Details of the Researcher

PHOTO

Takafumi Suzuki
Section
Graduate School of Medicine
Job title
Associate Professor
Degree

  • 博士（医学）（筑波大学）

e-Rad No.
70508308
Researcher ID
ABC-6582-2020
Profile

1997年 愛知県立時習館高等学校卒業、2001年 筑波大学第二学群生物学類 修了、日本学術振興会特別研究員DC1、2007年 筑波大学大学院人間総合科学研究科にて博士号(医学)を取得後、ERATO山本環境応答プロジェクト技術参事兼研究員、2008年より東北大学大学院医学系研究科医化学分野 助教、2016年より同分野 講師、2022年より同分野 兼 東北メディカル・メガバンク機構 准教授。若手研究者海外派遣プログラムや国際共同研究加速基金の支援を受けてアイルランドTrinity College Dublin、米国Fred Hutchinson Cancer Research Centerおよび英国Dundee大学など共同研究を展開。KEAP1-NRF2制御系の発見初期から20年以上一貫して同制御系の分子メカニズム解明に取り組んでいる。特に、KEAP1の多様なストレス感知機構の解明やNRF2機能の多面性の発見などに貢献。JAXAと協力して、世界に先駆けてNRF2欠失マウスの宇宙旅行を実現。分子生物学的およびマウス遺伝学を駆使してストレス応答の分子基盤および生理的意義の解明に取り組み、人類の健康長寿実現に貢献することを目指している。

Research History 7

  • 2022/04 - Present
    東北大学大学院医学系研究科／東北メディカル・メガバンク機構　分子医化学分野　准教授

  • 2016/04 - 2022/03
    Tohoku University Graduate School of Medicine　Faculty of Medicine

  • 2019/11 - 2020/02
    University of Dundee　Visiting Researcher

  • 2019/07 - 2019/07
    Fred Hutchinson Cancer Center　Visiting Researcher

  • 2008/04 - 2016/03
    東北大学大学院医学系研究科　医化学分野　助教

  • 2010/09 - 2011/01
    Trinity College Dublin　Visiting Researcher

  • 2007/04 - 2008/03
    Japan Science and Technology Agency

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Education 3

  • 筑波大学大学院博士課程人間総合科学研究科

    2003/04 - 2007/03

  • 筑波大学大学院修士課程医科学研究科

    2001/04 - 2003/03

  • University of Tsukuba

    1997/04 - 2001/03

Committee Memberships 1

  • Redox Biology　Editorial Board

    2024 - Present

Professional Memberships 5

  • 日本酸化ストレス学会

    2023 - Present

  • Association for Redox Research & Development Initiatives

    2021/04 - Present

  • THE JAPANESE CANCER ASSOCIATION

    2009 - Present

  • THE MOLECULAR BIOLOGY SOCIETY OF JAPAN

    2009 - Present

  • THE JAPANESE BIOCHEMICAL SOCIETY

    2002 - Present

Research Interests 5

  • ストレス応答

  • Cytoprotection

  • 生化学

  • 分子生物学、生化学

  • Keap1-Nrf2 system

Research Areas 3

  • Life sciences / Pathobiochemistry /

  • Life sciences / Medical biochemistry /

  • Life sciences / Molecular biology /

Awards 17

  1. Excellent poster award

    2023/11　The Environmental Response VI　Squamous cell carcinogenesis elicited by NRF2L30F plus Trp53R172H mutations.

  2. 若手優秀賞

    2023/10　第96回日本生化学会大会　含セレン抗酸化酵素欠失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

  3. Mishima Kaiun Academic Award

    2022/07　Mishima Kaiun Memorial Foundation

  4. 奨学賞金賞

    2022/01　東北大学医学部

  5. 若手優秀賞

    2021/11　第94回日本生化学会大会　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

  6. 優秀ポスター発表賞

    2021/05　第87回日本生化学会東北支部例会　Distinct Regulations of HO-1 Gene Expression for Stress Response and Substrate Induction.

  7. 優秀ポスター発表賞

    2021/05　第87回日本生化学会東北支部例会　Keap1 H2O2センサーの機能と生理的重要性の解明

  8. 日本生化学会東北支部奨励賞

    2018/05　第84回日本生化学会東北支部例会

  9. 第13回柿内三郎記念奨励研究賞

    2016/09

  10. Young Investigator’s Award

    2016/05　The 9th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide, and the 16th Annual Scientific Meeting of the Nitric Oxide Society of Japan

  11. 若手優秀発表賞

    2015/12　第３８回日本分子生物学会年会 第８８回日本生化学会 合同大会　新規変異体創出によるストレスセンサーKeap1のシステイン残基の機能解明

  12. 奨学賞銀賞

    2014/01　東北大学医学部

  13. 最優秀演題賞

    2013/07　第61回日本耳鼻咽喉科学会東北地方連合学術講演会　転写因子Nrf2の舌癌予防効果

  14. ベストプレゼン賞

    2013/01　第6回東北大学リトリート大学院生研究発表会　ミエロイド系細胞における酸化ストレス防御機構破綻ががん転移に及ぼす影響

  15. 日本生化学会東北支部優秀論文賞

    2012/05　日本生化学会東北支部　Select heterozygous Keap1 mutations have a dominant-negative effect on wild-type Keap1 in vivo.

  16. 日本生化学会大会 優秀プレゼンテーション賞

    2009/10　第８２回日本生化学会大会

  17. Most Impressive Poster Presentation Bronze Award

    2006/11　The 8th AEARU Joint Workshop on Life Sciences

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Papers 81

  1. Systemic activation of NRF2 contributes to the therapeutic efficacy of clinically-approved KRAS-G12C anti-cancer drugs. International-journal Peer-reviewed

    Liam Baird, Lin Zhang, Takanori Hidaka, Lyu Xi, Ke Wang, Keiko Tateno, Tatsuro Iso, Takafumi Suzuki, Kazuki Kumada, Fumiki Katsuoka, Kengo Kinoshita, Masayuki Yamamoto

    British journal of cancer　2025/09/01

    DOI： 10.1038/s41416-025-03162-7 　

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    BACKGROUND: The development and clinical success of KRASG12C inhibitors was a landmark achievement in anti-cancer drug development, as oncogenic KRAS had long been considered an intractable therapeutic target. Patients with KRAS mutant lung cancers frequently present with co-mutations in the KEAP1-NRF2 pathway, and because genetic activation of NRF2 results in resistance to all current anti-cancer therapies, we were motivated to explore how aberrant activation of NRF2 impacts the clinical response to KRASG12C inhibitors. METHODS: A broad range of techniques, including genetic knockouts, scRNA-seq and surface plasmon resonance, were used to determine the effect of KRASG12C drugs on NRF2. RESULTS: At physiologically-relevant concentrations, both of the clinically-approved KRASG12C inhibitors Sotorasib and Adagrasib also function as inducers of NRF2. Mechanistically, the same cysteine-targeting functionality which allows these electrophilic drugs to inhibit the mutant KRASG12C protein also facilitates their binding to cysteine-based sensors in KEAP1, resulting in the upregulation of the NRF2-dependent gene expression program. CONCLUSIONS: The activation of NRF2 by KRAS-G12C inhibitors represents a unique example of anti-cancer drugs which positively regulate the activity of a protein which is normally considered to be an oncogene. In both the malignant cells of the tumour and immune cells within the microenvironment, activation of NRF2 by electrophilic KRAS inhibitors positively contributes to the clinical efficacy of these drugs by promoting anti-cancer immunity. This unprecedented situation, in which the NRF2-dependent oxidative stress response is induced globally within cancer patients, has a number of important clinical implications, particularly in relation to ongoing combination chemotherapy clinical trials, as well as for selecting patient populations which may derive the most benefit from G12Ci anti-cancer drugs.

  2. CD5L is a target of transcription factor Nrf2. International-journal Peer-reviewed

    Sharadha Dayalan Naidu, Abel D Ang, Charlotte Lim Jia Yee, Oliver J Read, Tom S Dixon, Elena V Knatko, Aileen Sandilands, Maureen Higgins, Dorothy Kisielewski, John D Hayes, Tadashi Honda, Takafumi Suzuki, Masayuki Yamamoto, Albena T Dinkova-Kostova

    Biochemical and biophysical research communications　776　152225-152225　2025/06/18

    DOI： 10.1016/j.bbrc.2025.152225 　

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    CD5 antigen-like (CD5L), also known as apoptosis inhibitor expressed by macrophages (AIM), is a secreted protein produced by macrophages, which has both cell-autonomous and non-autonomous functions: it has been implicated in multiple biological processes, including inflammation, infection, and fibrosis. The transcriptional regulation of CD5L is complex, and a comparison of the proteomes of bone marrow-derived macrophages from mice with graded expression of transcription factor NF-E2 p45-related factor 2 (Nrf2) indicated that Nrf2 controls expression of the CD5L gene. Using genetic and pharmacological means to increase or decrease Nrf2 activity, we found a correlation between the abundance of Nrf2 and CD5L expression in both murine macrophages and primary human monocyte-derived macrophages. Furthermore, the potency of small-molecule Nrf2 activators with distinct mechanisms of action and different potencies, correlated with the extent of CD5L expression, both at the mRNA and the secreted protein levels. Conversely, depletion of Nrf2 resulted in a significant decrease in CD5L mRNA levels. Chip-seq analysis showed Nrf2 binding 20,000 bp upstream of the Cd5l promoter, a region containing sequences resembling the antioxidant response element (ARE, 5'-TGACNNNGC-3') Nrf2-binding motif. Deletion of two of these sequences by CRISPR/Cas9 gene editing led to a profound decrease in CD5L mRNA levels, confirming the critical role of these ARE-like sequences in controlling CD5L expression. Recombinant CD5L (rCD5L) suppressed transforming growth factor β (TGFβ)-directed fibrogenic responses in human lung fibroblasts, suggesting that Nrf2 activators, such as the clinically used omaveloxolone (RTA-408), could protect against pulmonary fibrosis by boosting the levels of CD5L.

  3. Selenoprotein-mediated redox regulation shapes the cell fate of HSCs and mature lineages Peer-reviewed

    Yumi Aoyama, Hiromi Yamazaki, Koutarou Nishimura, Masaki Nomura, Tsukasa Shigehiro, Takafumi Suzuki, Weijia Zang, Yota Tatara, Hiromi Ito, Yasutaka Hayashi, Yui Koike, Miki Fukumoto, Atsushi Tanaka, Yifan Zhang, Wataru Saika, Chihiro Hasegawa, Shuya Kasai, Yingyi Kong, Yohei Minakuchi, Ken Itoh, Masayuki Yamamoto, Shinya Toyokuni, Atsushi Toyoda, Tomokatsu Ikawa, Akifumi Takaori-Kondo, Daichi Inoue

    Blood　2025/03/13

    DOI： 10.1182/blood.2024025402 　

  4. 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

  5. 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>

  6. The NRF2 inducer CDDO-2P-Im provokes a reduction in amyloid β levels in Alzheimer’s disease model mice Peer-reviewed

    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

    The Journal of Biochemistry　2024/09/11

    DOI： 10.1093/jb/mvae060 　

    ISSN： 0021-924X 1756-2651

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    <jats:title>Abstract</jats:title> <jats:p>Alzheimer’s disease (AD) is the most common aetiology 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.</jats:p>

  7. Electrophiles and Keap1-Nrf2 protein-protein interaction inhibitors for prevention and treatment of chronic disease

    Sharadha Dayalan Naidu, Dina Dikovskaya, Annamarie J. Cafferkey, Miroslav Novak, Takafumi Suzuki, Elena V. Knatko, Terry W. Moore, Geoffrey Wells, Albena T. Dinkova-Kostova

    Free Radical Biology and Medicine　2024/06

    DOI： 10.1016/j.freeradbiomed.2024.04.016 　

    ISSN： 0891-5849

  8. 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 　

  9. 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　2024/03

    DOI： 10.1007/s10157-023-02427-w 　

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

    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 　

    ISSN： 0021-924X 1756-2651

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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.

