TOHOKU UNIVERSITY Researchers - Kazuhiko Igarashi

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Kazuhiko Igarashi

Section

Graduate School of Medicine

Job title

Professor

Degree

医学博士（東北大学）

researchmap

https://researchmap.jp/read0122128

J-GLOBAL ID

200901035284244121

Profile

1993 Assistant Professor, Department of Biochemistry, Tohoku University School of Medicine

1995 Lecturer, Institute of Basic Medical Sciences, University of Tsukuba

1998 Associate Professor, Department of Biochemistry, Tohoku University School of Medicine

1999 Professor, Department of Biochemistry, Hiroshima University School of Medicine and Graduate School of Biomedical Sciences

2005- Professor, Department of Biochemistry, Tohoku University Graduate School of Medicine

2008-2013 Vice Dean, Tohoku University Graduate School of Medicine

2015-2017 Vice Dean, Tohoku University Graduate School of Medicine

2017-2019 Dean, Tohoku University Graduate School of Medicine

2020- Member, Science Council of Japan

Education 2

Tohoku University　Graduate School of Medicine

1987/04 - 1991/03
Tohoku University　School of Medicine

1981/04 - 1987/03

Committee Memberships 1

日本生化学会　理事

2006/10 - Present

Professional Memberships 5

American Society for Biochemistry and Molecular Biology
日本免疫学会
日本癌学会
THE MOLECULAR BIOLOGY SOCIETY OF JAPAN
日本生化学会(2006/10- 理事)

Research Interests 10

iron
cancer
S-adenosylmethionine
heme
chromatin
transcription factor
lymphoid cell differentiation
hematopoiesis
cell differentiation
regulation of gene expression

Research Areas 3

Life sciences / Molecular biology /
Life sciences / Pathobiochemistry /
Life sciences / Medical biochemistry /

Awards 4

Toyoichi Ohtawara Award

2023/03　KAKETSUKEN
Reviewer Award, Grant-in-Aid for Scientific Research

2017/09
JSPS Prize

2006/03　Japan Society for the Promotion of Science
Young Investigator Award

1996/10　The Japanese Biochemical Society

Papers 321

Transcription factor BACH1 promotes epithelial-mesenchymal transition by repressing iron metabolism-related genes

Shuichiro Hayashi, Mitsuyo Matsumoto, Liang Liu, Miho Tanaka, Michiaki Unno, Kazuhiko Igarashi

Biochemical and Biophysical Research Communications　2025/06

DOI： 10.1016/j.bbrc.2025.151898 　
Target of rapamycin signaling regulates starch degradation via α-glucan water dikinase in a unicellular red alga

Sota Komiya, Imran Pancha, Hiroki Shima, Kazuhiko Igarashi, Kan Tanaka, Sousuke Imamura

Plant Physiology　2025/03/28

DOI： 10.1093/plphys/kiaf106 　
Heme regulates protein interactions and phosphorylation of BACH2 intrinsically disordered region in humoral response

Miki Watanabe-Matsui, Shun Kadoya, Kei Segawa, Hiroki Shima, Tadashi Nakagawa, Yuko Nagasawa, Shuichiro Hayashi, Mitsuyo Matsumoto, Mariko Ikeda, Akihiko Muto, Kyoko Ochiai, Long C. Nguyen, Katsumi Doh-Ura, Mikako Shirouzu, Keiko Nakayama, Kazutaka Murayama, Kazuhiko Igarashi

iScience　28　(1)　111529-111529　2025/01
Publisher: Elsevier BV
DOI： 10.1016/j.isci.2024.111529 　

ISSN： 2589-0042
Absolute quantification of BACH1 and BACH2 transcription factors in B and plasma cells reveals their dynamic changes and unique roles

Takeshi Kurasawa, Akihiko Muto, Mitsuyo Matsumoto, Kyoko Ochiai, Kazutaka Murayama, Kazuhiko Igarashi

The Journal of Biochemistry　2024/12/02

DOI： 10.1093/jb/mvae065 　
造血幹前駆細胞におけるSAM合成によるDNAの安定化とp53経路抑制を介した恒常性の維持

古川瑛次郎, 加藤浩貴, 佐野沙矢香, 燕艶, 道又大吾, 田中裕也, 櫻井一貴, 小野寺晃一, 市川聡, 福原規子, 大西康, 横山寿行, 三枝大輔, 藤原亨, 五十嵐和彦, 張替秀郎

日本血液学会学術集会　86回　O1-4　2024/10
Publisher: (一社)日本血液学会
Intracellular biliverdin dynamics during ferroptosis. International-journal

Kazuma Nakajima, Hironari Nishizawa, Guan Chen, Shunichi Tsuge, Mie Yamanaka, Machi Kiyohara, Riko Irikura, Mitsuyo Matsumoto, Kozo Tanaka, Rei Narikawa, Kazuhiko Igarashi

Journal of biochemistry　2024/09/28

DOI： 10.1093/jb/mvae067 　

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Ferroptosis is a cell death mechanism mediated by iron-dependent lipid peroxidation. Although ferroptosis has garnered attention as a cancer-suppressing mechanism, there are still limited markers available for identifying ferroptotic cells or assessing their sensitivity to ferroptosis. The study focused on biliverdin, an endogenous reducing substance in cells, and examined the dynamics of intracellular biliverdin during ferroptosis using a biliverdin-binding cyanobacteriochrome. It was found that intracellular biliverdin decreases during ferroptosis and that this decrease is specific to ferroptosis among different forms of cell death. Furthermore, the feasibility of predicting sensitivity to ferroptosis by measuring intracellular biliverdin was demonstrated using a ferroptosis model induced by the re-expression of the transcription factor BACH1. These findings provide further insight into ferroptosis research and are expected to contribute to the development of cancer therapies that exploit ferroptosis.
BTB and CNC homology 1 deficiency disrupts intestinal IgA secretion through regulation of polymeric immunoglobulin receptor expression

Riku Hamada, Akari Yonezawa, Kenji Matsumoto, Takakazu Mitani, Tomohisa Takagi, Akihiko Muto, Kazuhiko Igarashi, Yuji Naito, Yasuki Higashimura

American Journal of Physiology-Gastrointestinal and Liver Physiology　327　(3)　G414-G423　2024/09/01
Publisher: American Physiological Society
DOI： 10.1152/ajpgi.00215.2023 　

ISSN： 0193-1857

eISSN： 1522-1547

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The transcriptional repressor Bach1 has been implicated in diverse intestinal functions, but the effects of Bach1 on IgA-mediated mucosal immunity remain unclear. We demonstrate here that Bach1 deficiency causes abnormal secretion of IgA into the intestinal lumen, although the proportions of IgA-producing cells were not altered. Furthermore, Bach1 regulates the expression of pIgR, which plays an important role in the transepithelial transport of IgA, at the posttranscriptional level.
BACH1 inhibits senescence, obesity, and short lifespan by ferroptotic FGF21 secretion. International-journal

Hironari Nishizawa, Mitsuyo Matsumoto, Mie Yamanaka, Riko Irikura, Kazuma Nakajima, Keisuke Tada, Yoshiaki Nakayama, Morichika Konishi, Nobuyuki Itoh, Ryo Funayama, Keiko Nakayama, Kazuhiko Igarashi

Cell reports　43　(7)　114403-114403　2024/06/27

DOI： 10.1016/j.celrep.2024.114403 　

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Ferroptosis is a type of regulated cell death characterized by iron-dependent lipid peroxidation. A model cell system is constructed to induce ferroptosis by re-expressing the transcription factor BACH1, a potent ferroptosis inducer, in immortalized mouse embryonic fibroblasts (iMEFs). The transfer of the culture supernatant from ferroptotic iMEFs activates the proliferation of hepatoma cells and other fibroblasts and suppresses cellular senescence-like features. The BACH1-dependent secretion of the longevity factor FGF21 is increased in ferroptotic iMEFs. The anti-senescent effects of the culture supernatant from these iMEFs are abrogated by Fgf21 knockout. BACH1 activates the transcription of Fgf21 by promoting ferroptotic stress and increases FGF21 protein expression by suppressing its autophagic degradation through transcriptional Sqstm1 and Lamp2 repression. The BACH1-induced ferroptotic FGF21 secretion suppresses obesity in high-fat diet-fed mice and the short lifespan of progeria mice. The inhibition of these aging-related phenotypes can be physiologically significant regarding ferroptosis.
Accelerated plasma-cell differentiation in Bach2-deficient mouse B cells is caused by altered IRF4 functions

Kyoko Ochiai, Hiroki Shima, Toru Tamahara, Nao Sugie, Ryo Funayama, Keiko Nakayama, Tomohiro Kurosaki, Kazuhiko Igarashi

The EMBO Journal　2024/04/11

DOI： 10.1038/s44318-024-00077-6 　
TANK Binding Kinase 1 Promotes BACH1 Degradation through Both Phosphorylation-Dependent and -Independent Mechanisms without Relying on Heme and FBXO22

Liang Liu, Mitsuyo Matsumoto, Miki Watanabe-Matsui, Tadashi Nakagawa, Yuko Nagasawa, Jingyao Pang, Bert K.K. Callens, Akihiko Muto, Kyoko Ochiai, Hirotaka Takekawa, Mahabub Alam, Hironari Nishizawa, Mikako Shirouzu, Hiroki Shima, Keiko Nakayama, Kazuhiko Igarashi

International Journal of Molecular Sciences　2024/04

DOI： 10.3390/ijms25084141 　
Cysteine restriction induces ferroptosis depending on the polyamine biosynthetic pathway in hepatic cancer cells

Keisuke Tada, Hironari Nishizawa, Hiroki Shima, Akihiko Muto, Motoshi Wada, Kazuhiko Igarashi

2024/03/03

DOI： 10.1101/2024.02.29.582667 　
Polyunsaturated fatty acids-induced ferroptosis suppresses pancreatic cancer growth.

Suda A, Umaru BA, Yamamoto Y, Shima H, Saiki Y, Pan Y, Jin L, Sun J, Low YLC, Suzuki C, Abe T, Igarashi K, Furukawa T, Owada Y, Kagawa Y

Scientific reports　2024/02/22

DOI： 10.1038/s41598-024-55050-4 　

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Despite recent advances in science and medical technology, pancreatic cancer remains associated with high mortality rates due to aggressive growth and no early clinical sign as well as the unique resistance to anti-cancer chemotherapy. Current numerous investigations have suggested that ferroptosis, which is a programed cell death driven by lipid oxidation, is an attractive therapeutic in different tumor types including pancreatic cancer. Here, we first demonstrated that linoleic acid (LA) and α-linolenic acid (αLA) induced cell death with necroptotic morphological change in MIA-Paca2 and Suit 2 cell lines. LA and αLA increased lipid peroxidation and phosphorylation of RIP3 and MLKL in pancreatic cancers, which were negated by ferroptosis inhibitor, ferrostatin-1, restoring back to BSA control levels. Similarly, intraperitoneal administration of LA and αLA suppresses the growth of subcutaneously transplanted Suit-2 cells and ameliorated the decreased survival rate of tumor bearing mice, while co-administration of ferrostatin-1 with LA and αLA negated the anti-cancer effect. We also demonstrated that LA and αLA partially showed ferroptotic effects on the gemcitabine-resistant-PK cells, although its effect was exerted late compared to treatment on normal-PK cells. In addition, the trial to validate the importance of double bonds in PUFAs in ferroptosis revealed that AA and EPA had a marked effect of ferroptosis on pancreatic cancer cells, but DHA showed mild suppression of cancer proliferation. Furthermore, treatment in other tumor cell lines revealed different sensitivity of PUFA-induced ferroptosis; e.g., EPA induced a ferroptotic effect on colorectal adenocarcinoma, but LA or αLA did not. Collectively, these data suggest that PUFAs can have a potential to exert an anti-cancer effect via ferroptosis in both normal and gemcitabine-resistant pancreatic cancer.
BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility.

