyama

    BLOOD　88　(10)　758-758　1996/11

    ISSN： 0006-4971

  451. Activation of the erythroid transcription factor NF-E2, in MEL cell differentiation.

    T Nagai, K Igarashi, K Furuyama, H Fujita, N Hayashi, M Yamamoto, S Sassa

    BLOOD　88　(10)　757-757　1996/11

    ISSN： 0006-4971

  452. マウスmafK遺伝子の神経組織における発現と神経特異的なプロモーターによる発現調節

    本橋 ほづみ, 五十嵐 和彦, 中福 雅人, 山本 雅之

    日本分子生物学会年会プログラム・講演要旨集　19　438-438　1996/08/01

  453. 転写因子ECHのドメイン解析と細胞質-核移行による機能制御

    伊東 健, 小宅 達也, 林 典夫, 五十嵐 和彦, 山本 雅之

    日本分子生物学会年会プログラム・講演要旨集　19　603-603　1996/08/01

  454. 新しい転写因子Bachファミリーの解析

    小宅 達也, 伊東 健, 林 典夫, 西澤 誠, 本橋 ほづみ, 山本 雅之, 五十嵐 和彦

    日本分子生物学会年会プログラム・講演要旨集　19　603-603　1996/08/01

  455. Point mutation of .DELTA.-aminolevulic acid synthetase and abnormality of processing in mitochondrion.

    古山和道, 宗像浩, 藤田博美, 山本雅之, 林典夫

    日本分子生物学会年会プログラム・講演要旨集　19th　478　1996/07

  456. マウスはい発生におけるGATA‐2遺伝子の発現

    太田潤, 峯岸直子, 諏訪部徳芳, 高橋智, 林典夫, 山本雅之

    日本分子生物学会年会プログラム・講演要旨集　19th　785　1996/07

  457. Erythrocyte differentiation and transcription factors.

    MINEGISHI NAOKO, YAMAMOTO MASAYUKI

    Annual Review 血液　1996　52-65　1996/01

    Publisher: (株)中外医学社

  458. Regulation of mouse mast cell protease 6 gene expression by transcription factor encoded by the ┣DBmi(/)-┫DB locus.

    Morii E, Tsujimura T, Jippo T, Hashimoto K, Takebayashi K, Nomura S, Yamamoto M, Kitamuta Y

    Blood　88　2488-2494　1996

  459. In vitro differentiation of ES cells lacking the erythroid-specific delta-aminolevulinate synthase gene.

    H Harigae, M Yamamoto, H Fujita, P Weinstock, S Sassa

    BLOOD　86　(10)　1972-1972　1995/11

    ISSN： 0006-4971

  460. Upregulation of the erythroid transcription factor, NF-E2, by DMSO and hemin: Distinctive mechanisms.

    T Nagai, K Igarashi, K Furuyama, H Fujita, N Hayashi, M Yamamoto, S Sassa

    BLOOD　86　(10)　2693-2693　1995/11

    ISSN： 0006-4971

  461. Genomic structure and gene expression of mouse GATA-2 gene.

    MINEGISHI NAOKO, OTA JUN, SUWABE NORIYOSHI, HAYASHI NORIO, YAMAMOTO MASAYUKI

    日本分子生物学会年会プログラム・講演要旨集　18th　334　1995/11

  462. Structure and regulation of the genes encoding GATA factors and NF-E2.

    YAMAMOTO MASAYUKI, MOTOHASHI HOZUMI, ONODERA KO, TAKAHASHI SATOSHI, MINEGISHI NAOKO, ITO KEN, YOMOGIDA KENTARO, IGARASHI KAZUHIKO

    日本分子生物学会年会プログラム・講演要旨集　18th　169　1995/11

  463. SMALL MAF PROTEINS HETERODIMERIZE WITH FOS AND MAY ACT AS COMPETITIVE REPRESSORS OF THE NF-E2 TRANSCRIPTION FACTOR (VOL 15, PG 2188, 1995)

    K KATAOKA, K IGARASHI, K ITOH, KT FUJIWARA, M NODA, M YAMAMOTO, M NISHIZAWA

    MOLECULAR AND CELLULAR BIOLOGY　15　(6)　3461-3461　1995/06

    ISSN： 0270-7306

  464. ABUNDANT GLOBIN MESSENGER-RNA EXPRESSION BUT THE LACK OF HEMOGLOBIN-SYNTHESIS IN A PH(1) CHROMOSOME-POSITIVE HUMAN LEUKEMIA-CELL LINE, YN-1

    T NAGAI, H HARIGAE, K FURUYAMA, H MUNAKATA, N HAYASHI, K ENDO, M YAMAMOTO, S SASSA

    BLOOD　84　(10)　A22-A22　1994/11

    ISSN： 0006-4971

  465. NEGATIVE REGULATION OF THE ERYTHROPOIETIN GENE-EXPRESSION BY GATA-2 TRANSCRIPTION FACTOR

    S IMAGAWA, T IZUMI, N MINEGISHI, M YAMAMOTO, Y MIURA

    BLOOD　84　(10)　A283-A283　1994/11

    ISSN： 0006-4971

  466. TPA-MEDIATED INHIBITION OF ERYTHROID-DIFFERENTIATION INVOLVES DOWN-REGULATION OF THE ERYTHROID-SPECIFIC TRANSCRIPTION FACTOR NF-E2

    T NAGAI, K IGARASHI, H FUJITA, N HAYASHI, M YAMAMOTO, S SASSA

    BLOOD　84　(10)　A15-A15　1994/11

    ISSN： 0006-4971

  467. 血球分化とGATA転写因子 Invited Peer-reviewed

    本橋ほづみ, 山本雅之

    医学のあゆみ　169　856-857　1994

  468. Human erythropoietic protoporphyria: Identification of a mutation at the splice donor site of intron 7 causing exon 7 skipping of the ferrochelatase gene

    Yoshitsugu Nakahashi, Hiroaki Miyazaki, Yoichi Kadota, Yuji Naitoh, Kyoichi Inoue, Masayuki Yamamoto, Norio Hayashi, Shigeru Taketani

    Human Molecular Genetics　2　(7)　1069-1070　1993/07

    DOI： 10.1093/hmg/2.7.1069 　

    ISSN： 0964-6906

Show all ︎Show first 5

Presentations 115

  1. Molecular Basis of Keap1-Nrf2 System Regulation of Inflammation International-presentation

    1st Nature Immunology - Cellular & Molecular Immunology Joint Conference　2015/06/17

  2. Keap1-Nrf2制御系の分子基盤と疾患

    日本ケミカルバイオロジー学会 第10回年会　2015/06/11

  3. Renal erythropoietin producing cells for anemia and fibrosis International-presentation

    10th International Luebeck EPO Conference　2015/06/03

  4. 東日本大震災からの創造的復興と東北メディカル・メガバンクプロジェクト

    第69回日本交通医学会総会　2015/05/30

  5. 酸化ストレスと生体防御機構ー消化器疾患におけるNrf2とKeap1の役割

    第101回日本消化器病学会　2015/04/23

  6. 東北メディカル・メガバンク計画の目標と進捗状況

    日本医学会総会　2015/04/12

  7. Understanding the Future of Human Evolution International-presentation

    Nobel Prize Dialogue Tokyo2015　2015/03/01

  8. 未来型の医療と東北メディカル・メガバンクプロジェクト

    第44回日本皮膚アレルギー・接触皮膚炎学会総会　2014/11/25

  9. 環境ストレスへの生体応答の分子基盤

    第56回日本先天代謝異常学会総会　2014/11/13

  10. エリスロポエチン産生細胞とエリスロポエチン遺伝子の発現制御機構

    日本血液学会学術集会　2014/11

  11. Molecular Basis of the Keap1-Nrf2 System Regulating Environmental Stress Response International-presentation

    Nobel Conference　2014/10/08

  12. Erythropoietin production in neural and neural crest cells during primitive erythropoiesis International-presentation

    19th Hemoglobin Switching Conference　2014/09/04

  13. 腎臓EPO産生細胞を巡る最近の話題 Recent Topics of Renal Erythropoietin Producing Cells

    第59回日本透析医学会学術集会・総会　2014/06/13

  14. 環境ストレス応答研究と東北メディカル・メガバンクプロジェクト

    日本病院薬剤師会東北ブロック第4回学術大会　2014/05/31

  15. Erythropoietin Gene Regulation and Chronic Kidney Disease International-presentation

    7th Congress of the International Society for Hemodialysis Venue　2014/04/25

  16. Renal Erythropoietin Producing Cells for Anemia and Fibrosis International-presentation

    International Society of Nephrology Nexus Symposium　2014/04/03

  17. Nrf2-Keap-A regulator of redox signaling International-presentation

    17th Biennial Meeting of Society for Free Radical Research International　2014/03/25

  18. Erythroid commitment of hematopoietic stem cells International-presentation

    The 75th Annual Meeting,Japanese Society of Hematology　2013/10/11

  19. Inducible and Tissue-specific Erythropoietin Gene Regulation International-presentation

    4th International Symposium of the Collaborative Research Centre Sonderforschungsbereich 699　2013/07/19

  20. Biological response to oxidative stress International-presentation

    The 3rd International Conference on Anti-Aging Medicine　2013/06/29

  21. The Keap1-Nrf2 System for Environmental Response International-presentation

    The 35th Naito Conference　2013/06/09

  22. エリスロポエチン遺伝子の発現制御メカニズム

    第86回日本内分泌学会学術集会　2013/04/26

  23. 酸化ストレス応答の分子メカニズムと病態

    第50回日本臨床分子医学会学術集会　2013/04/13

  24. Molecular Basis Connecting Environmental Stress to Gene Expression Regulation

    第85回日本生化学会大会シンポジウム　2012/12/16

  25. 酸化・低酸素ストレスと腎疾患

    第42回日本腎臓学会西部学術大会　2012/10/26

  26. 東日本大震災からの医療復興と東北メディカル・メガバンクプロジェクト

    日本人類遺伝学会第57回大会　2012/10/25

  27. Keap1-Nrf2系機能の分子および遺伝学基盤

    日本遺伝学会84回大会　2012/09/26

  28. Keap1-Nrf2システム機能の分子構造基盤

    第71回日本癌学会学術総会シンポジウム　2012/09/20

  29. Molecular Basis of Keap1-Nrf2 System Function” International-presentation

    6th International Congress of Asian Society of Toxicology (ASIATOX-VI)　2012/07/18

  30. Keap1-Nrf2 System: A Master Regulator of Redox Signaling International-presentation

    The 33rd NAITO Conference　2012/06/26

  31. Molecular Basis of Keap1-Nrf2 System Function International-presentation

    Oxygen Club California Conference　2012/06/20

  32. Keap1-Nrf2 system and hematopoiesis International-presentation

    18th Hemoglobin Switching Meeting　2012/06/08

  33. Hypoxia-inducible and tissue-specific erythropoietin gene regulation International-presentation

    Keystone Symposia on Advances in Hypoxic Signaling　2012/02/12

  34. The Nrf2-Keap1 system of oxidative/electrophilic stress response: mechanism and diseases. International-presentation

    Kit I. Tong, Masayuki Yamamoto

    Joint Annual Meeting of the Molecular Biology Society of Japan and the Japanese Biochemical Society, 2008 (BMB2008)　2008/12/09

  35. The Nrf2-Keap1 Stress Response System International-presentation

    Masayuki Yamamoto

    CBI International Symposium on Pathway/Network to Disease and Drug Discovery Specially Focused on “Nuclear Receptors and Metabolic Syndrome”.　2008/10/23

  36. Gata1 Gene Regulation and GATA1-related Leukemia. International-presentation

    Masayuki Yamamoto, Moriguchi T, Suzuki M, Shimizu R

    The 16th Conference on Hemoglobin Switching　2008/10/11

  37. Induction of Hyperproliferative Fetal Megakaryopoiesis by an N-terminally Truncated GATA1 Mutant. International-presentation

    Ritsuko Shimizu, Engel JD, Yamamoto M

    The 16th Conference on Hemoglobin Switching　2008/10/11

  38. The Nrf2-Keap1 System and Cancer. International-presentation

    Masayuki Yamamoto

    AACR conference on “Chemical and Biological Aspect of Inflammation and Cancer　2008/10/11

  39. Structural basis and cancer-related mutations of the Nrf2-Keap1 system. International-presentation

    Masayuki Yamamoto

    Scientific Colloquium, PHILIP MORRIS Research Laboratories GmbH　2008/09/26

  40. The Nrf2-Keap1 Stress Response System: Molecular Basis of Adaptive Responses to Food and Oxygen. International-presentation

    Masayuki Yamamoto

    11th SAC Seminar on “NEW TRENDS IN CHEMICAL TOXICOLOGY　2008/09/22

  41. Structural basis and cancer-related mutations of the Nrf2-Keap1 system. International-presentation

    Masayuki Yamamoto

    John Hopkins University Seminar　2008/09/18

  42. In vivo functional analysis of two 5-aminolevulinate synthase isozymes and heme oxygenase-1 in mouse. International-presentation

    Masayuki Yamamoto

    NIDDK “Heme Regulation During Erythropoiesis”　2008/09/16

  43. Regulation and Function of Epo and EpoR in Genetically Modified Mice. International-presentation

    Norio Suzuki, Naoshi Obara, Xiaoqing Pan, Lorenz Poellinger, Masayuki Yamamoto

    NIDDK “Heme Regulation During Erythropoiesis　2008/09/08

  44. Analysis of Gatal Gene Regulation Using BAC Transgenic Mouse System. International-presentation

    Mikiko Suzuki, Takashi Moriguchi, Atsushi Hasegawa, Ritsuko Shimizu, Masayuki Yamamoto

    The 21st Naito Conference on “Nuclear Dynamics and RNA [I]　2008/06/24

  45. Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. International-presentation

    Yamamoto

    The 3rd International Workshop on “International Workshop on Cell Regulations in Division and Arrest under Stress　2008/04/06

  46. 89. The environmental response to food and oxygen. International-presentation

    Masayuki Yamamoto

    JST-ERATO Environmental Response Project International Symposium on “The Environmental Response”.　2007/12/21

  47. 88. Molecular Mechanisms of Adaptive Responses to Food and Oxygen. International-presentation

    Masayuki Yamamoto

    The International Conference on Food Factors for Health Promotion (ICOFF2007),　2007/11/29

  48. 酸化ストレス応答の分子基盤と疾患

    山本 雅之

    CKDと心血管イベント Expert Meeting特別講演　2007/11/27

  49. 親電子性物質・酸化ストレス応答の分子機構

    山本 雅之

    第７回 システム生物医学研究会　2007/11/21

  50. 親電子性物質・活性酸素応答の分子メカニズム

    山本 雅之

    東海医学会講演会　2007/11/13

  51. 87. The Nrf2-Keap1 Stress Response System. International-presentation

    Masayuki Yamamoto

    The 23rd Kumamoto Medical Bioscience Symposium on New Insights into Metabolic Disorders and Vascular Disease,　2007/11/12

  52. GATA因子と白血病

    山本 雅之

    第２回 つくば医科学研究交流会 ランチョンセミナー　2007/11/10

  53. 86. Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. International-presentation

    Masayuki Yamamoto

    Distinguished Professor’s Seminar at University of Arizona,　2007/11/02

  54. 84. Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. International-presentation

    Masayuki Yamamoto

    NIEHS Seminar,　2007/10/30

  55. 83. Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. International-presentation

    Masayuki Yamamoto

    National University of Singapore – Tohoku University/Centre of Excellence Joint Symposium “Basic and Clinical Research on Signal Transduction Diseases”.　2007/09/05

  56. 親電子性物質・活性酸素応答の分子メカニズム

    山本 雅之

    臨床研セミナー （財）東京都医学研究機構　2007/08/10

  57. 82. Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. International-presentation

    Masayuki Yamamoto

    he 3rd DECODE for Biological Responses International Meeting.　2007/08/04

  58. 親電子性物質・活性酸素応答の分子メカニズム」

    山本 雅之

    第5回フリーラジカルと脳疾患 東日本研究会特別講演　2007/07/28

  59. 環境応答の分子機構

    山本 雅之

    第5回RCGMフロンティアシンポジウム「ゲノム医学―基礎から未来医療へ」　2007/07/27

  60. GATA転写因子群の機能異常と白血病

    山本 雅之

    第17回 日本産婦人科・新生児血液学会シンポジウム「ダウン症候群と一過性骨髄造血（TAM）」　2007/06/30

  61. 細胞の癌化とその抑制における転写因子の役割

    山本 雅之

    文部科学省がん特定領域研究「遺伝情報システム異常と発がん」 癌研究会吉田富三記念講堂　2007/06/30

  62. 親電子性物質・酸化ストレス応答の分子メカニズム

    山本 雅之

    循環器内科リサーチセミナー　2007/05/30

  63. 81. Genetic Analysis of Mouse GATA-related Leukemia and Leukemic Stem Cells. International-presentation

    Masayuki Yamamoto

    Gordon Research Conference on Red Cells,　2007/05/20

  64. 酸化ストレス応答と呼吸器疾患

    山本 雅之

    第47回日本呼吸器学会学術講演会　2007/05/12

  65. 親電子性物質・活性酸素応答の分子メカニズム

    山本 雅之

    日本生化学会東北支会シンポジウム　2007/05/12

  66. GATA転写因子群の機能異常と白血病

    山本 雅之

    第50回 東北小児白血病研究会　2007/04/28

  67. 80. Functional analyses of GATA-2 with knockdown and conditional knockout mice. International-presentation

    Masayuki Yamamoto

    EMBO WORKSHOP ON The Role and Control of GATA Factors in Tissue Development and Disease　2007/04/14

  68. 79. ALAS-E and sideroblastic anemia. International-presentation

    Masayuki Yamamoto

    The 2007 International BioIron Society Scientific Program, Kyoto,　2007/04/02

  69. 生体の環境応答制御機構

    山本 雅之

    太陽紫外線防御研究委員会第17回シンポジウム特別講演　2007/03/16

  70. 親電子性物質・活性酸素応答の分子メカニズム

    山本 雅之

    第14回 医学7専攻研究セミナー　2007/02/27

  71. 親電子性物質・活性酸素応答の分子メカニズム

    山本 雅之

    国立癌センターセミナー　2007/02/26

  72. Reguatory Mediations of Gata1 Gene Expression Using Transgenic System. International-presentation

    Masayuki Yamamoto

    AACR-JCA Joint Conference in the Forefront of Basic and Translational Cancer Research.　2007/01/21

  73. Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. International-presentation

    Masayuki Yamamoto

    International Symposium on the Redox-Sensitive Transcription Factors as Potential Therapeutic Targets,　2006/10/21

  74. Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism International-presentation

    Masayuki Yamamoto

    Wolfson Lecture Theatre, Biomedical Research Centre.　2006/09/18

  75. Regulation of Mouse Gata1 Gene Expression in Erythroid Progenitors. International-presentation

    Masayuki Yamamoto

    The 15th Hemoglobin Switching Conference at St John's College, Oxford,　2006/09/15

  76. Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. International-presentation

    Masayuki Yamamoto

    Scientific Colloquium at PHILIP MORRIS Research Laboratories, Koln, Germany.　2006/09/13

  77. Molecular Mechanisms of Nrf2-Keap1 Response against Oxidative and Electrophilic Stresses. International-presentation

    Masayuki Yamamoto

    “Redox: Redox Sensor Mechanisms against Electrophiles” (organized by Koji Uchida and Tom Kensler) The 20th IUBMB Congress and 11th FAOBMB Congress, Kyoto　2006/06/18

  78. GATA-2 and hematopoietic stem cells. International-presentation

    Masayuki Yamamoto

    The 3rd International Conference on GATA Transcription Factors in Health and Disease,　2006/06/16

  79. Regulation by Nrf2-Keap1 System of Cellular Defense against Electrophiles and Oxidative Stress. International-presentation

    Masayuki Yamamoto

    Trinity College Seminar, Trinity College, Dublin, Ireland.　2006/05/25

  80. Regulation by Nrf2-Keap1 System of Cellular Defense Mechanisms against Electrophiles and Carcinogenesis. International-presentation

    Masayuki Yamamoto

    CNIO Cancer Conference on "Inflammation and Cancer", CNIO, Madrid,　2006/05/22

  81. Introductory lecture: Molecular mechanisms of Nrf2-Keap1 response against oxidative and electrophilic stresses. International-presentation

    Masayuki Yamamoto

    57th Mosbacher Kolloquium 2006 on "Redox Signalling: Mechanisms and Biological Impact"　2006/04/06

  82. Gene expression regulation and domain function of hematopoietic GATA factors. International-presentation

    Masayuki Yamamoto

    Virchow-Lectures in Molecular Medicine (fr&uuml;heres Virchow-Colloquium) des Biomedizinischen Forschungszentrums der Charit&eacute;.　2006/04/04

  83. Molecular mechanisms of Nrf2-Keap1 response against oxidative and electrophilic stresses. International-presentation

    Masayuki Yamamoto

    IMB Seminar, Academia Sinica, Taipei,　2006/03/07

  84. Transgenic complementation analysis of Nrf2-Keap1 system regulating cellular defense mechanisms against electrophiles and reactive oxygen species. International-presentation

    Masayuki Yamamoto

    HUGO Asia-Pacific 06; Animal Models of Human Diseases, Academia Sinica, Taipei.　2006/03/06

  85. Regulation of erythropoietin gene expression. International-presentation

    Masayuki Yamamoto

    Keystone Symposia on “Hypoxia and Development, Physiology and Disease”,　2006/01/16

  86. Transcription factor regulation of cellular defense mechanisms against electrophiles and reactive oxygen species International-presentation

    Masayuki Yamamoto

    The 18th Naito Conference on “Innate Immunity in Biology and Medical Science”,　2005/10/25

  87. Gene expression regulation and domain function of hematopoietic GATA factors. International-presentation

    Masayuki Yamamoto

    “Dynamic systems in the regulation of gene expression”　2005/10/19

  88. Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. International-presentation