  11. Generation and analysis of NRF2-activated esophageal squamous cell carcinoma mouse model

    Takafumi Suzuki

    Cancer Science　2024

  12. C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape (vol 8, 8037, 2018)

    Takafumi Suzuki

    Scientific Reports　2024

    DOI： 10.1038/S41598-024-55265-5 　

  13. 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 　

  14. A NRF2-induced secretory phenotype activates immune surveillance to remove irreparably damaged cells Peer-reviewed

    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

  15. Insights into the Regulation of GFR by the Keap1-Nrf2 Pathway Peer-reviewed

    Kengo Kidokoro, Hiroyuki Kadoya, David Z. I. Cherney, Megumi Kondo, Yoshihisa Wada, Reina Umeno, Seiji Kishi, Hajime Nagasu, Kojiro Nagai, Takafumi Suzuki, Tamaki Sasaki, Masayuki Yamamoto, Yashpal S. Kanwar, Naoki Kashihara

    Kidney360　2023/10

    DOI： 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.

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

    Ritsuko Shimizu, Ikuo Hirano, Atsushi Hasegawa, Mikiko Suzuki, Akihito Otsuki, Taguchi K, Fumiki Katsuoka, Akira Uruno, Norio Suzuki, Yumoto A, Okada R, Shirakawa M, Dai Shiba, Satoru Takahashi, Takafumi Suzuki, Masayuki Yamamoto

    Communications biology　6　2023/08/25

    DOI： 10.1038/s42003-023-05251-w 　

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    Spaceflight-related stresses impact health via various body systems, including the haematopoietic and immune systems, with effects ranging from moderate alterations of homoeostasis to serious illness. Oxidative stress appears to be involved in these changes, and the transcription factor Nrf2, which regulates expression of a set of cytoprotective and antioxidative stress response genes, has been implicated in the response to spaceflight-induced stresses. Here, we show through analyses of mice from the MHU-3 project, in which Nrf2-knockout mice travelled in space for 31 days, that mice lacking Nrf2 suffer more seriously from spaceflight-induced immunosuppression than wild-type mice. We discovered that a one-month spaceflight-triggered the expression of tissue inflammatory marker genes in wild-type mice, an effect that was even more pronounced in the absence of Nrf2. Concomitant with induction of inflammatory conditions, the consumption of coagulation-fibrinolytic factors and platelets was elevated by spaceflight and further accelerated by Nrf2 deficiency. These results highlight that Nrf2 mitigates spaceflight-induced inflammation, subsequent immunosuppression, and thrombotic microangiopathy. These observations reveal a new strategy to relieve health problems encountered during spaceflight.

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

    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.

  18. Molecular Basis of the KEAP1-NRF2 Signaling Pathway Peer-reviewed

    Takafumi Suzuki, Jun Takahashi, Masayuki Yamamoto

    Molecules and Cells　2023/03/31

    DOI： 10.14348/molcells.2023.0028 　

  19. The isoquinoline PRL-295 increases the thermostability of Keap1 and disrupts its interaction with Nrf2 Peer-reviewed

    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)　2022/01/21

    DOI： 10.1016/j.isci.2021.103703 　

    ISSN： 2589-0042

    eISSN： 2589-0042

  20. Gene expression changes related to bone mineralization, blood pressure and lipid metabolism in mouse kidneys after space travel Peer-reviewed

    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 　

    ISSN： 0085-2538

    eISSN： 1523-1755

  21. Nrf2 plays a critical role in the metabolic response during and after spaceflight Peer-reviewed

    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)　2021/12

    DOI： 10.1038/s42003-021-02904-6 　

    eISSN： 2399-3642

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

    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　2021/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s42003-021-02334-4 　

    ISSN： 2399-3642

    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.

  23. Molecular basis for the disruption of Keap1–Nrf2 interaction via Hinge & Latch mechanism Peer-reviewed

    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)　2021/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s42003-021-02100-6 　

    eISSN： 2399-3642

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    <title>Abstract</title>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.

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

    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　2021/08/16

    Publisher: American Society for Microbiology

    DOI： 10.1128/mcb.00236-21 　

    ISSN： 1098-5549

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    <jats:p> Heme oxygenase-1 (HO-1) is the key enzyme for heme catabolism and cytoprotection. Whereas <jats:italic>HO-1</jats:italic> gene expression in response to various stresses has been investigated extensively, the precise mechanisms by which <jats:italic>HO-1</jats:italic> gene expression is regulated by the HO-1 substrate heme remain elusive. To systematically examine whether stress-mediated induction and substrate-mediated induction of <jats:italic>HO-1</jats:italic> utilize similar or distinct regulatory pathways, we developed an HO-1-DsRed-knock-in reporter mouse in which the <jats:italic>HO-1</jats:italic> gene is floxed by loxP sites and the <jats:italic>DsRed</jats:italic> 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 <jats:italic>in vivo</jats:italic> and <jats:italic>ex vivo</jats:italic> . 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 <jats:italic>HO-1</jats:italic> induction and NRF2-independent substrate-mediated <jats:italic>HO-1</jats:italic> induction. Thus, the <jats:italic>HO-1</jats:italic> 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. </jats:p>

  25. Novel method for evaluating the health condition of mice in space through a video downlink. Peer-reviewed

    Yumoto A, Kokubo T, Izumi R, Shimomura M, Funatsu O, Tada MN, Ota-Murakami N, Iino K, Shirakawa M, Mizuno H, Kudo T, Takahashi S, Suzuki T, Uruno A, Yamamoto M, Shiba D

    Experimental animals　70　(2)　236-244　2021/01/22

    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.

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

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

    Journal of Biological Chemistry　296　100169-100169　2021

    Publisher: Elsevier BV

    DOI： 10.1074/jbc.ra120.016551 　

    ISSN： 0021-9258

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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.

  27. Environmental pollutants and the immune response International-journal Peer-reviewed

    Takafumi Suzuki, Takanori Hidaka, Yoshito Kumagai, Masayuki Yamamoto

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

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41590-020-0802-6 　

    ISSN： 1529-2908

    eISSN： 1529-2916

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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.

  28. Nrf2 contributes to the weight gain of mice during space travel Peer-reviewed

    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)　2020/12

    Publisher: Springer Science and Business Media {LLC}

    DOI： 10.1038/s42003-020-01227-2 　

    eISSN： 2399-3642

  29. Geldanamycin-Derived HSP90 Inhibitors Are Synthetic Lethal with NRF2. International-journal Peer-reviewed

    Baird L, Suzuki T, Takahashi Y, Hishinuma E, Saigusa D, Yamamoto M.

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

    Publisher: American Society for Microbiology

    DOI： 10.1128/mcb.00377-20 　 10.1128/MCB.00377-20 　

    ISSN： 0270-7306

    eISSN： 1098-5549

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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.

  30. Erratum: Author Correction: Nrf2 contributes to the weight gain of mice during space travel (Communications biology (2020) 3 1 (496))

    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　2020/10/07

    DOI： 10.1038/s42003-020-01292-7 　

    eISSN： 2399-3642

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

    Takafumi Suzuki

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology　33　(11)　12253-12263　2019/08/30

    DOI： 10.1096/fj.201900217r 　

    ISSN： 0892-6638

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    Multiple clinical studies have shown that bardoxolone methyl, a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2), is effective in increasing glomerular filtration rate in patients with chronic kidney disease. However, whether an Nrf2 activator can protect tubules from proteinuria-induced tubular damage via anti-inflammatory and antioxidative stress mechanisms is unknown. Using an Institute of Cancer Research-derived glomerulonephritis (ICGN) mouse model of nephrosis, we examined the effects of dihydro-CDDO-trifluoroethyl amide (dh404), a rodent-tolerable bardoxolone methyl analog, in protecting the tubulointerstitium; dh404 markedly suppressed tubular epithelial cell damage in the renal interstitium of ICGN mice. The tubular epithelial cells of ICGN mice showed a decrease in the size and number of mitochondria, as well as the breakdown of the crista structure, whereas the number and ultrastructure of mitochondria were maintained by the dh404 treatment. To further determine the effect of dh404 on mitochondrial function, we used human proximal tubular cells in vitro. Stimulation with albumin and free fatty acid increased mitochondrial reactive oxygen species (ROS). However, dh404 administration diminished mitochondrial ROS. Our data show that dh404 significantly reduced proteinuria-induced tubular cell mitochondrial damage, suggesting that improved redox balance and mitochondrial function and suppression of inflammation underlie the cytoprotective mechanism of Nrf2 activators, including bardoxolone methyl, in diabetic kidney disease.-Nagasu, H., Sogawa, Y., Kidokoro, K., Itano, S., Yamamoto, T., Satoh, M., Sasaki, T., Suzuki, T., Yamamoto, M., Wigley, W. C., Proksch, J. W., Meyer, C. J., Kashihara, N. Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function.

  32. 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.e4　2019/07

    Publisher: Elsevier {BV}

    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.

  33. C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape International-journal 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)　8037-8037　2018/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41598-018-26269-9 　

    ISSN： 2045-2322

    eISSN： 2045-2322

  34. Structural instability of IκB kinase β promotes autophagic degradation through enhancement of Keap1 binding. Peer-reviewed

    Takafumi Suzuki

    PloS one　13　(11)　e0203978　2018/11/30

    DOI： 10.1371/journal.pone.0203978 　

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    IKKβ, an essential kinase of NF-κB signaling, is composed of an N-terminal kinase domain (KD) and a C-terminal scaffolding domain, containing a ubiquitin-like domain (ULD). The Hsp90 chaperon has special responsibility for folding of protein kinases including IKKβ. Here, we found that Hsp90 inhibition induced IKKβ degradation, which is partially mediated by Keap1. Geldanamycin (GA), a Hsp90 inhibitor, enhances association of IKKβ with Keap1 through the binding site in KD, and translocates IKKβ to detergent-insoluble fractions leading to its autophagic degradation. An electrophile tBHQ suppressed Keap1-mediated proteasomal Nrf2 degradation but not autophagic IKKβ degradation. Substitution mutation of Leu353 to Ala in the ULD destabilizes IKKβ, enhances its association with Keap1, translocates it to detergent-insoluble fractions, and causes its autophagic degradation. These results suggest that Keap1 is involved in the degradation of structural destabilized IKKβ and negative regulation of NF-κB under proteotoxic stress.

  35. 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

    The Journal of Immunology　201　(2)　635-651　2018/07/15

    Publisher: The American Association of Immunologists

    DOI： 10.4049/jimmunol.1800040 　

    ISSN： 0022-1767

    eISSN： 1550-6606

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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.