Eduardo Pinheiro Amaral, Sivaranjani Namasivayam, Artur Trancoso Lopo de Queiroz, Fukutani E, Kerry Hilligan, Aberman K, Logan Fisher, Caio César Barbosa Bomfim, Keith Kauffman, Buchanan J, Santuo L, Pedro Gazzinelli-Guimaraes, Diego Costa, Teixeira MA, Barreto-Duarte B, Gurgel Rocha, CA, Santana MF, Marcelo Cordeiro-Santos, Daniel Barber, Robert Wilkinson, Igor Kramnik, Kazuhiko Igarashi, Thomas Scriba, Katrin Mayer-Barber, Bruno Andrade, Alan Sher

Nature microbiology　2023/12/08

DOI： 10.1038/s41564-023-01523-7 　

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Oxidative stress triggers ferroptosis, a form of cellular necrosis characterized by iron-dependent lipid peroxidation, and has been implicated in Mycobacterium tuberculosis (Mtb) pathogenesis. We investigated whether Bach1, a transcription factor that represses multiple antioxidant genes, regulates host resistance to Mtb. We found that BACH1 expression is associated clinically with active pulmonary tuberculosis. Bach1 deletion in Mtb-infected mice increased glutathione levels and Gpx4 expression that inhibit lipid peroxidation. Bach1^-/- macrophages exhibited increased resistance to Mtb-induced cell death, while Mtb-infected Bach1-deficient mice displayed reduced bacterial loads, pulmonary necrosis and lipid peroxidation concurrent with increased survival. Single-cell RNA-seq analysis of lungs from Mtb-infected Bach1^-/- mice revealed an enrichment of genes associated with ferroptosis suppression. Bach1 depletion in Mtb-infected B6.Sst1^S mice that display human-like necrotic lung pathology also markedly reduced necrosis and increased host resistance. These findings identify Bach1 as a key regulator of cellular and tissue necrosis and host resistance in Mtb infection.
Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice. International-journal

Koki Nagai, Tetsuya Niihori, Akihiko Muto, Yoshikazu Hayashi, Taiki Abe, Kazuhiko Igarashi, Yoko Aoki

Blood advances　2023/04/26

DOI： 10.1182/bloodadvances.2022008462 　

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Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is an inherited bone marrow failure syndrome characterized by congenital fusion of the forearm bones. RUSAT is largely caused by missense mutations that are clustered in a specific region of the MDS1 and EVI1 complex locus (MECOM). EVI1, a transcript variant encoded by MECOM, is a zinc finger transcription factor involved in hematopoietic stem cell maintenance that induce leukemic transformation when overexpressed. Mice with exonic deletions in Mecom show reduced hematopoietic stem and progenitor cells (HSPCs). However, the pathogenic roles of RUSAT-associated MECOM mutations in vivo have not yet been elucidated. To investigate the impact of the RUSAT-associated MECOM mutation on the phenotype, we generated knock-in mice harboring a point mutation (translated into EVI1 p.H752R and MDS1-EVI1 p.H942R), which corresponds to an EVI1 p.H751R and MDS1-EVI1 p.H939R mutation identified in a patient with RUSAT. Homozygous mutant mice died at embryonic day 10.5-11.5. Heterozygous mutant mice (Evi1KI/+ mice) grew normally without radioulnar synostosis. Male Evi1KI/+ mice aged 5-15 weeks exhibited lower body weight and those aged 16 weeks and older showed low platelet counts. Flow cytometric analysis of bone marrow cells revealed a decrease in HSPCs in Evi1KI/+ mice at 8-12 weeks. Moreover, Evi1KI/+ mice showed delayed leukocyte and platelet recovery after 5-fluorouracil-induced myelosuppression. These findings suggest that Evi1KI/+ mice recapitulate the bone marrow dysfunction in RUSAT, similar to that caused by loss-of-function Mecom alleles.
Ferroptosis model system by the re-expression of BACH1. International-journal

Riko Irikura, Hironari Nishizawa, Kazuma Nakajima, Mie Yamanaka, Guan Chen, Kozo Tanaka, Masafumi Onodera, Mitsuyo Matsumoto, Kazuhiko Igarashi

Journal of biochemistry　2023/04/24

DOI： 10.1093/jb/mvad036 　

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Ferroptosis is a regulated cell death induced by iron-dependent lipid peroxidation. The heme-responsive transcription factor BTB and CNC homology 1 (BACH1) promotes ferroptosis by repressing the transcription of genes involved in glutathione (GSH) synthesis and intracellular labile iron metabolism, which are key regulatory pathways in ferroptosis. We found that BACH1 re-expression in Bach1-/- immortalized mouse embryonic fibroblasts (iMEFs) can induce ferroptosis upon 2-mercaptoethanol removal, without any ferroptosis inducers. In these iMEFs, GSH synthesis was reduced, and intracellular labile iron levels were increased upon BACH1 re-expression. We used this system to investigate whether the major ferroptosis regulators glutathione peroxidase 4 (Gpx4) and apoptosis-inducing factor mitochondria-associated 2 (Aifm2), the gene for ferroptosis suppressor protein 1, are target genes of BACH1. Neither Gpx4 nor Aifm2 was regulated by BACH1 in the iMEFs. However, we found that BACH1 represses AIFM2 transcription in human pancreatic cancer cells. These results suggest that the ferroptosis regulators targeted by BACH1 may vary across different cell types and animal species. Furthermore, we confirmed that the ferroptosis induced by BACH1 re-expression exhibited a propagating effect. BACH1 re-expression represents a new strategy for inducing ferroptosis after GPX4 or system Xc- suppression, and is expected to contribute to future ferroptosis research.
[Gene regulatory networks operated by iron-heme metabolism: focusing on the erythroid differentiation system].

Kato H, Igarashi K

[Rinsho ketsueki] The Japanese journal of clinical hematology　2023/01/01

DOI： 10.11406/rinketsu.64.406 　

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Recently, attention has been focused on how metabolites regulate cellular differentiation. Heme synthesis is greatly enhanced during erythroid differentiation. Heme is used for hemoglobin synthesis, which is needed for oxygen transport by red blood cells. Additionally, several pieces of evidence revealed that heme may control gene expression to fulfill erythroblast terminal maturation. For instance, heme binds to and inactivates the transcription factor BTB Domain And CNC Homolog 1 (BACH1), thereby inducing the globin gene expression, which is the repressive target of BACH1. Moreover, heme induces autophagy/mitophagy-related gene expressions, which are the targets of the transcription factor GATA1 and may promote erythrocyte maturation by itself. Heme may directly bind to guanine tetramer (G-quadruplex) regions of genomic DNA, thereby regulating nearby gene expressions. Here, we present an overview of the mechanism by which iron-heme metabolism regulates gene regulatory networks by focusing on the erythroid differentiation system. Additionally, we discuss the prospects of future research regarding iron-heme metabolism.
Exploring novel functions of BACH2 in the acquisition of antigen-specific antibodies. International-journal

Kyoko Ochiai, Kazuhiko Igarashi

International immunology　2022/12/27

DOI： 10.1093/intimm/dxac065 　

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BACH2 [BTB (broad-complex, tramtrak and bric à brac) and CNC (cap 'n' collar) homolog 2] is known as a transcriptional repressor and broadly functions in regulating immune cell differentiation. Here, we focus on BACH2 function in B cells, where BACH2 was first shown to play an important role in the immune system. In B cells, BACH2 orchestrates the gene regulatory network that promotes class-switch and affinity-maturation of antibodies and simultaneously represses plasma-cell differentiation. In this context, BACH2 regulates gene expression by modulating chromatin organization, cooperatively with other transcription factors and chromatin regulators, such as IRF4 (interferon regulatory factor 4) and PC4 (positive coactivator 4), respectively. In addition, our recent observation raises the possibility that BACH2 has diverse functions, such as those in gene activation. Since dysfunction of BACH2 leads to the onset of human immune deficiencies, revealing new functions of BACH2 may give a cue to solve how BACH2 contributes to preventing these diseases.
Heme-dependent induction of mitophagy program during differentiation of murine erythroid cells. International-journal

Masatoshi Ikeda, Hiroki Kato, Hiroki Shima, Mitsuyo Matsumoto, Eijiro Furukawa, Yan Yan, Ruiqi Liao, Jian Xu, Akihiko Muto, Tohru Fujiwara, Hideo Harigae, Emery H Bresnick, Kazuhiko Igarashi

Experimental hematology　118　21-30　2022/12/05

DOI： 10.1016/j.exphem.2022.11.007 　

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Although establishment and maintenance of mitochondria are essential for the production of massive amounts of heme in erythroblasts, mitochondria must be degraded upon terminal differentiation to red blood cells (RBCs), thus creating a biphasic regulatory process. Previously, we reported that iron deficiency in mice promotes mitochondrial retention in RBCs, suggesting that a proper amount of iron and/or heme is necessary for the degradation of mitochondria during erythroblast maturation. Because the transcription factor GATA1 regulates autophagy in erythroid cells, which involves mitochondrial clearance (mitophagy), we investigated the relationship between iron or heme and mitophagy by analyzing the expression of genes related to GATA1 and autophagy and the impact of iron or heme restriction on the amount of mitochondria. We found that heme promotes the expression of GATA1-regulated mitophagy-related genes and the induction of mitophagy. GATA1 might induce the expression of the autophagy-related genes Atg4d and Stk11 for mitophagy through a heme-dependent mechanism in murine erythroleukemia (MEL) cells and a genetic rescue system with G1E-ER-GATA1 erythroblast cells derived from Gata1-null murine embryonic stem cells. These results provide evidence for a biphasic mechanism in which mitochondria are essential for heme generation, and the heme generated during differentiation promotes mitophagy and mitochondrial disposal. This mechanism provides a molecular framework for understanding this fundamentally important cell biological process.
Elucidation of the Role of FAM210B in Mitochondrial Metabolism and Erythropoiesis. International-journal

Chie Suzuki, Tohru Fujiwara, Hiroki Shima, Koya Ono, Kei Saito, Hiroki Kato, Koichi Onodera, Satoshi Ichikawa, Noriko Fukuhara, Yasushi Onishi, Hisayuki Yokoyama, Yukio Nakamura, Kazuhiko Igarashi, Hideo Harigae

Molecular and cellular biology　42　(12)　e0014322　2022/11/14

DOI： 10.1128/mcb.00143-22 　

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Mitochondria play essential and specific roles during erythroid differentiation. Recently, FAM210B, encoding a mitochondrial inner membrane protein, has been identified as a novel target of GATA-1, as well as an erythropoietin-inducible gene. While FAM210B protein is involved in regulate mitochondrial metabolism and heme biosynthesis, its detailed function remains unknown. Here, we generated both knockout and knockdown of endogenous FAM210B in human induced pluripotent stem-derived erythroid progenitor (HiDEP) cells using CRISPR/Cas9 methodology. Intriguingly, erythroid differentiation was more pronounced in the FAM210B-depleted cells, and this resulted in increased frequency of orthochromatic erythroblasts and decreased frequencies of basophilic/polychromatic erythroblasts. Comprehensive metabolite analysis and functional analysis indicated that oxygen consumption rates and the NAD (NAD+)/NADH ratio were significantly decreased, while lactate production was significantly increased in FAM210B deletion HiDEP cells, indicating involvement of FAM210B in mitochondrial energy metabolism in erythroblasts. Finally, we purified FAM210B-interacting protein from K562 cells that stably expressed His/biotin-tagged FAM210B. Mass spectrometry analysis of the His/biotin-purified material indicated interactions with multiple subunits of mitochondrial ATP synthases, such as subunit alpha (ATP5A) and beta (ATP5B). Our results suggested that FAM210B contributes prominently to erythroid differentiation by regulating mitochondrial energy metabolism. Our results provide insights into the pathophysiology of dysregulated hematopoiesis.
Harnessing the Therapeutic Potential of the Nrf2/Bach1 Signaling Pathway in Parkinson's Disease.

Ahuja M, Kaidery NA, Dutta D, Attucks OC, Kazakov EH, Gazaryan I, Matsumoto M, Igarashi K, Sharma SM, Bobby Thomas

Antioxidants (Basel, Switzerland)　2022/09/09

DOI： 10.3390/antiox11091780 　

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Parkinson's disease (PD) is the second most common neurodegenerative movement disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although a complex interplay of multiple environmental and genetic factors has been implicated, the etiology of neuronal death in PD remains unresolved. Various mechanisms of neuronal degeneration in PD have been proposed, including oxidative stress, mitochondrial dysfunction, neuroinflammation, α-synuclein proteostasis, disruption of calcium homeostasis, and other cell death pathways. While many drugs individually targeting these pathways have shown promise in preclinical PD models, this promise has not yet translated into neuroprotective therapies in human PD. This has consequently spurred efforts to identify alternative targets with multipronged therapeutic approaches. A promising therapeutic target that could modulate multiple etiological pathways involves drug-induced activation of a coordinated genetic program regulated by the transcription factor, nuclear factor E2-related factor 2 (Nrf2). Nrf2 regulates the transcription of over 250 genes, creating a multifaceted network that integrates cellular activities by expressing cytoprotective genes, promoting the resolution of inflammation, restoring redox and protein homeostasis, stimulating energy metabolism, and facilitating repair. However, FDA-approved electrophilic Nrf2 activators cause irreversible alkylation of cysteine residues in various cellular proteins resulting in side effects. We propose that the transcriptional repressor of BTB and CNC homology 1 (Bach1), which antagonizes Nrf2, could serve as a promising complementary target for the activation of both Nrf2-dependent and Nrf2-independent neuroprotective pathways. This review presents the current knowledge on the Nrf2/Bach1 signaling pathway, its role in various cellular processes, and the benefits of simultaneously inhibiting Bach1 and stabilizing Nrf2 using non-electrophilic small molecules as a novel therapeutic approach for PD.
BACH1による膵臓癌細胞の細胞内自由鉄の増加は上皮間葉移行に影響する(BACH1 promotes epithelial-mesenchymal transition by enhancing cellular labile iron level in pancreatic cancer cell)

松本光代, 五十嵐和彦

日本癌学会総会記事　81回　P-3144　2022/09
Publisher: (一社)日本癌学会
ISSN： 0546-0476
Autocitrullination and Changes in the Activity of Peptidylarginine Deiminase 3 Induced by High Ca²⁺ Concentrations.