    Masayuki Yamamoto

    Advances in Enzyme Regulation Meeting,　2005/10/03

  89. Nrf2-Keap1 pathway and cancer chemoprevention. International-presentation

    Masayuki Yamamoto

    Invited Special Lectures in 10th Japanese-German Workshop on Molecular and Cellular Aspects of Carcinogenesis.　2005/09/29

  90. Control of GATA factors. International-presentation

    Masayuki Yamamoto

    Gordon Conference on Red Cells.　2005/06/12

  91. Hematopoietic malignancies related to GATA transcription factors. International-presentation

    Masayuki Yamamoto

    USA-Japan Cooperative Cancer Research Program on “Animal Models of hematological malignancies in Hematopoiesis”,　2005/05/22

  92. Inducible and cell-type specific regulation of erythropoietin gene expression. International-presentation

    Masayuki Yamamoto

    JST-ERATO International Symposium on “Molecular Mechanism of Environmental Response to Food and Oxygen”.　2005/05/10

  93. Transcription factor regulation of cellular defense mechanism and cancer chemoprevention. International-presentation

    Masayuki Yamamoto

    Symposium on “Transcription factor as targets for chemoprevention”.　2005/04/16

  94. Nrf2-Keap1 Regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. International-presentation

    Masayuki Yamamoto

    The 2nd International Symposium on DNA Metabolism and Chromatin Dynamics in Cellular Responses, Hiroshima University, Hiroshima.　2004/12/16

  95. Nrf2-Keap1 Regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. International-presentation

    Masayuki Yamamoto

    The 2nd International Symposium on DNA Metabolism and Chromatin Dynamics in Cellular Responses,　2004/11/11

  96. Nrf2-Keap1 Regulation of Cellular Defense Mechanisms against Electrophiles and Reactive Oxygen Species. International-presentation

    Masayuki Yamamoto

    Institute of Cochin, Paris,　2004/11/09

  97. GATA factors regulation of hematopoiesis. International-presentation

    Masayuki Yamamoto

    Institute of Cochin, Paris,　2004/11/08

  98. Fine Regulation of GATA-1 and GATA-2 Gene Expression In Vivo. International-presentation

    Masayuki Yamamoto

    The 14th Conference on Hemoglobin Switching.　2004/09/10

  99. Transcription Factor Regulation of Cellular Defense Mechanisms against Electrophiles and Reactive Oxygen Species. International-presentation

    Masayuki Yamamoto

    Scientific Colloquium, PHILIP MORRIS Research Laboratories,　2004/07/09

  100. GATA factors regulation of hematopoiesis. International-presentation

    Masayuki Yamamoto

    Erasmus University, Rotterdam,　2004/07/06

  101. Nrf2-Keap1: Regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. International-presentation

    Masayuki Yamamoto

    Erasmus University, Rotterdam,　2004/07/05

  102. Nrf2-Keap1: Regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. International-presentation

    Masayuki Yamamoto

    15th international Symposium on Microsomes and Drug Oxidations: Chemical Biology in the Postgenomic Era.　2004/06/04

  103. Nrf2-Keap1 System: A New Stress Response Mechanism. International-presentation

    Masayuki Yamamoto

    Department of Cell and Development al Biology,　2004/04/16

  104. Nrf2-Keap1 System: A New Stress Response Mechanism. International-presentation

    Masayuki Yamamoto

    East Wing Auditorium, Johns Hopkins University,　2004/04/13

  105. Transcription factor regulation of drug metabolizing and antioxidant enzymes and cancer chemoprevention. International-presentation

    Masayuki Yamamoto

    The 8th Korea-Japan Cancer Research Workshop “Molecular Mechanisms of Tumor Suppression”,　2003/12/19

  106. Transcription factor regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. International-presentation

    Masayuki Yamamoto

    The Second International Symposium on Redox Life Science.　2003/08/20

  107. Transcription factor regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. International-presentation

    Masayuki Yamamoto

    Seminars in Cell and Developmental Biology, Karolinska Institute,　2003/07/01

  108. Erythropoietin expression is required for neovascularization in the retinopathy of prematurity and is regulated by HLF/Hif-2a. International-presentation

    Masayuki Yamamoto

    6th International L&uuml;beck Conference on the Pathophysiology and Pharmacology of Erythropoietin and other Hematopoietic Growth factors.　2003/06/26

  109. Erythropoietin expression is required for neovascularization in the retinopathy of prematurity and is regulated by HLF/Hif-2a. International-presentation

    Masayuki Yamamoto

    6th International L&uuml;beck Conference on the Pathophysiology and Pharmacology of Erythropoietin and other Hematopoietic Growth Factors,　2003/06/26

  110. Nrf2-Keap1 Regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. International-presentation

    Masayuki Yamamoto

    JBS Bio-Frontier Symposium 2003, Tsukuba Convention Center,　2003/06/05

  111. GATA-2 function in HSC and progenitor. International-presentation

    Masayuki Yamamoto

    Gordon Research Conference on Red Cells.　2003/05/25

  112. Transcription factor regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. The Charles E. Dohme Memorial Symposium for “Protection against Cancer: Genes and Chemistry”. International-presentation

    Masayuki Yamamoto

    Vernon B. Mountcastle Auditorium,　2003/04/22

  113. IN VIVO FUNCTION OF GATA-1 AND GATA-2--Transgenic Complementation Rescue Analysis of Transcription Factor Function. International-presentation

    Masayuki Yamamoto

    Department of Cellular and Developmental Biology Seminar,　2003/04/18

  114. Nrf2 and its protein-protein interactions regulate drug-dependent gene induction. International-presentation

    Masayuki Yamamoto

    Experimental Biology-ASPET 2003,　2003/04/14

  115. Leukemia in GATA-1 knockdown mouse. International-presentation

    Leukemia in GATA, knockdown mouse

    USA-JAPAN Cancer Seminar.　2003/02/12

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Industrial Property Rights 3

  1. Nrf2活性化のバイオマーカー

    山本 雅之, 宇留野 晃

    Property Type: Patent

  2. 糖尿病の予防または治療剤

    山本 雅之, 宇留野 晃

    Property Type: Patent

  3. Nrf1調節剤のスクリーニング方法

    山本 雅之

    Property Type: Patent

Research Projects 95

  1. Regulation of signal transduction via crosstalk between supersulfide and selenium

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Transformative Research Areas (A)

    Institution: Tohoku University

    2021/09/10 - 2026/03/31

  2. Deciphering Molecular Basis for the Anti-Oxidative Stress Response and Application of the Basis for Disease Prevention and Therapy

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (S)

    Institution: Tohoku University

    2019/06/26 - 2024/03/31

  3. 生体の酸化ストレス応答の分子メカニズム解明とその疾病予防・治療への応用

    山本 雅之, 田口 恵子, 鈴木 隆史

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(A)

    Institution: 東北大学

    2019/04/01 - 2020/03/31

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    私たちは常に外界からのストレスに曝されており、それに対する応答は生体の恒常性維持に必須である。酸素、紫外線、大気や食物中の化学物質などが重要な環境由来ストレスとなっているが、これらのストレス因子の増加は生体内レドックスバランスの撹乱を招来し、多くの疾患の共通基盤を形成している。超高齢化社会での健康長寿を実現するためには、生体の酸化ストレス応答機構全容の理解とその制御メカニズムの詳細な解明が極めて重要である。本申請研究では、生体の酸化ストレス応答機構において中心的な役割を果たしている KEAP1-NRF2 制御系の機能メカニズムの解明に挑むとともに、ストレス関連疾患の予防・治療に対する同制御系の貢献を明らかにする。特に、生体が KEAP1 を利用して過剰な酸素によるストレスを感知するメカニズムとそのストレス感知が生体防御遺伝子群の発現の変化を惹起するメカニズムの解明に挑戦する。本申請研究は、NRF2 活性化による疾病予防・治療の有効性やその健康長寿実現への貢献を実証するものと期待される。 本年度は、１）KEAP1-NRF2制御系による酸化ストレス感知メカニズムの解析、２）KEAP1-NRF2制御系の構造機能連関解析、３）加齢関連疾患モデル動物を用いたNRF2活性化の有効性検証を行うため、それぞれの解析に必要な実験系のセットアップを主に実施した。

  4. Elucidation of cytoprotective mechanisms by structural analysis of stress sensor Keap1

    Yamamoto Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Research (Exploratory)

    Institution: Tohoku University

    2018/06/29 - 2020/03/31

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    Stress sensor Keap1 is a key factor that controls ubiquitination reaction of transcription factor Nrf2 and plays a central role in the stress defense mechanism. Keap1 regulates Nrf2 ubiquitination in response to various stress stimuli. Regarding the molecular basis of the stress response, it has been suggested that the structural change of the Keap1 protein is the key, but the details are unknown. In this study, we aimed to clarify how the activity of the ubiquitin ligase complex containing Keap1 is inactivated by stress stimulation, and challenged to elucidate the molecular mechanism of Nrf2 activation in our body.

  5. Promotion of oxygen biology on the basis of international networks

    Mori Yasuo, MIKI hiroaki, MIURA kyoko, SUMIMOTO hideki, ITOH ken, UCHIDA kouji

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Institution: Kyoto University

    2015/11/06 - 2019/03/31

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    Our innovative area "Oxygen Biology" was able to make significant accomplishments in two different aspects. The first is to establish international networks, which form bases to enhance the recognition of our research accomplishments. More specifically, we edited a special issue "Oxygen Physiology: sensors and ion channels" (January issue of 2015), in which leaders of the field including members of our innovative area "Oxygen Biology" contributed reviews, for Pflugers Archiv. - European Journal of Physiology, the internationally recognized journal in the field of physiology. The second is the support to individual international collaborations, which were carried out among members of the innovative area together and the laboratories in universities and research institutes in Europe, north America, and Asia. Obtained data were summarized and published as papers in international journals.

  6. Mechanisms of leukemogenesis by the leukemia-driving enhancer

    Yamamoto Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (A)

    Institution: Tohoku University

    2015/04/01 - 2019/03/31

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    Chromosomal rearrangement between 3q21 and 3q26 provokes leukemia with poor prognosis. The rearrangement induces misexpression of both misexpression of EVI1 gene and reduction of GATA2 gene expression by translocation of the GATA2 gene enhancer. Here we asked whether GATA2 haploinsufficiency in addition to EVI1 misexpression contributed to leukemogenesis by using a 3q21q26 mouse model that recapitulates the GATA2 enhancer-driven EVI1 misexpression coupled with a Gata2 heterozygous deletion. Of note, the Gata2 heterozygous deletion promoted the EVI1-provoked leukemogenesis. While EVI1-misexpressed blast-like cells retained some limited ability to differentiate into myeloid cells, simultaneous loss of one Gata2 allele suppressed the myeloid differentiation and promoted the expansion of these blast-like cells. These results demonstrate that Gata2 heterozygous deletion accelerates EVI1 misexpression leukemia by inducing proliferation and differentiation defect of leukemia cells.

  7. Oxygen biology: a new criterion for integrated understanding of life

    Mori Yasuo, INOUE masahiro, MIURA kyoko, SUMIMOTO hideki, ITOH ken, UCHIDA kouji, SUEMATSU makoto, SOGA tomoyoshi, TANIGUCHI naoyuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Institution: Kyoto University

    2014/07/10 - 2019/03/31

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    In order to demonstrate oxygen environment as molecular entities in living organisms, technical cores which give technique supports to area members were formed. In the area meetings, scientific achievements of area members were reported annually, and the direction of area managements, the strategy to foster young researchers, and the evaluation standard to call for area members were discussed. Many domestic and international symposia and workshops were organized along with annual meetings of different societies were held by our area. Aiming at enhancing networks among young scientists, meetings were arranged twice in collaboration with the innovative area "Dying Codes". Moreover, a special issue entitled "Oxygen Biology", to which area members contributed chapters, was arranged by our area and published in the Japanese scientific magazine "Cell".

  8. Systemic mechanisms of response to hypoxic stresses

    Yamamoto Masayuki, SEKINE Hiroki, HIRANO Ikuo, NEZU Masahiro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Institution: Tohoku University

    2014/07/10 - 2019/03/31

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    A lack of oxygen causes harmful hypoxic stress in cells and organs, while oxygen is also a source of harmful oxidative stressors, including reactive oxygen species. Because oxygen is delivered into every organ by erythrocytes, cellular oxygen levels largely depend on the circulation of erythrocytes. Erythrocyte production is mainly controlled by the erythroid growth factor erythropoietin (Epo) which is secreted by REP (renal Epo producing) cells in a hypoxia-inducible manner. This study elucidated the regulatory mechanism of Epo production in REP cells, and demonstrated that defects in the mechanism are closely associated with the pathogenesis and progression of many types of diseases through the synergistic effects of hypoxic and oxidative stresses. These results confirm that therapeutic strategies targeting the cellular mechanisms of adaptation to hypoxic or oxidative stress, which are currently going on clinical trials, are plausible for treating a variety of diseases.

  9. Mecahistic analysis of a protective response of skin tissue to UV genotoxicity

    IKEHATA Hironobu, MORITA Masanobu, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2015/04/01 - 2018/03/31

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    We studied the mechanism of the response of mutation induction suppression (MIS), a protective response of skin tissue to UV genotoxicity, using a mechanistic model based on the Keap1-Nrf2 system, which controls antioxidative responses in mammalian cells. We performed an analysis of global gene expression changes in the MIS response and detected the induction of genes related to apoptosis and cell proliferation, which suggests that MIS is based on a tissue turnover mechanism with apoptosis and hyperplasia. The analysis has also suggested that the Keap1-Nrf2 system functions in the tissue recovery process from the skin damage produced after UV exposures. We also estimated the amounts of UV-induced DNA damage necessary for the MIS induction.

  10. The role of Nrf2 in development and carcinogenesis of NASH using gene rescue mice

    ISHIGE Kazunori, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: University of Tsukuba

    2015/04/01 - 2017/03/31

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    We generated Sqstm1 and Nrf2 double knockout (DKO) mice and demonstrated that these DKO mice developed mature-onset steatohepatitis. We revealed the mechanism for the development of steatohepatitis in DKO mice as follows: (1) Deficiency of Nrf2 led to hypersensitivity to endotoxin of Kupffer cells and resulted in inflammatory response in the DKO livers. (2) Acceleration of intestinal permeability caused by down-regulation of Zo-1 and Claudin1 in Nrf2 deficiency and increased endotoxin from intestinal microbiota by Sqstm1 deficiency led to an overload of serum endotoxin. (3) These hyper-endotoxemia drove inflammatory signaling in livers directly, and also led to inflammation of adipose tissue. (4) These enhanced inflammatory signaling could cause progression of steatohepatitis in DKO livers. We plan to compare DKO and Nrf2 gene rescued mice, and research the detail of the mechanism for development of NASH and the contribution of each organ in the near future.

  11. Elucidation of the mechanism of epithelial stem cell niche and its reproduction

    Hayashi Ryuhei, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Osaka University

    2014/04/01 - 2017/03/31

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    In this study, we aimed to elucidate the epithelial stem cell niche using the corneal epithelial stem cells as a model of stem cell niche focusing on N-cadherin and NRF2, and developed a new corneal epithelial culture system-based on the information obtained there. As a result, we clarified a part of the mechanism for regulation of N-cadherin expression, and also showed that this mechanism also contributes to normal differentiation of corneal epithelium. From the results of this research, we successfully differentiated corneal epithelial (stem) cells from pluripotent stem cells. In addition, it was found that activation of NRF2 remarkably increases corneal epithelial stem cell survival activity. Moreover, based on the results of this research, we succeeded in development of conservation method for epithelial stem cells focusing on NRF2 activation mechanism.

  12. The role of Nrf2 in oxidative stress-mediated insulin resistance

    Akira Uruno, YAMAMOTO MASAYUKI, YAGISHITA YOKO

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2014/04/01 - 2017/03/31

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    The numbers of type 2 diabetes mellitus patients are increasing due to the change of life pattern. As it is important to clarify the parthenogenesis of diabetes mellitus, we tried to clarify it. We generated conditional knockout mice of selenocysteine transfer RNA (Trsp) gene by using rat insulin promoter Cre (TrspRIPKO). The TrspRIP KO mice displayed increments of oxidative stress in hypothalamus.We also found that the mice displayed insulin and leptin resistance to develop obesity and diabetes mellitus. Obesity and diabetes mellitus due to oxidative stress were diminished by activation of Nrf2 signaling in hypothalamus.These results indicate that Nrf2 is a promising target for treatment and prevention of obesity and diabetes mellitus.

  13. Search for novel physiological function of transcriptional factor Nrf2

    Suzuki Takafumi, SEKI Shiori, HIRAMOTO Keiichiro, NAGANUMA Eriko, TAKAHASHI Nobuyuki, SATO Hiroshi, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2014/04/01 - 2017/03/31

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    Nrf2 regulates the cellular response to oxidative/electrophilic stresses, and loss of Keap1 increases Nrf2 protein level. As Keap1-null mice die of esophageal hyperkeratosis, whole-body phenotypes of Nrf2 hyperactivation in adult animals remain to be delineated. To circumvent this problem, we deleted esophageal Nrf2 in Keap1-null mice. These mice survived until adulthood, but developed polyuria with low osmolality and bilateral hydronephrosis. This novel phenotype appears to be attributable to defects in water reabsorption caused by a reduction in the level of the AQP2 channel in the kidney. This phenotype was recapitulated by renal tubular deletion of Keap1, which generated symptoms of nephrogenic diabetes insipidus, demonstrating that Nrf2 activation in developing tubular cells causes a water reabsorption defect. Our approach to rescue mice from the lethal first hit of Keap1 ablation serves as a useful tool to study novel functions of Nrf2.

  14. The regulatory role of Nrf2 in pathogenesis and carcinogenesis of NASH using gene rescued mice

    ISHIGE Kazunori, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: University of Tsukuba

    2014/04/01 - 2017/03/31

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    We generated Sqstm1 and Nrf2 double knockout (DKO) mice as the noble NASH animal model. We revealed the mechanism for the development of steatohepatitis in DKO mice as follows: (1) Deficiency of Nrf2 led to hypersensitivity to endotoxin of Kupffer cells and resulted in the inflammatory response in the DKO livers. (2) Acceleration of intestinal permeability which was caused by down-regulation of Zo-1 and Claudin1 in Nrf2 deficiency and increased endotoxin from intestinal microbiota by Sqstm1 deficiency led to an overload of serum endotoxin. (3) These hyper-endotoxemia drove inflammatory signaling in livers directly, and also led to inflammation of adipose tissue. (4) These enhanced inflammatory signaling could cause progression of steatohepatitis in DKO livers. We plan to compare DKO and Nrf2 gene rescued mice, and explore the detail of the mechanism for development of NASH and the carcinogenesis in contribution of each organ in the near future.

  15. The role of Nrf2 in pancreatic beta-cells; a study of new pancreatic beta-cell specific Nrf2 activation model mice

    Yoko Yagishita, URUNO Akira, YAMAMOTO Masayuki, NAGANUMA Eriko, DATE Fumiko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Research Activity Start-up

    Institution: Tohoku University

    2014/08/29 - 2016/03/31

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    A transcription factor Nrf2 plays critical roles in the response to oxidative and electrophilic stresses. To clarify the role of Nrf2 in pancreatic β-cells, we generated new pancreatic β-cell-specific Nrf2 activation model mice. Rat insulin promoter (RIP) has been utilized to generate Cre recombinase expressing transgenic mice for Cre-loxP-mediated conditional knockout mice in pancreatic β-cells; however, several lines of RIP-Cre mice were reported to display ectopic expression of Cre recombinase. We newly established Nrf2 activation model mice by using Cre expressing transgenic mice mediated by bacterial artificial chromosome (BAC) including mouse Ins1 gene. This new established mouse line displayed pancreatic β-cell-specific expression of Cre recombinase, and successfully demonstrated that Nrf2 protects pancreatic β-cells against streptozotocin-induced cell damages.

  16. Identification of leukemia-initiating cells in an inv(3)(q21q26) mouse model

    Yamamoto Masayuki, SUZUKI MIKIKO

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2014/04/01 - 2016/03/31

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    Chromosomal translocation and inversion between 3q21 and 3q26 gives rise to acute myeloid leukemia with poor diagnosis. Overexpression of EVI1 gene located on 3q26 driven by GATA2 distal hematopoietic enhancer located on 3q21 is a major cause of leukemogenesis. We previously generated a transgenic mouse model (3q21q26 mouse) recapitulating inv(3)(q21q26) allele by linking two bacterial artificial chromosome clones. To identify leukemia-initiating cells in leukemia with inv(3)(q21q26), we analyzed the leukemic 3q21q26 mouse bone marrow cells. The 3q21q26 mice developed leukemia in which B cell marker B220+ and myeloid cell marker Gr1+ populations were expanded. In these leukemic cells, B220+/Gr1-/c-Kit+ cells exhibited blast-like morphology and have colony-forming ability. In addition, nude mice, into which B220+/Gr1-/c-Kit+ cells were transplanted, developed leukemia. These results indicate that B220+/Gr1-/cKit+ cells contained leukemia-initiating cells in the leukemic 3q21q26 mice.

  17. Roles of stress-responsive transcription factors in health and disease

    YAMAMOTO Masayuki, KATSUOKA Fumiki, URUNO Akira, SUZUKI Norio

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (A)

    Institution: Tohoku University

    2012/04/01 - 2015/03/31

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    Transcription factor Nrf2 regulates a broad cytoprotective response to environmental stresses through induction of cellular defense enzymes. Keap1 is an adaptor protein for cullin3-based ubiquitin E3 ligase and negatively regulates Nrf2. This notion has been best demonstrated in animal models, showing that Nrf2-null mice are sensitive to a wide variety of electrophiles and reactive oxygen species (ROS). Keap1 possesses reactive cysteine residues that act as sensors for electrophilic and oxidative stresses. We have verified this model through structure biology, mouse/zebrafish genetics, and human cancer analyses. Elevated expression of NRF2 target genes confers advantages on the growth of cancer cells through the metabolic reprogramming. Thus, the Keap1-Nrf2 system opens a new avenue to the understanding of the signal transduction and regulatory processes underlying the stress response and cancer progression.