  36. Phenethyl Isothiocyanate, a Dual Activator of Transcription Factors NRF2 and HSF1. Peer-reviewed

    Takafumi Suzuki

    Molecular nutrition & food research　62　(18)　1700908-1700908　2018/06/19

    Publisher: Wiley

    DOI： 10.1002/mnfr.201700908 　

    ISSN： 1613-4125

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    Cruciferous vegetables are rich sources of glucosinolates which are the biogenic precursor molecules of isothiocyanates (ITCs). The relationship between the consumption of cruciferous vegetables and chemoprotection has been widely documented in epidemiological studies. Phenethyl isothiocyanate (PEITC) occurs as its glucosinolate precursor gluconasturtiin in the cruciferous vegetable watercress (Nasturtium officinale). PEITC has multiple biological effects, including activation of cytoprotective pathways, such as those mediated by the transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) and the transcription factor heat shock factor 1 (HSF1), and can cause changes in the epigenome. However, at high concentrations, PEITC leads to accumulation of reactive oxygen species and cytoskeletal changes, resulting in cytotoxicity. Underlying these activities is the sulfhydryl reactivity of PEITC with cysteine residues in its protein targets. This chemical reactivity highlights the critical importance of the dose of PEITC for achieving on-target selectivity, which should be carefully considered in the design of future clinical trials.

  37. 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　2018/05/15

    Publisher: Wiley

    DOI： 10.1111/gtc.12579 　

    ISSN： 1365-2443 1356-9597

  38. Keap1による多様なストレス感知機構 Invited

    鈴木 隆史, 山本 雅之

    実験医学 (羊土社)　36　705-710　2018

  39. 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

  40. Stress-sensing mechanisms and the physiological roles of the Keap1-Nrf2 system during cellular stress. Peer-reviewed

    Takafumi Suzuki

    The Journal of biological chemistry　292　(41)　16817-16824　2017/08/24

    DOI： 10.1074/jbc.r117.800169 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  41. Infiltration of M1, but not M2, macrophages is impaired after unilateral ureter obstruction in Nrf2-deficient mice. Peer-reviewed

    Takafumi Suzuki

    Scientific reports　7　(1)　2017/08/18

    DOI： 10.1038/s41598-017-08054-2 　

    ISSN： 2045-2322

    eISSN： 2045-2322

  42. Systemic Activation of NRF2 Alleviates Lethal Autoimmune Inflammation in Scurfy Mice. Peer-reviewed

    Suzuki T, Murakami S, Biswal SS, Sakaguchi S, Harigae H, Yamamoto M, Motohashi H

    Mol Cell Biol.　37　(15)　2017/05/15

    DOI： 10.1128/MCB.00063-17. 　

  43. 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

  44. The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice Peer-reviewed

    Higashi, C., Kawaji, A., Tsuda, N., Hayashi, M., Saito, R., Yagishita, Y., Suzuki, T., Uruno, A., Nakamura, M., Nakao, K., Furusako, S., Yamamoto, M.

    European Journal of Pharmacology　802　76-84　2017

    DOI： 10.1016/j.ejphar.2017.02.044 　

    ISSN： 0014-2999

    eISSN： 1879-0712

  45. Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus Peer-reviewed

    Suzuki, T., Seki, S., Hiramoto, K., Naganuma, E., Kobayashi, E.H., Yamaoka, A., Baird, L., Takahashi, N., Sato, H., Yamamoto, M.

    Nature Communications　8　14577　2017

    DOI： 10.1038/ncomms14577 　

    ISSN： 2041-1723

  46. The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin Peer-reviewed

    Hidaka, T., Ogawa, E., Kobayashi, E.H., Suzuki, T., Funayama, R., Nagashima, T., Fujimura, T., Aiba, S., Nakayama, K., Okuyama, R., Yamamoto, M.

    Nature Immunology　18　(1)　64-73　2017

    DOI： 10.1038/ni.3614 　

    ISSN： 1529-2908

    eISSN： 1529-2916

  47. 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

  48. 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 　

  49. 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

    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

  50. 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

  51. Absolute amounts and status of the Nrf2-Keap1-Cul3 complex within cells Peer-reviewed

    Iso, T., Suzuki, T., Baird, L., Yamamoto, M.

    Molecular and Cellular Biology　36　(24)　3100-3112　2016

    DOI： 10.1128/MCB.00389-16 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  52. 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　2015/11

    DOI： 10.1126/scisignal.aad0667 　

    ISSN： 1945-0877

    eISSN： 1937-9145

  53. Molecular basis of the Keap1-Nrf2 system Peer-reviewed

    Takafumi Suzuki, Masayuki Yamamoto

    FREE RADICAL BIOLOGY AND MEDICINE　88　(Part B)　93-100　2015/11

    DOI： 10.1016/j.freeradbiomed.2015.06.006 　

    ISSN： 0891-5849

    eISSN： 1873-4596

  54. 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

  55. Keap1 inhibition attenuates glomerulosclerosis Peer-reviewed

    Yoichi Miyazaki, Akihiro Shimizu, Ira Pastan, Keiko Taguchi, Eriko Naganuma, Takafumi Suzuki, Tatsuo Hosoya, Takashi Yokoo, Akihiko Saito, Toshio Miyata, Masayuki Yamamoto, Taiji Matsusaka

    NEPHROLOGY DIALYSIS TRANSPLANTATION　29　(4)　783-791　2014/04

    DOI： 10.1093/ndt/gfu002 　

    ISSN： 0931-0509

    eISSN： 1460-2385

  56. Toward clinical application of the Keap1-Nrf2 pathway Peer-reviewed

    Suzuki, T., Motohashi, H., Yamamoto, M.

    Trends in Pharmacological Sciences　34　(6)　340-346　2013/06

    DOI： 10.1016/j.tips.2013.04.005 　

    ISSN： 0165-6147

  57. 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

  58. 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

    Publisher: 2

    DOI： 10.1158/1940-6207.CAPR-12-0401-T 　

    ISSN： 1940-6207 1940-6215

    eISSN： 1940-6215

  59. Roles nrf2 plays in myeloid cells and related disorders. International-journal Invited Peer-reviewed

    Eri Kobayashi, Takafumi Suzuki, Masayuki Yamamoto

    Oxidative medicine and cellular longevity　2013　529219-529219　2013

    Publisher: Hindawi Publishing Corporation

    DOI： 10.1155/2013/529219 　

    ISSN： 1942-0900

    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.

  60. ユビキチンープロテアソーム系によるKeap1-Nrf2経路の制御機構 Invited

    鈴木隆史, 山本雅之

    医学のあゆみ　243　(6)　525-529　2012/11/10

    Publisher:

    ISSN： 0039-2359

  61. 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

  62. 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

  63. 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.

  64. 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

  65. 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

  66. 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

  67. 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

  68. 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

  69. 「環境応答と転写因子」 (転写制御とエピジェネティクスーゲノムでコードに向けてー)

    鈴木隆史, 山本雅之

    転写制御とエピジェネティクスーゲノムでコードに向けてー　143-149　2008/10

  70. Physiological significance of reactive cysteine residues of keap1 in determining Nrf2 activity 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

  71. 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

  72. 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

  73. 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 Invited

    鈴木隆史, 山本雅之

    実験医学　24　1737-1743　2006/10

  74. 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

  75. 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

  76. The distal sequence element of the selenocysteine tRNA gene is a tissue-dependent enhancer essential for mouse embryogenesis 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

  77. Pi class glutathione S-transferase genes are regulated by Nrf2 through an evolutionarily conserved regulatory element in zebrafish Peer-reviewed

    T Suzuki, Y Takagi, H Osanai, L Li, M Takeuchi, Y Katoh, M Kobayashi, M Yamamoto

    BIOCHEMICAL JOURNAL　388　(1)　65-73　2005/05

    DOI： 10.1042/BJ20041860 　

    ISSN： 0264-6021

  78. MafT, a new member of the small Maf protein family in zebrafish 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

  79. 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

  80. 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

  81. Gene regulation of the zebrafish Six4 in the cranial sensory placodes.

    Kobayashi M, Suzuki T, Yamamoto M

    Development, Growth & Differentiation.　43　S99　2001

Show all ︎Show first 5

Misc. 16

  1. 宇宙環境マウス実験からヒト健康長寿研究へ Invited

    鈴木隆史

    細胞　2023/11/22

  2. 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

  3. 環境ストレス応答の分子メカニズムと生理的意義の解明

    鈴木隆史

    東北医学雑誌(Web)　134　(1)　2022

    ISSN： 0040-8700

  4. 宇宙マウス実験からヒト健康・長寿研究への還元を目指して Invited

    鈴木隆史, 山本雅之

    医学のあゆみ　279　(6)　632-639　2021

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

    Publisher: (一社)日本癌学会

    ISSN： 0546-0476

  13. 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

  14. 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

  15. CLARA-CELL SPECIFIC KEAP1 CONDITIONAL KNOCKOUT MICE HAVE STRONG NRF2 ACTIVATION BUT ARE SENSITIVE TO BLEOMYCIN-INDUCED LUNG INJURY

    Jonathan M. Maher, Takafumi Suzuki, Keiko Teguchi, Yukie Kawatani, Momoko Kimura, Hozumi Motohashi, Yukio Ishii, Masayuki Yamamoto