Sawata M, Shima H, Kazutaka Murayama, Toshitaka Matsui, Igarashi K, Funabashi K, Ite K, Kizawa K, Takahara H, Masaki Unno

ACS omega　2022/08/08

DOI： 10.1021/acsomega.2c02972 　

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Peptidylarginine deiminases (PADs) are enzymes that catalyze the Ca²⁺-dependent conversion of arginine residues into proteins to citrulline residues. Five PAD isozymes have been identified in mammals. Several studies have shown that the active-site pockets of these isozymes are formed when Ca²⁺ ions are properly bound. We previously characterized the structures of PAD3 in six states. Among these, we identified a "nonproductive" form of PAD3 in which the active site was disordered even though five Ca²⁺ ions were bound. This strange structure was probably obtained as a result of either high Ca²⁺ concentration (∼260 mM)-induced denaturation during the crystallization process or high Ca²⁺-concentration-induced autocitrullination. While autocitrullination has been reported in PAD2 and PAD4 for some time, only a single report on PAD3 has been published recently. In this study, we investigated whether PAD3 catalyzes the autocitrullination reaction and identified autocitrullination sites. In addition to the capacity of PAD3 for autocitrullination, the autocitrullination sites increased depending on the Ca²⁺ concentration and reaction time. These findings suggest that some of the arginine residues in the "nonproductive" form of PAD3 would be autocitrullinated. Furthermore, most of the autocitrullinated sites in PAD3 were located near the substrate-binding site. Given the high Ca²⁺ concentration in the crystallization condition, it is likely that Arg372 was citrullinated in the "nonproductive" PAD3 structure, the structure was slightly altered from the active form by citrulline residues, and probably inhibited Ca²⁺-ion binding at the proper position. Following Arg372 citrullination, PAD3 enters an inactive form; however, the Arg372-citrullinated PAD3 are considered minor components in autocitrullinated PAD3 (CitPAD3), and CitPAD3 does not significantly decrease the enzyme activity. Autocitrullination of PAD3 could not be confirmed at the low Ca²⁺ concentrations seen in vivo. Future experiments using cells and animals are needed to verify the effect of Ca²⁺ on the PAD3 structure and functions in vivo.
BACH1 Expression Is Promoted by Tank Binding Kinase 1 (TBK1) in Pancreatic Cancer Cells to Increase Iron and Reduce the Expression of E-Cadherin. International-journal

Liang Liu, Mitsuyo Matsumoto, Miki Matsui-Watanabe, Kyoko Ochiai, Bert K K Callens, Long Chi Nguyen, Yushi Kozuki, Miho Tanaka, Hironari Nishizawa, Kazuhiko Igarashi

Antioxidants (Basel, Switzerland)　11　(8)　2022/07/27

DOI： 10.3390/antiox11081460 　

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BTB and CNC homology 1 (BACH1) represses the expression of genes involved in the metabolism of iron, heme and reactive oxygen species and promotes metastasis of various cancers including pancreatic ductal adenocarcinoma (PDAC). However, it is not clear how BACH1 is regulated in PDAC cells. Knockdown of Tank binding kinase 1 (TBK1) led to reductions of BACH1 mRNA and protein amounts in AsPC-1 human PDAC cells. Gene expression analysis of PDAC cells with knockdown of TBK1 or BACH1 suggested the involvement of TBK1 and BACH1 in the regulation of iron homeostasis. Ferritin mRNA and proteins were both increased upon BACH1 knockdown in AsPC-1 cells. Flow cytometry analysis showed that AsPC-1 cells with BACH1 knockout or knockdown contained lower labile iron than control cells, suggesting that BACH1 increased labile iron by repressing the expression of ferritin genes. We further found that the expression of E-cadherin was upregulated upon the chelation of intracellular iron content. These results suggest that the TBK1-BACH1 pathway promotes cancer cell metastasis by increasing labile iron within cells.
BACH1-Hemoxygenase-1 axis regulates cellular energetics and survival following sepsis.

Cai L, Arbab AS, Tae Jin Lee, Ashok Sharma, Bobby Thomas, Igarashi K, Raju RP

Free radical biology & medicine　2022/06/09

DOI： 10.1016/j.freeradbiomed.2022.06.005 　

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Sepsis is a complex disease due to dysregulated host response to infection. Oxidative stress and mitochondrial dysfunction leading to metabolic dysregulation are among the hallmarks of sepsis. The transcription factor NRF2 (Nuclear Factor E2-related factor2) is a master regulator of the oxidative stress response, and the NRF2 mediated antioxidant response is negatively regulated by BTB and CNC homology 1 (BACH1) protein. This study tested whether Bach1 deletion improves organ function and survival following polymicrobial sepsis induced by cecal ligation and puncture (CLP). We observed enhanced post-CLP survival in Bach1^-/- mice with a concomitantly increased liver HO-1 expression, reduced liver injury and oxidative stress, and attenuated systemic and tissue inflammation. After sepsis induction, the liver mitochondrial function was better preserved in Bach1^-/- mice. Furthermore, BACH1 deficiency improved liver and lung blood flow in septic mice, as measured by SPECT/CT. RNA-seq analysis identified 44 genes significantly altered in Bach1^-/- mice after sepsis, including HMOX1 and several genes in lipid metabolism. Inhibiting HO-1 activity by Zinc Protoporphyrin-9 worsened organ function in Bach1^-/- mice following sepsis. We demonstrate that mitochondrial bioenergetics, organ function, and survival following experimental sepsis were improved in Bach1^-/- mice through the HO-1-dependent mechanism and conclude that BACH1 is a therapeutic target in sepsis.
The Cys‐Pro motifs in the intrinsically disordered regions of the transcription factor BACH1 mediate distinct and overlapping functions upon heme binding

Kei Segawa, Kazuhiko Igarashi, Kazutaka Murayama

FEBS Letters　2022/06
Publisher: Wiley
DOI： 10.1002/1873-3468.14338 　
Congenital sideroblastic anemia model due to ALAS2 mutation is susceptible to ferroptosis. International-journal

Koya Ono, Tohru Fujiwara, Kei Saito, Hironari Nishizawa, Noriyuki Takahashi, Chie Suzuki, Tetsuro Ochi, Hiroki Kato, Yusho Ishii, Koichi Onodera, Satoshi Ichikawa, Noriko Fukuhara, Yasushi Onishi, Hisayuki Yokoyama, Rie Yamada, Yukio Nakamura, Kazuhiko Igarashi, Hideo Harigae

Scientific reports　12　(1)　9024-9024　2022/05/30

DOI： 10.1038/s41598-022-12940-9 　

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X-linked sideroblastic anemia (XLSA), the most common form of congenital sideroblastic anemia, is caused by a germline mutation in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene. In XLSA, defective heme biosynthesis leads to ring sideroblast formation because of excess mitochondrial iron accumulation. In this study, we introduced ALAS2 missense mutations on human umbilical cord blood-derived erythroblasts; hereafter, we refer to them as XLSA clones. XLSA clones that differentiated into mature erythroblasts showed an increased frequency of ring sideroblast formation with impaired hemoglobin biosynthesis. The expression profiling revealed significant enrichment of genes involved in ferroptosis, which is a form of regulated cell death induced by iron accumulation and lipid peroxidation. Notably, treatment with erastin, a ferroptosis inducer, caused a higher proportion of cell death in XLSA clones. XLSA clones exhibited significantly higher levels of intracellular lipid peroxides and enhanced expression of BACH1, a regulator of iron metabolism and potential accelerator of ferroptosis. In XLSA clones, BACH1 repressed genes involved in iron metabolism and glutathione synthesis. Collectively, defective heme biosynthesis in XLSA clones could confer enhanced BACH1 expression, leading to increased susceptibility to ferroptosis. The results of our study provide important information for the development of novel therapeutic targets for XLSA.
mTORC1-independent translation control in mammalian cells by methionine adenosyltransferase 2A and S-adenosylmethionine. International-journal

Mahabub Alam, Hiroki Shima, Yoshitaka Matsuo, Nguyen Chi Long, Mitsuyo Matsumoto, Yusho Ishii, Nichika Sato, Takato Sugiyama, Risa Nobuta, Satoshi Hashimoto, Liang Liu, Mika K Kaneko, Yukinari Kato, Toshifumi Inada, Kazuhiko Igarashi

The Journal of biological chemistry　298　(7)　102084-102084　2022/05/27

DOI： 10.1016/j.jbc.2022.102084 　

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Methionine adenosyltransferase (MAT) catalyzes the synthesis of S-adenosylmethionine (SAM). As the sole methyl-donor for methylation of DNA, RNA, and proteins, SAM levels affect gene expression by changing methylation patterns. Expression of MAT2A, the catalytic subunit of isozyme MAT2, is positively correlated with proliferation of cancer cells; however, how MAT2A promotes cell proliferation is largely unknown. Given that the protein synthesis is induced in proliferating cells and that RNA and protein components of translation machinery are methylated, we tested here whether MAT2 and SAM are coupled with protein synthesis. By measuring ongoing protein translation via puromycin labeling, we revealed that MAT2A depletion or chemical inhibition reduced protein synthesis in HeLa and Hepa1 cells. Furthermore, overexpression of MAT2A enhanced protein synthesis, indicating that SAM is limiting under normal culture conditions. In addition, MAT2 inhibition did not accompany reduction in mechanistic target of rapamycin complex 1 activity but nevertheless reduced polysome formation. Polysome-bound RNA sequencing revealed that MAT2 inhibition decreased translation efficiency of some fraction of mRNAs. MAT2A was also found to interact with the proteins involved in rRNA processing and ribosome biogenesis; depletion or inhibition of MAT2 reduced 18S rRNA processing. Finally, quantitative mass spectrometry revealed that some translation factors were dynamically methylated in response to the activity of MAT2A. These observations suggest that cells possess an mTOR-independent regulatory mechanism that tunes translation in response to the levels of SAM. Such a system may acclimate cells for survival when SAM synthesis is reduced, whereas it may support proliferation when SAM is sufficient.
IRF2BP2 is a novel HNF4α co-repressor: Its role in gluconeogenic gene regulation via biochemically labile interaction. International-journal

Takumi Kouketsu, Rina Monma, Yuri Miyairi, Shun Sawatsubashi, Hiroki Shima, Kazuhiko Igarashi, Akira Sugawara, Atsushi Yokoyama

Biochemical and biophysical research communications　615　81-87　2022/05/18

DOI： 10.1016/j.bbrc.2022.04.133 　

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Hepatocyte nuclear factor 4α (HNF4α) has essential roles in controlling the expression of a variety of genes involved in key metabolic pathways, including gluconeogenesis in the liver. The mechanistic and physiological significance of peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) for HNF4α-mediated transcriptional activation models for gluconeogenic genes is well characterized. However, the transcriptional repression of HNF4α for those genes remains to be examined. In this study, we applied novel proteomic techniques to evaluate the interactions of HNF4α, including those with biochemically labile binding proteins. Based upon our experiments, we identified interferon regulatory factor 2 binding protein 2 (IRF2BP2) as a novel HNF4α co-repressor. This interaction could not be detected by conventional immunoprecipitation. IRF2BP2 repressed the transcriptional activity of HNF4α dependent on its E3 ubiquitin ligase activity. Deficiency of the IRF2BP2 gene in HepG2 cells induced gluconeogenic genes comparable to that of forskolin-treated wild-type HepG2 cells. Together, these results suggest that IRF2BP2 represents a novel class of nuclear receptor co-regulator.
Genetic BACH1 deficiency alters mitochondrial function and increases NLRP3 inflammasome activation in mouse macrophages

Pooja Pradhan, Vijith Vijayan, Karsten Cirksena, Falk F.R. Buettner, Kazuhiko Igarashi, Roberto Motterlini, Roberta Foresti, Stephan Immenschuh

Redox Biology　2022/05

DOI： 10.1016/j.redox.2022.102265 　

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BTB-and-CNC homologue 1 (BACH1), a heme-regulated transcription factor, mediates innate immune responses via its functional role in macrophages. BACH1 has recently been shown to modulate mitochondrial metabolism in cancer cells. In the current study, we utilized a proteomics approach and demonstrate that genetic deletion of BACH1 in mouse macrophages is associated with decreased levels of various mitochondrial proteins, particularly mitochondrial complex I. Bioenergetic studies revealed alterations of mitochondrial energy metabolism in BACH1-/- macrophages with a shift towards increased glycolysis and decreased oxidative phosphorylation. Moreover, these cells exhibited enhanced mitochondrial membrane potential and generation of mitochondrial reactive oxygen species (mtROS) along with lower levels of mitophagy. Notably, a higher inducibility of NLRP3 inflammasome activation in response to ATP and nigericin following challenge with lipopolysaccharide (LPS) was observed in BACH1-deficient macrophages compared to wild-type cells. Mechanistically, pharmacological inhibition of mtROS markedly attenuated inflammasome activation. In addition, it is shown that inducible nitric oxide synthase and cyclooxygenase-2, both of which are markedly induced by LPS in macrophages, are directly implicated in BACH1-dependent regulation of NLRP3 inflammasome activation. Taken together, the current findings indicate that BACH1 is critical for immunomodulation of macrophages and may serve as a target for therapeutic approaches in inflammatory disorders.
CmNDB1 and a Specific Domain of CmMYB1 Negatively Regulate CmMYB1-Dependent Transcription of Nitrate Assimilation Genes Under Nitrogen-Repleted Condition in a Unicellular Red Alga