  18. Crosstalk between chromosome modification and transcription factors in the differentiation of hematopoietic cells

    KITAMURA Toshio, SAKAUE Asako, YAMAMOTO Masayuki, ISHIKAWA Fumihiko, MIYAWAKI Atsushi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Institution: The University of Tokyo

    2010/04/01 - 2015/03/31

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    We have demonstrated that the mutation of ASXL1 an epigenetic factor induces a myelodysplastic syndromes-like disease in mouse using mouse bone marrow transplant models. Concerning the molecular mechanisms, we have identified that suppression of PRC2 functions lead to derepression of HoxA9 and miR125a, playing critical roles in cell transformation and suppression of cell differentiation. In addition, we have identified a series of ASXL1 binding proteins, and investigate the physiological roles of ASXL1 in normal hematopoiesis. We also developed a novel G0 marker which expresses mVenus fluorescent protein only in cells in the G0 phase. We have now established and started the characterization of the transgenic mice expressing this G0 marker in hematopoietic cells.

  19. Analysis of leukemogenesis caused by disruption of gene regulatory mechanisms mediated by multiple transactivation domains

    YAMAMOTO Masayuki, SHIMIZU Ritsuko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2012/04/01 - 2014/03/31

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    GATA1 is a transcription factor essential for comprehensive regulation of genes involved in erythroid/megakaryocytic cell differentiation, utilizing two separate transactivation domains (TADs) located in amino(N)- and carboxyl(C)-terminal region of the molecule, respectively. Acute megakaryoblastic leukemia (AMKL) in children with Down syndrome is associated with GATA1 lacking N-TAD. We established transgenic mouse lines expressing mutant GATA1s lacking either N-TAD or C-TAD and analyzed the function of the domains in mice. We found that both N-TAD and C-TAD are important for fetal hematopoiesis. We also found that the disturbed function due to the lack of one TAD could be compensated by the functional enhancement of the other TAD in erythroid cells, whereas lack of N-TAD function could not be compensated in megakaryocytes. These results indicate that a skewed transactivation activity caused by single function of C-TAD is involved in the onset of Down syndrome AMKL.

  20. Mechanism of Nrf2-mediated self-renewal of hematopoietic stem cells

    YAMAMOTO Masayuki, SHIMIZU Ritsu

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2011 - 2011

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    It has been known that intracellular reaction oxygen specie (ROS)levels influence the maintenance of the stem cells. Nrf2 is a transcription factor that regulates the expression of antioxidant enzymes. In this study we analyzed the function of Nrf2 on hematopoietic system in mice. We found that Nrf2 negatively regulate cell-cycle progression of hematopoietic stem cells and contribute to the lineage commitment of multipotential progenitors.

  21. The role of Keap1-Nrf2 system in oxidative stress response of pancreatic β-cells

    URUNO Akira, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Research Activity Start-up

    Institution: Tohoku University

    2010 - 2011

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    Nrf2 (NF-E2-related factor 2)is a basic region-leucine zipper-type transcription factor, which belongs to the Cap' n' collar family. Nrf2 is activated by various stresses including electrophiles, reactive oxygen species (ROS), reactive nitrogen species (RNS), and heavy metals, and coordinately induces anti-oxidant enzymes. Keap1 (Kelch-like ECH-associated protein 1)is an adaptor protein for Cullin3-base ubiquitin E3 ligase and acts as a sensor for stresses, which strictly regulates the Nrf2 activity. We found that both Nrf2 and Keap1 are expressed in isolated islets from mice, and expression of Nrf2-target genes is upregulated by electrophiles, ROS and RNS. In addition, theβ-cell-damaged diabetes model mice crossed with Nrf2 hetero knockout showed elevated blood glucose levels and smaller islet size. Thus, these results support our contention that the Keap1-Nrf2 system plays important roles in the maintenance of pancreatic β-cells. The results further suggest that the Keap1-Nrf2 system may be involved in the pathogenesis of diabetes mellitus in stress conditions.

  22. The functional analysis of a transcriptional factor GATA3 in an inner ear development.

    HOSHINO Tomofumi, HAYASHI Kentaro, TABUCHI Keiji, HARA Akira, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: University of Tsukuba

    2010 - 2011

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    Because the transcriptional factor GATA3 express in otic vesicles and inner ears, it is suggested that GATA3 is important for the developmental pathway of the inner ear. Little is known about the function of GATA3 in developmental pathway because of lethality of Gata3 knockout mouse. Then, we used the new approach, a transgenic rescue technique. This clarified that part of Gata3-null-ears occurs to inner ear malformation. This result indicates GATA3 is indispensable to form the inner ear from the otic vesicle.

  23. Novel prevention of development of life style-related liver diseases and liver carcinogenesis through an activation of transcription factor induced by functional foods

    UTSUNOMIYA Hirotoshi, ISHII Tetsuro, SHODA Junichi, TAKAHASHI Hiroshi, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    2009 - 2011

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    Nrf2 is a transcription factor that exerts an in vivo defense mechanism against oxidative stress. Therefore, we studied whether Nrf2 inhibits onset and progression of NASH in the animal model of NASH induced by a mechionine-and choline-deficient(MCD) diet. Nrf2 has an inhibitory effect against the onset and progression of MCD-induced NASH through the induction of detoxifying and antioxidative stress gene molecules. It is suggested that Nrf2 is an important target for the treatment of NASH.

  24. Molecular Mechanisms of Adaptive Responses to Food and Oxygen

    YAMAMOTO Masayuki, KATSUOKA Fumiki, MINEGISHI Naoko, MOTOHASHI Hozumi, KUROKAWA Hirofumi, SUZUKI Norio, MORIGUCHI Takashi, SUZUKI Takafumi, TAGUCHI Keiko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Creative Scientific Research

    Institution: Tohoku University

    2007 - 2011

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    Environmental stress response system allows organisms to keep cellular homeostasis. In this study, weexamined Keap1-Nrf2-mediated oxidative and xenobiotic defense system, and identified novel molecular mechanisms for stress-sensing system and their association with diseases. We alsoidentified diverse and elaborate gene regulatory mechanisms in response to hypoxic stressthrough the comprehensive analysis of erythropoietin gene regulatory regions.

  25. 転写因子Nrf1の神経細胞恒常性維持機構の解明

    山本 雅之, 勝岡 史城

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 挑戦的萌芽研究

    Institution: 東北大学

    2010 - 2010

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    アルツハイマー病、パーキンソン氏病などに代表される神経変性疾患は、高齢化社会において、生活の質を脅かす疾患の一つである。そかし、その病態の発症・進行の機構は不明な点が多い。bZIP型転写因子のNrf1の欠失マウスは、異常タンパク質の蓄積を伴ったヒトの進行性神経変性疾患に極めて類似した症状を示す。本計画では、Nrf1欠失マウスの解析を通して、その破綻・異常タンパク質の蓄積に至る分子機構を理解することで、ヒトの神経変性疾患に対する新たな知見を得ることを目的とする。 Nrf1欠失マウス由来の神経初代培養細胞を用いたマイクロアレイ解析を実施した。その結果、Nrf1の欠失で発現に影響を受ける遺伝子は、これまでに報告されてきたNrf2が制御する生体防御関連の標的遺伝子とは異なる事が示された。また、Nrf1欠失マウス脳組織においての遺伝子発現解析を実施し、同様の結果を得ている。したがって、Nrf1は、Nrf2とは異なる標的遺伝子の発現制御を介して、神経細胞の恒常性の維持に寄与していると考えられた。Nrf1が直接制御する標的遺伝子の同定を試みるために、Nrf1のクロマチン免疫沈降解析(ChIP)を計画した。ChIP解析に用いる抗体の検討を行ったが特異性の高い抗体は得られなかったので、申請計画に記したように、Nrf1のパートナー因子である小Maf群因子に対する抗体を用いて、ChIPシークエンス解析を実施した。その結果、小Mafの結合部位は、Ataxin-1などの神経変性と関連した遺伝子の制御領域に結合していることが明らかなり、病態発症との関連が示唆された。上記の結果の一部は、学会発表として報告し、また、誌上発表の予定である。

  26. From the ER to the plasma membrane : Vesicular transport of membrane skeleton units and the diseases

    INABA Mutsumi, SATO Kota, AGUI Takashi, INANAMI Osamu, OTSUKA Yayoi, WATANABE Nobuhisa, YAMAMOTO Masayuki, TAKAKUWA Yuichi, OHTA Hiroshi, UMEMURA Takashi, HIKASA Yoshiaki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (A)

    Institution: Hokkaido University

    2007 - 2009

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    The long-range goal of this project is to investigate the mechanism for assembly and functional organization of the red cell membrane skeleton. Here, we analyzed the synthesis, quality control, interaction with an erythroid scaffolding protein ankyrin in the endoplasmic reticulum (ER), and the ER exit signal of anion exchanger 1 (AE1) and its mutants. The results obtained together indicate that the membrane skeletal network is assembled in the ER membrane as a small unit followed by vesicular transport to the plasma membrane.

  27. Roles of transcription factors for carcinogenesis and carcinogenesisdefense

    MASAYUKI Yamamoto, RITSUKO Shimizu, KINUKO Ohneda

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Priority Areas

    2005 - 2009

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    In this study, we investigated roles transcription factors play on carcinogenesis and carcinogenesis defense in vivo, focusing on the Nrf2 and GATA transcription factors. We have found that co-operative function of Nrf2 and Keap1, which mediates cellular stress response, is important for the cancer carcinogenesis defense so that the failure in Nrf2-Keap1 system leads to the onset of cancer and poor prognosis. We have further found that deregulated function of GATA factors, which act as key molecules in hematopoietic homeostasis, causes leukemogenesis.

  28. Genetic and Epigenetic Dysregulation in Cancer

    NODA Tetsuo, TAYA Youichi, ISHIKAWA Fuyuki, HANAOKA Fumio, YAMAMOTO Masayuki, HATAKEYAMA Masanori, NAKAMURA Takuro, TAKAI Yoshimi, NIWA Ohtsura, HIROHASHI Setsuo, SHIMOTONO Kunitada, SAYA Hideyuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Priority Areas

    2004 - 2009

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    The research area for "Genetic and Epigenetic Dysregulation in Cancer" was organized to elucidate the molecular mechanisms for the process of cancer initiation and progression. This board for the research consists of section chiefs and leading investigators in this area and has been working to promote research activities of principle investigators through varied types of activity, such as the organization of researchers and the evaluation of their activities. We also organized workshops to promote information exchange among investigators. Our activity has substantially contributed for the promotion of research activity and the production of many novel scientific findings by investigators in the area.

  29. 転写因子の発現量依存的な細胞運命決定機構の解明

    山本 雅之

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 萌芽研究

    2006 - 2007

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    申請者らは,GATA-1と構造的に高い相同性を有する転写因子であるGATA-2が,GATA-1との機能的相補性を有することを鑑み,GATA-1とGATA-2の機能分担、ネットワーク制御、さらに、それらの合計発現量が血球細胞の運命決定に与える影響を解析する必要があると考える。そこで、これら両者の発現量を個体レベルで明らかにするために、申請書らが既に樹立した、Gata1遺伝子発現制御領域下で赤色蛍光蛋白質(dsRed2)を発現するトランスジェニックマウスとGata2遺伝子座に相同組換え法で緑色蛍光蛋白質(GFP)をノックインしたマウス、及びそれらを交配した複合改変マウスを用いて、以下の解析をおこなった。これらのマウスの造血細胞における蛍光蛋白質発現を、フローサイトメーター(FACS)を用いて定量的かつ定性的に測定し、FACSにより分取した後に、コロニー法などでin vitro分化誘導することにより、その分化能を調べた。また、GATA-1とGATA-2を共発現する細胞の同定と解析を行い、細胞の増殖・分化・アポトーシスにおける2つのGATA因子の発現量を単一細胞レベルで明らかにすることを試みた。さらに、既に樹立されているGata1およびGata2遺伝子の部分破壊マウスや条件付き遺伝子破壊マウス、及びそれらを交配した複合改変マウスをの血液細胞の解析を行い、2つの転写因子の発現量変化が細胞運命に与える影響を調べた。また、レトロウイルス遺伝子導入系を用いて、GATA-1とGATA-2を高中低の様々な発現量で未分化前駆細胞に導入することにより、細胞運命決定に与える影響を検討した。これらの結果、GATA-1、GATA-2の発現量がその機能に大きく影響することが示唆された。

  30. 動脈硬化の進行防止における転写因子Nrf2の役割

    山本 雅之, MAHER Jonathan Michael

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特別研究員奨励費

    2005 - 2007

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    近年一般的に認知されるに至った活性酸素種や食物に含まれる親電子性物質によりもたらされる酸化ストレスは、DNAやタンパク質、脂質などの生体高分子を酸化することで傷害を与えるため、ガンや糖尿病などの生活習慣病を引き起こす素因になると考えられている。一方、生体内に存在するプロスタグランジンJ_2(PGJ_2)などの生理活性物質もまた、内因性の親電子性物質として作用し炎症の終焉に貢献する。すなわち、酸化ストレスは外来物質や代謝副生成物だけではなく、細胞内情報伝達におけるセカンドメッセンジャーとしても機能している.このような酸化ストレスに対し,細胞はすみやかに生体応答を発動することで、その恒常性維持と適応に努めている.この生体応答の制御機構において重要な機能を担っているのが,Keap1-Nrf2システムである。Nrf2欠損マウスあるいは、Keap1欠損マウスと高脂血症モデルマウスとして、apoE欠損マウスを交配し、それぞれの複合変異マウスにおける動脈硬化の進行について検討している。あるいは、生化学・分子生物学的な解析とマウス発生工学的手法による個体レベルの解析、さらには構造生物学的なアプローチも取り入れて、多角的にKeap1-Nrf2システムによる分子レベルの制御機構を解析した。その結果、動脈硬化におけるNrfr2-Keap1制御系の重要性が明らかになりつつある。

  31. Study for the molecular mechanism of oxidative stress responsive transcription

    YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: University of Tsukuba

    2005 - 2006

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    In this study, we achieved following results : 1. Identification of interacting proteins with transcription factor Nrf2 To identify cooperative factors of Nrf2, we purified proteins that specifically interact with recombinant Nrf2 protein and analyzed by mass spectrometry. As a result, TRRAP, TIF1β, TIF1γ, BAF53a, BRG1 were identified as novel interacting proteins with Nrf2. It was demonstrated that BRG1 interacts with Nrf2 and selectively mediates HO-1 gene induction in response to the oxidative stress. 2. Analysis of functional domains of Nrf2 in living cell. To analyze the effect of interacting proteins, stable knockdown cell lines of BRG1 and TRRAP were established and recruitment of Nrf2 and BRG1 was investigated. In BRG1 knockdown cell, Nrf2 binding to ARE was not changed, but the recruitment of BRG1 was abolished by the Nrf2 knockdown. By TRRAP knockdown, Nrf2-ARE binding was enhanced. We are now examining the recruitment of Nrf2 and other Nrf2-interacting proteins to ARE using Tetracycline-inducible Nrf2 expression cells. 3. Construction of reporter gene responsive to electrophile, diethyl maleate (DEM). To screen molecules involved in the activation of Nrf2 using a siRNA library, reporter gene with human NQO1 or HO-1 promoter fused with green fluorescence protein or thymidine kinase gene was constructed. We are almost the step to transfect the reporter construct into culture cells and start to screening.

  32. Molecular pathology for down-regulation of erythroid-specific genes in prion diseases

    INABA Mutsumi, HORIUCHI Motohiro, INANAMI Osamu, UMEMURA Takashi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (A)

    Institution: Hokkaido University

    2004 - 2006

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    AHSP is an erythroid-specific molecular chaperone that stabilizes newly synthesised a-globin. Previous studies demonstrated that mRNA levels of AHSP were specifically reduced in hematopoietic tissues of prion-infected animals. The purpose of the present study is to clarify the mechanism for down-regulation of AHSP transcription. A series of truncation and mutation analyses on 2.5-kb 5' upstream region of the AHSP gene in MELhide8 cells and electrophoretic mobility shift assay showed that the minimal 5'-promoter region located at-328-286 to the translation initiation site including a GATA binding motif. Either of two upstream GATA elements at-403 and-381 enhanced reporter gene transcription only in the presence of the minimal GATA element described above. These findings indicate that an erythroid-specific transcription factor GATA-1 is essential to AHSP gene expression and suggest that the down-regulation of AHSP involves changes in GATA-1 transcriptional activation. There was no significant change in gene expression of AHSP, a-globin, b-globin, GATA-1, EKLF, and NF-E2 in MELhide8 cells when the cells were incubated with brain homogenates from scrapie-infected mice for up to 120 hours. Moreover, MELhide8 cells exhibited no accumulation of PrPsc even after 16 passages. These data demonstrated that Prrc has no direct effect on AHSP gene expression in erythroid cells. Instead, IL-6 significantly and IL-1β weakly reduced the expression of AHSP mRNA levels and the AHSP promoter-reporter gene expression in MELhide8 cells in a dose-dependent manner. The reduction was recovered in the presence of the inhibitor of the STAT3 pathway, suggesting that the signal transduction of an inflammatory cytokine IL-6 through STAT3 pathway would modulate GATA-1/AHSP promoter interaction and subsequently causes down-regulation of the AHSP gene.

  33. Gene manipulation of hypoxia inducible gene regulation

    IMAGAWA Shigehiko, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: University of Tsukuba

    2004 - 2005

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    Erythropoietin (Epo) gene expression is negatively regulated by GATA, which binds to the GATA site in the Epo promoter, and also positively regulated by hypoxia inducible factor-1 (HIF-1), which binds to the hypoxia responsive element (HRE) in the Epo enhancer. The disorders associated with anemia of chronic disease (ACD) are characterized by a deficiency of Epo, leading to Epo being considered as a treatment. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), which increase the binding activity of GATA and inhibit Epo promoter activity, are increased in patients with ACD. In a previous study, we demonstrated the ability of K-7174 (a GATA-specific inhibitor) to improve Epo production that had been inhibited by IL-1β or TNF-α treatment in Hep3B cells in vitro and in an in vivo mouse assay (FASEB J 17:1742; 2003). However, K-7174 was injected intraperitoneally into the mice. We examined the ability of K-11706, a novel GATA-specific inhibitor that has a 1,000-fold higher affinity than K-7174, to improve Epo production following inhibition by IL-1β or TNF-α in Hep3B cells in vitro. Oral administration of K-11706 reversed the decreases of hemoglobin, serum Epo, reticulocyte counts and CFU-E induced by IL-1β or TNF-α. These results raise the possibility of using orally administered K-11706 as a novel drug for treating ACD (Blood 104:4300; 2004). In oxygenated cells, hypoxia inducible factor-1 (HIF-1) α subunits are rapidly degraded by a mechanism that involves ubiquitination by the von Hippel-Lindau tumor suppressor E3 ligase complex using 2-oxoglutarate as a substrate. We examined the effect of 2-oxoglutarate on the production of Epo and vascular endothelial growth factor (VEGF). The expression of Epo and VEGF protein were dose-dependently downregulated in Hep3B cells by the addition of 2-oxoglutarate. The promoter activity of VEGF-luciferase was dose-dependently downregulated by the addition of 2-oxoglutarate. Gel mobility shift assays revealed that the addition of 2-oxoglutarate dose-dependently inhibited HIF-1 binding activity, but did not affect GATA binding activity. Western blot analysis revealed that 2-oxoglutarate dose-dependently inhibited the HIF-1α protein level in Hep3B cells in hypoxic conditions. However, MG132 (the proteasome inhibitor) rescued the inhibition of HIF-1α protein expression by 2-oxoglutarate. Furthermore, under hypoxic conditions, 2-oxoglutarate dose-dependently inhibited tube formation in in vitro angiogenesis assays. These results indicate that 2-oxoglutarate treatment may be useful for the inhibition of angiogenesis.

  34. Molecular mechanisms for hemato-vascular formation

    YAMAMOTO Masayuki, SHIMIZU Ritsuko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: University of Tsukuba

    2003 - 2004

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    We have established green fluorescent protein (GFP) knock-in knockout mice (G2-GFP), in which the GFP gene was inserted into Gata2 gene under the hematopoietic specific promoter/ first exon and analyzed the phenotypes of GFP expressing cells. The percentage of GFP positive cells was 0.5 % in the bone marrow mononuclear cells. These GFP positive cells, expressing c-Kit without any staining lineage markers (Lin), had a potential to develop several lineage committing cells on the OP9 cell layer, suggesting that GFP-positive cells were belonging to either the population of hematopoietic progenitor cells or that of hematopoietic stem cells. The expression of cellular proliferation-related molecules, such as c-Myc, Cyclin A2 and Cyclin B1, in the GFP-positive cells were higher than those in the GFP-negative cells. In addition, more than 30 % of the cells in the population of Lin-/c-Kit^+/GFP^+ accumulated in S/G2/M phase. These findings indicated that GATA-2 had an important role for the transcriptional regulation of genes relating to cell cycle progression of the immature hematopoietic progenitor cells. To further investigate the function of GATA-2 on the hematopoietic cell proliferation in vivo, we established Gata2 gene conditional knockout allele (G2-CKO), in which GATA-2 cDNA sandwiched between two loxP sequences was inserted into the translation initiation site of Gata2 gene. Because the simple Gata2 gene knockout mice were embryonic lethal, this G2-CKO mouse line might be one of the most appropriate means to examine the function of GATA-2 on bone marrow hematopoiesis. We intercrossed the compound GATA-2 targeting mice (G2^<CKO/GFP>) with Mx1-Cre transgenic mice, in which the expression of Cre recombinase was induced by the treatment of interferon, and successfully generated the triple compound mouse colony (Gata2^<CKO/GFP>::Mx1-Cre). We are now ready for bone marrow transplantation analyses using the bone marrow cells of these mice to examine the function of GATA-2 for adult hematopoiesis.