    DRUG METABOLISM REVIEWS　39　383-384　2007

    ISSN： 0360-2532

  16. 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

Show all ︎Show first 5

Books and Other Publications 1

  1. 人体の細胞生物学 : カラー図解

    坂井, 建雄, 石崎, 泰樹

    日本医事新報社　2018/11

    ISBN: 9784784932320

Presentations 124

  1. KEAP1-NRF2システム制御機構の解明に向けた構造生物学的解析 Invited

    水島 恒裕, 高木 賢治, 磯 達朗, 鈴木 隆史, 山本 雅之

    97回日本生化学会大会

  2. KEAP1-NRF2システムによる多様なストレス感知機構 Invited

    鈴木 隆史, 山本 雅之

    第97回日本生化学会大会

  3. KEAP1による酸化ストレス感知機構の生理機能解明

    佐藤 美羽, 矢口 菜穂子, 飯島 拓矢, 伊藤 栞大, 鈴木 隆史, 山本 雅之

    第97回日本生化学会大会

  4. KEAP1による酸化ストレス感知機構の生理機能解明

    佐藤 美羽, 矢口 菜穂子, 飯島 拓矢, 伊藤 栞大, 鈴木 隆史, 山本 雅之

    第97回日本生化学会大会

  5. Experimental Demonstration of Immunological Influences by NRF2-addicted Cancers

    Wen Huaichun, Anqi Zhang, 鈴木 隆史, 山本 雅之

    第97回日本生化学会大会

  6. KEAP1変異とNRF2変異が招来する異なる表現型解明を目指した食道扁平上皮細胞培養系樹立

    新田 修司, 高橋 洵, 松本 麻寛, 佐藤 美羽, 鈴木 隆史, 山本 雅之

    第97回日本生化学会大会　2024/11/08

  7. KEAP1-NRF2制御系を標的とした創薬の情勢 Invited

    鈴木隆史

    LINK-J 東北大学「共創型創薬研究への挑戦」～共創的創薬に向けてアカデミア研究基盤とバイオバンクに期待されるもの～　2024/10/22

  8. Nrf2 activation improves experimental rheumatoid arthritis

    Anqi Zhang, 鈴木 隆史, 安達 紗希, 吉田 瑛紀, 山本 雅之

    日本生化学会 東北支部 第90回例会・シンポジウム　2024/06/01

  9. KEAP1による酸化ストレス感知機構の生理的機能解明

    佐藤美羽, 矢口菜穂子, 鈴木隆史, 山本雅之

    日本生化学会 東北支部 第90回例会・シンポジウム　2024/06/01

  10. Experimental Demonstration of Immunological Effects by NRF2-activated Cancers

    Huaichun Wen, Anqi Zhang, Takafumi Suzuki, Masayuki Yamamoto

    日本生化学会 東北支部 第90回例会・シンポジウム　2024/05/31

  11. NRF2とKEAP1変異が招来する異なる表現形解明を目指した食道扁平上皮細胞培養系樹立

    新田修司, 高橋洵, 松本麻寛, 佐藤美羽, 鈴木隆史, 山本雅之

    日本生化学会 東北支部 第90回例会・シンポジウム　2024/05/31

  12. NRF2 Activation Improves Rheumatoid Arthritis of SKG Mice.

    2022/11/11

  13. Nrf2 activation improves Rheumatoid arthritis of SKG mice.

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

    2022/05/27

  14. 微小重力下でのNrf2によるヒラメ筋可塑性制御機能

    林卓杜, 工藤崇, 藤田諒, 藤田晋一郎, 布施谷清香, 鈴木陸, 濱田理人, 岡田理沙, 村谷匡史, 芝大, 鈴木隆史, 蕨栄治, 山本雅之, 高橋智

    第94回日本生化学会大会

  15. Distinct Regulations of HO-1 Gene Expression for Stress Response and Substrate Induction.

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

    第94回日本生化学会大会　2021/11/05

  16. 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

    矢口菜穂子, 鈴木隆史, 山本雅之

    第94回日本生化学会大会　2021/11/05

  17. Distinct Regulations of HO-1 Gene Expression for Stress Response and Substrate Induction

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

    第87回日本生化学会東北支部例会　2021/05/29

  18. Keap1 H2O2センサーの機能と生理的重要性の解明

    矢口菜穂子, 鈴木隆史, 山本雅之

    第87回日本生化学会東北支部例会　2021/05/29

  19. Keap1-Nrf2系によるストレス応答メカニズムとその生理的意義 Invited

    鈴木隆史

    第44回Okayama Nephro-Talk　2021/04/20

  20. Investigation of Nrf2 activation mechanism using HO-1-DsRed reporter mouse system.

    Anqi Zhang, Saki Adachi, Takafumi Suzuki, Masayuki Yamamoto

    Tohoku University Graduate School of Medicine The 13th Retreat Conference　2021/02/28

  21. Establishment of Hmox1-DsRed reporter mouse system.

    Anqi Zhang, Saki Adachi, Tomonori Hosoya, Ken Itoh, Takafumi Suzuki, Masayuki Yamamoto

    2020/05/30

  22. Investigation of Nrf2 activation mechanism using HO-1-DsRed reporter mouse system.

    Anqi Zhang, Saki Adachi, Takafumi Suzuki, Masayuki Yamamoto

    Tohoku University Graduate School of Medicine The 13th Retreat Conference　2020/01/12

  23. 生体防御機構Keap1-Nrf2系のHinge&Latchモデルの検証

    堀江悠太, 磯達朗, 井上仁, 鈴木隆史, 小柴生造, 山本雅之

    第１２回東北大学大学院医学系研究科リトリート大学院生研究発表会　2019/01/12

  24. 転写因子Nrf2の活性化は関節リウマチの症状を緩和するか

    安達紗希, 吉田瑛紀, 長沼絵理子, 鈴木隆史, 山本雅之

    第１２回東北大学大学院医学系研究科リトリート大学院生研究発表会　2019/01/12

  25. システイン反応性Nrf2誘導剤に対する応答を欠失したKeap1変異体の創出

    鈴木隆史, 村松亜紀, 斎藤良太, 磯達朗, 山本雅之

    第91回日本生化学大会,　2018/09/24

  26. Keap1酸化ストレスセンサーの機能解析

    村松亜紀, 鈴木隆史, 斎藤良太, 磯達朗, 須田博美, 守田匡伸, 山本雅之

    第91回日本生化学大会,　2018/09/24

  27. Keap1-Nrf2系によるストレス応答メカニズムとその生理的意義

    鈴木隆史

    第84回日本生化学会東北支部例会 奨励賞受賞講演　2018/05/19

  28. 尿細管発生期における転写因子Nrf2の恒常的活性化は腎性尿崩症を引き起こす

    鈴木隆史, 関詩織, 長沼絵理子, 高橋信行, 佐藤博, 山本雅之

    ConBio2017　2017/12/06

  29. TBE-31はKeap1Cys151を介してNrf2を活性化し抗炎症に働く

    村松亜紀, 鈴木隆史, Dinkova-Kostova, 山本雅之

    ConBio2017　2017/12/06

  30. 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

    第40回生命科学系学会合同年次大会　2017/12/06

  31. 酸化ストレス応答におけるKeap1の構造・相互作用解析

    井上仁, 村松亜紀, 鈴木隆史, 磯達朗, 小柴生造, 山本雅之

    第56回NMR討論会　2017/11/14

  32. Keap1-Nrf2系による酸化ストレス防御機構

    Takafumi SUZUKI

    第7回日本分子状水素医学生物学会年会　2017/10/29

  33. Keap1-Nrf2システムによる酸化ストレス応答機構

    鈴木隆史, 山本雅之

    第17回日本蛋白質学会大会　2017/06/20

  34. 尿細管発生期における転写因子Nrf2の恒常的活性化は腎性尿崩症を引き起こす

    鈴木隆史, 関詩織, 長沼絵里子, 高橋信行, 佐藤博, 山本雅之

    第60回 日本腎臓学会学術会　2017/05/26

  35. Air pollution activates Aryl hydrocarbon receptor in murine epidermis, leading to Atopic dermatitis-like pathologies. International-presentation

    Takanori Hidaka, Eri H Kobayashi, Takafumi Suzuki, Masayuki Yamamoto

    The 41st Annual Meeting of the Japanese Society for Investigative Dermatology　2016/12/09

  36. 19F標識技術を利用したKeap1-Nrf2タンパク質の構造機能解析

    小柴生造, 渡部暁, 碇正臣, 松田夏子, 磯達郎, 鈴木隆史, 木川隆則, 山本雅之

    第39回 日本分子生物学会年会　2016/12/01

  37. オートファジー破綻がもたらす病態のNrf2を標的とした治療戦略

    田口恵子, 鈴木隆史, 山本雅之

    第10回オートファジー研究会・第4回新学術「オートファジー」班会議　2016/10/14

  38. Keap1センサーシステイン残基による多様なストレス感知機構

    鈴木隆史, 山本雅之

    第89回日本生化学会大会　2016/09/25

  39. A novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice. International-presentation

    Higashi C, Hayashi M, Tsuda N, Kawaji A, Nakao K, Satoh F, Nakamura M, Furusako S, Saito R, Suzuki T, Uruno A, Yamamoto M

    32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis　2016/09/14

  40. Keap1の反応性システイン残基による多様なストレス感知機構

    鈴木隆史, 山本雅之

    第69回日本酸化ストレス学会学術集会　2016/08/30

  41. Protein 19F Labeling Strategy for In-Cell NMR and Functional Analyses. International-presentation

    Seizo Koshiba, Satoru Watanabe, Masaomi Ikari, Natsuko Matsuda, Tatsuo Iso, Tatafumi Suzuki, Masayuki Yamamoto, Tananori Kigawa

    XXVIIth ICMRBS　2016/08/21

  42. Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response. International-presentation

    Suzuki T, Saito R, Hiramoto K, Asami S, Naganuma E, Suda H, Iso T, Yamamoto H, Morita M, Baird L, Furusawa Y, Negishi T, Ichinose M, Yamamoto M

    The 9th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide, and the 16th Annual Scientific Meeting of the Nitric Oxide Society of Japan　2016/05/20

  43. AhR activation induces atopic dermatitis. International-presentation

    Takanori Hidaka, Eri Kobayashi, Takafumi Suzuki, Taku Fujimura, Setsuya Aiba, Masayuki Yamamoto

    The 26th Annual Meeting of Korean Society for Investigative Dermatology,　2016/03/25

  44. Air pollution activates Aryl hydrocarbon receptor of un-differentiated keratinocytes, leading to Atopic dermatitis-like pathologiesn. International-presentation

    Takanori Hidaka, Eri H Kobayashi, Takafumi Suzuki, Masayuki Yamamoto

    46th Annual Meeting of the European Society for Dermatological Research.　2016/03/25

  45. Keap1-Nrf2系による生体防御機構

    Takafumi SUZUKI

    第64回脳研・高度先進合同セミナー　2015/04/23

  46. Myeloid-specific transcriptional regulation by Nrf2. International-presentation

    Eri H. Kobayashi, Takafumi Suzuki, Masayuki Yamamoto

    The Keap1/Nrf2 Pathway in Health and Disease.　2015/01/06

  47. Keap1 Cys273 and Cys288 are functional sensors for 15d-PGJ2 to activate Nrf2 signaling. International-presentation

    Takafumi Suzuki, Ryota Saito, Kei-ichiro Hiramoto, Tatsuro Iso, Masayuki Yamamoto

    The Keap1/Nrf2 Pathway in Health and Disease.　2015/01/06

  48. Multiple Sensor Mechanism of the Keap1-Nrf2 System. International-presentation

    Takafumi Suzuki, Kai Takaya, Ryota Saito, Keiichiro Hiramoto, Tatsuro Iso, Masayuki Yamamoto

    Symposium for young ubiquitin researchers in Japan “New Era in the Ubiquitin Research”　2014/11/11

  49. Myeloid-specific transcription by Nrf2. International-presentation

    Eri H. Kobayashi, Takafumi Suzuki, Masayuki Yamamoto

    The Environmental Response IV.　2014/02/28

  50. Myeloid lineage-specific deletion of antioxidant system enhances tumor metastasis to the lung. International-presentation

    Keiichiro Hiramoto, Hironori Satoh, Takafumi Suzuki, Takashi Moriguchi, Tooru Shimosegawa, Masayuki Yamamoto

    The Environmental Response IV.　2014/02/28

  51. Regulatory Nexus of Synthesis and Degradation Deciphers Cellular Nrf2 Expression Levels. International-presentation

    Suzuki T, Shibata T, Takaya K, Shiraishi K, Kohno T, Hunitoh H, Tsuta K, Furuta K, Goto K, Hosoda F, Sakamoto H, Motohashi H, Yamamoto M

    The Environmental Response IV　2014/02/28

  52. Keap1-Nrf2システムの活性制御機構

    新学術領域「ユビキチンネオバイオロジー」平成25年度第２回班会議　2013/12/11

  53. Regulatory Nexus of Synthesis and Degradation Deciphers Cellular Nrf2 Expression Levels.

    鈴木隆史, 柴田龍弘, 高屋快, 本橋ほづみ, 山本雅之

    第86回日本生化学会大会　2013/09/11

  54. ストレスセンサーKeap1のユビキチンライゲース活性制御機構の解明

    新学術領域「ユビキチンネオバイオロジー」平成25年度第１回班会議　2013/07/26

  55. 転写因子Nrf2の舌癌予防効果

    大越明, 鈴木隆史, 小林俊光, 山本雅之

    第61回日本耳鼻咽喉科学会東北地方連合学術講演会　2013/07/20

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  56. Regulatory Nexus of Synthesis and Degradation Deciphers Cellular Nrf2 Expression Levels. International-presentation