Baifeng Zhou, Hiroki Shima, Kazuhiko Igarashi, Kan Tanaka, Sousuke Imamura

Frontiers in Plant Science　13　2022/03/11
Publisher: Frontiers Media SA
DOI： 10.3389/fpls.2022.821947 　

eISSN： 1664-462X

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Nitrogen assimilation is an essential process that controls plant growth and development. Plant cells adjust the transcription of nitrogen assimilation genes through transcription factors (TFs) to acclimatize to changing nitrogen levels in nature. However, the regulatory mechanisms of these TFs under nitrogen-repleted (+N) conditions in plant lineages remain largely unknown. Here, we identified a negative domain (ND) of CmMYB1, the nitrogen-depleted (−N)-activated TF, in a unicellular red alga <italic>Cyanidioschyzon merolae</italic>. The ND deletion changed the localization of CmMYB1 from the cytoplasm to the nucleus, enhanced the binding efficiency of CmMYB1 to promoters of nitrate assimilation genes, and increased the transcripts of nitrate assimilation genes under +N condition. A pull-down assay using an ND-overexpressing strain combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis helped us to screen and identify an unknown-function protein, the CmNDB1. Yeast two-hybrid analysis demonstrated that CmNDB1 interacts with ND. Similar to ND deletion, <italic>CmNDB1</italic> deletion also led to the nucleus localization of CmMYB1, enhanced the promoter-binding ratio of CmMYB1 to the promoter regions of nitrate assimilation genes, and increased transcript levels of nitrate assimilation genes under +N condition. Thus, these presented results indicated that ND and CmNDB1 negatively regulate CmMYB1 functions under the +N condition in <italic>C. merolae</italic>.
Ferroptosis: Regulation by competition between NRF2 and BACH1 and propagation of the death signal

Hironari Nishizawa, Mie Yamanaka, Kazuhiko Igarashi

The FEBS Journal　2022/02/02
Publisher: Wiley
DOI： 10.1111/febs.16382 　

ISSN： 1742-464X

eISSN： 1742-4658
Iron in Cancer Progression: Does BACH1 Promote Metastasis by Altering Iron Homeostasis? International-journal

Kazuhiko Igarashi, Hironari Nishizawa, Mitsuyo Matsumoto

Sub-cellular biochemistry　100　67-80　2022

DOI： 10.1007/978-3-031-07634-3_2 　

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The transcription factor BACH1, which is regulated by direct binding of prosthetic group heme, promotes epithelial-mesenchymal transition (EMT) and drives metastasis of diverse types of cancer cells. De-regulated target genes of BACH1 in cancer cells include those for glycolysis, oxidative phosphorylation, epithelial cell adhesion, and mesodermal cell motility. In addition, the canonical target genes of BACH1 include genes for the regulation of iron homeostasis. Importantly, cancer cells are addicted to iron. We summarize known functions of BACH1 in cancer and discuss how BACH1 may affect iron homeostasis in cancer cells to support their progression by increasing mobile iron within cells. The dependency on BACH1 for cancer progression may also confer upon cancer cells susceptibility to iron-dependent cell death ferroptosis. Finally, we discuss that the human transcription factors provide research opportunities for better understanding of cancer cell properties.
dbTMM: an integrated database of large-scale cohort, genome and clinical data for the Tohoku Medical Megabank Project.

Soichi Ogishima, Nagaie S, Mizuno S, Ishiwata R, Iida K, Shimokawa K, Takai-Igarashi T, Nakamura N, Nagase S, Nakamura T, Tsuchiya N, Nakaya N, Murakami K, Ueno F, Onuma T, Ishikuro M, Obara T, SHUNJI MUGIKURA, Hiroaki Tomita, Uruno A, Kobayashi T, Tsuboi A, Shu Tadaka, Fumiki Katsuoka, Akira Narita, Sakurai M, Makino S, Tamiya G, Aoki Y, Ritsuko Shimizu, Motoike IN, Koshiba S, Minegishi N, Kumada K, Nobukuni T, Suzuki K, Danjoh I, Nagami F, Tanno K, Ohmomo H, Asahi K, Atsushi SHIMIZU, Hozawa A, Kuriyama Shinichi, Tohoku Medical Megabank Project Study Group, Nobuo Fuse, Tominaga T, Kure S, Yaegashi N, kengo kinoshita, Makoto Sasaki

Human genome variation　2021/12/10

DOI： 10.1038/s41439-021-00175-5 　

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To reveal gene-environment interactions underlying common diseases and estimate the risk for common diseases, the Tohoku Medical Megabank (TMM) project has conducted prospective cohort studies and genomic and multiomics analyses. To establish an integrated biobank, we developed an integrated database called "dbTMM" that incorporates both the individual cohort/clinical data and the genome/multiomics data of 157,191 participants in the Tohoku Medical Megabank project. To our knowledge, dbTMM is the first database to store individual whole-genome data on a variant-by-variant basis as well as cohort/clinical data for over one hundred thousand participants in a prospective cohort study. dbTMM enables us to stratify our cohort by both genome-wide genetic factors and environmental factors, and it provides a research and development platform that enables prospective analysis of large-scale data from genome cohorts.
Distinctive nuclear zone for RAD51-mediated homologous recombinational DNA repair

Yasunori Horikoshi, Hiroki Shima, Jiying Sun, Wataru Kobayashi, Volker J. Schmid, Hiroshi Ochiai, Lin Shi, Atsuhiko Fukuto, Yasuha Kinugasa, Hitoshi Kurumizaka, Tsuyoshi Ikura, Yolanda Markaki, Shin-ichi Tate, Kazuhiko Igarashi, Thomas Cremer, Satoshi Tashiro

2021/11/30
Publisher: Cold Spring Harbor Laboratory
DOI： 10.1101/2021.11.29.470307 　

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Abstract Genome-based functions are inseparable from the dynamic higher-order architecture of the cell nucleus. In this context, the repair of DNA damage is coordinated by precise spatiotemporal controls that target and regulate the repair machinery required to maintain genome integrity. However, the mechanisms that pair damaged DNA with intact template for repair by homologous recombination (HR) without illegitimate recombination remain unclear. This report highlights the intimate relationship between nuclear architecture and HR in mammalian cells. RAD51, the key recombinase of HR, forms spherical foci in S/G₂ phases spontaneously. Using super-resolution microscopy, we show that following induction of DNA double-strand breaks RAD51 foci at damaged sites elongate to bridge between intact and damaged sister chromatids; this assembly occurs within bundle-shaped distinctive nuclear zones, requires interactions of RAD51 with various factors, and precedes ATP-dependent events involved the recombination of intact and damaged DNA. We observed a time-dependent transfer of single-stranded DNA overhangs, generated during HR, into such zones. Our observations suggest that RAD51-mediated homologous pairing during HR takes place within the distinctive nuclear zones to execute appropriate recombination.
Bach1 derepression is neuroprotective in a mouse model of Parkinson's disease. International-journal

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

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

DOI： 10.1073/pnas.2111643118 　

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Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by the loss of nigrostriatal dopaminergic neurons. Mounting evidence suggests that Nrf2 is a promising target for neuroprotective interventions in PD. However, electrophilic chemical properties of the canonical Nrf2-based drugs cause irreversible alkylation of cysteine residues on cellular proteins resulting in side effects. Bach1 is a known transcriptional repressor of the Nrf2 pathway. We report that Bach1 levels are up-regulated in PD postmortem brains and preclinical models. Bach1 knockout (KO) mice were protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity and associated oxidative damage and neuroinflammation. Functional genomic analysis demonstrated that the neuroprotective effects in Bach1 KO mice was due to up-regulation of Bach1-targeted pathways that are associated with both Nrf2-dependent antioxidant response element (ARE) and Nrf2-independent non-ARE genes. Using a proprietary translational technology platform, a drug library screen identified a substituted benzimidazole as a Bach1 inhibitor that was validated as a nonelectrophile. Oral administration of the Bach1 inhibitor attenuated MPTP neurotoxicity in pre- and posttreatment paradigms. Bach1 inhibitor-induced neuroprotection was associated with the up-regulation of Bach1-targeted pathways in concurrence with the results from Bach1 KO mice. Our results suggest that genetic deletion as well as pharmacologic inhibition of Bach1 by a nonelectrophilic inhibitor is a promising therapeutic approach for PD.
メチオニンアデノシルトランスフェラーゼ2Aによる哺乳類細胞のmTORC1非依存的な翻訳制御機構(mTORC1-independent translational regulation of mammalian cells by methionine adenosyltransferase 2A)

Mahabub Alam, Shima Hiroki, Nguyen Long C., Matsumoto Mitsuyo, Sugiyama Takato, Nobuta Risa, Hashimoto Satoshi, Matsuo Yoshitaka, Inada Toshifumi, Igarashi Kazuhiko

日本生化学会大会プログラム・講演要旨集　94回　[2T15a-666)]　2021/11
Publisher: (公社)日本生化学会
ビリベルジン結合型シアノバクテリオクロムを用いたフェロトーシス高感受性細胞の検出

中嶋一真, 西澤弘成, 成川礼, 松本光代, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　94回　[P-498]　2021/11
Publisher: (公社)日本生化学会
転写因子BACH1が活性化するフェロトーシス細胞由来抗老化シグナルモデル

西澤弘成, 松本光代, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　94回　[2T13a-487)]　2021/11
Publisher: (公社)日本生化学会
Identification and Functional Characterization of a Novel Androgen Receptor Coregulator, EAP1. International-journal

Atsushi Yokoyama, Takumi Kouketsu, Yuri Otsubo, Erika Noro, Shun Sawatsubashi, Hiroki Shima, Ikuro Satoh, Sadafumi Kawamura, Takashi Suzuki, Kazuhiko Igarashi, Akira Sugawara

Journal of the Endocrine Society　5　(11)　bvab150　2021/11/01

DOI： 10.1210/jendso/bvab150 　

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The androgen receptor (AR) plays an essential role in the development of prostate cancer, and androgen-deprivation therapy is used as a first-line treatment for prostate cancer. However, under androgen-deprivation therapy, castration-resistant prostate cancer inevitably arises, suggesting that the interacting transcriptional coregulators of AR are promising targets for developing novel therapeutics. In this study, we used novel proteomic techniques to evaluate the AR interactome, including biochemically labile binding proteins, which might go undetected by conventional purification methods. Using rapid immunoprecipitation mass spectrometry of endogenous proteins, we identified enhanced at puberty 1 (EAP1) as a novel AR coregulator, whereas its interaction with AR could not be detected under standard biochemical conditions. EAP1 enhanced the transcriptional activity of AR via the E3 ubiquitin ligase activity, and its ubiquitination substrate proteins included AR and HDAC1. Furthermore, in prostate cancer specimens, EAP1 expression was significantly correlated with AR expression as well as a poor prognosis of prostate cancer. Together, these results suggest that EAP1 is a novel AR coregulator that promotes AR activity and potentially plays a role in prostate cancer progression.
Protocol for in vitro BCR-mediated plasma cell differentiation and purification of chromatin-associated proteins. International-journal

Kyoko Ochiai, Hiroki Shima, Tsuyoshi Ikura, Marissa C Franke, Evelyn P Sievert, Roger Sciammas, Kazuhiko Igarashi

STAR protocols　2　(3)　100633-100633　2021/09/17

DOI： 10.1016/j.xpro.2021.100633 　

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Molecular-level understanding of plasma cell (PC) differentiation has been modeled using lipopolysaccharide (LPS) stimulation in vitro. However, this system does not involve the B-cell receptor (BCR)-a critical component of B cell biology. Here, we present a protocol for in vitro PC differentiation system dependent on BCR signaling that easily scales up for cell number-demanding applications, including protein complex purification. We describe how to set up this system and detail applications for endogenous complex purification of chromatin-associated proteins. For further details on the use and execution of this protocol, please refer to Sciammas et al. (2011) and Ochiai et al. (2018, 2020).
幹細胞から赤血球への通り道メチオニン代謝によるエピゲノム調節をかいした赤血球造血制御(Methionine metabolism controls erythropoiesis by epigenetic regulation)

加藤浩貴, Long Nugyen, 石井悠翔, 松本光代, 三枝大輔, 舟山亮, 岡江寛明, 藤原亨, 武藤哲彦, 中山啓子, 有馬隆博, Scadden David, 五十嵐和彦, 張替秀郎

日本血液学会学術集会　83回　PSY-4　2021/09
Publisher: (一社)日本血液学会
エピゲノムによるがんの表現型多様性及び可塑性の制御 BACH1遺伝子制御ネットワークによる膵癌細胞の多様性と転移の制御

五十嵐和彦, 西澤弘成, 松本光代

日本癌学会総会記事　80回　[S13-3]　2021/09
Publisher: (一社)日本癌学会
ISSN： 0546-0476
The transcription factor BACH1 at the crossroads of cancer biology: From epithelial–mesenchymal transition to ferroptosis

Kazuhiko Igarashi, Hironari Nishizawa, Yuriko Saiki, Mitsuyo Matsumoto

Journal of Biological Chemistry　297　(3)　101032-101032　2021/09
Publisher: Elsevier BV
DOI： 10.1016/j.jbc.2021.101032 　

ISSN： 0021-9258
膵β細胞におけるグルコース応答性転写因子ChREBPの機能制御因子の探索

横山敦, 野呂英理香, 岡本好司, 松澤拓郎, 吉川雄朗, 島弘季, 五十嵐和彦, 菅原明

日本内分泌学会雑誌　97　(1)　319-319　2021/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
Lipid peroxidation and the subsequent cell death transmitting from ferroptotic cells to neighboring cells. International-journal

Hironari Nishizawa, Mitsuyo Matsumoto, Guan Chen, Yusho Ishii, Keisuke Tada, Masafumi Onodera, Hiroki Kato, Akihiko Muto, Kozo Tanaka, Kazuhiko Igarashi