  35. Transcription factor regulation of malignant cell transformation and its repression

    YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Priority Areas

    Institution: University of Tsukuba

    2003 - 2004

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    In this study we have studied transcription factor regulation of malignant cell transformation and its repression exploiting hematopoietic transcription factors and leukemia as a model system. GATA-1 is essential for the development of erythroid and megakaryocytic lineages and mutations leading to the production of N-terminus truncated form GATA-1 are frequently found in the Down syndrome-related acute megakaryoblastic leukemia (AMKL-DS) patients. We found that GATA-1 gene knockdown female (GATA-1.05/X) mice frequently develop a hematopoietic disorder that resembles myelodysplastic syndrome characterized by the accumulation of progenitors. We have demonstrated that GATA-1.05/X mice suffer from two distinct types of acute leukemias. Since GATA-1 is an X chromosomal gene, two types of hematopoietic cells reside within heterozygous GATA-1 knockdown mice, bearing either an active wild-type GATA-1 allele or an active mutant GATA-1.05 allele. In the latter hematopoietic progenitors, low-level GATA-1 expression is sufficient to support survival, but not differentiation, leading to the accumulation of progenitors that are easily targeted by oncogenic stimuli. Since such leukemia cases have not been observed in GATA-1-null/X mutant mice and since transgenic expression of wild-type GATA-1 rescue GATA-1.05/X mice from the leukemia, we conclude that the residual GATA-1 activity in the knockdown mice contributes to the development of the malignancy. In addition, wild-type GATA-1 promoted AMKL-DS leukemic cells to mature erythroid cells, but truncated form GATA-1 could not, suggesting that defect of GATA-1 is one of the leukemogenic factors.

  36. Analysis of lymph node metastasis of oral cancer by using peroxiredoxin I knockout mouse

    YOSHIDA Hiroshi, YAMAMOTO Masayuki, ISHII Tetsuro, YANAGAWA Toru

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: University of Tsukuba

    2002 - 2004

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    Prx I deficient mouse was established by gene trapping method. Embryonic stem (ES) cells with a retroviral gene trap vector inserted into the Prx I locus (Omni bank no.OST422296) were transferred to a foster mother to generate chimeric animals (Lexicon Genetics Inc.). The genetic background was uniformized to C57BL/6 by back cross. B16 murine melanoma cells (1x10^5 cells/body) were inoculated into the mouse foot pad of three groups (wild-type, heterozygous, and homozygous Prx I deficient mouse) and lymph node metastasis and lung metastasis were observed. When genetic background was C57/129Sv, lymph node and lung metastasis were reduced by Prx I loss. However, after 5 generation back cross and uniformized C57BL/6 genetic background, there was no significant difference in lymph node and lung metastasis between wild-type and Prx I homozygous deficient mice. When another cell line (LLC cell, derived form lung cancer : 3x10^6 cells/body) was inoculated in these groups, there was no difference. By using Matrigel as a matrix of tumor growth, we inoculated the mixture of B16 cells (1x105 cells /body) and the gel into subcutaneous and investigated the vascularization, but there was no significant difference. On the other hand we investigated the stress response of A170 oxidative stress, which is regulated by same transcription factor Nrf2 as Prx I to analyze how oxidative stress protein was induce by oxidative stress. And we also investigated GATA-1 transgenic mouse, because Prx I and GATA-1 were both related with red blood cell abnormality.

  37. Sensitive detection of air-born mutagens and their evaluation using gene knockout mice

    AOKI Yasunobu, MATSUMOTO Michi, YAMAMOTO Masayuki, NOHMI Takehiko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (A)

    Institution: National Institute for Environmental Studies

    2002 - 2004

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    A transcription factor, Nrf2, is essential for expression of phase II enzymes and antioxidant enzymes, and contributes to a protection system against xenobiotics. We intended to reveal how mutant frequency is increased under Nrf2-deficient condition. We used gpt delta mice as a model animal for determining characteristics of in vivo mutagenesis caused by environmental mutagens. Intratracheal instillation of mutagens such as benzo[a]pyrene (B[a]P) and 1,6-dinitropyrene(1,6-DNP) caused to increase the mutant frequency linearly depending of the dose, and in vivo mutagenic potency of 1,6-DNA was shown to be higher than that of B[a]P. A predominant base substitution caused by B[a]P and 1,6-DNP was G>T and G>A, respectively, and positions of mutation hotspots on gpt gene was different between these compounds. Exposure of diesel exhaust for 12 weeks at the concentration of 3 mg/m^3 resulted to elevate the mutant frequency depending on duration of exposure. As a result of intratracheal instillation, mutagenicity of diesel exhaust particles (DEP) was shown to be derived from the extract of DEP. A predominant base substitution induced by exposure of diesel exhaust, as well as administration of DEP, was G>A, and the positions of mutation hotspots were identical to those of 1,6-DNP, suggesting that major mutagens in diesel exhaust are nitropyrenes and related compounds. We produced Nrf2-deficient gpt delta mice, and B[a]P was administered to lungs of the Nrf2(+/-) and Nrf2(-/-) mice. The mutant frequency in B[a]P-treated Nrf2(-/-) mice became twice compared to Nrf2(+/-) mice.

  38. 転座関連遺伝子及び転写因子による細胞分化とがん化の分子機構

    瀬戸 加大, 森下 和広, 山本 雅之, 大根田 絹子, 鈴木 律朗

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 愛知県がんセンター(研究所)

    2000 - 2004

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    瀬戸は、粘膜関連リンパ組織(MALT)リンパ腫に特異的に認められる染色体転座、t(11,18)(q21,q21)に関与する遺伝子API2-MALT1について、造血器細胞における機能の解析をするために細胞株や骨髄幹細胞にAPI2-MALT1遺伝子を導入した。Hela細胞株や増殖因子依存性の細胞株ではUV刺激、抗がん剤などによるアポトーシスを抑制する能力があることが明らかとなった。また、API2-MALT1と相互作用する蛋白としてTRAF2、smac、HtrA2などアポトーシスを制御する蛋白を明らかにした。また、悪性リンパ腫のゲノム異常をアレイCGHで検索したところ、病型特異的なゲノム異常が存在することが明らかとなった。 森下は、Evi1転座関連遺伝子の機能を明らかにするためにEvi1遺伝子欠損マウスの造血発生異常を検討し、造血幹細胞の維持・増殖異常及び、血管発生異常を同定した。遺伝子発現解析にてGATA-2遺伝子の転写低下、プロモーター解析によりEvi1はGATA-2の直接の転写調節に係わることがわかった。Evi1は白血病細胞内にてGATA-2転写を亢進させ、白血病幹細胞の増殖維持に関係していることが示唆され白血病発症機構の一端を解明した。t(1,3)転座関連遺伝子としてEVI1遺伝子ファミリーであるMEL1遺伝子を単離し、機能解析によりEVI1と同様の転写因子機能を持っていることがわかり白血病発症機構も類似することが示唆された。

  39. 分化方向性の制御から挑む再生医工学

    山本 雅之, 小林 聡

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 萌芽研究

    Institution: 筑波大学

    2002 - 2003

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    分化方向性の制御を維持するモデルとして,造血幹細胞を選び,以下の解析を行った. (1)造血幹細胞の自己複製能維持に必要な転写因子を同定することを目指し,幹細胞の維持に重要と考えられる転写因子GATA-2の発現制御機構を解析した.GATA-2遺伝子の発現をGFPレポータータンパク質で解析できるトランスジェニックマウスを作製し,9.5日胚のpara-aortic splan chnopleura,同13.5日胚の胎児肝でのGATA-2遺伝子の発現を解析した.その結果,GATA-2遺伝子の転写制御に必須なシスエレメントを含む領域を同定することに成功した.現在,さらに結合領域を絞り込むために,同トランスジェニック法とin vivo footprint法による解析を行っている.今後は,その結合配列に対するトランス因子を同定するために,One-Hybrid法を行うことを予定しており,フローサイトメトリーにて分取したGFP陽性細胞からcDNAライブラリーを作成中である. (2)造血幹細胞の性質を有した細胞株を作成することは,幹細胞自体の稀少性の点から,今後の解析にたいへん有用である.そこで温度感受性T抗原を,胎児造血幹細胞に発現しているトランスジェニックマウスの作製に取り組み,成功した.今後,同トランスジェニックマウスから得られる血液幹細胞を用いて,血液細胞系の分化に重要な転写因子群の発現プロファイルを網羅的に解析し,分化の方向に働く転写因子群とその拮抗因子群を同定する予定である.同定後,分化に拮抗する因子群を,レトロウイルス系を用いて,分化抑制状態にある各種培養細胞や,分化抗原を発現する骨髄細胞に導入し,分化/脱分化の制御を試みる.

  40. Molecular mechanisms for the assembly of the red cell membrane skeleton during erythroid cell development

    INABA Mutsumi, TAKAKUWA Yuichi, SAITO Masayuki, MAEDA Yoshimitsu, INANAMI Osamu, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: HOKKAIDO UNIVERSITY

    2002 - 2003

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    The "unit-assembly hypothesis" for red cell membrane skeleton during erythroid development was investigated. Stable transfectants of major constituents of red cell transmembrane proteins were developed in K562 and HEK293 cells using retroviral vectors. Band 3 and glycophorinCweretransportedtotheplasmamembranevia the ER/Golgi pathway. Band 3-binding domain of ankyrin (AnkN90) and protein 4.1 showed membranous localization in the cytoplasm with co-localization with markers for the ER and the Golgi apparatus in band 3-transfeted cells despite of the difference in erythroid differentiation. Endogenous membrane skeletal proteins including ankyrin, protein 4.1, and spectrin also exhibited membranous distribution. These results indicate that the assembly of membrane skeletal proteins occurs at an early stage of erythroidal development on the surface of the ER but not on the inner surface of the plasma membrane. Stable expression of band 3 caused a reduction in a proliferation rate of K562 cells to approximately 70% that of non-transfected cells. Reduced production of hemoglobin suggestive of erythroid differentiation was also observed. However, no significant changes in intracellular localization of skeletal proteins and cell morphology was detected Synthesis and assembly to the ER of skeletal proteins involving spectrin and subsequent synthesis and localization to the plasma membrane of band 3 were observed in erythroid precursor cells from peripheral blood of cattle in two phase liquid culture system, indicating that the assembly of membrane skeletal proteins to the ER occurs in physiolosical erythropoiesis. The present study demonstrated that the assembly of the red cell membrane skeleton is an event which takes place at early stages of erythroid development on the ER. The exact mechanism by which a small unit of the ekeleton formed on intracellular vesicles are integrated in the plasma membrane remained to be clarified.

  41. 赤芽球の増殖・分化・アポトーシスの制御におけるGATA因子の役割の解明

    山本 雅之

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 筑波大学

    2002 - 2003

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    本研究は、赤血球の増殖・分化・アポトーシスの制御とその破綻がもたらす造血器腫瘍の形成過程において,血球系GATA転写因子が果たす役割を解明することを目的として行っている.本年度は,GATA-1遺伝子ノックダウンマウス雌ヘテロ接合体(GATA-1.05/X)に発症する白血病の病態について,GATA-1.05/X574例と野生型225例について検討した.その結果,GATA-1.05/Xは平均寿命388日であり,野生型と比較して有意に短命であった.死亡マウスのうち,観察し得た98例全てに脾腫大が観察された.死亡時期は100日前後と350日以降の2峰性のピークを呈し,前者はc-kit陽性の赤芽球細胞系列の,後者はCD19陽性のBリンパ球系列の異常増殖が観察された.c-kit陽性白血病細胞は形態的に未分化であり,in vitro培養系で分化誘導が可能であった.一方CD19陽性細胞に伴う白血病は脾臓のほか全身のリンパ節腫大を伴っており,ヒト骨髄異形成症侯群類似の表現型を呈していた.また,トランスジェニックレポーターマウスを用い,GATA-1,GATA-2遺伝子の時期・細胞系列特異的な発現制御機構の解析を進めた.GATA-1遺伝子については赤血球への発現を再現性良く示す人工的なGATA-1 minigeneを開発し,GATA-1 hematopoietic enhancer(G1HE)のコア配列と,IEの5'側にそれぞれ存在するdoubleGATA配列とCACCC配列が,いずれもG1HRDの機能に必須であることを見出した.また,GATA-2の造血組織における発現を再現性よく示すレポーターマウスを解析し,GATA-2遺伝子の発現制御機構が,para-aortic splanchnopleuraや卵黄嚢を中心とする初期造血の時期と,胎児肝の時期とで異なっていることを明らかにした.

  42. Gene Modification of Oxygen Responsiveness by Erythropoietin Gene

    IMAGAWA Shigehiko, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: University of Tsukuba

    2001 - 2003

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    Erythropoietin (Epo) gene expression is negatively regulated by GATA, which binds to the GATA site in the Epo promoted and also positively regulated by hypoxia inducible factor-1(HIF 1), which binds to the hypoxia responsive element (HRE) in the Epo enhancer. We have the following results along with this evidence 1) N^G-monomethyl L-arginine (L-NMMA) has been increased in the patients with chronic renal failure. The addition of L-NMMA(NOS inhibitor) into the Hep3B cells, inhibits NO・cGMP production, increases GATA binding activity and mRNA expression, ad inhibits Epo promoter activity and induces the anemia with renal disease (Blood 96 : 1716-1722, 2000). However, pre-treatment with L-arginine reversed the anemia with renal disease in vitro Hep3B cells and in an in vivo mouse assay (Kidney Int 61 : 39604, 2002) 2) The addition of H_2O_2 inhibits Epo gene expression by increasing GATA binding activity and inducing degradation of HIF-1α(J Cell Physiol 186 : 260-267, 2001) 3) The addition of cadmium inhibits Epo gene expression by inhibiting the binding activity of HIF-1, not by GATA (Arch. Toxicol 77 : 267-273, 2003) 4) Mouse Epo gene expression is also negatively regulated by GATA, which bonds to the GATA site in the mouse Epo promoter like human Epo gene (Int J Hematol 74 : 376 381, 2002) 5) To better understand how human adapt to hypoxia, the levels of Hb, serum Epo and VEGF were measured in 106 patients with severe obstructive sleep apnea-hypopnea syndrome. The results indicated that temporal hypoxic stimulation increases Hb. Furthermore, a minor increase in Epo and a substantial increase in VEGF were found (Blood 98:1255-1257, 2001) 6) K-7174 (a GATA-specific inhibitor) improved Epo production that had been inhibited by IL-1β and TNF-α, which have been increased in the patients with anemia of chronic disease or L-treatment in Hep3B cells in vitro, and in an in vivo mouse assay (FASEB J 17 : 1742-1744, 2003) Recently, we have analyzed Epo gene expression system by transgenic mice with BAC to identify the kidney inducible element (KIE). Peritubular capillary interstitial cells are the major Epo productive cells. KIE is located between 22〜8Kbp upstream from CAP site (In preparation)

  43. Construction of a repertoire of genetically altered mice for evaluating the toxicity of chemicals

    MAEDA Shuichiro, YAMAMOTO Masayuki, KOIZUMI Akio, NAKAJIMA Tamie, KAGAMI Yoshihiro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (A)

    2001 - 2003

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    Currently, more than 100,000 chemicals have been used in industry. These chemicals have been released to the environment without any toxicological evaluation. To regulate these chemicals properly, the development of methods for toxicological assessment is required. Thus, we performed experiments to develop a repertoire of genetically altered mice for evaluating the toxicity of chemicals. The results of our experiments are as follows. 1)We established an extremely rapid, sensitive, easy, and specific assay for dioxin and dioxin like chemicals (Maeda, S.) 2)In the search for dioxin-responsive genes in the mouse fetal brain we used differential mRNA display and DNA microarray and found that secreted frizzled-related protein 2 and c-myc genes that encode a Wnt modulator and a Wnt target, respectively, were up-regulated by perinatal exposure of mice to dioxin (Maeda, S. & Kagami, Y.). 3)Nrf2-null mice were very sensitive to acetaminophane and very often suffered from acute hepatotoxicity (Yamamoto, M.) 4)When AhRR, which was identified as a repressor of AhR, was deleted in mouse, the induction of AhR target genes were increased and prolonged (Yamamoto, M.). 5)We have conducted genetic analyses of individuals highly susceptible to goiter and found two linked regions on chromosome 3 and 4. We have sequenced solute carrier family genes, SLC26A1 and SLC2A9. The sequence, however, suggested that these two genes were not associated with familial goiter (Koizum, A.). 6)The role of peroxisome proliferators-activated receptor a (PPARa) in the di (2-ethylhexyl) phthalate (DEHP)-induced reduction of fertility, which was assessed by measuring the numbers of pups born and pups lived more than 16 weeks per breeding pair, was assessed using Sv/129 wild-type and PPARa-null mice. Our results suggested that the reduction of fertility without the maternal or paternal genital organ toxicity found in DEHP-exposed wild-type mice is partly caused by a signal triggering energy overconsumption via PPARa in the maternal body (Nakajima, T.).

  44. 転写制御複合体形成のダイナミクスとその生物機能の解明

    山本 雅之, 深水 昭吉, 太田 力, 田中 俊之, 本橋 ほづみ, 青田 聖恵

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(C)

    Institution: 筑波大学

    2002 - 2002

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    2003年1月23日(木)から25日(土)にわたり、つくば国際会議場中ホール300において、転写研究会を開催した。演題は計58題で出席者はのべ300人におよんだ。会議は、大きく分類して1)基本転写因子に関する研究7題2)クロマチンレベルでの転写制御機構10題3)転写活性化機構2題4)転写抑制化機構3題4)個体発生における転写因子の役割17題5)高次生命現象における転写因子の役割17題6)蛋白質の3次元構造解析2題であった。プレゼンテーションは、発表15分、質疑応答3分で行われた。発表は液晶発表を主としたが、スライド発表およびOHPによる発表を併用した。また、6から7演題ごとに、20分間の休憩を設けた。いずれの発表に対しても、制限時間をこえる質問が寄せられ、活発な討論が行われた。また、会議の連絡および宣伝を目的としてインターネット上にホームページを開設した。ホームページには、会議の主旨、プログラムおよび会場の案内などを掲載して、出席者への便宜を謀った。なお、出席者および発表者への連絡は主にメールにより行った。当研究会は、転写に関する研究者の交流をはかることにより、共同研究などの萌芽となることを目的のひとつとするので、今後も本研究会を継続して開催することにより、より一層の成果が得られるものと考えられる。

  45. Investigation of biological function of thioredoxin by construction of thioredoxin knock down mice

    MASUTANI Hiroshi, YAMAMOTO Masayuki, YODOI Junji

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: KYOTO UNIVERSITY

    2001 - 2002

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    AIM: We investigated the function of thioredoxin (TRX) by analyzing activation mechanism of the thioredoxin gene. RESULTS: 1) We demonstrated that the TRX gene is induced by hemin or tertial butylhydroquinone (tBHQ) through antioxidant responsive element (ARE) by Nrf2. We showed a mechanism of a differential regulation of the antioxidant responsive element (ARE) by a switch of its binding factors. We also showed TRX -dependent redox regulation of the ARE in electrophile response (JBC, 2001; Oncogene, 2003). These results suggest the role of TRX in erythroid differentiation and host defense against reperfusion injury and chemical carcinogensis. 2) We demonstrated that the TRX gene is induced by nerve growth factor (NGF) through cyclic AMP responsive element by CREB. We also showed critical Roles of TRX in NGF-Mediated Signal Transduction and Neurite Outgrowth in PC 12 Cells. (J. of Neuroscience, 2003). 3) We cloned mouse TRX genome and are preparing t TRX knock-down mice. We also prepared TRX RNAi vector. We analyzed TRX binding protein-2 (TBP-2), a negative regulator of t TRX and are preparing TBP-2 knock out mice and transgenic mice. 4) We showed a mechanism of oxidative stress-induced apoptosis (EMBO J., 2002). We showed a mechanism of apoptosis by 3-methylcholanthrene, a polycyclic aromatic hydrocarbon (JBC, 2002).

  46. Functional Contribution of Small Maf Proteins in Hematopoietic Cells

    MOTOHASHI Hozumi, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: University of Tsukuba

    2001 - 2002

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    (1) Transcriptional regulation of mafG gene. Three independent promoters were identified by 5'-RACE in mafG gene. A 7 kbp-genomic fragment containing the mafG promoters were able to direct tissue-specific reporter gene expression in brain, lens, lung and kidney, but not in hematopoietic cells of transgenic mouse. We are going to test additional 3 kbp fragment downstream of mafG gene. (2) Subtraction analysis of mafG-null megakaryocytes. mRNA derived from proplatelet formation (PPF)-defective mafG-/-::mafK+/- megakaryocytes were subtracted by mRNA of control wild type megakaryocytes. Several clones obtained from the subtraction were found to be related to cytoskeletal proteins, such as actin and tubulin. One novel clone, named #325, was also obtained, and it was found to be conserved among various vertebrates from fish to human. The expression of #325 increased according to the differentiation of immature hematopoietic cells to megakaryocytes. We are generating #325-overexpressing transgenic mouse and disaipting #325 gene in mouse to examine the in vivo function of the gene. (3) Analysis of MafG C-terminal region. MafG C-terminal region was deleted to generate MafGAC. The mutant molecule also repressed the transcription as well as the wild type MafG when they were overexpressed in cultured cells, When the synergistic transcriptional activity of MafGAC with p45 was compared to that of MafG, MafGAC showed much stronger transcriptional activity than wild type MafG. We are going to test the function of MafGAC in vivo.