    Takafumi Suzuki, Tatsuhiro Shibata, Kai Takaya, Hozumi Motohashi, Masayuki Yamamoto

    The 35rd NAITO conference on The Ubiquitin-Proteasome System, From Basic Mechanisms to Pathophysiological Roles,　2013/07/09

  57. Keap1-Nrf2システムによる酸化ストレス防御機構

    第31回Kidney, Hypertension & Endocrine Seminar　2013/05/27

  58. ミエロイド系細胞における酸化ストレス防御機構破綻ががん転移に及ぼす影響

    平本圭一郎, 佐藤大希, 鈴木隆史, 山本雅之

    平成24年度「個体レベルでのがん研究支援活動」公開シンポジウム　2013/02/06

  59. Aryl Hydroxarbon Receptorを介した大気汚染物質によるアトピー性皮膚炎の発症機序

    日高高徳, 小林枝里, 鈴木隆史, 相場節也, 山本雅之

    第6回リトリート大学院生研究発表会　2013/01/19

  60. ミエロイド系細胞における酸化ストレス防御機構破綻ががん転移に及ぼす影響

    平本圭一郎, 佐藤大希, 鈴木隆史, 山本雅之

    第6回リトリート大学院生研究発表会　2013/01/19

  61. 特定のヘテロ型Keap1変異体は野性型Keap1に対してドミナントネガティブに働く

    鈴木隆史, Jonathan Maher, 山本雅之

    第71回日本癌学会学術総会　2012/09/19

  62. がん微小環境における酸化ストレス防御機構の意義

    鈴木隆史

    新学術領域研究「がん微小環境ネットワークの統合的研究」班会議　2012/07/05

  63. In vivo validation of the multiple sensing mechanism of the Keap1-Nrf2 system. International-presentation

    Takafumi Suzuki, Kai Takaya, Hozumi Motohashi, Thomas W Kensler, Masayuki Yamamoto

    The 33rd NAITO conference on Oxygen Biology: Hypoxia, Oxidative stress and Diseases　2012/06/26

  64. Select heterozygous Keap1 mutations have a dominant-negative effect on wild-type Keap1 in vivo.

    鈴木隆史, Jonathan Maher, 山本雅之

    第78回日本生化学会東北支部例会　2012/05/26

  65. 4NQO誘発舌がんにおけるKeap1-Nrf2系の役割

    大越明, 鈴木隆史, 小林俊光, 山本雅之

    第147回日本耳鼻咽喉科学会宮城県地方部会学術講演会　2012/03/18

  66. トランスジェニックマウスを用いたKeap1-Nrf2システムの機能解析

    鈴木隆史, 山本雅之

    東北大学Network Medicine GCOE冬の合宿2012　2012/02/04

  67. 含セレン蛋白質とNrf2による酸化ストレス防御機構の脳発達時期における役割

    大越明, 鈴木隆史, 西島維知子, 山本雅之

    第34回日本分子生物学会年会　2011/12/13

  68. Select heterozygous Keap1 mutations have a dominant-negative effect on wild-type Keap1 in vivo. International-presentation

    Takafumi Suzuki, Jonathan Maher, Masayuki Yamamoto

    16th World Congress on Advances in Oncology and 14th International Symposium on Molecular Medicine　2011/10/06

  69. マウス遺伝学解析に基盤とするKeap1-Nrf2システムの解明

    山本雅之, 鈴木隆史, 田口恵子, 本橋ほづみ

    第70回日本癌学会学術総会　2011/10/03

  70. Keap1による多様なストレス感知機構の実証

    高屋快, 鈴木隆史, 山本雅之

    第84回日本生化学会　2011/09/21

  71. Keap1による多様なストレス感知機構

    高屋快, 鈴木隆史, 本橋ほづみ, 山本雅之

    新学術領域研究「活性酸素シグナル」第６回班会議　2011/05/14

  72. Complementary Contribution of Nrf2 Gene Battery and Selenoproteins to Antioxidative Stress Response International-presentation

    Takafumi Suzuki

    Seminar of School of Biochemistry and Immunology Trinity College Dublin　2011/01/27

  73. Complementary contribution of Nrf2 gene battery and selenoproteins to antioxidative stress response. International-presentation

    Masayuki Yamamoto, Takafumi Suzuki, Yukie Kawatani, Vincent Kelly

    9th international Symposium on Selenium in Biology and Medicine Selenium 2010.　2010/05/31

  74. Deletion of selenocysteine tRNA gene results in compensatory gene induction of cytoprotective enzymes by Nrf2. International-presentation

    Takafumi Suzuki, Yukie Kawatani, Akira Okoshi, Vincent Kelly, Masayuki Yamamoto

    9th international Symposium on elenium in Biology and Medicine Selenium 2010.　2010/05/31

  75. Hematopoietic deficiency of Nrf2 and selenoproteins leads to severe defects in erythrocytes and lymphocytes. International-presentation

    Yukie Kawatani, Takafumi Suzuki, Vincent Kelly, Masayuki Yamamoto

    9th international Symposium on elenium in Biology and Medicine Selenium 2010.　2010/05/31

  76. Cytoprotective systems of skin by selenoproteins and Nrf2. International-presentation

    Mariko Takayama, Takafumi Suzuki, Kai Takaya, Ryuhei Okuyama, Masayuki Yamamoto

    9th international Symposium on elenium in Biology and Medicine Selenium 2010.　2010/05/31

  77. 含セレン蛋白質とNrf2による酸化ストレスに対する２段階防御

    山本雅之, 鈴木隆史, 川谷幸恵, 大越明, ケリー・ビンセント

    日本生化学会大会　2009/10/21

  78. 含セレン蛋白質とNrf2による２段階生体防御機構

    鈴木隆史, 川谷幸恵, 大越明, Vincent Kelly, 山本雅之

    日本生化学会大会　2009/10/21

  79. Nrf2-Keap1ストレス応答系は両刃の剣：発癌支持作用と化学発癌予防作用

    山本雅之, 柴田龍弘, 太田力, Kit Tong, 黒河博文, 鈴木隆史, 田口恵子, 本橋ほづみ

    第６８回日本癌学会学術総会　2009/10/01

  80. 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

    第６８回日本癌学会学術総会　2009/10/01

  81. Double-edged Sword of the Nrf2-Keap1 Stress Response System; Carcinogenesis and Cancer Chemoprevention.

    Masayuki Yamamoto, Tatsuhiro Shibata, Ohta Tsutomu, Kit Tong, Hirofumi Kurokawa, Takafumi Suzuki, Keiko Taguchi, Hozumi Motohashi

    第68回 日本癌学会学術総会シンポジウム　2009/10/01

  82. Select heterozygous Keap1 mutations have a dominant-negative effect on wildtype Keap1 in vivo. International-presentation

    Takafumi Suzuki, Jonathan Maher, Yukie Kawatani, Masayuki Yamamoto

    International symposium 2009 on Signaling Functions of Reactive Oxygen Species　2009/06/18

  83. 生体におけるKeap1/Nrf2制御系の機能貢献と応答機構

    本橋ほづみ, 藤田理恵, 鈴木隆史, Kit Tong, 黒河博文, 山本雅之

    第62回日本酸化ストレス学会　2009/06/11

  84. 含セレン蛋白質とNrf2による２段階生体防御機構

    鈴木隆史, 川谷幸恵, Vincent Kelly, 山本雅之

    第62回日本酸化ストレス学会　2009/06/11

  85. Select heterozygous Keap1 mutations have a dominant-negative effect on wild type Keap1 in vivo International-presentation

    Takafumi Suzuki, Jonathan Maher, Yukie Kawatani, Masayuki Yamamoto

    JST-international symposium “Molecular Mechanism of Environmental Response to Food and Oxygen III”　2009/02/09

  86. Clara-cell specific Keap1 conditional knockout mice have pulmonary hyperkeratosis and hyperplasia, and are sensitive to bleomycin-induced lung Injury International-presentation

    Jonathan Maher, Takafumi Suzuki, Keiko Taguchi, Yukie Kawatani, Momoko Kimura, Hozumi Motohashi, Jeffrey Whitsett, Masahito Ebina, Yukio Ishii, Masayuki Yamamoto

    JST-international symposium “Molecular Mechanism of Environmental Response to Food and Oxygen III”　2009/02/09

  87. Deletion of selenocysteine tRNA gene results in compensatory gene induction of cytoprotective enzymes by Nrf2 International-presentation

    Yukie Kawatani, Takafumi Suzuki, Vincent Kelly, Masayuki Yamamoto

    JST-international symposium “Molecular Mechanism of Environmental Response to Food and Oxygen III”　2009/02/09

  88. Keap1変異体によるドミナントネガティブ効果のトランスジェニックレスキュー法を用いた検証

    鈴木隆史, Jonathan Mahe, 川谷幸恵, 山本雅之

    日本分子生物学会　2008/12/09

  89. 転写因子Nrf2の恒常的活性化による組織学的変化

    田口恵子, Jonathan, M. Mahe, 川谷幸恵, 鈴木隆史, 山本雅之

    2008年度がん若手ワークショップ　2008/09/03

  90. Deletion of Selenocysteine tRNA Gene in macrophages and liver results in compensatory gene induction of cytoprotective enzymes by Nrf2

    鈴木隆史

    第二回セレン研究会　2008/08/04

  91. SeCys-tRNA遺伝子条件付き遺伝子破壊マウスを用いた造血幹細胞におけるNrf2の生理的意義

    川谷幸恵, 鈴木隆史, Vincent Kelly, 山本雅之

    第二回セレン研究会　2008/08/04

  92. トランスジェニックレスキュー法を用いたKeap1変異体によるドミナントネガティブ効果の検証

    鈴木隆史, Jonathan Mahe, 山本雅之

    遺伝情報DECODE平成２０年度合同班会議　2008/06/30

  93. SeCys-tRNA遺伝子条件付き破壊マウスを用いた造血組織におけるNrf2の生理的意義

    川谷幸恵, 鈴木隆史, Vincent Kelly, 山本雅之

    遺伝情報DECODE平成２０年度合同班会議　2008/06/30

  94. Clara-cell specific Keap1 conditinal knockout mice have strong Nrf2 activation but are sensitive to bleomycin-induced lung injury. International-presentation

    Jonathan Maher, Takafumi Suzuki, Keiko Taguchi, Yukie Kawatani, Hozumi Motohashi, Yukio Ishii, Masayuki Yamamoto

    The 21st NAITO conference on Nuclear Dynamics and RNA [I]　2008/06/24

  95. Phenotypic analyses of constitutive Nrf2 activation by partially disruption of Keap1 International-presentation

    Keiko Taguchi, Martin Y. Pfeiffer, Jonathan M. Maher, Yukie Kawatani, Takafumi Suzuki, Masayuki Yamamoto

    Environmental Response Project International Symposium “The Enviromental Response” in Tsukuba　2007/12/21