Cell death & disease　12　(4)　332-332　2021/03/29

DOI： 10.1038/s41419-021-03613-y 　

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Ferroptosis regulated cell death due to the iron-dependent accumulation of lipid peroxide. Ferroptosis is known to constitute the pathology of ischemic diseases, neurodegenerative diseases, and steatohepatitis and also works as a suppressing mechanism against cancer. However, how ferroptotic cells affect surrounding cells remains elusive. We herein report the transfer phenomenon of lipid peroxidation and cell death from ferroptotic cells to nearby cells that are not exposed to ferroptotic inducers (FINs). While primary mouse embryonic fibroblasts (MEFs) and NIH3T3 cells contained senescence-associated β-galactosidase (SA-β-gal)-positive cells, they were decreased upon induction of ferroptosis with FINs. The SA-β-gal decrease was inhibited by ferroptotic inhibitors and knockdown of Atg7, pointing to the involvement of lipid peroxidation and activated autophagosome formation during ferroptosis. A transfer of cell culture medium of cells treated with FINs, type 1 or 2, caused the reduction in SA-β-gal-positive cells in recipient cells that had not been exposed to FINs. Real-time imaging of Kusabira Orange-marked reporter MEFs cocultured with ferroptotic cells showed the generation of lipid peroxide and deaths of the reporter cells. These results indicate that lipid peroxidation and its aftereffects propagate from ferroptotic cells to surrounding cells, even when the surrounding cells are not exposed to FINs. Ferroptotic cells are not merely dying cells but also work as signal transmitters inducing a chain of further ferroptosis.
Novel candidate factors predicting the effect of S-1 adjuvant chemotherapy of pancreatic cancer. International-journal

Katsutaka Mitachi, Kyohei Ariake, Hiroki Shima, Satoko Sato, Takayuki Miura, Shimpei Maeda, Masaharu Ishida, Masamichi Mizuma, Hideo Ohtsuka, Takashi Kamei, Kazuhiko Igarashi, Michiaki Unno

Scientific reports　11　(1)　6541-6541　2021/03/22

DOI： 10.1038/s41598-021-86099-0 　

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The collagen gel droplet-embedded drug sensitivity test (CD-DST) was revealed to be useful for predicting the effect of S-1 adjuvant chemotherapy for pancreatic ductal adenocarcinoma (PDAC). However, collection of an adequate number of PDAC cells is difficult due to the surrounding fibroblasts. Thus, the aim of this study was to discover novel biomarkers to predict chemosensitivity based on the CD-DST results. Proteomics analysis was performed using liquid chromatography tandem mass spectrometry (LC-MS/MS). Candidate proteins were validated in patients with 5-FU CD-DST results via immunohistochemistry (IHC). The relationships between the candidate proteins and the effect of the adjuvant S-1 were investigated via IHC. Among the 2696 proteins extracted by LC-MS/MS, C1TC and SAHH could accurately predict the CD-DST results. Recurrence-free survival (RFS) was significantly improved in the IHC-positive group compared with the IHC-negative group in both factors. The negative group did not show a significant difference from the group that did not receive S-1. The double-positive group was associated with significantly prolonged RFS compared to the no adjuvant chemotherapy group. C1TC and SAHH have been shown to be useful biomarkers for predicting 5-FU sensitivity as a substitute for the CD-DST in adjuvant chemotherapy for PDAC.
Bach1 plays an important role in angiogenesis through regulation of oxidative stress. International-journal

Farina Mohamad Yusoff, Tatsuya Maruhashi, Ki-Ichiro Kawano, Ayumu Nakashima, Kazuaki Chayama, Satoshi Tashiro, Kazuhiko Igarashi, Yukihito Higashi

Microvascular research　134　104126-104126　2021/03

DOI： 10.1016/j.mvr.2020.104126 　

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Bach1 is a known transcriptional repressor of the heme oxygenase-1 (HO-1) gene. The purpose of this study was to determine whether angiogenesis is accelerated by genetic ablation of Bach1 in a mouse ischemic hindlimb model. Hindlimb ischemia was surgically induced in wild-type (WT) mice, Bach1-deficient (Bach1-/-) mice, apolipoprotein E-deficient (ApoE-/-) mice, and Bach1/ApoE double-knockout (Bach1-/-/ApoE-/-) mice. Blood flow recovery after hindlimb ischemia showed significant improvement in Bach1-/- mice compared with that in WT mice. Bach1-/-/ApoE-/- mice showed significantly improved blood flow recovery compared with that in ApoE-/- mice to the level of that in WT mice. Migration of endothelial cells in ApoE-/- mice was significantly decreased compared with that in WT mice. Migration of endothelial cells significantly increased in Bach1-/-/ApoE-/- mice compared with that in ApoE-/- mice to the level of that in WT mice. The expression levels of HO-1, peroxisome proliferator-activated receptor γ co-activator-1α, angiopoietin 1, and fibroblast growth factor 2 in endothelial cells isolated from Bach1-/-/ApoE-/- mice were significantly higher than those in ApoE-/- mice. Oxidative stress assessed by anti-acrolein antibody staining in ischemic tissues and urinary 8-isoPGF2α excretion were significantly increased in ApoE-/- mice compared with those in WT and Bach1-/- mice. Oxidative stress was reduced in Bach1-/-/ApoE-/- mice compared with that in ApoE-/- mice. These findings suggest that genetic ablation of Bach1 plays an important role in ischemia-induced angiogenesis under the condition of increased oxidative stress. Bach1 could be a potential therapeutic target to reduce oxidative stress and potentially improve angiogenesis for patients with peripheral arterial disease.
Study Profile of the Tohoku Medical Megabank Community-Based Cohort Study. Peer-reviewed

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

Journal of epidemiology　31　(1)　65-76　2021/01/05

DOI： 10.2188/jea.JE20190271 　

ISSN： 0917-5040

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BACKGROUND: We established a community-based cohort study to assess the long-term impact of the Great East Japan Earthquake on disaster victims and gene-environment interactions on the incidence of major diseases, such as cancer and cardiovascular diseases. METHODS: We asked participants to join our cohort in the health check-up settings and assessment center based settings. Inclusion criteria were aged 20 years or over and living in Miyagi or Iwate Prefecture. We obtained information on lifestyle, effect of disaster, blood, and urine information (Type 1 survey), and some detailed measurements (Type 2 survey), such as carotid echography and calcaneal ultrasound bone mineral density. All participants agreed to measure genome information and to distribute their information widely. RESULTS: As a result, 87,865 gave their informed consent to join our study. Participation rate at health check-up site was about 70%. The participants in the Type 1 survey were more likely to have psychological distress than those in the Type 2 survey, and women were more likely to have psychological distress than men. Additionally, coastal residents were more likely to have higher degrees of psychological distress than inland residents, regardless of sex. CONCLUSION: This cohort comprised a large sample size and it contains information on the natural disaster, genome information, and metabolome information. This cohort also had several detailed measurements. Using this cohort enabled us to clarify the long-term effect of the disaster and also to establish personalized prevention based on genome, metabolome, and other omics information.
Comparative proteomic analysis to identify the novel target gene of angiotensin II in adrenocortical H295R cells.

Ryo Ito, Hiroki Shima, Koji Masuda, Ikuko Sato, Hiroki Shimada, Atsushi Yokoyama, Katsuhiko Shirahige, Kazuhiko Igarashi, Akira Sugawara

Endocrine journal　68　(4)　441-450　2020/12/26

DOI： 10.1507/endocrj.EJ20-0144 　

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Angiotensin II (Ang II) is a well-known peptide that maintains the balance of electrolytes in the higher vertebrates. Ang II stimulation in the adrenal gland induces the synthesis of mineralocorticoids, mainly aldosterone, through the up-regulation of aldosterone synthase (CYP11B2) gene expression. Additionally, it has been reported that Ang II activates multiple signaling pathways such as mitogen-activated protein kinase (MAPK) and Ca2+ signaling. Although Ang II has various effects on the cellular signaling in the adrenal cells, its biological significance, except for the aldosterone synthesis, is still unclear. In this study, we attempted to search the novel target gene(s) of Ang II in the human adrenal H295R cells using a proteomic approach combined with stable isotopic labeling using amino acid in cell culture (SILAC). Interestingly, we found that Ang II stimulation elevated the expression of phosphofructokinase type platelet (PFKP) in both protein and mRNA levels. Moreover, transactivation of PFKP by Ang II was dependent on extracellular-signal-regulated kinase (ERK) 1/2 activation. Finally, we observed that Ang II treatment facilitated glucose uptake in the H295R cells. Taken together, we here identified PFKP as a novel target gene of Ang II, indicating that Ang II not only stimulates steroidogenesis but also affects glucose metabolism.
Chromatin Protein PC4 Orchestrates B Cell Differentiation by Collaborating with IKAROS and IRF4. International-journal

Kyoko Ochiai, Mari Yamaoka, Amrutha Swaminathan, Hiroki Shima, Hitoshi Hiura, Mitsuyo Matsumoto, Daisuke Kurotaki, Jun Nakabayashi, Ryo Funayama, Keiko Nakayama, Takahiro Arima, Tomokatsu Ikawa, Tomohiko Tamura, Roger Sciammas, Philippe Bouvet, Tapas K Kundu, Kazuhiko Igarashi

Cell reports　33　(12)　108517-108517　2020/12/22

DOI： 10.1016/j.celrep.2020.108517 　

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The chromatin protein positive coactivator 4 (PC4) has multiple functions, including chromatin compaction. However, its role in immune cells is largely unknown. We show that PC4 orchestrates chromatin structure and gene expression in mature B cells. B-cell-specific PC4-deficient mice show impaired production of antibody upon antigen stimulation. The PC4 complex purified from B cells contains the transcription factors (TFs) IKAROS and IRF4. IKAROS protein is reduced in PC4-deficient mature B cells, resulting in de-repression of their target genes in part by diminished interactions with gene-silencing components. Upon activation, the amount of IRF4 protein is not increased in PC4-deficient B cells, resulting in reduction of plasma cells. Importantly, IRF4 reciprocally induces PC4 expression via a super-enhancer. PC4 knockdown in human B cell lymphoma and myeloma cells reduces IKAROS protein as an anticancer drug, lenalidomide. Our findings establish PC4 as a chromatin regulator of B cells and a possible therapeutic target adjoining IKAROS in B cell malignancies.
FABP7 Regulates Acetyl-CoA Metabolism Through the Interaction with ACLY in the Nucleus of Astrocytes. International-journal Peer-reviewed

Yoshiteru Kagawa, Banlanjo Abdulaziz Umaru, Hiroki Shima, Ryo Ito, Ryo Zama, Ariful Islam, Shin-Ichiro Kanno, Akira Yasui, Shun Sato, Kosuke Jozaki, Subrata Kumar Shil, Hirofumi Miyazaki, Shuhei Kobayashi, Yui Yamamoto, Hiroshi Kogo, Chie Shimamoto-Mitsuyama, Akira Sugawara, Norihiro Sugino, Masayuki Kanamori, Teiji Tominaga, Takeo Yoshikawa, Kohji Fukunaga, Kazuhiko Igarashi, Yuji Owada

Molecular neurobiology　57　(12)　4891-4910　2020/12

DOI： 10.1007/s12035-020-02057-3 　

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Fatty acid binding protein 7 (FABP7) is an intracellular fatty acid chaperon that is highly expressed in astrocytes, oligodendrocyte-precursor cells, and malignant glioma. Previously, we reported that FABP7 regulates the response to extracellular stimuli by controlling the expression of caveolin-1, an important component of lipid raft. Here, we explored the detailed mechanisms underlying FABP7 regulation of caveolin-1 expression using primary cultured FABP7-KO astrocytes as a model of loss of function and NIH-3T3 cells as a model of gain of function. We discovered that FABP7 interacts with ATP-citrate lyase (ACLY) and is important for acetyl-CoA metabolism in the nucleus. This interaction leads to epigenetic regulation of several genes, including caveolin-1. Our novel findings suggest that FABP7-ACLY modulation of nuclear acetyl-CoA has more influence on histone acetylation than cytoplasmic acetyl-CoA. The changes to histone structure may modify caveolae-related cell activity in astrocytes and tumors, including malignant glioma.
Proteomic and metabolomic analyses uncover sex-specific regulatory pathways in mouse fetal germline differentiation International-journal Peer-reviewed

Hayashi, Y, Mori, M, Igarashi, K, Tanaka, K, Takehara, A, Ito-Matsuoka, Y, Kanai, A, Yaegashi, N, Soga, T, Matsui, Y

Biol. Reprod.　103　(4)　717-735　2020/10/05
Publisher: Oxford University Press (OUP)
DOI： 10.1093/biolre/ioaa115 　

ISSN： 0006-3363

eISSN： 1529-7268

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Regulatory mechanisms of germline differentiation have generally been explained via the function of signaling pathways, transcription factors, and epigenetic regulation; however, little is known regarding proteomic and metabolomic regulation and their contribution to germ cell development. Here, we conducted integrated proteomic and metabolomic analyses of fetal germ cells in mice on embryonic day (E)13.5 and E18.5 and demonstrate sex- and developmental stage-dependent changes in these processes. In male germ cells, RNA processing, translation, oxidative phosphorylation, and nucleotide synthesis are dominant in E13.5 and then decline until E18.5, which corresponds to the prolonged cell division and more enhanced hyper-transcription/translation in male primordial germ cells and their subsequent repression. Tricarboxylic acid cycle and one-carbon pathway are consistently upregulated in fetal male germ cells, suggesting their involvement in epigenetic changes preceding in males. Increased protein stability and oxidative phosphorylation during female germ cell differentiation suggests an upregulation of aerobic energy metabolism, which likely contributes to the proteostasis required for oocyte maturation in subsequent stages. The features elucidated in this study shed light on the unrevealed mechanisms of germ cell development.
遺伝情報を調節するメチル化連動システム S-アデノシルメチオニン代謝系による遺伝子発現の調節機構