  47. Functional analysis of BTEB and BTEB2 transcription factors by gene-targeting technology

    FUJII Yoshiaki, SOGAWA Kazuhiro, KOBAYASHI Akira, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    2001 - 2002

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    Mouse BTEB and BTEB2 are transcription factors with three-time-repeated C_2H_2 zinc finger motif and bind the GC-box consensus sequence. In order to investigate their physiological functions, we have constructed targeting vectors by replacing the first exon with structural genes for β-gal in translational coding phase and neo and made BTEB- and BTEB2-deficient mice by homologous recombination technology using these targeting vectors. Concerning the BTEB-null mice, they, either male or female, were born apparently normal according to the Mendelian genetics from mating between heterozygous BTEB (+/-) dams and grew normal. The male and female offspring were fertile. Judging from the expression pattern of BTEB during the mouse development showing that the dramatically increased expression of BTEB was observed in Purkinye cells of the cerebellum and pyramidal cell layers of the hippocampus at P7 when synapses start to form in the brain, we investigated the memory and motor activity. Although general behavioral activities such as locomotion, rearing, and movement were not so much affected in the BTEB (-/-) mutant mice, they showed clearly reduced activity levels in rotorod and contextual fear conditioning tests, probably due to defective functions of the cerebellum, and hippocampus, respectively. On the other hand, homozygous BTEB-2 (-/-) mice were not born, while heterozygous BTEB2 (+/-) mice were born normally. Detailed analysis of embryos revealed that fertilized BTEB (-/-) oocytes developed apparently normally until E3.5 and died at E4.5. One of the causes for the early embryonic death was considered to be defective expression of FGF4 which is known to be important factor for the early embryonic development and was clarified to be a target gene of BTEB2.

  48. APPLICATION OF GENE MANIPULATION TECHNOLOGY TO GENERATION OF MODEL ANIMALS FOR ENVIRONMENTAL ASSESSMENT

    YAMAMOTO Masayuki, HARADA Tamanori, AOKI Yasunobu, TAMAHASHI Satoru

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for University and Society Collaboration

    Institution: UNIVERSITY OF TSUKUBA

    2000 - 2001

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    1. Generation of AhR-overexpressing mouse. Mice carrying AhR cDNA driven by keratin14 promoter displayed inflammation and hyperkeratinization of the skin. These mice are now under examination whether they are more vulnerable to chemical carcinogens. 2. Generation of human AhR (hAhR)-knock-in mice. The mouse AhR gene was replaced with human AhR cDNA by homologous recombination in ES cells. By injecting the ES cells into blastcysts, we generated hAhR-knock-in mouse expressing human AhR molecule instead of mouse AhR. When exposed to 3-methylcholanthrene, hAhR-knock-in mice displayed the comparable induction of the phase I enzyme genes with the control animals. When TCDD was used, hAhR-knock in mice showed much weaker response than the control mice. We suspect that the response observed in hAhR-knock in mouse mimics that of the humans. This mouse will serve as an animal model for the assessment of the toxicity of environmental chemicals. 3. Analysis on the responses to environmental chemicals of Nrf2-deficient mice. Nrf2-deficient mice were challenged by several environmental chemicals to examine the significance of Nrf2 contribution in vivo. Nrf2-deficient mice were more sensitive to acetaminophen hepatotoxicity due to the increased level of active metabolic intermediates. Increased levels of DNA adducts was observed in Nrf2-null mutant mice after the exposure to diesel exhaust. Oral administration of benzo[a]pyrene caused severer gastric cancer in Nrf2-deficient mice than the control animals. These results indicate that Nrt2 is a key regulator of the protective responses against the toxicity of environmental chemicals.

  49. Development of monitoring system of toxic chemicals base on the Nrf2-dependent detoxification pathway

    YAMAMOTO Masayuki, KOBAYASHI Makoto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: University of Tsukuba

    2000 - 2001

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    Analysis using Nrf2-LacZ mice After feeding NrfZ-LacZ mice with dietary BHA for 3 days, accumulation of LacZ activity was observed in intestine, liver and peritoneal macrophages. The result suggested that Nrf2-LacZ mice are useful for detecting toxic chemicals in foods or medicines. In addition, we found a posttranseriptional accumulation of Nrf2 protein in response to electrophiles. Analysis of Nrf2 knockout mice Nrf2 knockout mice was susceptible to benzo[o]pyrene-induced neoplasia in the forestomach, diesel exhaust-induced hyperplasia and oxidative DNA adduct formation in the lung, and acetaminophen-induced hepatotoxicity. These results demonstrated that Nrf2 knockout mice are highly sensitive to carcinogen and/or oxidative stress, and that they will be useful for detecting toxic chemicals in foods or medicines. Zebrafish system for xenobiotic studies We showed that Nrf2-based induction of phase II detoxifying enzymes was conserved in fish and that a possibility of monitoring carcinogens using zebra fish system. Thus the GFP reporter construct fused to the transcriptional regulatory region of zebrafish GSTpi gene was prepared. In a transient reporter analysis, we could observed a GFP induction by electrophiles in zebra fish larvae. We are now trying to establish a stable transgenic zebrafish line which contains the construct.

  50. Molecular mechanism for the assembly of red cell membrane skeletons based on pathobiology of congenital hemolytic anemia in cattle

    INABA Mutsumi, TAKAKUWA Yuichi, ONO Ken-ichiro, YAMAMOTO Masayuki, MATSUKI Naoaki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: The University of Tokyo

    2000 - 2001

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    Stable transfectants of normal bovine band 3 (bebWT) or the mutant band 3 with R664X mutation (bebRX) were established in K562 cells and HEK293 cells using retoriviral vectors. Transfected cells expressing EGFP-bebWT and EGFP-bebRX, and N-terminal domain of ankyrin (AnkN90) in combination with band 3 proteins were also prepared. The bebWT and EGFP-bebWT showed stable expression on the plasma membrane of the transfected cells, whereas the mutant proteins, bebRX and EGFP-bebRX were degraded by Ub-proteasome system soon after synthesis on the ER or after retrograde transported from the Golgi apparatus to the ER. Stability of the bebWT was extremely reduced when bebRX was co-transfected. AnkN90 showed membrane localization within the cells and was destabilized in the cells that had the mutant band 3. These findings indicate that the mutant band 3 (bebRX) plays a dominant-negative role on the expression of normal band 3 and a partner in the membrane skeleton, ankyrin, and the interaction of band 3 with ankyrin occurs on the ER membrane soon after band 3 synthesis is started during erythroid development.

  51. Analysis of biological function of regulatory network composed of bZip transcription factors

    YAMAMOTO Masayuki, MOTOHASHI Hozumi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (A)

    Institution: University of Tsukuba

    2000 - 2001

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    Searching for target genes regulated by bZip network. Proplatelet formation, which is regarded as a major pathway of platelet production, is severely impaired in megakaryocytes obtained from mafG-/-::mafK+/- mutant bone marrow. In order to identify the target genes of small Mafproteins which are important for platelet production, we subtracted CDNA pool of mafG-/-::mafK+/- megakaryocytes from that of wild type megakaryocytes. CDNA clones coding cytoskeletal proteins, such as actin and tubulin, were obtained. One clone obtained from the subtraction, #325, encoded novel unknown protein. Expression level of #325 was high in megakaryocytes but low in erythoid cells. This expression profile suggested that #325 plays an important role in megakaryocytic differentiation, maturation and platelet production. Analysis of bZip network function in neuronal cells. MafG-/-::mafK+/- compound mice display severe motor disorder which becomes apparent at two months after birth. This sign resembled hereditary hyperekplexia in human, which is caused by functional insufficiency of glycine receptor. When we examined the expression levels of glycine reseptor subunit genes, both alpha and beta subunits were reduced. This result indicated that glycine receptor subunit genes are regulated through MARE directly or indirectly. Effect of small Maf proteins to subcellular localization of Bach proteins. Binding activity to MARE in the brain nuclear extract from mafG-/-::mafK+/- mice was examined by EGMSA, and we found that a shifted band comnosed of Bach/small Maf heterodimers is remarkably reduced in intensity. Interestingly, nuclear localization that Bach proteins was imuuHcu in mafG-/-::mafK;/- brain. It was concluded that small Maf proteins promote the nuclear localization of Bach, which depends on bZip structure of small Maf.

  52. Study on a new defence system against oxidative stress

    ISHII Tetsuo, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: University of Tsukuba

    1999 - 2001

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    We found that transcription factor Nrf2, known to interact with electrophile response elements or antioxidant responsive elements, regulates expression of detoxifying enzymes and antioxidant proteins such as HO-1, Prx I, A170 and the cystine transporter in murine peritoneal macrophages. Nrf2 was activated by various types of oxidative stress-causing agents : low levels of H_2O_2 that is added to the medium or produced by glucose oxidase in the culture medium, paraquat that produces superoxide, arsenite, cadmium, and electrophilic agents such as diethylmaleate and catechol. Nrf2 also controlled expression of genes encoding detoxifying enzymes such as GSTs and NQO1 in small intestine and liver by dietary 2(3)-t-butyl-4-hydroxyanisole (BHA). We found that dietary BHA induced intestinal and hepatic Prx I in a manner similar to the induction of GSTs. Thus, Nrf2 plays important roles in defense against various types of cytotoxic agents.

  53. 転写調節による造血分化制御

    仲野 徹, 田中 信之, 平井 久丸, 山本 雅之, 五十嵐 和彦, 小守 寿文, 北村 幸彦

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究(A)

    Institution: 大阪大学

    1998 - 2001

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    マウス胚性幹細胞から血液細胞への分化誘導法と、テトラサイクリンによるコンデイショナル遺伝子発現系を組み合わせて、GATA-2の機能解析をおこなった。その結果、GATA-2は未分化な造血前駆細胞の増殖を亢進させること、また赤血球・巨核球への分化を促進することがあきらかになった。また、GATA-1の機能ドメインを解析するために、GATA-1ノックダウンマウスの致死性をGATA-1遺伝子の発現制御領域制御下に種々のGATA-1変異体を発現するトランスジェニックマウスにより相補する実験をおこなった。その結果、Cフィンガー,Nフィンガーは両方とも個体レベルでのGATA-1機能に必須であることがあきらかになった。 mi遺伝子座がコードするbasic-helix-loop-helix leucine zipper型転写因子(MITF)はbasic domainの1アミノ酸の異常では抑制性の機能をもつのに対し、大半のアミノ酸を欠損することであらゆる機能を失った。また、MITFと結合するタンパク質としてzinc finger domainをもつMAZRを単離した。MAZRはマスト細胞で高発現しているプロテアーゼ遺伝子の転写活性をMITFと相乗的に高めていた。また、骨芽細胞分化、破骨細胞分化、骨形成におけるCbfa1の機能およびB細胞分化におけるBach1の機能を明らかにした。 AML1の成体における機能を明らかにするため、AML1のコンディショナル・ノックアウトマウスを作製し、T細胞特異的AML1欠損マウスおよびB細胞特異的AML1欠損マウスの解析を行った。T細胞特異的AML1欠損マウスは著しい胸腺低形成を示し、CD4,8陰性(DN)分画内ではCD25陽性CD44陰性(DN3)分画に細胞が蓄積し、それ以降の分化が抑制されていた。また、B細胞特異的AML1欠損マウスにおいてもB細胞の分化障害を認めた。 以上のように、種々の血液細胞系列における転写因子の機能を明らかにすることができた。

  54. Transcriptional mechanisms controlling organized function in vertebrate

    FUJII-KURIYAMA Yoshiaki, HANDA Hiroshi, KATO Shigeaki, ISHII Syunsuke, NABESHIMA Youichi, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Priority Areas (A)

    Institution: Tohoku University

    1997 - 2001

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    For 4 years of investigation term supported under the research project of Scientific Research in Priority Areas, approximately 900papers have been published in the international journals with an aerage citation index of 8.3 per paper. Both quantity and quality of the published papers of this research project have clearly made substantial contribution to the field of transcriptional regulation. The research groups consisted of two subgroups which pursued pursued the two main projects : 1)Mechanism of interactions between transcription factors and molecular mechanisms mechanisms of expression of thir transcriptional actiuity, 2)Search for target genes targeting technology. The steering steering commitee of this project promsted the communication and discussion between two subgroups to occelerate the progress in research work and hold symposia on transcriptional reeyulation to publisigze the results obtained by the research group. The results are enormous ranging from novel transcription factors, coactiwators, corepressors and and foctors involved in transcription elongaion and initiation Target genes and functions of the transcription factors have been elucidated by gene targeting technology. Undifferentiated states of stem cells have been clarified to be maintained by teh expression of transcription repressons.

  55. Nrf2による新しい酸化ストレス応答機構の解析

    山本 雅之

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 萌芽的研究

    Institution: 筑波大学

    1999 - 2000

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    今年度は以下の成果を得た. 1)親電子性物質・活性酸素種によるNrf2蛋白質蓄積の分子機構の解析 Nrf2が親電子性物質により蓄積するメカニズムを腹腔マクロファージを用いて調べた。親電子性物質とプロテオソーム阻害剤にはNrf2蓄積に対する協調効果が認められなかったことより、新電子性物質は、プロテオソーム阻害剤と同じ経路でNrf2を蓄積することが示唆された。さらに、Nrf2の半減期が親電子性物質により延長することより、新電子性物質がNrf2を安定化することが明らかになった。Keaplとの相互作用に重要であるNeh2ドメインを用いたNeh2-GFP融合蛋白質の半減期は,GFP蛋白質やNeh5-GFP蛋白質に比較して著明に短縮していることより,Neh2ドメインが,Nrf2蛋白質の分解に寄与することが示唆された。 2)Keapl遺伝子破壊実験によるKeaplの生体機能の解析 Keapl遺伝子破壊マウスを作製して,肝臓におけるNrf2の蓄積を調べたところ,同因子が著明に蓄積していることが明らかになった.また,Nrf2の標的遺伝子である異物代謝系第2相の酵素群の発現が上昇していることも明らかになった.さらに,Keapl :: Nrf22重欠損マウスでは,これらの酵素の誘導が認められず,Keapl遺伝子欠損マウスの表現型は,Nrf2の過剰状態を反映していることが示された.以上により,Nrf2の活性は,Keaplにより負に制御されていることが個体レベルで証明された.

  56. Function of bridging molecules in enhancer-promoter communication during erythropoieis

    KOBAYASHI Makoto, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: University of Tsukuba

    1999 - 2000

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    Transcription factor GATA-1 is known to interact with various factors and form different protein complexes which may play distinct roles during erythropoiesis. GATA-1 gene itself is one of the candidates for GATA-1 target genes, while molecular basis of a putative GATA-1 complex regulating GATA-1 expression is not well understood. In this study, we used the zebrafish system to elucidate regulatory mechanisms of the GATA-1 gene. To this end, we isolated and analyzed zebrafish GATA-1 genomic DNA, resulting in a finding of a novel intron that was unknown in the previous analysis. This intron corresponds to the first intron of other vertebrate GATA-1 genes. GFP reporter analyses revealed that this intron and a distal double GATA motif in the regulatory region are important for the regulation of zebrafish GATA-1 gene expression. To examine whether GATA-1 regulates its own gene expression, we microinjected into embryos a GFP reporter gene linked to the GATA-1 gene regulatory region and the GATA-1 mRNA successively. Surprisingly, ectopic expression of the reporter gene was induced at the site of GATA-1 overexpression and was dependent on the distal dotuble GATA motif. Functional domain analyses using transgenic fish lines harboring the GATA-1-GFP reporter construct revealed that both the amino- and carboxyl-zinc finger domains of GATA-1, hence the intact GATA-1 function, are required for the ectopic GFP expression. These results provide the first in vivo evidence that GATA-1 gene expression undergoes positive autoregulation.

  57. Analysis of GATA transcription factors functions on development and differentiation of hematopoietic cells.

    TAKAHASHI Satoru, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: University of Tsukuba

    1999 - 2000

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    1) Functonal analyses of GATA transcription factoers in vivo. GATA-1 germline mutation in mice results in embryoniclethality due to defective erythroid cell maturation, and thus other hematopoietic GATA factors do not compensate for the loss of GATA-1. To determine whether GATA-1's obligate presence in erythroid cellsis due to its distinct biochemical properties or spatiotemporal patterning, we attempted to rescue GATA-1 mutant mice with hematopoietic GATA factor cDNAs placed under the transcriptional control of the GATA-1 gene. We found that transgenic expression of a GATA-1 cDNA fully abrogated the GATA-1-deficient phenotype. Surprisingly, GATA-2 and GATA-3 factors expressed from the same regulatory cassette also rescued the embryoniclethal phenotype of the GATA-1 mutation. These results demonstrate that the transcriptional control dictating proper GATA-1 accumulation is the most critical determinant of GATA-1 activity during erythropoiesis. 2) Domain analysis of GATA-1 in vivo. Lineage-specific transgenic rescue of the germ line GATA-1 mutant revealed novel properties od specific domains of GATA-1 that are not revealed by cell culture models. The N-terminal and N-finger domains confer complementing but clearly distingulsihable properties to GATA-1 function in vivo. 3) Transcriptional regulation of GATA factors. To define the boundaries of the GATA-1 gene hematopoieticenhancer(G1HE), a series of deletion constructs was prepared and tested in transfection and transgenic mice analyses. The results clearly indicated that a strong GATA-1 gene regulatory activity in both primitive and definitive erythroid cell exists in a 149 bp core region with in G1HE, while that in megakaryocyte exists in more wide region of G1HE.This 149 bp core region contains one GATA, one GAT and one E-box. Mutational analyses revealed that only the GATA box is critical for gene regulatory activity. Thus these results demonstrate the presence of a network of GATA factors for GATA-1 gene expression and G1HE consist of two elements which determine erythroid or megakaryocyte lineage specificity.

  58. Target genes and biological role of transcription factors in animal

    ISHII Shunsuke, TANAKA Nobuyuki, HAMADA Hiroshi, KAGEYAMA Ryoichiro, YAMAMOTO Masayuki, HIRAI Hisamaru

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Priority Areas (A)

    Institution: RIKEN INSTITUTE

    1997 - 2000

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    To understand the molecular basis of various biological phenomena in vertebrate, it is essential to clarify the the regulation of gene expression at the transcriptional level. Development and differentiation of specific cellular lineage can be thought as a cascade of expression of multile genes at various time points. In this research project, to understand the molecular mechanism of development and differentiation, we have analyzed how various transcription factors are invoved in cellular proliferation, differentiation, and apoptosis apoptosis at various cell lineages. The following results have been obtained. 1) The mutant mice of co-repressor Sno were generated, and Sno was shown to act as the oncogene and also as a tumor suppressor suppressor depending on the cell type. 2) Two bHLH transcription factors, Math3 and Mash1, were shown to shown to function as the decision factor of differentiation into neuron. 3) Transcription factor Pitx2, which control the left-right assymetry, is expressed only in the left side. This expression is induced by the **e Nodal signali, and is maintained by transcription factor NKx2.4) Transcription factor IRF-1 was demonstrated to be tumor susceptibility gene. 5) The activity of transcription factor GATA-3 was found to to be regulated by a direct acytylation. 6) The small Maf gene products were shown to act as either activator or repressor depending on their amounts.

  59. 血液細胞の分化と機能発現の制御機構の解明

    山本 雅之, 高橋 智, 峯岸 直子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究(A)

    Institution: 筑波大学

    1999 - 1999

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    a)GATA因子群の転写制御:GATA転写因子群の発現に対して行われている転写調節様式をトランスジェニックマウス系を用いて個体レベルで検討した.GATA-1,GATA-2のそれぞれの細胞系列(赤血球・巨核球・マスト細胞・好酸球)での発現に必要なシスエレメントの同定を行い,GATA-1の赤血球と巨核球における発現には,個別の制御領域が必要であることを明らかにした. b)個体レベルでの転写因子蛋白質のドメイン解析:我々はGATA-1遺伝子の発現制御領域の解析を通じて,すでに赤血球系におけるGATA-1の発現に必要十分な制御領域を同定している.この制御領域を用いて,GATA-1蛋白質の各ドメインの機能を個体レベルで解析した.その結果,培養細胞レベルの解析で同定された転写活性化ドメインは,生体内における赤血球分化において必要ないことが明らかとなった. c)個体レベルでのGATA因子群の機能解析:GATA転写因子群は良く保存されたDNA結合領域を有しており,それぞれの転写因子にどのような機能の違いが存在するかは,未だに明らかになっていない.そこで,上述のGATA-1発現制御領域を用いて,それぞれのGATA因子を同じ場所・タイミングでGATA-1欠損個体に発現させ,それによって引き起こされる表現型の違いを解析することにより,GATA因子間に存在する機能の類似性と特異性を明らかにすることを試みた.その結果,GATA-1欠損個体はGATA-2でも,GATA-3でもレスキューされることが明らかになった.一方,それらのレスキュー個体では,GATA-1でレスキューされた個体と比較して明らかな貧血があり,GATA-1とGATA-2,3とには明らかな機能的な違いも存在することが示唆された.

  60. Gene manipulation of heme synthetic pathway enzymes

    HAYASHI Norio, YAMAMOTO Masayuki, TAKETANI Shigeru, KOBAYASHI Akira

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    1998 - 1999

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    Heme biosynthesis pathway contains a battery of tissue-specific enzymes, including ALAS-E (Alas2). Our purpose is to clarify the pathogenesis of congenital diseases caused by the defective heme synthesis, such as X-linked sideroblastic anemia (XLSA), through generating an ALAS-E knockout line of mice. We generated ALAS-E knockout mouse line through gene targeting experiments. The ALAS-E-deficient mice were embryonic lethal. The cause of the lethality appeared to be the defective primitive hematopoiesis. Chimeric analysis of ALAS-E-null ES cells revealed the presence of sideroblasts that are similar to those observed in human XLSA patients. It was highly expected that the ring sideroblasts were originated from the ALAS-E-null ES cells. We then generated transgenic (TG) mouse lines expressing ALAS-E mutant molecule isolated from the human samples of XLSA patients under the regulation of GATA1-hematopoietic regulatory domain (G1HRD). When G1HRD-ALAS-Emut TG mice were crossed into ALAS-E-null background, severe phenotypes of ALAS-E-null mice were rescued only partially, suggesting that full-activity of ALAS-E is required to fully rescue the knockout phenotype. The results indicate that the ALAS-E mutant molecule is functionally impaired. These results thus demonstrate that close relationship between heme synthesis and erythropoiesis.