  96. Deciphering Key Reactive Cysteines that Determine Nrf2 Activation In Vivo. International-presentation

    Takafumi Suzuki, Tae Yamamoto, Akira Kobayashi, Junko Wakabayashi, Jonathan Maher, Hozumi Motohashi, Masayuki Yamamoto

    The 2nd JST-ERATO Yamamoto Environmental Response Project International Symposium “The Enviromental Response” in Tsukuba　2007/12/21

  97. Hematopoietic Cell Differentiation in SeCys tRNA Gene Conditional Knockout Mice. International-presentation

    Yukie Kawatani, Takafumi Suzuki, Vincent Kelly, Susumu Nishimura, Masayuki Yamamoto

    The 2nd JST-ERATO Yamamoto Environmental Response Project International Symposium “The Enviromental Response” in Tsukuba　2007/12/21

  98. Clara-Cell Specific Keap1 Conditional Knockout Mice have strong Nrf2 Activation but are Sensitive to Bleomycin-induced lung Injury. International-presentation

    Jonathan Maher, Takafumi Suzuki, Keiko Taguchi, Yukie Kawatani, Hozumi Motohashi, Yukio Ishii, Masayuki Yamamoto

    The 2nd JST-ERATO Yamamoto Environmental Response Project International Symposium “The Enviromental Response” in Tsukuba　2007/12/21

  99. Clara-Cell Specific Keap1 Conditional Knockout Mice have strong Nrf2 Activation but are Sensitive to Bleomycin-induced lung Injury. International-presentation

    Jonathan Maher, Takafumi Suzuki, Keiko Taguchi, Yukie Kawatani, Hozumi Motohashi, Yukio Ishii, Masayuki Yamamoto

    The 8 th International ISSX Meeting in Sendai　2007/10/09

  100. Deletion of the Selenocysteine tRNA Gene (Trsp) in Macrophage and Liver Results in Compensatory Gene Induction of Cytoprotective Enzymes by the Nrf2 Transcription Factor International-presentation

    Takafumi Suzuki, Vincent P. Kelly, Osamu Nakajima, Satoru Takahashi, Hozumi Motohashi, Susumu Nishimura, Masayuki Yamamoto

    The 8th AEARU Joint Workshop on Life Sciences　2006/11/04

  101. Molecular Mechanisms of Nrf2-Keap1 Response against Oxidative and Electrophilic Stresses. International-presentation Invited

    Masayuki Yamamoto, Kit I. Tong, Akira Kobayashi, Takafumi Suzuki, Tae Yamamoto, Hozumi Motohashi, Ken Itoh

    The 20th IUBMB Congress and 11th FAOBMB Congress　2006/06/18

  102. Molecular Mechanisms of Nrf2-Keap1 Response against Oxidative and Electrophilic Stress. International-presentation Invited

    Masayuki Yamamoto, Kit Y. Tong, Akira Kobayashi, Takafumi Suzuki, Tae Yamamoto, Hozumi Motohashi, Ken Itoh

    20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress　2006/06/18

  103. Functional Analysis of Keap1 in vivo as a Electrophile-Responsive Regulator of Nrf2. International-presentation

    Takafumi Suzuki, Tae Yamamoto, Akira Kobayashi, Hozumi Motohashi, Masayuki Yamamoto

    The 1st Asia Pacific ISSX Meeting　2006/06/18

  104. Players Regulating and Supporting Cytoprotective Function of Nrf2. International-presentation Invited

    Hozumi Motohashi, Takafumi Suzuki, Hiromi Okawa, Kit tong, Fumiki Katsuoka, Akira Kobayashi, Masayuki Yamamoto

    The 1st Asia Pacific ISSX Meeting　2006/05/24

  105. Regulation by Nrf2-Keap1 System of Cellular Defense Mechanisms against Electrophiles and Carcinogenesis. International-presentation Invited

    Masayuki Yamamoto, Takafumi Suzuki, Kit Y. Tong, Akira Kobayashi

    CNIO Cancer Conference on "Inflammation and Cancer"　2006/05/22

  106. Transgenic complementation analysis of Nrf2-Keap1 system regulating cellular defense mechanisms against electrophiles and reactive oxygen species. International-presentation Invited

    Masayuki Yamamoto, Takafumi Suzuki, Tae Yamamoto, Hiromi Okawa, Hozumi Motohashi

    HUGO Asia-Pacific 06; Animal Models of Human Diseases　2006/03/06

  107. Macrophage-specific disruption of selenocysteine tRNA gene revealed Nrf2-mediated compensatory mechanisms. International-presentation

    Takafumi Suzuki, Vincent Kelly, Osamu Nakajima, Hozumi Motohashi, Susumu Nishimura, Masayuki Yamamoto

    JST-ERATO Yamamoto Environmental Response Project International Symposium　2005/03/10

  108. Transcriptional regulation of zebrafish GSTP gene. International-presentation

    Takafumi Suzuki, Yaeko Takagi, Hitoshi Osanai, Makoto Kobayashi, Masayuki Yamamoto

    JBS Bio-Frontier Symposium 2003　2003/06/05

  109. Identification of the phylogenic conservation of the Nrf2-Keap1 system regulating detoxification and antioxidant enzymes. International-presentation

    Makoto Kobayashi Ken Itoh, Takafumi Suzuki, Hitoshi Osanai, Keizo Nishikawa, Yasutake Katoh, Yaeko Takagi, Masayuki Yamamoto

    5th International Conference on Zebrafish Development & Genetics　2002/06/12

  110. Gene regulation of the zebrafish Six4 in the cranial sensory placodes International-presentation

    Makoto Kobayashi, Takafumi Suzuki, Masayuki Yamamoto

    14th International Congress of Development Biology　2001/07/08

  111. Squamous cell carcinogenesis elicited by NRF2L30F plus Trp53R172H mutations.

    Jun Takahashi, Takafumi Suzuki, Miu Sato, Shuji Nitta, Nahoko Yaguchi, Tatsuki Muta, Masayuki Yamamoto

    The Environmental Response VI, Sendai, Japan

  112. Compensatory activation of Nrf2 in Selenoprotein Deficiency Requires Keap1 Cys226/Cys613 Residues.

    Miu Sato, Nahoko Yaguchi, Takafumi Suzuki, Masayuki Yamamoto

    The Environmental Response VI, Sendai, Japan

  113. NRF2 activation improves experimental rheumatoid arthritis.

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

    The Environmental Response VI, Sendai, Japan

  114. NRF2 activation improves experimental rheumatoid arthritis.

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

    The Environmental Response VI, Sendai, Japan

  115. Molecular basis of stress response by the KEAP1-NRF2 system.

    Takafumi SUZUKI, Tatsuro Iso, Jun Takahashi, Anqi Zhang, Huaichun Wen, Miu Sato, Shuji Nitta, Takuya Iijima, Nahoko Yaguchi, Aki Muramatsu, Ryota Saito, Masayuki Yamamoto

    The Environmental Response VI, Sendai, Japan

  116. Molecular basis of stress response by the KEAP-1NRF2 system.

    Takafumi Suzuki, Masayuki Yamamoto

    The Environmental Response VI, Sendai, Japan

  117. Nrf2 activation improves experimental rheumatoid arthritis

    Anqi Zhang, 鈴木 隆史, 安達 紗希, 吉田 瑛紀, 山本 雅之

    第96回日本生化学会大会

  118. 含セレン抗酸化酵素欠失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

    佐藤 美羽, 矢口 菜穂子, 鈴木 隆史, 山本 雅之

    第96回日本生化学会大会

  119. 含セレン抗酸化酵素欠失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

    佐藤 美羽, 矢口 菜穂子, 鈴木 隆史, 山本 雅之

    第96回日本生化学会大会

  120. NRF2活性化型食道扁平上皮癌マウスモデルの確立とその解析

    高橋 洵, 牟田 達紀, 佐藤 美羽, 矢口 菜穂子, 鈴木 隆史, 大沼 忍, 石田 孝宣, 海野 倫明, 亀井 尚, 山本 雅之

    第82回 日本癌学会学術総会

  121. Keap1 Cys226/Cys613 Residues are Required for Compensatory Activation of Nrf2 in Selenoprotein Deficiency.

    Miu Sato, Nahoko Yaguchi, Takafumi Suzuki, Masayuki Yamamoto

    Se2023 Internatinal Conference, KAIST, Daejeon, Korea, June 26-29, 2023 (Poster, Abstract p.122)

  122. Complementary Contribution of Nrf2 and Selenoproteins to Antioxidative Stress Response.

    Takafumi Suzuki, Miu Sato, Nahoko Yaguchi, Masayuki Yamamoto

    Se2023 Internatinal Conference, KAIST, Daejeon, Korea

  123. NRF2活性化食道扁平上皮癌マウスモデルの作製と解析

    高橋 洵, 牟田 達紀, 佐藤 美羽, 矢口 菜穂子, 鈴木 隆史, 山本 雅之

    日本生化学会 東北支部 第89回例会・シンポジウム

  124. 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

    第76回日本酸化ストレス学会学術集会

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Research Projects 45

  1. 宇宙が映す生命：スタディセクション（総括班）

    村谷 匡史, 柴 綾, 暮地本 宙己, 東谷 篤志, 藤田 知道, 高橋 智, 篠原 正浩, 秋山 泰身, 鈴木 隆史, 高橋 昭久, 吉田 圭介, 笹倉 靖徳, 笹原 信一朗

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 学術変革領域研究(A)

    Institution: 筑波大学

    2025/04/01 - 2030/03/31

  2. 宇宙環境ストレス応答の理解から挑む加齢性疾患の克服

    鈴木 隆史

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 学術変革領域研究(A)

    Institution: 東北大学

    2025/04/01 - 2030/03/31

  3. 宇宙マウス研究から健康長寿社会の実現に向けて

    山本雅之, 高橋智, 研究分担, 鈴木隆史

    Offer Organization: JAXA

    System: JAXA「きぼう」船内利用フラッグシップミッション

    Institution: JAXA

    2024 - 2029

  4. KEAP1-NRF2制御系による多様な環境ストレス感知機構の分子基盤解明

    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(B)

    Institution: 東北大学

    2025/04/01 - 2028/03/31

  5. KEAP1-NRF2系の機能回復による新規薬物療法の開発

    Offer Organization: 公益財団法人 小林がん学術振興会

    System: 先駆的研究（１）助成金

    2025/04 - 2026/03

  6. ファイトケミカル感知と生体防御機構の分子基盤の解明

    Offer Organization: 公益財団アサヒグループ財団

    System: 2025年度学術研究助成

    2025/04 - 2026/03

  7. NRF2活性化扁平上皮癌の悪性化機構解明と新規治療法開発

    鈴木隆史

    Offer Organization: 公益財団法人 高松宮妃癌研究基金

    System: 令和6年度研究助成金

    2025/04 - 2026/03

  8. KEAP1変異腺癌が高頻度に発生する機序の解明

    Offer Organization: 公益財団法人安田記念医学財団

    System: 癌研究助成金

    2025/01 - 2025/12

  9. Keap1-Nrf2制御系によるストレス応答の動的構造基盤の解明

    鈴木 隆史

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 基盤研究(C)

    Category: 基盤研究(C)

    Institution: 東北大学

    2022/04/01 - 2025/03/31

  10. Development of Adverse Events-free Local Anesthetics in Cryo-EM Structural Determination of Sodium Channels

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)