五十嵐和彦, Nguyen Long Chi, 石井悠翔, 加藤浩貴, 落合恭子, 松本光代, 島弘季

日本生化学会大会プログラム・講演要旨集　93回　[3S02m-03]　2020/09
Publisher: (公社)日本生化学会
TBK1-BACH1経路は鉄代謝を調節する(TBK1-BACH1 pathway controls iron metaboilsm)

劉亮, 松本光代, 松井美紀[渡部], 西澤弘成, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　93回　[1Z07-459)]　2020/09
Publisher: (公社)日本生化学会
N 1-methyladenosine (m1A) RNA modification: the key to ribosome control. International-journal Peer-reviewed

Hiroki Shima, Kazuhiko Igarashi

Journal of biochemistry　167　(6)　535-539　2020/06/01

DOI： 10.1093/jb/mvaa026 　

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RNA displays diverse functions in living cells. The presence of various chemical modifications of RNA mediated by enzymes is one of the factors that impart such functional diversity to RNA. Among more than 100 types of RNA modification, N1-methyladenosine (m1A) is found mainly in tRNA and rRNA of many living organisms and is known to be deeply implicated in the topology or function of the two classes of RNA. In this commentary article, we would like to deal with the functional significance of m1A in RNA, and also to describe one methyltransferase installing m1A in a large subunit rRNA, whose orthologue in Caenorhabditis elegans was discovered recently and was reported in this journal.
Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence. International-journal Peer-reviewed

Spencer A Haws, Deyang Yu, Cunqi Ye, Coral K Wille, Long C Nguyen, Kimberly A Krautkramer, Jay L Tomasiewicz, Shany E Yang, Blake R Miller, Wallace H Liu, Kazuhiko Igarashi, Rupa Sridharan, Benjamin P Tu, Vincent L Cryns, Dudley W Lamming, John M Denu

Molecular cell　78　(2)　210-223　2020/04/16

DOI： 10.1016/j.molcel.2020.03.004 　

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S-adenosylmethionine (SAM) is the methyl-donor substrate for DNA and histone methyltransferases that regulate epigenetic states and subsequent gene expression. This metabolism-epigenome link sensitizes chromatin methylation to altered SAM abundance, yet the mechanisms that allow organisms to adapt and protect epigenetic information during life-experienced fluctuations in SAM availability are unknown. We identified a robust response to SAM depletion that is highlighted by preferential cytoplasmic and nuclear mono-methylation of H3 Lys 9 (H3K9) at the expense of broad losses in histone di- and tri-methylation. Under SAM-depleted conditions, H3K9 mono-methylation preserves heterochromatin stability and supports global epigenetic persistence upon metabolic recovery. This unique chromatin response was robust across the mouse lifespan and correlated with improved metabolic health, supporting a significant role for epigenetic adaptation to SAM depletion in vivo. Together, these studies provide evidence for an adaptive response that enables epigenetic persistence to metabolic stress.
BACH1 Promotes Pancreatic Cancer Metastasis by Repressing Epithelial Genes and Enhancing Epithelial-Mesenchymal Transition. International-journal Peer-reviewed

Masaki Sato, Mitsuyo Matsumoto, Yuriko Saiki, Mahabub Alam, Hironari Nishizawa, Masahiro Rokugo, Andrey Brydun, Shinji Yamada, Mika K Kaneko, Ryo Funayama, Mamoru Ito, Yukinari Kato, Keiko Nakayama, Michiaki Unno, Kazuhiko Igarashi

Cancer research　80　(6)　1279-1292　2020/03/15

DOI： 10.1158/0008-5472.CAN-18-4099 　

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Pancreatic ductal adenocarcinoma (PDAC) is among the cancers with the poorest prognoses due to its highly malignant features. BTB and CNC homology 1 (BACH1) has been implicated in RAS-driven tumor formation. We focused on the role of BACH1 in PDAC, more than 90% of which have KRAS mutation. Knockdown of BACH1 in PDAC cell lines reduced cell migration and invasion, in part, by increasing E-cadherin expression, whereas its overexpression showed opposite effects. BACH1 directly repressed the expression of FOXA1 that is known to activate the expression of CDH1 encoding E-cadherin and to inhibit epithelial-to-mesenchymal transition. BACH1 also directly repressed the expression of genes important for epithelial cell adhesion including CLDN3 and CLDN4. In a mouse orthotopic implantation model, BACH1 was required for the high metastatic ability of AsPC-1 cells. IHC analysis of clinical specimens with a newly developed anti-BACH1 mAb revealed that high expression of BACH1 is a poor prognostic factor. These results suggest that the gene regulatory network of BACH1 and downstream genes including CDH1 contribute to the malignant features of PDAC by regulating epithelial-to-mesenchymal transition. SIGNIFICANCE: Greater understanding of the gene regulatory network involved in epithelial-to-mesenchymal transition of pancreatic cancer cells will provide novel therapeutic targets and diagnostic markers.
Increased expression of heme oxygenase-1 suppresses airway branching morphogenesis in fetal mouse lungs exposed to inflammation. International-journal Peer-reviewed

Yukio Arai, Masato Ito, Kosuke Tanaka, Junichi Ozawa, Yukiko Motojima, Kikumi Matsuoka, Kazuhiko Igarashi, Fumihiko Namba

Pediatric research　87　(3)　494-500　2020/02

DOI： 10.1038/s41390-019-0588-0 　

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BACKGROUND: Intrauterine inflammation affects fetal lung development. BTB and CNC homology 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1) and interleukin-6 (IL-6) genes. We investigated the role of Bach1 in the development of fetal mouse lungs exposed to lipopolysaccharide (LPS) using a whole fetal lung tissue culture system. METHODS: We isolated and cultured embryonic day 12.5 fetal mouse lungs from pregnant Bach1 knockout (-/-) and wild-type (WT) mice. Airway branching morphogenesis was assessed by microscopically counting peripheral lung buds after incubation with/without LPS. Expression levels of genes related to inflammation and oxidative stress were evaluated using quantitative PCR. Zinc protoporphyrin, HO-1-specific inhibitor, was used. RESULTS: Branching morphogenesis was observed in Bach1-/- and WT fetal mice lungs without LPS exposure; after exposure to LPS, the number of peripheral lung buds was suppressed in Bach1-/- group only. Basal messenger RNA (mRNA) and protein expression of HO-1 was significantly higher in Bach1-/- group than in WT group; IL-6 and monocyte chemoattractant protein-1 mRNA expression was significantly increased after LPS exposure in both groups. Zinc protoporphyrin mitigated the LPS-induced suppression of branching morphogenesis in Bach1-/- mice. CONCLUSION: The ablation of Bach1 suppresses airway branching morphogenesis after LPS exposure by increased basal expression levels of HO-1.
Aurora kinase A-mediated phosphorylation of mPOU at a specific site drives skeletal muscle differentiation. International-journal Peer-reviewed

Dhanasekan Karthigeyan, Arnab Bose, Ramachandran Boopathi, Vinay Jaya Rao, Hiroki Shima, Narendra Bharathy, Kazuhiko Igarashi, Reshma Taneja, Arun Kumar Trivedi, Tapas K Kundu

Journal of biochemistry　167　(2)　195-201　2020/02/01

DOI： 10.1093/jb/mvz088 　

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Aurora kinases are Ser/Thr-directed protein kinases which play pivotal roles in mitosis. Recent evidences highlight the importance of these kinases in multiple biological events including skeletal muscle differentiation. Our earlier study identified the transcription factor POU6F1 (or mPOU) as a novel Aurora kinase (Aurk) A substrate. Here, we report that Aurora kinase A phosphorylates mPOU at Ser197 and inhibit its DNA-binding ability. Delving into mPOU physiology, we find that the phospho-mimic (S197D) mPOU mutant exhibits enhancement, while the wild type or the phospho-deficient mutant shows retardation in C2C12 myoblast differentiation. Interestingly, POU6F1 depletion phenocopies S197D-mPOU overexpression in the differentiation context. Collectively, our results signify mPOU as a negative regulator of skeletal muscle differentiation and strengthen the importance of AurkA in skeletal myogenesis.
Cohort Profile: Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study): rationale, progress and perspective. International-journal Peer-reviewed

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

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

DOI： 10.1093/ije/dyz169 　

ISSN： 0300-5771
Ferroptosis is controlled by the coordinated transcriptional regulation of glutathione and labile iron metabolism by the transcription factor BACH1. International-journal Peer-reviewed

Hironari Nishizawa, Mitsuyo Matsumoto, Tomohiko Shindo, Daisuke Saigusa, Hiroki Kato, Katsushi Suzuki, Masaki Sato, Yusho Ishii, Hiroaki Shimokawa, Kazuhiko Igarashi

The Journal of biological chemistry　295　(1)　69-82　2020/01/03

DOI： 10.1074/jbc.RA119.009548 　

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Ferroptosis is an iron-dependent programmed cell death event, whose regulation and physiological significance remain to be elucidated. Analyzing transcriptional responses of mouse embryonic fibroblasts exposed to the ferroptosis inducer erastin, here we found that a set of genes related to oxidative stress protection is induced upon ferroptosis. We considered that up-regulation of these genes attenuates ferroptosis induction and found that the transcription factor BTB domain and CNC homolog 1 (BACH1), a regulator in heme and iron metabolism, promotes ferroptosis by repressing the transcription of a subset of the erastin-induced protective genes. We noted that these genes are involved in the synthesis of GSH or metabolism of intracellular labile iron and include glutamate-cysteine ligase modifier subunit (Gclm), solute carrier family 7 member 11 (Slc7a11), ferritin heavy chain 1 (Fth1), ferritin light chain 1 (Ftl1), and solute carrier family 40 member 1 (Slc40a1). Ferroptosis has also been previously shown to induce cardiomyopathy, and here we observed that Bach1-/- mice are more resistant to myocardial infarction than WT mice and that the severity of ischemic injury is decreased by the iron-chelator deferasirox, which suppressed ferroptosis. Our findings suggest that BACH1 represses genes that combat labile iron-induced oxidative stress, and ferroptosis is stimulated at the transcriptional level by BACH1 upon disruption of the balance between the transcriptional induction of protective genes and accumulation of iron-mediated damage. We propose that BACH1 controls the threshold of ferroptosis induction and may represent a therapeutic target for alleviating ferroptosis-related diseases, including myocardial infarction.
Bach1 promotes muscle regeneration through repressing Smad-mediated inhibition of myoblast differentiation. International-journal Peer-reviewed

Katsushi Suzuki, Mitsuyo Matsumoto, Yasutake Katoh, Liang Liu, Kyoko Ochiai, Yuta Aizawa, Ryoichi Nagatomi, Hiroshi Okuno, Eiji Itoi, Kazuhiko Igarashi

PloS one　15　(8)　e0236781　2020

DOI： 10.1371/journal.pone.0236781 　

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It has been reported that Bach1-deficient mice show reduced tissue injuries in diverse disease models due to increased expression of heme oxygenase-1 (HO-1)that possesses an antioxidant function. In contrast, we found that Bach1 deficiency in mice exacerbated skeletal muscle injury induced by cardiotoxin. Inhibition of Bach1 expression in C2C12 myoblast cells using RNA interference resulted in reduced proliferation, myotube formation, and myogenin expression compared with control cells. While the expression of HO-1 was increased by Bach1 silencing in C2C12 cells, the reduced myotube formation was not rescued by HO-1 inhibition. Up-regulations of Smad2, Smad3 and FoxO1, known inhibitors of muscle cell differentiation, were observed in Bach1-deficient mice and Bach1-silenced C2C12 cells. Therefore, Bach1 may promote regeneration of muscle by increasing proliferation and differentiation of myoblasts.
Stromal expression of hemopexin is associated with lymph-node metastasis in pancreatic ductal adenocarcinoma. International-journal Peer-reviewed

Yukie Suzuki, Tatsuyuki Takadate, Masamichi Mizuma, Hiroki Shima, Takashi Suzuki, Tomoyoshi Tachibana, Mitsuhiro Shimura, Tatsuo Hata, Masahiro Iseki, Kei Kawaguchi, Takeshi Aoki, Hiroki Hayashi, Takanori Morikawa, Kei Nakagawa, Fuyuhiko Motoi, Takeshi Naitoh, Kazuhiko Igarashi, Michiaki Unno

PloS one　15　(7)　e0235904　2020

DOI： 10.1371/journal.pone.0235904 　

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Pancreatic ductal adenocarcinoma is one of the most aggressive types of cancer. Certain proteins in the tumor microenvironment have attracted considerable attention owing to their association with tumor invasion and metastasis. Here, we used proteomics to identify proteins associated with lymph-node metastasis, which is one of the prognostic factors. We selected lymph node metastasis-positive and -negative patients (n = 5 each) who underwent pancreatectomy between 2005 and 2015 and subjected to comprehensive proteomic profiling of tumor stroma. A total of 490 proteins were detected by mass spectrometry. Software analysis revealed that nine of these proteins were differentially expressed between the two patient groups. We focused on hemopexin and ferritin light chain based on immunohistochemistry results. We assessed the clinicopathological data of 163 patients and found that hemopexin expression was associated with UICC N2 (p = 0.0399), lymph node ratio (p = 0.0252), venous invasion (p = 0.0096), and lymphatic invasion (p = 0.0232). Notably, in vitro assays showed that hemopexin promotes invasion of the pancreatic cancer cells. Our findings suggest that hemopexin is a lymph node metastasis-associated protein that could potentially serve as a useful therapeutic target or biomarker of pancreatic ductal adenocarcinoma.
Haploinsufficient tumor suppressor Tip60 negatively regulates oncogenic Aurora B kinase. International-journal Peer-reviewed