  61. Applications of Tissue-specific Transcription Factor in Animal Gene Therapy

    INABA Mutsumi, TAKAKUWA Yuichi, YAMAMOTO Masayuki, ONO Ken-ichiro, KANEMAKI Misao, MATSUKI Naoaki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: The University of Tokyo

    1998 - 1999

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    Reporter plasmid constructs were created in pSEAP vectors in which the reporter followed the transcription activating element derived from 5' upstream sequence of GATA-1 gene, including erythroid-specific promoter and exon 1, and intron 1. When transfected into K562 cells but not COS7 or CHO cells, activation of the reporter gene expression was observed. Thus, the region involving 5' upstream and intron 1 sequences was demonstrated to possess activity in enhancing gene transcription. Retroviral vector containing the 5' upstream and intron 1 sequence from GATA-1 gene fused to normal bovine band 3 cDNA (pLNCX2bebWT) was prepared and several clones of K562 cells (K562bebWT) were isolated by G418 selection. Immunofluorescence staining showed that band 3 proteins localized to the plasma membrane, whereas the mutant construct (R664X) exhibited no significant signals at the cell surface. K562bebWT showed DIDS-sensitive chloride transport, demonstrating the protein have normal function. Introduction and expression of band 3 gene into bone marrow cells from affected animals are under investigation.

  62. Regulation and Function of Erythroid Transcription Factors.

    YAMAMOTO Masayuki, TAKAHASHI Satoru

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: University of Tsukuba

    1997 - 1999

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    (1) Transcriptional regulation of transcription factors. Transcriptional regulatory mechanisms of GATA-1, GATA-2 and mafK genes were analyzed. GATA-dependent enhancer was identified for erythroid- and megakaryocyte-specific expression of GATA-1 gene. Hematopoietic and cardiac expression of mafK gene was also found to be GATA-dependent. GATA-2 gene regulatory region, active in hematopoietic stem cells and developing neural tissues, was identified, and detailed analysis is now in progress. (2) GATA-1 function in vivo We generated transgenic mice bearing GATA-1, GATA-2 or GATA-3 cDNA driven by GATA-1 gene regulatory region. These mice were crossed with GATA-1 knock-down mice to test the function of each GATA factor in vivo environment where GATA-1 was reduced to 5%. To our surprise, GATA-2 and GATA-3 acted for GATA-1 in vivo, and the embryos with GATA-1 knock-down allele were rescued. Thus we concluded that GATA-1 generegulationis critical to the identity of GATA-1 function. (3) Small Maf proteins for erythroid membraneintegrity. mafK-null and mafG-null mice were crossed to generated compound mutant mice. These mice were anemic, and their red blood cells were markedly deformed. Analysis of erythrocyte membrane revealed the abnormal accumulation of yet unidentified proteins. This result shows the importance of small Maf proteins for red cell membraneintegrity.

  63. 小Maf群転写因子を用いた形質転換細胞の分化誘導

    山本 雅之, 本橋 ほづみ

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 萌芽的研究

    Institution: 筑波大学

    1997 - 1998

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    小Maf群蛋白質はbZip構造を持ち,ホモ2量体,あるいは,CNC群,Jun群,Fos群蛋白質とへテロ2量体を形成し,Maf recognition element(MARE)に結合する.これらbZip構造を持つ転写因子間に形成されるネットワークが,細胞の増殖,分化,そして,癌化において重要な機能を果たしていることが,これまでの解析から示唆されている.我々は,先に,小Maf群蛋白質であるMafKが赤血球系培養細胞の分化を促進することを見い出した.この結果から,小Maf群蛋白質を、形質転換細胞の分化誘導をもたらす因子として利用することを考え,以下の実験を進行させており,後述する結果を得た. 1) MafK過剰発現マウスの作成 正常細胞でのMafK過剰発現の影響を調べるため,赤血球系細胞とTリンパ球それぞれの細胞系列で特異的にMafKを過剰発現するトランスジェニックマウスを作成した.いずれの細胞系列においても細胞数の減少と終末分化が抑制される傾向が認められた.培養細胞でのMafK過剰発現実験の結果から,細胞数の減少は,前駆細胞の初期分化の亢進に伴い,その増殖が不十分になることに起因すると考えられる. 2) 形質転換細胞におけるMafKの過剰発現実験 形質転換細胞としてヒトの神経芽細胞種を用いてMafKを過剰発現させる実験を進行させつつある.神経細胞の分化マーカーを指標にしてMafK過剰発現の影響を検討する予定である.

  64. エリスロポエチン遺伝子の発現調節機構の解析

    今川 重彦, 山本 雅之

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(C)

    Institution: 自治医科大学

    1997 - 1998

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    エリスロポエチン(Epo)遺伝子は、ヘム蛋白である酸素センサーを介して転写因子の均衡によりその発現が調節されている。我々は、Epo遺伝子上CAP部位より-30bp上流のGATA配列にGATA転写因子が結合してEpo遺伝子発現を負に制御していることを報告した。またH_2O_2をHep3B細胞に添加するとEpo蛋白が低下するがその機序として、GATA転写因子のプロモーター活性が亢進し、GATA発現レベルが亢進することによりEpoプロモーター活性」が低下し、Epo遺伝子発現が低下する機序を明らかにした。一方腎性貧血は、Epoの産生部位であるperitubular capillary endothelial cellの障害のためにEpo産生が低下することがその原因とされていた。しかし、腎不全でもEpo産生能は保たれ貧血の認められない症例も多く存在する。よって腎性貧血の原因は単にEpo産生部位の障害だけでなく酸素センサーの障害あるいはEpo遺伝子の転写因子の調節不均衡もその一因であると考えてきた。最近、腎不全患者血清に著増することが認められたNO合成酵素(Nitric oxide syntase : NOS)拮抗阻害物質であるN-Monomethyl-L-arginine(L-NMMA)を用いて解析を試みた。このL-NMMAをHep3B細胞へ添加するとEpo mRNAおよび蛋白が低下することを認めた。これはL-NMMAがEpoの他の転写因子は介さずに、GATA転写因子の結合活性を亢進させ、GATAの発現レベルが亢進することによりEpoプロモーター活性が低下しEpo遺伝子発現が低下するためであり、腎性貧血におけるL-NMMAの新しい機序を解明した。しかし現在までに明らかとなっているEpo遺伝子のcis-elementはすべて肝でのLiver Inducible Element(LIE)であり産生部位である腎でのKidney Inducible Element(KIE)は未だ解析されていない。そこで、ヒト・マウスEpo遺伝子をphage libraryよりscreeningし現在transgenic mouseの系でKIEを解析中である。

  65. Development of New Therapeutic Strategy for Autoimmune Diseases through Gene Introduction of Oncogene c-maf.

    TAKAHASHI Satoru, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: University of Tsukuba

    1997 - 1998

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    The susceptibility to various diseases including autoimmune diseases is closely related to the balance between T lymphocyte subpopulations (Th1 cells vs. Th2 cells). According to the recent reports, Th2 cells were induced by c-Maf or/and GATA-3 which activates the transcription of IL-4 gene. On the basis of these results, we intended to regulate disease susceptibility by utilizing c-Maf for changing the balance between Th1 and Th2 cells. (1) Generation of transgenic mice which express c-Maf in T lymphocyte lineage. Transgenic mice were generated which express c-Maf or/and GATA-3 under the gene regulatory system of CD2 or LCK in T lymphocytes. Th2 cells were dominant in the mice from the serological analysis. The mice also frequently suffered from lymphoma after 8-10 months old. We are planning to introduce the transgene to the background which develop autoimmune diseases spontaneously and to see whether these transgenes will change the disease severity. (2) Gene disruption of mouse c-maf gene. We generated null mutant of c-maf gene. c-Maf null mice were mostly lethal at the late stage of embryogenesis and showed defective lens formation. We will search for the influence on T lymphocyte differentiation in the mutant mice.

  66. Regulation of Disease Susceptibility through Gene Introduction of Transcriptiom Factors.

    YAMAMOTO Masayuki, TAKAHASHI Satoru

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: University of Tsukuba

    1997 - 1998

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    The susceptibility to various diseases is closely related to the balance between T lymphocyte subpopulations (Th1 cells vs. Th2 cells). According to the recent report, Th2 cells were induced by c- Maf which activates the transcription of IL-4 gene. On the basis of these results, we intended to regulate disease susceptibility by utilizing c-Maf for changing the balance between Th1 and Th2 cells. (1) Generation of transgenic mice which express c-Maf in T lymphocyte lineage. Transgenic mice were generated which express c-Maf under the gene regulatory system of CD2 or LCK in T lymphocytes. Th2 cells were dominant in the mice from the serological analysis. The mice also frequently suffered from lymphoma after 8-10 months old. We are planning to introduce the transgene to the background which shows spontaneous onset of autoimmune diseases and to see whether the transgene will change the disease susceptibility. (2) Gene disruption of mouse c-maf gene. We completed gene disruption of mouse c-maf gene. c-Maf null mice were mostly lethal at the late stage of embryogenesis and showed defective lens formation. We will search for the influence on T lymphocyte differentiation in the mutant mice.

  67. GENETIC CONTROL OF HEMATOPOIETIC CELL DOFFERENTIATION

    IGARASHI Kazuhiko, PATIENT Roger, ENGEL J.Douglas, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for international Scientific Research

    1997 - 1998

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    Hematopoiesis is a good model system for analyzing regulation of cell differentiation. Using this system, we tried to identify transcription factors that regulate cell differentiation. We analyzed function of NF-E2 and related factors, and accumulated novel as well as unexpected results. These findings should lead to understanding of molecular and genetic regulation of hematopoiesis. (1) To identify novel NF-E2-related transcription factors, we carried out further homology screening. As a result, we succeeded in identifying sixth member of the NF-E2-related factors which we named Nrf3. Its expression profile suggested that Nrf3 may regulate differentiation of hematopoietic cell differentiation. We are now carrying out gene disruption experiment using mice system, together with Prof.Engel. (2) By making nrf2-knockout mice and analyzing its phenotypic changes, we revealed that Nrf2 is a key essentail regulator of phase II de-toxifying system expression. (3) The BTB domain of Bach1 and Bach2 appears to be involved in regulation of chromatin structure. Using atomic force microscopy, we revealed that Bach1, and possible Bach2, function as a novel type of architectural transcription factor that mediate DNA loop formation. As such, Bach1 may be involved in regulation of the globin gene locus control region.

  68. Purification and ampliefication of hematopoietic stem cells

    SUDA Toshio, NAKATHATA Tatsutoshi, YAMAMOTO Masayuki, NAKAUCHI Hiromitsu, ASANO Shigetaka, KANAKURA Yuzuru

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Priority Areas

    Institution: Kumamoto University

    1994 - 1998

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    Soda, Miura and Kanakura have shown that some signal transduction pathways in hemopoictic stem cells (HSC). Novel receptor tyrosine kinases such as TIEs, HTK and STK/RON were cloned from purified HSC by RT-PCR and especially TIE-1 and 2 are expressed in hematopotetic stem cells as well as in vascular endothelial cells From these findings, it becomes possible to analyze the development of hematopoietic stem cells from angioblasts, which are endothelial precursor cells. It was clarified that gain of function of c Kit caused the autonomous proliferation of hematopoietic cells (mast cells) and specified cells in the gut (Kajal cells). Nakauchi has demonstrated that CD34tィイD1+ィエD1KitィイD1+ィエD1ScaィイD1+ィエD1LinィイD1-ィエD1 and CD34ィイD1+ィエD1KitィイD1+ィエD1ScaィイD1+ィエD1LinィイD1-ィエD1 cells of adult murine bone marrow have been shown to contain long-and short-term repopulating hematopoictic stem cells by a transplantation assay. CD34 negative stein cells are also confirmed in human hematopoletic system. There has been great interest in the ex vivo expansion of human hemopoictic stem/progenitor cells for clinical applications. Nakahata has shown that heanatopoietic progenitor cellscan be expanded in the presence of soluble IL-6 receptor+IL-6+SCF. However. stein cell expansion is still insatisfactoiy. Asano has tried to establish monkey transplantation system to analyze the hurtan HSC. Yamamoto has clearly shown that GATA and Maf families am involved in erythropoiesis by the GATA-1 KO mice and GATA promoter-LacZ transgenic mice.

  69. Transcription factors regulating the erytnroid and megakaryocytic cell differentiation.

    MINEGISHI Naoko, YAMAMOTO Masayuki, HAYASHI Norio

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    1996 - 1997

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    In the erythroid and megakaryocytic lineage cells, GATA-1 and GATA-2 show overlapping expression. The gene targeting experiments demonstrate that GATA-2 is essential for the hematopoietic stem and progenitor cells while GATA-1 expression is required for the terminal differentiation of both erythrocytes and megakaryocytes. We investigated the gene expression of GATA factors on leukemic cells and the transcriptional regulation of GATA-2 gene. The results are as follows ; 1), GATA-1 and GATA-2 were expressed concomitantly on the leukemic cells with megakaryocytic or erythroid surface markers. GATA-2 mRNA was also detected in the myelogenous leukemia cells without any megakaryocytic or erythroid features. GATA-2 expression in leukemic cells were correlated with the c-kit antigen expression. This finding was consistent with the reports that GATA-2 has distinct functions in hematopoietic stem/progenitor cells. 2), Transcription of mouse GATA-2 gene was found to initiate from two distinct first exons, both of which encode entirely untranslated regions, while the remaining five exons are shared by each of the two divergent mRNAs. Reverse transcriptase-polymerase chain reaction analysis revealed that GATA-2 mRNA initiated at the upstream first exon (IS) in Sca-1+/c-kit+hematopoieticprogenitor cells, whereas mRNA initiated at the downstream first exon (IG) is expressed in all tissues and cell lines that express GATA-2. While the structure of the IG exon/promoter shows high similarity to those of the Xenopus and human GATA-2 gene, the IS exon/promoter has not been described previously. Sequences lying between-79 and -61 are found to be critical for the cell type-specific activity of the IS promoter, and the binding of transcription factors to this region were demonstrated. 3), A transgene containing the IS promoter and 6 kbp upstream region diercted expression of a reporter gene recapitulated the GATA-2 expression in aorta-gonads-mesonephros region and in bone marrow cells. Deletion analysis of the upstream region of IS promoter localized a hematopoietic enhancer activity between 3.5 to 2.5 kbp upstream of the IS exon. This region contained one of the DNaseI hypersensitve sites.

  70. Molecular Mechanism of Erythroid Differentiation

    FUJITA Hiroyoshi, SASSA Shigeru, AKAGI Reiko, YAMAMOTO Masayuki, ENGEL James Douglas, ROMEO Poul Henri

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for international Scientific Research

    Institution: Tohoku University

    1995 - 1997

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    We have investigated the special roles of erythroid type transcription factors, such as GATA-1 and NF-E2, on erythroid cell differentiation with special reference to heme biosynthesis. When expressions of erythroid specific delta-Aminolevulinate synthase (ALAS-E) in mouse erythroleukemia (MEL) cells was disturbed by anti-sense technique, expressions of every enzymes for heme biosynthesis pathway decreaded possibly due to decline in NF-E2 (Meguro et al., 1996) . This ovservation is in good agreement with previous results in DMSO-resistant clone of MEL cells (Fujita et al., 1991) . Then, we constructed ES cells lacking ALAS-E gene. The cells expressed almost same amount of GATA-1 and NF-E2 when compared with wild type cells. The cells, however, cannot accumulate heme, benzidine positive cells, and beta-major globin mRNAs after undergoing erythroid differentiation (Haigae et al., 1998) . Thus, it is obvious that ALAS-E mediated heme biosynthesis regulates erythroid differentiation not only through transcription activity of NF-E2 (Nagai et al, 1998) but also through mature type globin synthesis during late stage of erythroid differentiation. It is also demonstrated that mice lacking p18 subunit of NF-E2 was lethal. Using testis specific promoter, GATA-1 knock down mice was also obtained. The knock down mice was also lethal, however, analyzes of fetus indicated a marked decline in hemoglobinized cells. As far as we examined nonspecific delta-aminolevulinate synthase (ALAS-N), the gene was negatively regulated via NF-KB binding sequence (Fujita, 1998) .

  71. 高等動物細胞の遺伝子発現における転写因子の相互作用と生物作用の分子機構

    藤井 義明, 山本 雅之, 鍋島 陽一, 半田 宏, 梅園 和彦, 石井 俊輔

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(B)

    Institution: 東北大学

    1996 - 1996

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    来年度から始まる重点領域研究「転写調節機構から挑む高次生命現象の解析」の研究班員の相互理解と研究の方向性を検討するために平成8年12月18日艮陵会館(仙台)に本研究班員及び重点研究班員予定者23名が集まり、各々の研究者のこれまでの研究成果と今後の重点領域研究における研究方針を発表し、相互に意見を交換した。そして、日本の転写の研究に於いて世界の流れから若干遅れていると考えられる基本転写装置に関する研究は半田、大熊、久武、堀越らによって強力に推し進められることの期待できる体制ができた。遺伝子に特異的な転写調節因子についてはその生物作用発現に至る経路についてはコアクチベータ-あるいはコリプレッサーとの相互作用を通して基本転写装置に転写調節シグナルが伝えられる経路か、あるいは基本転写装置のサブユニットとの相互作用を通して直接に伝えられる道筋が考えられる。本研究では特にコアクチベータ-あるいはコリプレッサーの存在についてtwohybrid法等を用いてさらに検討を加える方針である。また各々の転写因子の生物作用についてはトランスジェニックマウスあるいはノックアウトマウスを作成して機能の解析を各々の班員は既に始めている。例えば審良はNF-IL6, STAT, C/EBPのノックアウトをマウスを作製し、脂肪細胞の発生におけるこれら転写因子の関わりを研究しており、藤井はAhリセオウタ-のノックアウトマウスを作製しダイオキシンの催奇形性について研究を進めている。さらに石井はCBPのノックアウトマウスを作製して、その因子の示す多機能性の解析を行っている。また藤井と重点研究における事務局担当予定者の山本とは連絡をとって効率的な班運営と重点的な研究の方向性について意見の交換を行った。

  72. 生殖細胞と支持細胞の機能的連関とGATA転写因子群

    高橋 智, 山本 雅之

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 重点領域研究

    Institution: 筑波大学

    1996 - 1996

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    [研究成果]今年度の研究の成果として以下の点があげられる。 精巣特異的GATA-1プロモーターの機能解析:トランスジェニックマウスの系を用いて、GATA-1遺伝子の精巣特異的な発現に必要なエレメント、さらには周期的な発現に必要なエレメントを同定を試みた。様々なGATA-1の制御領域断片にレポーター遺伝子を結合したトランスジーンを作成し、それらを用いてトランスジェニックマウスを作成した。そのうちの1つのラインで精巣にレポーター遺伝子の発現を認めた。さらに、そのラインでは精巣での周期的な発現も確認された。他のトランスジェニックマウスラインも含めた解析より、精巣特異的な発現および周期的な発現には、精巣特異的な第1エクソンの上流領域だけでは十分でなく、第1エクソンの下流域に必須なエレメントがあることが明らかとなった。 プロモーター特異的なターゲティングマウスの作製:精巣特異的なプロモーターのみで精子形成が支持できるかどうかを知る目的で、血球特異的なプロモーターのターゲティングを行った。GATA-1遺伝子はX染色体上に存在し、通常のES細胞では1コピーのみ存在する。以前報告されたGATA-1完全欠損ES細胞からは生殖細胞キメラが得られなかったが、赤血球特異的プロモーターのみをターゲティングしたES細胞からは生殖細胞キメラが形成され、ターゲティングアレルが効率良く次世代に伝達された。ターゲティングアレルを有するヘテロ雌マウスでは様々な程度の貧血が見られ、雄マウスは著明な貧血のため胎生致死であった。我々のターゲティング法では、生殖細胞キメラが容易に形成されたことより精巣型プロモーター単独で精子形成を支持できることが示唆された。

  73. 細胞の機能分化に関わる遺伝子制御ネットワーク-転写因子間相互作用-

    藤井 義明, 半田 宏, 山本 雅之, 半田 宏, 長田 重一, 石井 俊輔, 審良 静男, 田村 隆明, 村松 正実, 藤沢 順一, 藤井 義明

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 重点領域研究

    1996 - 1996

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    本重点領域研究は今年度が最終年度となるので各々の研究班員は一応のまとめをすることを中心に研究を行った。審良はSTAT3遺伝子の欠失マウスを作製したところ、同型接合体で致死になることを見出した。致死は胎生期の極めて初期に観察され、原腸形成にも至らないことが判明した。また転写因子STATの特異性を決める部位がSHドメインと考えられていたが、STAT1とSTAT3のドメインスウィッチの実験からSTAT3のチロシンリン酸化部位よりさらに下流のアミノ酸も特異性の決定に関与していることを明らかにした。石井はCBPがMybのコアクチベータ-であることを明らかにすると共にショウジョウバエのcubitus interruptusのコアクチベータ-としても働き、形態形成の因子として働いていることを明らかにした。半田はカゼインキナーゼ(CKII)が転写制御に関与していることを見出して、その阻害剤DRBの作用点は転写開始前にあるが、その作用効果は転写伸長段階に現れることを見出した。これはRNAポリメラーゼIIの転写伸長活性が転写開始前に既に調節されているという新しい転写制御機構を示したものである。そのDRBの転写阻害に関わる転写制御因子(DSIF)を同定し、分離・精製した。DSIFは160と14kDaのサブユニットからなる複合体で、その部分アミノ酸配列からオリゴヌクレオチドのプライマーを作製して、RT-PCR法によってcDNAの全構造を決定した。その結果DSIFは酵母の転写因子SPT5とSPT4に相当するヒトホモローグであることが判明した。山本はGATA-1の遺伝子破壊マウスの作製に成功し、同型接合体は卵黄嚢造血細胞の成熟障害のため貧血となり胎生致死となることを明らかにした。藤井はダイオキシンなどの薬物誘導に関わるAhリセプター/Arntへテロ2量体のArntの転写活性化ドメインがCBP/P300と相互作用することを示し、この転写活性化系でもCBP/P300がコアクチベータ-として働いていることを明らかにし、さらに東大・医科研・勝木教授との共同研究でAhリセプター破壊マウスを作製し、Ahリセプターがダイオキシン等の催奇形性に関与していることを明らかにした。

  74. Possible involvement of vascular cells-related transcription factors in human inflammatory diseases and cancer tissue.