    Category: Grant-in-Aid for Challenging Research (Exploratory)

    Institution: Tohoku University

    2021/07/09 - 2024/03/31

  11. 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 Grant-in-Aid for Scientific Research (S)

    Category: Grant-in-Aid for Scientific Research (S)

    Institution: Tohoku University

    2019/06/26 - 2024/03/31

  12. 生体防御機能強化による宇宙ストレス克服法の開発

    代表:山本雅之

    Offer Organization: JAXA

    System: JAXA「きぼう」利用フィジビリティスタディ

    2019 - 2024

  13. 生体防御機構Keap1-Nrf2システムの活性制御メカニズムの解明

    Offer Organization: 公益財団法人ライフサイエンス振興財団

    System: 研究開発助成

    2023/04 -

  14. 宇宙研究からアプローチする適応・進化の理解と地球生命の未来予測

    Offer Organization: TIA連携プログラム探索推進事業 「かけはし」

    2022/04 - 2023/03

  15. Regulation of transcription factor Nrf2 activity by the stress sensor Keap1

    Suzuki Takafumi

    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

    2019/04/01 - 2022/03/31

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    Disruption of the response system to oxidative stress is closely related to the development of various diseases. To prevent such diseases, cells respond rapidly to oxidative stress and maintain homeostasis. The stress sensor Keap1 regulates the ubiquitination of the transcription factor Nrf2 and is a key factor that plays a central role in the oxidative stress defense mechanism. In this study, we aimed to identify the reactive oxygen species sensor of Keap1 and elucidate its physiological function, as well as the molecular basis of Nrf2 activation in the oxidative stress response. Furthermore, we aimed to elucidate the molecular mechanism of oxidative stress response by the Keap1-Nrf2 regulatory system through structure-function linkage analysis.

  16. 転写因子NRF2による扁平上皮がん悪性化機構の解明 Competitive

    鈴木隆史

    Offer Organization: 公益財団法人がん研究振興財団

    System: 第５４回がん研究振興財団 がん研究助成金（課題A）

    2022/01 -

  17. NRF2変異体発現扁平上皮がんモデルマウスの開発とがん悪性化機構の解明 Competitive

    鈴木隆史

    Offer Organization: 公益財団法人鈴木謙三記念医科学応用研究財団

    System: 令和３年度調査研究助成金

    Category: 助成課題２ 生活習慣病における医学、薬学の萌芽的研究

    2021/11 -

  18. 生体防御機構Keap1-Nrf2システムの活性制御メカニズムの解明

    鈴木隆史

    Offer Organization: 武田科学振興財団

    System: 医学系研究継続助成

    Institution: 東北大学大学院医学系研究科

    2020/04 - 2021/03

  19. Regulation of transcription factor Nrf2 activity by the stress sensor Keap1

    SUZUKI Takafumi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)

    Institution: Tohoku University

    2018 - 2021

    More details Close

    Nrf2 is a transcription factor that acts as defense system by regulating a group of genes involved in oxidative stress and xenobiotic metabolism. Keap1 functions as a sensor molecule and stops the ubiquitination reaction of Nrf2 when Keap1 senses oxidative stress. Stabilized Nrf2 accumulates in the nucleus and activates transcription of various target genes. In this study, we aim to elucidate the molecular basis of Nrf2 activation in the stress response, especially the regulation mechanism of ubiquitination by Keap1.

  20. Nrf2誘導剤による関節リウマチ緩和効果の検討 Competitive

    鈴木隆史

    Offer Organization: 公益財団法人 持田記念医学薬学振興財団

    System: 研究助成

    2021 -

  21. NRF2変異による扁平上皮がん悪性化機構の解明 Competitive

    鈴木隆史

    Offer Organization: 艮陵医学振興会

    System: 医学研究助成 研究B

    2021 -

  22. 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 基盤研究(A)

    Category: 基盤研究(A)

    Institution: 東北大学

    2019/04/01 - 2020/03/31

    More details Close

    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。

  23. 宇宙ストレス克服を目指した転写因子Nrf2の生理機能解析

    鈴木 隆史

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 新学術領域研究(研究領域提案型)

    Category: 新学術領域研究(研究領域提案型)

    Institution: 東北大学

    2018/04/01 - 2020/03/31

    More details Close

    酸化ストレスや外来毒物など地上での環境由来ストレスに対して、転写因子Nrf2が抗酸化・異物代謝に関わる遺伝子群の発現を誘導して、生体の恒常性維持に貢献する。Nrf2は、通常はユビキチンE3リガーゼであるKeap1によりユビキチン化され、プロテアソームにより迅速に分解されている。また、Keap1はストレスセンサーとしても機能し、ストレスを感知するとNrf2ユビキチン化を停止する。それにより安定化したNrf2は核内に蓄積して、生体防御酵素群の遺伝子の転写を活性化する。実際に、Nrf2欠失マウスは酸化ストレスによるダメージに脆弱になることから、Nrf2活性化は宇宙環境ストレスに対して防御的に働くものと予想され、Nrf2誘導剤がその予防に有効であると期待される。このような研究から、Nrf2活性化は宇宙ストレス克服の有効な手段になる可能性が高いと考え、それを検討・実証する目的で本研究の着想に至った。 JAXAが公募した国際宇宙ステーション（ISS）「きぼう」フィジビリティスタディに採択され、私たちはNrf2欠失マウスのISS長期滞在実験を進めた。2018年4月2日に野生型マウスおよびNrf2欠失マウスそれぞれ雄6匹ずつを打ち上げ、ISS「きぼう」に搭乗させた。約30日間の軌道上滞在を終え、5月6日に12匹全匹生存して帰還した。行動解析およびヘルスチェック後に解剖を行いサンプリングを行った。 野生型に比べてNrf2欠失マウスは軌道上飼育前後の体重増加率が有意に低下していた。軌道上での摂餌量は両者で有意な差はなかったことから、Nrf2欠失によってエネルギー代謝に影響が現れたものと考えられた。このことは、宇宙環境ストレスに対してNrf2欠失マウスが脆弱であることを示す。地上対照実験を2018年10月にJAXA筑波において実施し、軌道上実験と同様にサンプルを取得し現在解析を進めている。

  24. ストレスセンサーKeap1による転写因子Nrf2活性制御機構の解明 Competitive

    鈴木 隆史

    Offer Organization: 文科省科研費

    System: 国際共同研究加速基金

    2018 - 2020

  25. 宇宙ストレスにおける環境応答型転写因子Nrf2の役割 Competitive

    山本雅之

    Offer Organization: JAXA

    System: 「きぼう」利用フィジビリティスタディ

    2015 - 2020

  26. Stress Sensor Mechanism by the Keap1-Nrf2 System

    Suzuki Takafumi, YAMAMOTO Masayuki, ISO Tatsuro, MURAMATSU Aki, SAITO Ryota, BAIRD Liam, SUDA Hiromi, MORITA Masanobu

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Tohoku University

    2017/04/01 - 2019/03/31

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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 eleven cysteine residues retains the ability to target Nrf2 for degradation, but is unable to respond to cysteine-reactive Nrf2 inducers. Of the eleven mutated cysteine residues, we found that four are important for sensing hydrogen peroxide. Our analyses revealed that Keap1 utilizes 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. Importantly, 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.

  27. An investigation into the mechanism regulating the oxidative stress-dependent activation of the Keap1-Nrf2 pathway

    Baird Liam, Yamamoto Masayuki, Suzuki Takafumi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Tohoku University

    2016/04/01 - 2019/03/31

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    The Keap1-Nrf2 pathway is the body’s principle inducible defense against electrophilic and oxidative stress, and as such plays an important role in cellular homeostasis and human health. In order to study the molecular mechanism of Keap1-dependent Nrf2 regulation, I used a new mouse model of Nrf2 activation, in which the weak binding DLG motif has been mutated into an additional ETGE motif, which binds tightly to Keap1. Analysis of this mouse revealed no change in the oxidative stress response, suggesting that the release of the DLG motif is not required for Nrf2 activation in response to electrophilic inducers. This approach was complemented by in vitro studies of the Keap1-Cul3 complex, which revealed that the majority of Nrf2 inducers do not impact the composition of the Keap1-Cul3 complex.

  28. Elucidation of redox regulatory mechanisms by transcription factor network

    Itoh Ken

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Institution: Hirosaki University

    2014/07/10 - 2019/03/31

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    We identified the strong physical interaction between Nrf2 and ATF4, and demonstrated that they cooperatively regulates gene expression of a set of cytoprotective genes. We also showed that GCN1L1 regulates cell cycle and embryonic development in a GCN2-independent manner as well as GCN2-dependent amino acid starvation and UV response. We also demonstrated thata Keap1 senses a variety of stresses by using multiple cysteine residues and consequently, Nrf2 inducers can be classified into at least 5 subclasses. We also identified novel regulators of proteasome and an Nrf1 activator during proteasome inhibition.

  29. 宇宙ストレス克服を目指した転写因子Nrf2の生理機能解析 Competitive

    鈴木 隆史

    Offer Organization: 文科省科研費

    System: 新学術領域研究

    2018 - 2019

  30. 酸素ストレス感受性転写因子ネットワークによる生体内レドックス環境調節機構の解明 Competitive

    伊東健

    Offer Organization: 文科省科研費

    System: 新学術領域研究

    2014 - 2019

  31. 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 Grant-in-Aid for Scientific Research (B)

    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.

  32. Keap1-Nrf2系によるストレス感知機構の解明 Competitive

    鈴木 隆史

    Offer Organization: 文科省科研費

    System: 若手研究B

    2017 - 2018

  33. ストレスセンサーKeap1によるNrf2活性調節分子機構 Competitive

    鈴木 隆史

    Offer Organization: 武田科学振興財団

    System: 医学系研究助成（基礎）

    2018 -

  34. 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 Grant-in-Aid for Scientific Research (C)

    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.