Arnab Bose, Surabhi Sudevan, Vinay J Rao, Hiroki Shima, Arun Kumar Trivedi, Kazuhiko Igarashi, Tapas K Kundu

Journal of biosciences　44　(6)　2019/12

DOI： 10.1007/s12038-019-9963-6 　

ISSN： 0250-5991

eISSN： 0973-7138
To be red or white: lineage commitment and maintenance of the hematopoietic system by the "inner myeloid". International-journal Peer-reviewed

Hiroki Kato, Kazuhiko Igarashi

Haematologica　104　(10)　1919-1927　2019/10

DOI： 10.3324/haematol.2019.216861 　

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Differentiation of hematopoietic stem and progenitor cells is tightly regulated depending on environmental changes in order to maintain homeostasis. Transcription factors direct the development of hematopoietic cells, such as GATA-1 for erythropoiesis and PU.1 for myelopoiesis. However, recent findings obtained from single-cell analyses raise the question of whether these transcription factors are "initiators" or just "executors" of differentiation, leaving the initiation of hematopoietic stem and progenitor cell differentiation (i.e. lineage commitment) unclear. While a stochastic process is likely involved in commitment, it cannot fully explain the homeostasis of hematopoiesis nor "on-demand" hematopoiesis in response to environmental changes. Transcription factors BACH1 and BACH2 may regulate both commitment and on-demand hematopoiesis because they control erythroid-myeloid and lymphoid-myeloid differentiation by repressing the myeloid program, and their activities are repressed in response to infectious and inflammatory conditions. We summarize possible mechanisms of lineage commitment of hematopoietic stem and progenitor cells suggested by recent findings and discuss the erythroid and lymphoid commitment of hematopoietic stem and progenitor cells, focusing on the gene regulatory network composed of genes encoding key transcription factors. Surprising similarity exists between commitment to erythroid and lymphoid lineages, including repression of the myeloid program by BACH factors. The suggested gene regulatory network of BACH factors sheds light on the myeloid-based model of hematopoiesis. This model will help to understand the tuning of hematopoiesis in higher eukaryotes in the steady-state condition as well as in emergency conditions, the evolutional history of the system, aging and hematopoietic disorders.
細胞内SAM濃度レポーターに基づいたスクリーニング系による新規MAT2A阻害剤の同定

奈良和樹, 石井悠翔, 加藤浩貴, 島弘季, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　92回　[2T13m-06]　2019/09
Publisher: (公社)日本生化学会
ヘムシグナルによる転写因子BACH2のリン酸化と相互作用因子の制御

松井美紀, 角屋駿, 島弘季, 武藤哲彦, 松本光代, 白水美香子, 村山和隆, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　92回　[3T15m-03]　2019/09
Publisher: (公社)日本生化学会
膵β細胞におけるグルコース応答性転写因子ChREBPの機能制御因子の探索

横山敦, 野呂英理香, 松澤拓郎, 吉川雄朗, 島弘季, 五十嵐和彦, 菅原明

日本生化学会大会プログラム・講演要旨集　92回　[3T15m-04]　2019/09
Publisher: (公社)日本生化学会
Erratum for Shen et al., "Identification of a Novel Enhancer/Chromatin Opening Element Associated with High-Level γ-Globin Gene Expression". International-journal

Yong Shen, MacLean A Bassett, Aishwarya Gurumurthy, Rukiye Nar, Isaac J Knudson, Cameron R Guy, Alex Perez, Russell W Mellen, Masatoshi Ikeda, Mir A Hossain, Suming Huang, Kazuhiko Igarashi, Jörg Bungert

Molecular and cellular biology　39　(11)　2019/06/01

DOI： 10.1128/MCB.00168-19 　
Biophysical characterization of heme binding to the intrinsically disordered region of Bach1. International-journal Peer-reviewed

Segawa K, Watanabe-Matsui M, Tsuda K, Matsui T, Shirouzu M, Igarashi K, Murayama K

European biophysics journal : EBJ　48　(4)　361-369　2019/05

DOI： 10.1007/s00249-019-01364-5 　

ISSN： 0175-7571

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Transcriptional repressor Bach1 plays an important role in antioxidant response. Bach1 function is regulated by heme binding to the four cysteine-proline (CP) motifs in Bach1, which leads to inhibition of its activity. Three of these CP motifs are located N-terminal to the bZip (basic leucine zipper) domain that is responsible for DNA binding. Based on sequence analysis, the region surrounding these CP motifs was expected to be intrinsically disordered. Bach1 is one of few known intrinsically disordered proteins that accept multiple heme molecules for functional regulation, but the molecular mechanisms of heme binding and functional regulation remain unclear. Uncovering these mechanisms is important for understanding Bach1-mediated antioxidant response. Biophysical characterization revealed that 5-coordinated heme binding was unique to the CP motifs within the heme-binding region of Bach1, whereas 6-coordinated binding occurred nonspecifically. Comparison of the wild-type protein and a CP motif mutant indicated that the level of 6-coordinated heme binding was reduced in the absence of 5-coordinated heme binding. Analytical ultracentrifugation showed that the CP motif mutant protein had a more elongated conformation than the wild-type protein, suggesting that cysteines within the CP motifs contribute to intramolecular interactions in Bach1. Thus, heme binding at the CP motifs induces a global conformational change in the Bach1 heme-binding region, and this conformational change, in turn, regulates the biological activity of Bach1.
TLR4 activation alters labile heme levels to regulate BACH1 and heme oxygenase-1 expression in macrophages.

Sudan K, Vijayan V, Madyaningrana K, Gueler F, Igarashi K, roberta foresti, Roberto Motterlini, Stephan Immenschuh

Free radical biology & medicine　2019/04/24

DOI： 10.1016/j.freeradbiomed.2019.04.024 　

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Heme oxygenase (HO)-1, a stress-inducible enzyme that converts heme into carbon monoxide (CO), iron and biliverdin, exerts important anti-inflammatory effects in activated macrophages. HO-1 expression is mainly governed by a mutual interplay between the transcriptional factor NRF2 and the nuclear repressor BTB and CNC homology 1 (BACH1), a heme sensor protein. In the current study we hypothesized that alterations in the levels of intracellular labile heme in macrophages stimulated by lipopolysaccharide (LPS), a prototypical pro-inflammatory Toll-like receptor (TLR)4 agonist, are responsible for BACH1-dependent HO-1 expression. To this end, labile heme was determined in both mouse bone marrow-derived macrophages (mBMDMs) and human monocyte-derived macrophages (hMDMs) using an apo-horseradish peroxidase-based assay. We found that LPS raised the levels of labile heme, depressed BACH1 protein and up-regulated HO-1 in mBMDMs. In contrast, in hMDMs LPS decreased labile heme levels while increasing BACH1 expression and down-regulating HO-1. These effects were abolished by the TLR4 antagonist TAK-242, suggesting that TLR4 activation triggers the signaling cascade leading to changes in the labile heme pool. Studies using mBMDMs from BACH1-/- and NRF2-/- mice revealed that regulation of HO-1 and levels of labile heme after LPS stimulation are strictly dependent on BACH1, but not NRF2. A strong interplay between BACH1-mediated HO-1 expression and intracellular levels of labile heme was also confirmed in hMDMs with siRNA knockdown studies and following inhibition of de novo heme synthesis with succinylacetone. Finally, CORM-401, a compound that liberates CO, counteracted LPS-dependent down-regulation of HO-1 and restored levels of labile heme in hMDMs. In conclusion, alterations of labile heme levels in macrophages following TLR4 stimulation play a crucial role in BACH1-mediated regulation of HO-1 expression.
Lactate dehydrogenase C is required for the protein expression of a sperm-specific isoform of lactate dehydrogenase A. International-journal Peer-reviewed

Mina Dodo, Hiroshi Kitamura, Hiroki Shima, Daisuke Saigusa, Sisca Meida Wati, Nao Ota, Fumiki Katsuoka, Hatsune Chiba, Hiroaki Okae, Takahiro Arima, Kazuhiko Igarashi, Takeyoshi Koseki, Hiroki Sekine, Hozumi Motohashi

Journal of biochemistry　165　(4)　323-334　2019/04/01

DOI： 10.1093/jb/mvy108 　

ISSN： 0021-924X

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Metabolites are sensitive indicators of moment-to-moment cellular status and activity. Expecting that tissue-specific metabolic signatures unveil a unique function of the tissue, we examined metabolomes of mouse liver and testis and found that an unusual metabolite, 2-hydroxyglutarate (2-HG), was abundantly accumulated in the testis. 2-HG can exist as D- or L-enantiomer, and both enantiomers interfere with the activities of 2-oxoglutarate (2-OG)-dependent dioxygenases, such as the Jumonji family of histone demethylases. Whereas D-2-HG is produced by oncogenic mutants of isocitrate dehydrogenases (IDH) and known as an oncometabolite, L-2-HG was the major enantiomer detected in the testis, suggesting that a distinct mechanism underlies the testicular production of this metabolite. We clarified that lactate dehydrogenase C (LDHC), a testis-specific lactate dehydrogenase, is responsible for L-2-HG accumulation by generating and analysing Ldhc-deficient mice. Although the inhibitory effects of 2-HG on 2-OG-dependent dioxygenases were barely observed in the testis, the LDHA protein level was remarkably decreased in Ldhc-deficient sperm, indicating that LDHC is required for LDHA expression in the sperm. This unique functional interaction between LDH family members supports lactate dehydrogenase activity in the sperm. The severely impaired motility of Ldhc-deficient sperm suggests a substantial contribution of glycolysis to energy production for sperm motility.
Functional Heme Binding to the Intrinsically Disordered C-Terminal Region of Bach1, a Transcriptional Repressor Peer-reviewed

K. Segawa, M. Watanabe-Matsui, T. Matsui, K. Igarashi, K. Murayama

Tohoku J. Exp. Med.　247　(3)　153-159　2019/03

DOI： 10.1620/tjem.247.153 　

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Heme is one of the key factors involved in the oxidative stress response of cells. The transcriptional repressor Bach1 plays an important role in this response through its heme-binding activity. Heme inhibits the transcriptional-repressor activity of Bach1, and can occur in two binding modes: 5- and 6-coordinated binding. The Cys-Pro (CP) motif has been determined to be the heme-binding motif of Bach family proteins. The sequence of Bach1 includes six CP motifs, and four CP motifs are functional. With the aim of elucidating the molecular mechanism of heme-Bach1 regulation, we conducted biophysical analyses focusing on the C-terminal region of mouse Bach1 (residues 631-739) which is located after the bZip domain and includes one functional CP motif. UV-Vis spectroscopy indicated that the CP motif binds heme via 5-coordinated bond. A mutant, which included a cysteine to alanine substitution at the CP motif, did not show 5-coordination, suggesting that this binding mode is specific to the CP motif. Surface plasmon resonance revealed that the binding affinity and stoichiometry of heme with the Bach1 C-terminal region were KD = 1.37 × 10-5 M and 2.3, respectively. The circular dichroism spectrum in the near-UV region exhibited peaks for heme binding to the CP motif. No significant spectral shifts were observed in the far-UV region when samples with and without heme were compared. Therefore, disordered-ordered transition such as "coupled folding and binding" is not involved in the Bach1-heme system. Consequently, the heme response of this C-terminal region is accomplished by disorder-disorder conformational alteration.
Strategy towards tailored donor tissue-specific pancreatic islet isolation. International-journal Peer-reviewed

Yuki Miyazaki, Kazutaka Murayama, Ibrahim Fathi, Takehiro Imura, Youhei Yamagata, Kimiko Watanabe, Hiroshi Maeda, Akiko Inagaki, Yasuhiro Igarashi, Shigehito Miyagi, Hiroki Shima, Kazuhiko Igarashi, Takashi Kamei, Michiaki Unno, Masafumi Goto

PloS one　14　(5)　e0216136　2019

DOI： 10.1371/journal.pone.0216136 　

ISSN： 1932-6203
Target of rapamycin-signaling modulates starch accumulation via glycogenin phosphorylation status in the unicellular red alga Cyanidioschyzon merolae. Peer-reviewed

Pancha I, Shima H, Higashitani N, Igarashi K, Higashitani A, Kan Tanaka, Sousuke Imamura

The Plant journal : for cell and molecular biology　97　(3)　485-499　2018/11/28

DOI： 10.1111/tpj.14136 　

ISSN： 0960-7412
Infection perturbs Bach2- and Bach1-dependent erythroid lineage 'choice' to cause anemia. International-journal Peer-reviewed

Hiroki Kato, Ari Itoh-Nakadai, Mitsuyo Matsumoto, Yusho Ishii, Miki Watanabe-Matsui, Masatoshi Ikeda, Risa Ebina-Shibuya, Yuki Sato, Masahiro Kobayashi, Hironari Nishizawa, Katsushi Suzuki, Akihiko Muto, Tohru Fujiwara, Yasuhito Nannya, Luca Malcovati, Mario Cazzola, Seishi Ogawa, Hideo Harigae, Kazuhiko Igarashi