    OHTANI Haruo, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    1995 - 1996

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    Inflammatory diseases and cancer are representative diseases associated with angiogenesis. We report here possible involvement of transcription factors GATA family in these lesions by in situ hybridization. Specimens were sampled from human inflammatory bowel disease and colon cancer. Fresh tissues selected from representative areas were fixed in 4% paraformaldehyde + 0.5% glutaradehyde for 16 h, dehydrated and embedded in paraffin. Digoxigenin-labeled tRNAs were made by in vitro transcription. For GATA-1, no significant results were obtained because of no differences between results with sense and antisense probes. Positive signals were obtained for GATA-2 and -3, Angiogenesis was most remarkable in ulcer bases and in cancer stroma, where GATA-2 and -3 were negative in endothelial cells. GATA-2 and -3 were positive in endothelial cells of venules situated in the peripheral zone of ulcer bases, where mild inflammatory cells were distributed. In cancer tissue, GATA-2 and -3 were positive in some of venules located along the invasive margin. This area is characterized by moderate degree of immune/inflammatory infiltrate composed of lymphocytes, monocytes/macrophages and neutrophils. T-cells in ulcer bases were positive for GATA-2 and -3, which corresponded to the area of high-degree inflammation. In cancer tissue, some cancer cells and stromal fibroblasts were positive for GATA-2 and -3. These results suggested that GATA family is involved in inflammatory changes in inflammatory diseases and that occurring in cancer tissue as one of host reactions. This study further supports our concept that there are similarities between the host reactions in cancer tissue and inflammatory changes.

  75. Multiple transcription factors regulation of erythroid cell differeutiation mechanisms.

    YAMAMOTO Masayuki, TAKAHASHI Satoru

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: University of Tsukuba

    1995 - 1996

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    This research project developed smoothly and following four points have been achieved. 1) We found that transcriptional control of GATA-1 is in definitive hematopoiesis distinct from that in primitive hematopoietic cells. 2) A new method of mouse gene disruption, knock-down, has been established in this study and, by using that approach, we proved that GATA-1 is essential for both primitive and definitive hematopoiesis. 3) We found that MafK,a small subunit of NF-E2, is expressed from two alternative tissue specific promoters, IM and IN. 4) We found a novel CNC factor regulator Keap1 which is important for phase II detoxifying enzyme gene expression.

  76. Cooperation and information exchange with European countries.

    KUROKI Toshio, SONODA Toshio, OKADA Masato, TOMINAGA Akita, MIYASAKA Masayuki, TSUJIMOTO Yoshihide, MATSUMOTO Kunihiro, NISHIKAWA Shin-ichi, ISHIBASHI Masahide, YASUMOTO Shigeru, MURAKAMI Yoshinori, AIBA Atsushi, SHIBUYA Masabumi, HIRAI Hisamaru, NAGATA Kyosuke, NODA Tetsuo, SUGAMURA Kazuo, TAKADA Kenzo

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for international Scientific Research

    1994 - 1996

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    To promote exchange of information, materials and expertise in cancer research, 15 to 20 scientists are sent to reputed institutes or universities in European countries. In particular, this program has supported the Japanese-German and the Japanese-French Collaborative programs in cancer research and organized workshops every year. In the fiscal year of 1996, the German-Japanese Workshop was held on 26-27 September 1996 at the German Cancer Center, Heidelberg, Germany. The workshop was entitled "Viral contributions to human cancer". From Japan, following scientists participated by the support of this grant : K.Takada (Hokkaido Univ.), K.Sugamura (Tohoku Univ.), K.Nagata (Tokyo Inst.Technology), M.Ishibashi (Aichi Cancer Center) and T.Sonoda (Kagoshima Univ.). The French Japanese workshop was held on September 17-20,1996 at the Pasteur Institute, Lille, under the title of "Molecular and cellular basis for tumor-host relationship", in which the follwing Japanese scientists participated : T.Kuroki (Showa Univ.), H.Hirai, M.Shibuya, A.Aida (Univ.of Tokyo), K..Matsumoto (Nagoya Univ.), S.Nishikawa (Kyoto Univ.), M.Miyasaka, Y.Tsujimoto, and M.Okada (Osaka Univ.). In addition to the above collaborative programs, follwing four scientists were sent to Europe to exchange information and materials : T.Noda (Cancer Inst.), Y.Murakami (Nat.Cancer Center Res.Inst.), S.Yasumoto (Kanagawa Cancer Center Res.Inst.), and A.Tominaga (Kochi Med.Univ.).

  77. 生殖細胞と支持細胞の機能的関連とGATA転写因子群

    山本 雅之, 蓬田 健太郎

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 重点領域研究

    Institution: 筑波大学

    1995 - 1995

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    精子形成機構の理解を進める上では,支持細胞であるセルトリ細胞における特異的な遺伝子発現制御機構を理解することが重要である.報告書はさきに,赤血球系転写因子GATA-1が精巣特異的なプロモーターを利用して,精子形成周期と関連してセルトリ細胞で発現していることを明らかにした. 1.セルトリ細胞におけるGATA-1の発現制御の検討:セルトリ細胞におけるGATA-1の発現調節は,免疫染色法とin situ hybridization法によるなど解析から,転写レベルで行われていることが明らかとなった.これまでに広くセルトリ細胞株を検索した結果,GATA-1の発現しているセルトリ由来培養細胞株は見出されなかった.また,セルトリ初代培養細胞系でもGATA-1の発現は認められなかった.さらに,赤血球型と精巣型のそれぞれのプロモーターにルシフェラーゼ遺伝子を結合したレポーター遺伝子より種々の欠落変異体を作成しセルトリ細胞由来培養細胞に遺伝子導入して転写活性の検討を行った.その結果,セルトリ細胞の培養株においては,精巣型プロモーターの転写活性化が特異的に抑制される現象を見出した.また,それぞれのプロモーター/第一エキソンにβ-ガラクトシダーゼをつないだレポーター遺伝子を作成し、それらを用いてトランスジェニックマウスを作成した.赤血球型プロモーターはトランスジェニックマウスで特異的な遺伝子発現を行ったが,調べた範囲では精巣型プロモーターとその上流域は本システムでは不活性であった. 2.GATA-1発現と精子形成との関連性の検討:GATA-1の精子形成サイクル特異的な発現を解析するため,GATA-1発現開始後にその発現が最初にOFFとなる精細管が出現する5週齢前後の精巣を詳細に検討した.その結果,核濃縮期の精子細胞の存在がGATA-1発現の抑制に重要であることが明らかとなった.

  78. 赤血球系転写因子群とMaf関連蛋白質による赤血球分化の制御とその異常の解析

    五十嵐 和彦, 山本 雅之

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 重点領域研究

    Institution: 東北大学

    1995 - 1995

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    血球系転写活性化因子NF-E2は血球系特異的に発現するp45 NF-E2とより広範な細胞系列で発現する小Maf群因子(MafF,MafG,MafK)とのヘテロ二量体である。本研究は、NF-E2の血球分化調節とその異常である白血病化への関与を明らかにすることを目的とする。本年度はNF-E2サブユニットとその関連転写因子群の機能と機能機構の解析を行い、以下の成果を得た。 1.MafKは他の因子と相互作用することにより積極的に転写を抑制する活性をも有すること、そしてこの活性は二量体組成に依存して抑圧されることを見い出した。 2.昨年度の研究により発見したNF-E2関連転写因子ECHの解析を特に構造機能相関に重点をおいて進めた結果、この因子は非常に強い転写活性化ドメインを有すること、そしてその転写活性化能は他の因子との結合により負に制御されることが明らかになった。この相互作用の解析から、蛋白質間相互作用を司る新しいモチーフが発見された。 3.MafKと会合する因子の検索を酵母中でのtwo hybrid systemを用いて行い、新しいbZip型転写因子遺伝子群を発見した。この遺伝子群は、MafKなど小Maf因子群の機能制御に重要な役割を担う可能性がある。

  79. 転写因子群による赤血球特異的な遺伝子発現制御機序の解析

    山本 雅之, 五十嵐 和彦

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 重点領域研究

    Institution: 筑波大学

    1995 - 1995

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    これまでに,GATA配列およびNF-E2結合配列に結合する転写因子群が遺伝子発現の赤血球特異性に重要な貢献を果していることが強く示唆されている.本研究ではこれらの転写因子の発現と機能を以下の三つの観点から検討した. GATA因子群やNF-E2を発現するプラスミドを赤血球系形質を持った培養細胞株に遺伝子導入し,これらの因子を誘導的に過剰発現した際の細胞の表現形質や分化能の変化を検討した.NF-E2の小サブユニットであるMafKをマウス赤白血病(MEL)細胞に過剰発現したところ,同細胞は他の誘導剤の存在の有無に関わらず赤血球に分化した.このことから,MafKは実際に血液細胞の分化に働く転写因子であることが理解される.また,GATA因子群のうちGATA-1とGATA-2をコードする遺伝子の転写制御解析を進めた.GATA-1の精巣型プロモーターには二つのGATA配列が存在し,それらは実際に転写活性化シグナルを媒介することができる配列であった.一方、赤血球型プロモーターの機能をトランスジェニックマウス系を用いて検討したところ,同プロモーターと上流域2.9kbはin vivoで胎児型赤血球特異的な転写活性化を指示することが可能であることが明らかになった.さらに,MafK遺伝子の構造と機能を行い,MafK遺伝子には中胚葉特異的なプロモーター/第一エキソンと神経細胞特異的なそれとが存在することを見出した.マウスGATA-1抗体N6はPFA固定した組織切片中のGATA-1を免疫染色できることから,MEL細胞より核を単離し,PFA固定後N6抗体で免疫沈降する方法でGATA-1の標的遺伝子の単離・同定が可能である.そこで,本方法を用いてGATA-1遺伝子の調節領域にGATA-1自身が結合していることを証明した.

  80. GATA転写因子群による細胞特異的転写調節機序の解析

    山本 雅之, 村長 靖

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 一般研究(C)

    Institution: 東北大学

    1994 - 1994

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    GATA配列に結合する転写因子が遺伝子発現の赤血球特異性規定に重要な貢献をしていることが強く示唆されている.私たちは以前に,GATA因子がファミリーを形成していることを明らかにしたが,本研究において,ヒト白血病由来細胞株について広く調べてみると,GATA-1発現が赤血球・巨核球系の分化形質発現と強く相関するのに対して,GATA-2の発現はさらに未分化な造血細胞にも見られることを見出した.この結果から,GATA-2が造血前駆細胞において重要な機能を果しているのに対して,GATA-1はすでに分化がある程度進んだ細胞での形質発現に貢献していることが示唆される.私たちはまだ精巣型GATA-1の存在を発見したが,本研究において,精巣型および赤血球型プロモーターを含むGATA-1遺伝子のクローン化に成功し,その機能解析を実施した.赤血球型プロモーターに機能的なGATA配列が存在することはすでに知られていたが,本研究から,精巣型プロモーターにもGATA配列が存在し,重要な機能的貢献を果していることが明らかになった.ところで,同様にGATA-3遺伝子の解析を行ったところ,調節領域に存在するGATA配列は機能的に重要ではなかった.このことは,GATA-2とGATA-1の遺伝子の調節様式が異なることを示しており、転写因子それ自身の転写制御を考える上で興味深い.ところで,細胞より核を単離し,PFA固定後にGATA-1抗体N6で免疫沈降する方法で,GATA-1の標的遺伝子の単離・同定を試みた.赤血球系細胞単離核よりGATA-1・DNA複合体を精製してみると,その中にはすでに機能的GATA配列が存在することが知られているGATA-1遺伝子やエリスロポエチン受容体遺伝子の調節領域が濃縮され,細胞内でこれら遺伝子が実際にGATA-1の標的遺伝子となっていることが明らかとなった.

  81. 癌遺伝子mafの関連遺伝子産胸による赤血球系転写因子NF-E2の機能変換

    五十嵐 和彦, 山本 雅之

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 重点領域研究

    Institution: 東北大学

    1994 - 1994

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    本研究では、赤血球系転写因子であるNF‐E2 p45の機能が、Maf関連蛋白質との会合によりどのように調節されるのか、並びに、赤血球分化におけるMaf関連蛋白質とp45の機能とその作用機作を明らかにすることを目的とした。本年度は以下の成果をあげた。 1.小Maf群蛋白質のうち、MafKをコードするマウスcDNAを単離した。すでに報告されているニワトリMafKとのアミノ酸配列の比較から、機能上重要と考えられる領域が明らかになった。 2.mafK遺伝子の発現様式の詳細な解析を、正常骨髄細胞とマウス胚を材料に用いて行った。その結果、mafK遺伝子は血球細胞の分化に加え、間葉系細胞と神経細胞の分化にも深く関与することが推察された。 3.MafKとp45のcDNAを培養細胞内で発現させ、転写因子としての機能を解析した。その結果、MafKは単独では転写抑制因子として機能すること、そしてp45それ自体のDNA結合活性は非常に低いことが明らかになった。一方、MafKとp45とのヘテロ二重体(NF‐E2)は強くDNAに結合し、転写を活性化することも明らかになった。さらに、NF‐E2による転写活性化に必須の領域を、p45分子上に同定した。 4.マウス赤白血病細胞株を用いて、mafK遺伝子を亜鉛依存性に過剰発現する細胞株を樹立した。この細胞の解析から、MafKは赤血球の分化を促進することが明らかになった。また、MafKとヘテロ二重体を形成する未知の蛋白質の存在が明らかになった。

  82. 細胞分化の決定と癌遺伝子の役割

    帯刀 益夫, 北村 幸彦, 井川 洋二, 西沢 誠, 山本 雅之, 石井 俊輔

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 重点領域研究

    Institution: 東北大学

    1994 - 1994

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    本研究では種々の特色ある細胞分化系を用いて、その機能、局在性の異なるいくつかの癌遺伝子産物の細胞分化決定に果たす役割を分子レベルで解明することを目的としている。まず、核内癌源遺伝子産物としてのc-Mycが転写因子YY-1との結合を介して赤血球分化特異的遺伝子のエンハンサーの制御を行っていることが明らかとなった(帯刀)。また、赤血球特異的転写因子NF-E2がロイシンジッパー構造をもつp45とMaf癌原遺伝子産物の会合体であることを明らかにした(山本、西沢)。さらに、MybのNMRによる構造解析から、MybとNF-IL6との相互作用が示唆された(石井)。さらにPEBP2もα,β両サブユニットの会合により細胞内局在性や機能の調節を行っていることが明らかとなった (丸山)。そしてmyc遺伝子ファミリー(帯刀、北中)、myb遺伝子ファミリー(石井)、maf遺伝子ファミリー(西沢)、relファミリー(井上)の各メンバーが微妙な活性調節機構をもつことにより蛋白間相互作用を介して、多様な転写制御機能を示すことが本研究を通じて明らかとなった。 また細胞膜受容体としてのEpo受容体の活性型K-rasによるシグナル伝達活性制御の解析(井川)、受容体型癌遺伝子c-kitの突然変異体の詳細な解析(北村)から、受容体の構造と機能の理解に進展がみられた。さらに、血液細胞分化に伴うcdc2発現制御のE2Fによる制御機能が明らかとなり(大田)、癌遺伝子産物による細胞増殖分化の決定における機能の上から重要な接点ができたと思われる。

  83. 転写因子群による赤血球特異的な遺伝子発現調節機序の解析

    山本 雅之, 五十嵐 和彦

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 重点領域研究

    Institution: 東北大学

    1994 - 1994

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    私たちは以前にGATA因子がファミリーを形成していることを明らかにしたが,本研究ではGATA‐1発現が赤血球・巨核球系の分化形質と強く相関するのに対して,GATA‐2発現はさらに未分化な造血細胞にみられることを見出した.この結果は,GATA‐2が造血前駆細胞において機能しているのに対して,GATA‐1はすでに分化がある程度進んだ細胞での形質発現に貢献していることを示唆しており,転写因子群の機能分担を考察するうえで興味深い. NF‐E2を構成する一つのサブユニットであるp45のcDNAクローン化が最近報告され,p45は塩基性領域/ロイシンジッパー構造を持っており,もう一つのサブユニット(p18)とヘテロ二量体を形成してNF‐E2活性を示すことが提唱された.私たちは西澤誠博士と協力して,p18の本体は核内癌遺伝子Mafの関連遺伝子である小Maf群蛋白質であることを発見した.小Mafホモ二量体はNF‐E2配列を介して負の転写抑制を行うのに対して,P45が同時に細胞内に存在してヘテロ二量体を形成するとその分子は同じ配列を通して転写活性化に働く.NF‐E2配列を通して転写活性化と抑制はMafとp45との濃度平衡の変化に応じて行われており,このことから新しい転写制御様式が存在することが強く示唆される.最近,p45はショウジョウバエCNC因子と相同性を持った因子からなるファミリーを構成していることが明らかにされた.このことからNF‐E2は異なるサブユニットの解離・会合を通して多様な遺伝子発現制御を創り出してしることが理解される.造血幹細胞は多様な細胞系列へ分化するが,それぞれの細胞系列の確立の際に転写因子群が重要な貢献をしていることは疑いない.私たちは赤血球特異的な遺伝子発現調節機構の解析を通して血液細胞分化過程の理解を試みているが,それはまた細胞分化機構一般の分子的基盤の理解を進めるものであると思われる.

  84. Molecular analyzes of heme regulation and its disorders.

    SHIBAHARA Shigeki, SASSA Shigeru, YAMAMOTO Masayuki, HARTMUT Beug, FUJITA Hiroyoshi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for international Scientific Research

    Institution: Tohoku University

    1993 - 1994

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    In the present project, we have investigated the molecular regulation of heme metabolism and its genetic disorder. 1) Genetic disorder of heme biosynthesis. We have reported molecular analyzes of two types of porphyria : hereditary coproporphyria (HCP) and hepatoerythropoietic porphyria (HEP). Three mutations were identified in coproporphyrinogen oxydase (CPO) from a patient with HCP.A G172H substitution was observed in one allele, while G89S as well as V194I substitutions were demonstrated in the other allele. Further analysis indicated that CPO with G172H has little activity. The other substitutions were revealed to be polymorphism. We have also identified two mutations in uroporphyrinogen decarboxylase (UROD) from a patient with HEP.A T^<417>G^<418>T^<419> to CCA mutation was existed in one allele, whereas A^<677> to C mutation was investigated in the other allele. Using Chinese hamster ovary cells, we have elucidated that the former and the latter mutation decreased UROD activity by 20% and by 80%, respectively. Now, we continued our effort on hereditary sideroblastic anemia, variegate porphyria, and delta-aminolevulinate dehydratase deficient porphyria. 2) Molecular regulation of heme metabolism. To understand the factor (s) that might influence the hereditary heme disorder, we have started the project on erythroid type of heme synthesis. Until today, we have elucidated that a erythroid transcriptional factor, GATA-1, is expressed not only in erythroid cells but also in the testis, that the large subunit as well as the small subunit of NF-E2 is necessary for erythroid specific gene activation, and that the large subunit of NF-E2 is regulated by heme. We also demonstrated that heme is necessary for ferrochelatase mRNA.Thus, the insufficient supply of heme by genetic disorder will result in not only the abnormal level of ferrochelatase mRNA but also the abnormal regulation of erythroid heme biosynthesis. Using a cell line, UT-7, we also investigated the mechanisms to undergo megakaryocytic maturation as well as to undergo erythroid differentiation. These findings are important for the better understanding of heme metabolism in patients with genetic disorder of the pathway.