  35. ストレス応答型転写因子Nrf2の新規生理機能の発見 Competitive

    鈴木 隆史

    Offer Organization: 文科省科研費

    System: 基盤研究C

    2014 - 2016

  36. ストレスセンサーKeap1のユビキチンライゲース活性制御機構の解明

    鈴木 隆史

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 新学術領域研究(研究領域提案型)

    Category: 新学術領域研究(研究領域提案型)

    Institution: 東北大学

    2013/04/01 - 2015/03/31

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    ストレスセンサーKeap1は転写因子Nrf2のユビキチン化反応を制御し酸化ストレス防御機構の中心的役割を担う鍵因子である。申請者らの研究成果からKeap1-Nrf2システムは多様なストレス刺激に応答してユビキチン化反応を制御すること、またその制御機構として「閂と蝶番モデル」を提唱した。しかし、その実証は未だ不十分である。本研究はこの成果を発展させ、ストレスセンサーKeap1によるユビキチンリガーゼ活性制御機構の解明によりNrf2活性化メカニズムを明らかにすることを目的とする。まず、閂と蝶番モデルを実証するために、ダブル蝶番Nrf2分子を創出し機能的実証を試みた。ダブル蝶番Nrf2分子の安定発現株の作成に成功したが、これまでの解析では野生型Nrf2とのストレス応答の違いは見出されていない。ダブル蝶番Nrf2分子のノックインマウスの作製にも成功したので、個体レベルの解析から「閂と蝶番モデル」の検証を今後行いたい。また、センサーシステイン残基の使い分けを実証するために各種システイン残基変異体を作製し検証を行った。その結果、C288がプロスタグランジンに対するセンサーとして機能的に働くことを示すことに成功した。さらに、ストレス感知不全Keap1分子を創出するために、Keap1分子のシステイン残基について様々な組み合わせ変異を導入することを試みた結果、Nrf2抑制能を保持したままKeap1分子上の約半数のシステイン残基を欠失した変異分子を創出することに成功した。今後、このKeap1変異分子の解析を行い、システイン残基に依存しない新たなタイプのNrf2誘導剤の探索を行う。以上の解析結果は、Keap1分子のユビキチン化反応制御機構の理解につながると期待される。

  37. 非小細胞性肺がんを標的とするNrf2活性阻害剤’Chemo-sensitizer’の開発 Competitive

    山本雅之

    Offer Organization: AMED

    System: 次世代がん研究シーズ戦略的育成プログラム

    2014 - 2015

  38. ストレスセンサーKeap1のユビキチンライゲース活性制御機構の解明 Competitive

    鈴木 隆史

    Offer Organization: 文科省科研費

    System: 新学術領域

    2013 - 2014

  39. がん微小環境における酸化ストレス防御機構の意義 Competitive

    鈴木 隆史

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 新学術領域研究(研究領域提案型)

    Category: 新学術領域研究(研究領域提案型)

    Institution: 東北大学

    2011/04/01 - 2013/03/31

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    含セレン酵素群および転写因子Nrf2は酸化ストレス防御機構の中心的役割を担う。研究開始前にNrf2ががん微小環境形成において重要な役割を担い転移抑制に働くことが示唆されていた。特に、全身Nrf2欠損マウスではがん細胞転移が促進することが示唆されたが、ミエロイド系細胞における活性酸素種シグナルの関与が考えられたが未だ詳細は不明であった。本研究ではこの成果を発展させ、がん微小環境における酸化ストレス防御機構の意義を明らかにすることを目的とした。平成２３年度にミエロイド系細胞特異的含セレン酵素群合成破綻マウスでは抑制性ミエロイド系細胞(MDSC)において活性酸素種の増加が見られ、がん転移が増加することがわかった。平成２４年度ではミエロイド系細胞特異的Nrf2遺伝子破綻マウス作製に成功した。このマウスのMDSCにおいても活性酸素種の増加が観察され、肺への転移が増加することが明らかになった。さらに、ミエロイド系細胞特異的含セレン酵素群およびNrf2の両者の二重欠損マウス作製にも成功した。この二重欠失マウスにおいては、さらに顕著な活性酸素種の増加およびがん転移の増加が観察された。以上の結果から、含セレン酵素群およびNrf2がミエロイド系細胞の活性酸素種レベルを調節することにより、そのがん抑制機能を制御することが明らかになった。この研究成果は、がん微小環境のミエロイド系細胞における酸化ストレス防御機構の意義の一端を明らかにするものである。この知見はミエロイド系細胞の活性酸素種レベルの制御、特に含セレン酵素群およびNrf2の活性制御を標的とした新たなががん転移の治療に非常に有益な情報を与えるものである。

  40. Generation of disease models for neurodegenerative disorders by deleting selenoprotein synthesis Competitive

    SUZUKI Takafumi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Tohoku University

    2010 - 2011

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    We generated disease models for neurodegenerative disorders by deleting selenoproteins, a major member of antioxidant enzymes. We have found that transcriptional factor Nrf2 activate in the selenoprotein-deficient neuronal tissue. In the absence of Nrf2, selenoprotein deficiency in neuronal tissue cause severe degenerative phenotype. These results reveal that selenoproteins are essential for maintaining homeostasis of neuronal tissue, and that Nrf2 has cytoprotective role against loss of selenorpoteins.

  41. The missing link between proliferation and oxidative stress regulation in hematopoietic stem cells Competitive

    MINEGISHI Naoko, SUZUKI Takahumi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Category: Grant-in-Aid for Scientific Research (C)

    2009 - 2011

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    Long-term dormancy in proliferation and strong defense response against oxidative stresses, prevent the senescence and tumorigenesis of hematopoietic stem cells. Here, we show that GATA2, a transcription factor essential for the life-long maintenance of hematopoietic stem cells, directly activates the transcription of several genes regulating cell proliferation, as well as genes regulating oxidative status. Furthermore, mice deficient in transcription factor Nrf2, which inclusively regulates oxidative stress response genes, show the different kinetics of hematopoietic stem/progenitor cells from wild type mice. These results indicate that cell proliferation and defense against oxidative stresses have shared regulatory components in hematopoietic stem cells.

  42. 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 Grant-in-Aid for Creative 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.

  43. Physiological function analysis of stress sensor Keap1 Competitive

    SUZUKI Takafumi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (Start-up)

    Category: Grant-in-Aid for Young Scientists (Start-up)

    Institution: Tohoku University

    2008 - 2009

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    In this study, we investigated the physiological function of stress sensor Keap1 by mouse genetics. We have found that partial repression of Keap1 leads to activation of transcriptional factor Nrf2, resulting in up-regulation of detoxifying enzymes and anti-oxidant proteins, which is effective for cytoprotection. We have further found that functional Keap1 homodimer is essential for Nrf2 repression, which is disrupted by stress stimuli.

  44. 生体防御遺伝子群の誘導機構の解析 Competitive

    鈴木隆史

    Offer Organization: 日本学術振興会

    System: 特別研究員（DC1）

    2004/04 - 2007/03

  45. 生体防御遺伝子誘導の分子メカニズムの解明

    鈴木 隆史

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特別研究員奨励費

    Category: 特別研究員奨励費

    Institution: 筑波大学

    2004 - 2006

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    酸化ストレス防御に働くグルタチオンペルオキシダーゼや、チオレドキシンン還元酵素などの酵素群は、セレン(Se)を含むタンパク質(Selenoprotein)である。そのため,Se欠乏状態では,Selenoprotein合成の不足から酸化ストレス応答機構の破綻が引き起こされる。一方、同状態では,グルタチオンS-転移酵素やキノンレダクターゼなど,転写因子Nrf2の標的遺伝子である生体防御遺伝子群が誘導されることから、Nrf2制御系による代償的生体防御機構が示唆された。これを明らかにするために,Se欠乏状態に類似したSelenoprotein群系全般の機能低下状態を創出し,Nrf2制御系の動態を検討した.SeはSelenocysteine(SeCys)残基として存在しており,Selenoproteinの合成にはSeCys-tRNAが必須なので,SeCys-tRNA遺伝子破壊により全Selenoproteinの欠失を試みた。しかしながら、同tRNAの完全欠損マウスは胎生3.5日で致死なので、生体におけるNrf2制御系の貢献を明らかにできなかった。そこで、Cre-loxPシステムを利用した条件付きSeCys-tRNA遺伝子破壊マウスを作製し、マクロファージあるいは肝細胞において特異的にSeCys-tRNA遺伝子を破壊した.その結果,Selenoproteinの減少,それに伴うNrf2制御系の活性化が、マクロファージあるいは肝細胞いずれにおいても観察された.これは,Selenoproteinの減少により細胞内酸化ストレスが増大し,それに応答してNrf2が活性化され、生体防御遺伝子群を誘導したものと考えられる.この結果から,酸化ストレス防御におけるSelenoprotein群系とNrf2制御系には機能的相互作用が存在することが確認された.

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Teaching Experience 5

  1. 保健学科検査技術科学専攻 卒業研究　東北大学医学部

  2. 高次修練　東北大学医学部

  3. 基礎修練　東北大学医学部

  4. 基礎ゼミ　東北大学医学部

  5. 医化学講義・実習　東北大学医学部

Social Activities 1

  1. 宇宙マウス実験からヒト健康・長寿研究への還元を目指して

    令和４年度東北地区国立大学法人等技術職員研修特別講演

    2022/09/06 -

Media Coverage 8

  1. 生体の巧妙な酸化ストレス防御の仕組みを解明し論文として発表しました

    https://www.megabank.tohoku.ac.jp/news/59336

    2024/09

    Type: Internet

  2. 食道扁平上皮がんにおいて生体防御遺伝子が高頻度に変異する原因を解明 Myself

    https://www.nikkei.com/article/DGXZRSP670625_Z10C24A4000000/

    2024/04/19

    Type: Internet

  3. ストレス対応で宇宙環境に身体をアジャスト！

    https://humans-in-space.jaxa.jp/kibouser/pickout/73107.html

    2021/10

    Type: Internet

  4. 宇宙長期滞在で加速する加齢変化を転写因子 Nrf2が食い止めることを発見

    https://www.nikkei.com/article/DGXLRSP540059_Z00C20A9000000/

    2020/09

    Type: Internet

  5. 酸化ストレスを感知する仕組みを解明 ―何重にも張り巡らされたストレス感知のための巧妙な仕組み―

    https://www.amed.go.jp/news/release_20190717-02.html

    2019/07

    Type: Internet

  6. 腎性尿崩症の新たな発症メカニズムを発見 ‐胎児・乳児期の環境ストレスは腎性尿崩症を引き起こす‐

    https://www.tohoku.ac.jp/japanese/2017/02/press20170223-01.html

    2017/02

    Type: Internet

  7. 酸化ストレス防御にはたらく転写因子Nrf2の量的調節機構の解明

    https://www.tohoku.ac.jp/japanese/2016/10/press20161007-01.html

    2016/10

    Type: Internet

  8. Nrf2転写因子による炎症抑制メカニズムを解明―細胞保護効果のある物質を用いた新たな抗炎症薬開発の可能性―

    https://www.amed.go.jp/news/release_20160523-02.html　AMED

    2016/05

    Type: Internet

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Academic Activities 12

  1. Reviewers of Cancer Science

    2022/10/01 - 2023/09/30

    Activity type: Peer review

  2. Reviewers of Experimental Animals

    2023 - 2023

    Activity type: Peer review

  3. Reviewers acknowledgements 2017

    2017 - 2017

    Activity type: Peer review

  4. シンポジウム「KEAP1-NRF2-sMAFシステム制御の分子基盤」オーガナイザー

    2024/11/07 -

    Activity type: Competition, symposium, etc.

  5. 市民講座「宇宙と健康」

    2023/11/05 -

    Activity type: Academic society, research group, etc.

  6. 国際シンポジウムThe Environmental Response V

    2019/09/09 -

    Activity type: Academic society, research group, etc.

  7. 新学術領域研究 酸素生物学・ダイイングコード合同若手会議

    2018/01/30 -

    Activity type: Academic society, research group, etc.

  8. 第89回日本生化学会大会

    2016/09/24 -

    Activity type: Academic society, research group, etc.

  9. 国際シンポジウムThe Environmental Response IV

    2014/02/28 -

    Activity type: Academic society, research group, etc.

  10. 日本生化学会東北支部会

    2013/05/11 -

    Activity type: Academic society, research group, etc.

  11. 国際シンポジウムMolecular Mechanism of Environmental Response to Food and Oxygen III

    2009/02/09 -

    Activity type: Academic society, research group, etc.

  12. 国際シンポジウムThe Environmental Response

    2007/12/21 -

    Activity type: Academic society, research group, etc.

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Other 1

  1. Institutional Program for Young Researcher Overseas Visits