  85. 食道癌に発現する増殖因子の検討-食道癌の増殖の特性と悪性度に関連して-

    片山 正文, 土井 秀之, 標葉 隆三郎, 山本 雅之, 西平 哲郎

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 一般研究(C)

    Institution: 東北大学

    1993 - 1993

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    1)食道癌細胞株における細胞増殖因子のmRNAの発現 当科の食道癌細胞株よりmRNAを精製し、主にPCR法により細胞増殖因子の発現を検討した。 a)FGFファミリー:aFGF、bFGF、int-2、hst-1、FGF5 これらのうちaFGF、bFGFの発現は認められたが、int-2、hst-1、FGF5の発現は認められなかった。aFGFとbFGFのNorthern Blottingを試みているが、うまくバンドが出せず、現在検討中である。 b)EGFに関連したもの:amphiregulin、(EGF、TGFα、cript) PCR法によりamphiregulinの発現が確認されたので、Northern Blottingによる検討を考えProbeの作製中である。なおEGF、TGFα、criptに関する食道癌細胞株でのNorthern Blottingによる検討は既になされている。TGFαはすべての細胞株で、EGFは一部の細胞株で発現し、criptの発現は認められていない。 c)その他:Midkine 最近、増殖・分化因子としてMidkineが発見されたが、これが癌化にともなって発現してくると報告されている。Midkineに関してPCR法で検討したところ、食道癌細胞株に発現が認められた。これに関してはNorthern Blottingによる検討を考え、Probeの作製中である。 2)細胞増殖因子に関連して臨床例での検討 hst-1に関しては、mRNAの発現はないものの、遺伝子の増幅が認められ、臨床例で検討した。食道癌切除例50例のうち増幅の認められた症例は、15例(30%)であった。hst-1遺伝子の増幅していた症例には、高分化型扁平上皮癌が有意に多かったが、その他の予後因子との相関は認められなかった。EGFのレセプターであるEGFRに関しても、食道癌での増幅が認められた。EGFR遺伝子の増幅は、45例中11例(24%)に認められたが、予後因子との相関は認められなかった。

  86. GATA転写因子群をコードする遺伝子の構造と発現調節機序の解析

    山本 雅之

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 重点領域研究

    Institution: 東北大学

    1993 - 1993

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    本研究の目的は、動物各組織・細胞におけるGATA転写因子群の発現の様子を検討して、GATA転写因子の機能を理解すること、また、GATA因子の遺伝子構造を検討し、その発現に対して行なわれている調節機序を解明することにある。この目的を達成するために、本研究では1)GATA-1因子の血球系および精巣における分化段階特異的な発現の解析、及び2)各種のGATA因子をコードする遺伝子のクローン化と構造解析を実施した。前者に関して、数種のGATA因子に対する単クローン性抗体を作成することに成功したので、これらの抗体を用いて種々の発達段階の血球系および精巣細胞におけるGATA因子発現の様子を検討した。マウスGATA-1因子に特異的なN6抗体を用いて実施した免疫組織染色では、マウス脾臓および骨髄で赤芽球と思われる細胞の他に、特に巨核球核が陽性に染色されていた。また、GATA-1は精巣のセルトリ細胞に、精巣の発達時期および精子成熟サイクルに特有のパターンを示して発現していることを見出した。一方、GATA-2は巨核球、肥満細胞に加えて、未分化血液前駆細胞に発現していた。後者について、マウス遺伝子ライブラリーより精巣型および赤血球型プロモーターを含むGATA-1遺伝子クローンを得て、それらの詳細な構造解析を実施した。その結果、すでに赤血球型プロモーターの上流に機能的に重要なGATA配列の存在が報告されているが、精巣型プロモーターにもGATA配列が存在していることが明らかになった。そこで、その機能を詳細に解析する目的で、セルトリ細胞の一次培養系調製法を確立した。GATA-2やGATA-3遺伝子の構造を詳細に決定したところ、これらGATA群をコードする遺伝子の構成は各因子間で、また、種を越えてたいへんよく保存されていることを見出した。これらの研究を通して、GATA転写因子群が細胞・組織特異的な転写調節に機能していること、また、その発現が巧妙に調節されている様子がさらに明らかになった。

  87. ヘム生合成異常による病態の分子機構:鉄芽球性貧血および骨髄性プロトポルフィリン症

    林 典夫, 山本 雅之, 竹谷 茂

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 重点領域研究

    Institution: 東北大学

    1993 - 1993

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    5-アミノレブリン酸合成酵素(ALAS)異常と関連があるとされる鉄芽球性貧血とフェロキラターゼ異常が原因とされる骨髄性プロトポルフィリン症について、、病因解明と治療法の開発に資することを目的として、遺伝子レベルでの病態解析を行なった。先ず赤血球型(ALAS-E)と非特異型(ALAS-N)のALASイソ酵素およびフェロキラターゼの遺伝子について生化学的、分子・細胞生物学的研究を進め、これによって得られた様々な知見に基づき、これら酵素遺伝子異常の解析を行った。その結果、以下の様な日本人患者についての最初の成果が得られた。 1)骨髄性プロトポルフィリン症におけるフェロキラターゼ遺伝子変異の解析:昨年度までに、米国白人1例、次いで日本人2例につき、EBウイルスで株化したリンパ球を材料としてフェロキラターゼ遺伝子変異を解析し、第1例については既に報告した。本年度は、前年よりの日本人症例の解析をさらに進め、本酵素遺伝子の変異を確認した。即ち、第1例ではイントロン9、第2例ではイントロン7の5'端(供与部位)の塩基にG→A変異があり、異常スプライシングにより、それぞれエキソン9、エキソン7が欠失したmRNAが作られていた。 2)鉄芽球性貧血におけるALA合成酵素異常の解析:前年度に引続き、日本人X-染色体連関性鉄芽球性貧血患者)1例のEBウイルス株化リンパ球を材料として、ALAS-E遺伝子の変異を検索した。即ち、ALAS-E遺伝子の各エキソン附近をPCR法により増幅し、解析を行ったところ、第5エキソン内に点変異A→T(Asp→Val)が見出された。しかし、本点変異を持つALASを大腸菌に発現させ、同様に発現させた正常ALASと酵素活性を比較したところ、著しい差異はないように思われた。ピリドキサールリン酸結合部位付近や各エキソン-イントロン境界領域等には変異は検出されなかったことから、5'調節領域の異常の可能性を含め、今後さらには幅広い解析が必要である。

  88. 細胞分化の決定と癌遺伝子の役割

    帯刀 益夫, 丸山 光生, 北村 幸彦, 井川 洋二, 山本 雅之, 石井 俊輔

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: がん特別研究

    Institution: 東北大学

    1993 - 1993

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    細胞分化の決定における癌遺伝子の役割について、特徴ある細胞分化系において、癌遺伝子産物が細胞分化の制御にどのように関与するかの分子機構を解析した。まず、c-MycやIdなどHLHモチーフをもつ転写制御因子が血球分化の決定に負の因子として働くことを示し、これらと直接相互作用をする因子の遺伝子クローニングを行い、MIDA1と呼ぶ遺伝子を得た。MIDA1は分化の決定時にその発現が転換し、増殖の正の制御因子として働くことを示した(帯刀)。c-Mybと直接結合して負の調節をする因子Lassinをクローニングし、これが増殖の制御をすることを示した(石井)。赤血球分化の特異的転写因子であるNF-E2は、45kd蛋白とmaf癌遺伝子産物とが会合して配列特異的にDNAに結合して転写の制御を行うことを明らかにした。また、同じく赤血球特異的転写因子であるGATA-1の造血幹細胞から分化する際の発現のパターンを解析した(山本)。胚性幹(ES)細胞からin vitroで造血細胞へ分化誘導できる系の開発を行い、多分化能をもち、赤血球へと分化誘導可能な細胞株を樹立した(井川)。白斑,貧血,不妊などの症状を示す変異マウスの原因遺伝子であるc-kit(受容体型癌遺伝子)とそのリガンドであるSlの変異を遺伝子レベルで詳しく解析し、多様な変異のパターンがあることを示した(北村)。

  89. Analysis of the erythroid-specific gene expression by GATA trenscription factors

    YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for General Scientific Research (C)

    Institution: Tohoku University

    1992 - 1993

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    To understand functional roles that GATA factors play during erythroid cell differentiation, we examined the expression of GATA factors at both mRNA and protein levels. We also examined the structure of the genes encoding GATA factors. The results of expression analysis of GATA factors in leukemia-derived cell lines suggest that GATA-1 is essential for the development of erythroid/megakaryocytic cells, whereas GATA-2 is important for much earlier stage of cells in hematopoietic lineage. To define which GATA factor actually binds to a particular GATA sequence in vivo, we isolated DNA/GATA-1 complex from nuclei of mouse erythroleukemia cells by using anti-GATA-1 monoclonal antibody. We found genes which are expressed specifically in erythroid lineage cells in the immunoprecipitate. In contrast, we could not find genes which have GATA sites but are expressed in cells different from erythroid lineage. This finding indicates that GATA-1 binds only to the GATA sequences in the regulatory region for erythroid genes and suggests that GATA-1 is important for erytyroid gene expression. We found that GATA-1 is also expressed in mouse testis. Whereas the primary structure of this factor is completely the same as that in erythroid cells, the expression of testis form GATA-1 mRNA was found to be driven by the testis-specific promoter. We determined human GATA-2 and chicken GATA-3 genes, and found that the organization of these genes are very well conserved between species and between each GATA factor. Based on these results, we concluded that GATA factors function as regulators of thissue-specific gene expression.

  90. Structure and function of the regulatory region of the gene encoding non-specific form delta-aminolevulinate synthase

    HAYASHI Norio, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for General Scientific Research (B)

    Institution: Tohoku University

    1992 - 1993

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    Heme is essential for all eukaryotic cells because of its role as a prosthetic group for a number of proteins, and its intracellular concentration is highly regulated. The first and the rate-limiting step of heme biosynthesis in animals is catalyzed by delta-aminolevulinate(ALA) synthase. There are two tissue-specific isozymes of ALA synthase : the erythroid- specific ALA synthase (ALAS-E) and the non-specific ALA synthase (ALAS-N). To understand the molecular mechanisms contorolling the heme biosynthetic pathway, it is a prerequisite to analyze the structure and function of the ALA synthase genes. We attempted isolation and characterization of the gene encoding rat ALAS-N.The ALAS-N gene was found to span more than 14kb in the rat genome, encompassing 11 exons, Analysis of the promoter region of the gene revealed several potential cos-acting regulatory elements. Comparison of the organization of rat ALAS-N gene with that of the ALAS-E gene in mouse suggests that the ancestral gene for ALA synthase in animals was probably composed of 11 exons, and both ALAS-N and ALAS-E genes were derived from this ancestral gene. The proximal regulatory region of the human ALAS-E gene was also analyzed. The results indicated that binding sites for erythroid transcription factors are clustered within 120 bp upstream form the transcription initiation site. RNA blot hybridization analysis was used to examine the developmental stage-specific transcription of ALAS-N and ALAS-E genes in fetal, newborn and adult rat liver. The results demonstrated that, while ALAS-E is the key enzyme which supplies large quantities of heme for hemoglobin synthesis, ALAS-N functions to supply heme to the P-450 system in the liver and also functions as a housekeeper gene to supply heme for respiratory cytochromes and other hemoproteins in various tissues.

  91. 細胞分化の決定と癌移伝子の役割

    帯刀 益夫, 丸山 光生, 北村 幸彦, 井川 洋二, 山本 雅之, 石井 俊輔

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: がん特別研究

    Institution: 東北大学

    1992 - 1993

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    細胞分化の決定における癌遺伝子の働きを分子レベルで解明することを目的として、色々な分化系で解析した。 c-Mycの赤白血病(MEL)細胞の分化決定における役割を、c-myc人工改変遺伝子の導入により解析し、機能ドメインを明らかにした。c-Mycやこれと似たドメイン構造をもつId蛋白と会合して働く制御蛋白の遺伝子クローニングを行ない、Zuotin(Z-DNA結合蛋白)とホモロジーをモツ蛋白を同定した。現在その機能解析をすゝめている。(帯刀) Myb蛋白の機能解析から、Mybはロイシンジッパー構造を介してホモダイマーを形成すると、DNA結合活性を失なう。また、同ジ領域に別の蛋白(インヒビター)が結合することを見出し、その遺伝子をクローニングし、65Kダルトンのロ シンジッパーをもつ蛋白であることが明らかとなった。(石井) 血液細胞の分化の決定に関与する転写因子GATA-1,2について、ヒト白血病細胞を用いて解析し、GATA-1とGATA-2の発現量の変化と細胞分化段階と強い相関があることを見出した。(山本) ES細胞から血液細胞への分化誘導系を用いて、分化とリンフォカイン,その受容体の作用の関係を明らかにするため、エリスロポエチン受容体遺伝子のターゲッティングを行なっている。(井川) マスト細胞分化決定におけるc-kit遺伝子の役割を、この遺伝子の変異であるW変異マウスについて解析し、c-kit遺伝子の発現がマスト細胞、メラノサイトと、赤芽球,生殖細胞で異なる調節を受けていることを明らかにした。(北村)

  92. ヘム生合成異常による病態の分子機構:鉄芽球性貧血および骨髄性プロトポルフィリン症

    林 典夫, 山本 雅之, 竹谷 茂

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 重点領域研究

    Institution: 東北大学

    1992 - 1992

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    遺伝的ヘム生合成異常のなかで、5-アミノレブリン酸合成酵素(ALAS)異常が指摘されている鉄芽球性貧血とフェロキラターゼ欠損が原因とされる骨髄性プロトポルフィリン症(EPP)について、遺伝子レベルでの解析を試みた。その結果、昨年度までにヒト両酵素遺伝子の構成や5'調節領域の構造を解明し、EPPの一例(米国白人)についてフェロキラターゼ遺伝子変異を同定したのに続き、本年度には、次のような知見を得た。 1.日本人EPP最初の解析例として、EBウイルスで株化した患者リンパ球を材料にフェロキラターゼ遺伝子の変異を調べた。その結果、第1例ではイントロン9、第2例ではイントロン7の5'端の塩基にG→A変異があり、異常スプライシングにより、それぞれエキソン9、エキソン7が欠失したmRNAが作られていることが知られた。なお、第2例では、エキソン7内にアミノ酸置換を与えないの塩基変異G→Cが1箇所見出された。 2.赤血球型ALAS(ALAS-E)遺伝子の機能解析:1)赤血球系細胞における遺伝子発現調節に重要なシス因子群を含むALAS-E遺伝子5'調節領域の機能をCAT assay法により解析したところ、赤血球特異的遺伝子発現には上流側のGATA配列の寄与が特に大きいことが示唆された、2)白血病細胞株を用いた実験により、赤血球への分化にはALAS-Eの誘導を介したヘムの供給が重要であることが明らかにされた。 3.日本人鉄芽球性貧血におけるALAS-E遺伝子解析の第1例として、X-染色体連関性鉄芽球性貧血患者(ビタミンB_6不応性)について、EBウイルス株化リンパ球を材料にALAS-E遺伝子の変異を調べたが、B_6応答性症例について最近米国で報告されたようなピリドキサールリン酸結合部位付近の異常などは検出されなかった。5'調節領域の異常の可能性を含め、今後さらに解析を進める予定である。

  93. ヘム生合成異常による病態の分子機構:鉄芽球性貧血および骨髓性プロトポルフィリン症

    林 典夫, 山本 雅之, 武谷 茂

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 重点領域研究

    Institution: 東北大学

    1991 - 1991

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    ヘム生合成経路でそれぞれ最初と最後に位置し、ヘム生合成調節のうえで最も重要な役割を果している5ーアミノレブリン酸合成酵素(ALAS)とフェロキラタ-ゼ(FC)の遺伝的異常による病態について、特に、i)鉄芽球性貧血におけるALAS異常の病態への関与、並びにii)骨髄性プロトポルフィリン症(EPP)におけるフェロキラタ-ゼ異常の実体を分子レベルで解明することを目的とした研究計画を実施し、次ぎのような成果を得た。 1)鉄芽球性貧血およびEPPにおける遺伝子上の変異解明の基礎として、ヒト遺伝子ライブラリ-より赤血球型ALAS(ALAS‐E)およびFCの遺伝子クロ-ンを単離し、その構造解析を行い、FC遺伝子のイントロンーエクソン境界の全て、ALAS‐Eについてはその一部の塩基配列を決定した。さらに、5'‐調節領域の解析を行った結果、ALAS‐Eでは、GATA‐1やAP‐1の結合配列、CACCC配列、CCAAT配列などの赤血球系細胞での遺伝子発現調節に重要なシス因子群の存在が知られた。FCでも同様の配列が見られたが、CCAAT配列は存在しなかった。なお、両酵素遺伝子には典型的なTATAA配列は見られない。また、フェロキラタ-ゼ遺伝子の局在部位は第18染色体であると同定された。 2)EPPにおけるFC遺伝子変異の解析のため、本症患者1例(米国白人)のEBウイルスで株化したリンパ球を材料として、FCmRNAの細胞内レベルや転写速度、cDNAや遺伝子DNAの構造などを解析した。その結果、異常対立遺伝子の第1イントロンのアクセプタ-部位の1塩基置換(C→T)があり、これに起因するスプライシングの異常により、作られるmRNA.から第2エクソン部分が欠失していることが伴明した。 今後、以上の成果に基づき、鉄芽球性貧血でのALAS‐E異常や本邦EPP症例におけるFC遺伝子の変異などの解析をさらに進める予定である。

  94. 転写因子GATA(NF‐EI)群をコ-ドする遺伝子の構造と発現調節機序の解析

    山本 雅之, 林 典夫

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 重点領域研究

    Institution: 東北大学

    1991 - 1991

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    私たちは以前に、ニワトリのGATA‐2およびGATA‐3因子のcDNAをクロ-ン化し、その構造を報告した。これら因子のニワトリ各組織・細胞における発現を調ベてみると、GATA‐3因子mRNAは主としてTリンパ球と脳にその発現がみられた。GATA‐3因子の発現様式が動物系に一般的に観察される現象なのか否かを知る目的で、次いでヒトおよびマウスのGATA‐3因子のcDNAクロ-ン化に取り組んだ。両種のTリンパ球由来のcDNAライブラリ-をニワトリGATA‐3因子のcDNAをプロ-ブにしてスクリ-ニングしたところ、タンパク質全長をコ-ドするcDNaクロ-ンが得られ、その解析の結界、GATA‐3因子の構造は種を越えてたいへんよく保存されていること、またその発現パタ-ンもTリンパ球および神経細胞を中心にしている点で共通していることが明らかになった。過去のデ-タの検索からTリンパ球におけるGATA‐3因子の標的遺伝子の候補として、各種のT細胞受容体(TCR)遺伝子を見出したので、TCRδ遺伝子のエンハンサ-領域に見出されたGATA配列をモデルとして取りあげ、GATA‐3因子がこのcis‐acting elementを介してin vivoで実際に転写活性化する能力があることを実証した(MCB 11,2778ー2784,(1991))。 ヒトおよびニワトリのGATA‐3遺伝子のクロ-ン化および構造解析に着手し、現在その解析を進めている。当初、それぞれのcDNAクロ-ンの最も5'側の約500bpを用いてスクリ-ニングを行なったのであるが、その過程で目的のGATA‐3遺伝子コ-ドするクロ-ンの他に、それの約1/10程度の強さのシグナルを与えるクロ-ン群が両種の場合ともに単離されてきた。その後の解析の結果、これらはいずれの場合もGATA‐2因子の遺伝子であることが判明したので、これらについても現在解析中である。GATA‐3因子遺伝子の場合のもっとも5'側には非翻訳領域をコ-ドする小型のエクソンが存在することがこれまでに明らかになっている。

  95. Coupled Expression of The Genes Encoding The Constituents of The Glycine Cleavage System in Chicken

    HIRAGA Koichi, YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for General Scientific Research (C)

    Institution: Toyama Medical and Pharmaceutical University

    1987 - 1988

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    several clones of cDNA encoding qlycine decarboxylase, a constituent of the glycine cleavage system, were isolated from chicken liver cDNA expression libraries with a specific antibody. The overlapping cDNA clones evenly coded in an identical and open reading frame for the partial primary structures of the enzyme, and sequence of the 3,490 base long glycine decarboxylse cDNA was determined. H-protein cDNA was also cloned by immunoscreening, and this encoded the precursor from of chicken h-protein of 164 amino acid residues within the 840 base long cDNA sequence. Using both cDNA fragments we could analyze the mode of expression of the glycine decarboxylase and h-protein genes. Glycine decarboxylase mRNA aboundance varied in parallel with the content of the enzyme system in liver, kidney, and brain, which reveal specific activities of the overall reaction at a tatio of 35:11:1. in contrast, heart, spleen, and skeletal muscle mitochondria inactive in the reaction contained significant but small amounts of active H-protein and its mRNAs, whereas glycine decarboxylase and its mRNA were not found, indicationg that tissue-specific distribution of the enzyme system is primarily determined by expression of the hlycine decarboxylase gene. We defined them as the basal expression of the H-protein gene. Excluding the basal expression, relative efficiencies of run-off transcription on the glycine decarboxylase and H-protein genes appeared to be equal and the equimolar level of glycine decarboxylase and H-protein mRNAs are maintaianed in liver, kidney, and brain, irrespective of the difference in the amounts of expression of the genes. It is suggested that the magnitude of the glycine cleavage activity is specified by the coordinate mechanism which resides in regulation for biosynthesis of the components of the glycine cleavage system, except that the glycine decarboxylase gene expression alone is repressed in the cells of mesenchymal origin.

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    環境応答破綻がもたらす炎症の慢性化機構と治療戦略

  2. 転写因子CNCファミリーのシグナル調節の神経精神疾患に関わる研究

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    本研究では、アルツハイマー病等の研究に必要な最先端技術を導入し創薬活動に展開する

  3. Nrf2活性化による神経保護再生作用の検証

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    転写因子Nrf2の活性を人為的に制御することによる、 疾患治療に対する新たなアプローチを検証する。

  4. EPO産生調節機構の解明

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    EPO産生細胞の同定分離およびその利用、EPO遺伝子発現の分子調節機構の解明および、in vivo rescue sysytemとEPO derivativesの考案

  5. ME3738のアセトアミノフェン誘発肝傷害防御機構へのNrf2／Keap1系の介在性に関する研究

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    Nrf2を欠損した（Nrf2？／？)トランスジェニックマウスを用い、ME3738がアセトアミノフェンの肝傷害を抑制するかどうかについて評価する

  6. 発癌性物質や酸化ストレスに応答する生体防御系センサーの構造基盤

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    酸素および親電子性分子と総称される一群の毒性化学物質は空気・食物などから体内に取り込まれ、癌、動脈硬化、糖尿病などの原因となる。一方、動物細胞は酸素毒性や親電子性分子を感知する仕組み備えており、細胞内に活性酸素や親電子性分子が出現すると、抗酸化応答系や解毒代謝酵素群が働き、これらのストレスは速やかに消去される。このような適応・応答機構の存在は以前から知られていた。しかし、細胞がどのように酸化ストレスや親電子性分子を感知し、それらに対抗する生体防御遺伝子群の誘導・活性化をしているかは長年の謎であった。代表者らは、Keap1が分子センサーとして親電子性分子や酸化ストレスを感知し、転写因子Nrf2を活性化することで生体防御酵素群の発現を制御していることを発見した。本研究では、生体防御センシングの中核をなすKeap1-Nrf2による酸化ストレス感知とNrf2-MafによるDNA配列認識と転写活性化の分子機構を構造生物学（X線、電子線単粒子解析）と細胞生物学の手法を駆使して解明する。

  7. エリスロポエチンの研究

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    エリスロポエチンの研究

  8. 酸化ストレス応答の研究

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    酸化ストレス応答の研究

  9. エリスロポエチンの発現制御研究

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    エリスロポエチンの発現制御研究

  10. 酸化ストレス応答と発癌の研究

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    酸化ストレス応答と発癌の研究

  11. 薬物代謝系の制御機構の解明と薬剤に対する生体側の感受性決定因子の探索

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    薬物代謝系の制御機構の解明と薬剤に対する生体側の感受性決定因子の探索

  12. 総括実施型「環境応答プロジェクト」

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    総括実施型「環境応答プロジェクト」

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