Nature immunology　19　(10)　1059-1070　2018/10

DOI： 10.1038/s41590-018-0202-3 　

ISSN： 1529-2908

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Elucidation of how the differentiation of hematopoietic stem and progenitor cells (HSPCs) is reconfigured in response to the environment is critical for understanding the biology and disorder of hematopoiesis. Here we found that the transcription factors (TFs) Bach2 and Bach1 promoted erythropoiesis by regulating heme metabolism in committed erythroid cells to sustain erythroblast maturation and by reinforcing erythroid commitment at the erythro-myeloid bifurcation step. Bach TFs repressed expression of the gene encoding the transcription factor C/EBPβ, as well as that of its target genes encoding molecules important for myelopoiesis and inflammation; they achieved the latter by binding to their regulatory regions also bound by C/EBPβ. Lipopolysaccharide diminished the expression of Bach TFs in progenitor cells and promoted myeloid differentiation. Overexpression of Bach2 in HSPCs promoted erythroid development and inhibited myelopoiesis. Knockdown of BACH1 or BACH2 in human CD34+ HSPCs impaired erythroid differentiation in vitro. Thus, Bach TFs accelerate erythroid commitment by suppressing the myeloid program at steady state. Anemia of inflammation and myelodysplastic syndrome might involve reduced activity of Bach TFs.
Oral recombinant methioninase (o-rMETase) is superior to injectable rMETase and overcomes acquired gemcitabine resistance in pancreatic cancer Peer-reviewed

Kei Kawaguchi, Kentaro Miyake, Qinghong Han, Shukuan Li, Yuying Tan, Kentaro Igarashi, Tasuku Kiyuna, Masuyo Miyake, Takashi Higuchi, Hiromichi Oshiro, Zhiying Zhang, Sahar Razmjooei, Sintawat Wangsiricharoen, Michael Bouvet, Shree Ram Singh, Michiaki Unno, Robert M. Hoffman

Cancer Letters　432　251-259　2018/09/28
Publisher: Elsevier Ireland Ltd
DOI： 10.1016/j.canlet.2018.06.016 　

ISSN： 1872-7980 0304-3835
Identification of a Novel Enhancer/Chromatin Opening Element Associated with High-Level γ-Globin Gene Expression. Peer-reviewed

Shen Y, Bassett MA, Gurumurthy A, Nar R, Isaac Knudson, Guy CR, Perez A, Mellen RW, Ikeda M, Hossain MA, Huang S, Igarashi K, Bungert J

Molecular and cellular biology　2018/09/14

DOI： 10.1128/mcb.00197-18 　

ISSN： 0270-7306

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The organization of the five β-type globin genes on chromosome 11 reflects the timing of expression during erythroid cell development, with the embryonic ε-globin gene being located at the 5' end, followed by the two fetal γ-globin genes, and with the adult β- and δ-globin genes being located at the 3' end. Here, we functionally characterized a DNase I-hypersensitive site (HS) located 4 kb upstream of the Gγ-globin gene (HBG-4kb HS). This site is occupied by transcription factors USF1, USF2, EGR1, MafK, and NF-E2 in the human erythroleukemia cell line K562 and exhibits histone modifications typical for enhancers. We generated a synthetic zinc finger (ZF) DNA-binding domain targeting the HBG-4kb HS (HBG-4kb ZF). The HBG-4kb ZF interacted with the target site in vitro and in the context of cells with a high affinity and specificity. Direct delivery of the HBG-4kb ZF to K562 and primary human erythroid cells caused a reduction in γ-globin gene expression which was associated with decreased binding of transcription factors and active histone marks at and downstream of the HS. The data demonstrate that the HBG-4kb HS is important for fetal globin production and suggest that it may act by opening chromatin in a directional manner.
O-GlcNAcylation Signal Mediates Proteasome Inhibitor Resistance in Cancer Cells by Stabilizing NRF1. International-journal Peer-reviewed

Hiroki Sekine, Keito Okazaki, Koichiro Kato, M Morshedul Alam, Hiroki Shima, Fumiki Katsuoka, Tadayuki Tsujita, Norio Suzuki, Akira Kobayashi, Kazuhiko Igarashi, Masayuki Yamamoto, Hozumi Motohashi

Molecular and cellular biology　38　(17)　2018/09/01

DOI： 10.1128/MCB.00252-18 　

ISSN： 0270-7306

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Cancer cells often heavily depend on the ubiquitin-proteasome system (UPS) for their growth and survival. Irrespective of their strong dependence on the proteasome activity, cancer cells, except for multiple myeloma, are mostly resistant to proteasome inhibitors. A major cause of this resistance is the proteasome bounce-back response mediated by NRF1, a transcription factor that coordinately activates proteasome subunit genes. To identify new targets for efficient suppression of UPS, we explored, using immunoprecipitation and mass spectrometry, the possible existence of nuclear proteins that cooperate with NRF1 and identified O-linked N-acetylglucosamine transferase (OGT) and host cell factor C1 (HCF-1) as two proteins capable of forming a complex with NRF1. O-GlcNAcylation catalyzed by OGT was essential for NRF1 stabilization and consequent upregulation of proteasome subunit genes. Meta-analysis of breast and colorectal cancers revealed positive correlations in the relative protein abundance of OGT and proteasome subunits. OGT inhibition was effective at sensitizing cancer cells to a proteasome inhibitor both in culture cells and a xenograft mouse model. Since active O-GlcNAcylation is a feature of cancer metabolism, our study has clarified a novel linkage between cancer metabolism and UPS function and added a new regulatory axis to the regulation of the proteasome activity.
MEK inhibitor trametinib in combination with gemcitabine regresses a patient-derived orthotopic xenograft (PDOX) pancreatic cancer nude mouse model Peer-reviewed

Kei Kawaguchi, Kentaro Igarashi, Kentaro Miyake, Thinzar M. Lwin, Masuyo Miyake, Tasuku Kiyuna, Ho Kyoung Hwang, Takashi Murakami, Jonathan C. Delong, Shree Ram Singh, Bryan Clary, Michael Bouvet, Michiaki Unno, Robert M. Hoffman

Tissue and Cell　52　124-128　2018/06/01
Publisher: Elsevier Ltd
DOI： 10.1016/j.tice.2018.05.003 　

ISSN： 1532-3072 0040-8166
A novel liver metastasis-correlated protein of pancreatic neuroendocrine neoplasm (PanNEN) discovered by proteomic analysis. International-journal Peer-reviewed

Mitsuhiro Shimura, Masamichi Mizuma, Tatsuyuki Takadate, Yasutake Katoh, Takashi Suzuki, Masahiro Iseki, Tatsuo Hata, Shuichi Aoki, Yukie Suzuki, Naoaki Sakata, Hideo Ohtsuka, Hiroki Hayashi, Takanori Morikawa, Kei Nakagawa, Fuyuhiko Motoi, Takeshi Naitoh, Kazuhiko Igarashi, Hironobu Sasano, Michiaki Unno

Oncotarget　9　(36)　24291-24303　2018/05/11

DOI： 10.18632/oncotarget.25110 　

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The aim of this study was to identify novel liver metastasis-correlated proteins of PanNEN by proteomics to compare pancreatic tumor (PT) with paired metastatic liver tumor (LT). Of 118 surgical cases with PanNEN, 7 cases with formalin-fixed paraffin-embedded (FFPE) tissues of both PT and paired LT were evaluated by proteomics. Tumor cells were selectively collected from FFPE tissues by laser capture microdissection. A total of 3,722 proteins were detected from extracted peptides by mass spectrometry-based shotgun analysis. Selection of the candidate proteins expressed differently between PT and LT were performed by semi-quantitative comparison in silico and confirmation with immunohistochemistry. We focused on ANXA6, CNPY2, RAB11B and TUBB3, all of which had higher expressions in LT. In all surgical cases with FFPE samples, liver recurrence-free survival (RFS) was evaluated in correlation to the expression of the candidate proteins in PT by immunohistochemistry. Liver RFS was significantly poorer in CNPY2 positive patients than in negative patients (10-year liver RFS; 39.8% vs. 92.3%, p = 0.012). Also, liver RFS tended to be poorer in ANXA6 positive patients than in those who were negative (10-year liver RFS; 51.4% vs. 95.0%, p = 0.099). In the multivariate analysis, the independent predictors of liver RFS were CNPY2 positivity (HR: 6.19, 95 % CI: 1.47-42.79, p = 0.011) and tumor size ≥ 42 mm (HR: 4.63, 95 % CI: 1.03-23.23, p = 0.045). In conclusion, CNPY2 is a novel liver metastasis-correlated protein of PanNEN.
Endogenous purification of NR4A2 (Nurr1) identified poly(ADP-ribose) polymerase 1 as a prime coregulator in human adrenocortical H295R cells Peer-reviewed

Erika Noro, Atsushi Yokoyama, Makoto Kobayashi, Hiroki Shimada, Susumu Suzuki, Mari Hosokawa, Tomohiro Takehara, Rehana Parvin, Hiroki Shima, Kazuhiko Igarashi, Akira Sugawara

International Journal of Molecular Sciences　19　(5)　2018/05/08
Publisher: MDPI AG
DOI： 10.3390/ijms19051406 　

ISSN： 1422-0067 1661-6596
Bach2 promotes B cell receptor–induced proliferation of b lymphocytes and represses cyclin-dependent kinase inhibitors Peer-reviewed

Yuichi Miura, Mizuho Morooka, Nicolas Sax, Rahul Roychoudhuri, Ari Itoh-Nakadai, Andrey Brydun, Ryo Funayama, Keiko Nakayama, Susumu Satomi, Mitsuyo Matsumoto, Kazuhiko Igarashi, Akihiko Muto

Journal of Immunology　200　(8)　2882-2893　2018/04/15
Publisher: American Association of Immunologists
DOI： 10.4049/jimmunol.1601863 　

ISSN： 1550-6606 0022-1767
Dysregulated heme oxygenase-1low M2-like macrophages augment lupus nephritis via Bach1 induced by type I interferons Peer-reviewed

Daiga Kishimoto, Yohei Kirino, Maasa Tamura, Mitsuhiro Takeno, Yosuke Kunishita, Kaoru Takase-Minegishi, Hiroto Nakano, Ikuma Kato, Kiyotaka Nagahama, Ryusuke Yoshimi, Kazuhiko Igarashi, Ichiro Aoki, Hideaki Nakajima

Arthritis Research and Therapy　20　(1)　64　2018/04/10
Publisher: BioMed Central Ltd.
DOI： 10.1186/s13075-018-1568-1 　

ISSN： 1478-6362 1478-6354
Zinc finger-IRF composite elements bound by Ikaros/IRF4 complexes function as gene repression in plasma cell. Peer-reviewed

Ochiai K, Kondo H, Yasunobu Okamura, Shima H, Kurokochi Y, Kimura K, Funayama R, Nagashima T, Nakayama K, Yui K, Kinoshita K, Igarashi K

Blood advances　2　(8)　883-894　2018/04/01

DOI： 10.1182/bloodadvances.2017010413 　

ISSN： 2473-9529

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The transcription factor (TF) interferon regulatory factor-4 (IRF4) promotes both germinal center (GC) reactions and plasma cell (PC) differentiation by binding to alternative DNA motifs including AP-1-IRF composite elements, Ets-IRF composite elements (EICEs), and interferon sequence response elements (ISREs). Although all of these motifs mediate transcriptional activation by IRF4, it is still unknown how some of the IRF4 target genes are downregulated upon PC differentiation. Here, we revealed a molecular mechanism of IRF4-mediated gene downregulation during PC differentiation. By combining IRF4 chromatin immunoprecipitation sequence and gene expression analysis, we identified zinc finger-IRF composite elements (ZICEs) in IRF4 binding regions aligned with genes whose expression was downregulated in PCs. The zinc finger TFs Ikaros and Aiolos were identified as IRF4 binding partners in PCs, and Ikaros but not Aiolos was essential for IRF4 binding to the ZICE sequence and for PC differentiation. The Ebf1 gene, which positively controls B-cell activation and GC reactions, was identified as one of the Ikaros/IRF4 target genes. Importantly, while the ZICE embeds the ISRE motif, IRF4 bound the ZICE motif as heterodimers with Ikaros for repression of target genes, which include Ebf1 In contrast, if the zinc finger motif is juxtaposed to the EICE motif, the Ikaros/PU.1/IRF4 complex functioned to activate target gene expression. Our findings revealed a novel mode of IRF4 activity upon PC differentiation where upon forming an Ikaros/IRF4 DNA-bound complex, a subset of genes is repressed.
Phosphorylation of BACH1 switches its function from transcription factor to mitotic chromosome regulator and promotes its interaction with HMMR Peer-reviewed

Jie Li, Hiroki Shima, Hironari Nishizawa, Masatoshi Ikeda, Andrey Brydun, Mitsuyo Matsumoto, Hiroki Kato, Yuriko Saiki, Liang Liu, Miki Watanabe-Matsui, Kenji Iemura, Kozo Tanaka, Takuma Shiraki, Kazuhiko Igarashi

Biochemical Journal　475　(5)　981-1002　2018/03/15
Publisher: Portland Press Ltd
DOI： 10.1042/BCJ20170520 　

ISSN： 1470-8728 0264-6021

eISSN： 1470-8728
Transcription Factor IRF8 Governs Enhancer Landscape Dynamics in Mononuclear Phagocyte Progenitors. International-journal Peer-reviewed

Daisuke Kurotaki, Jun Nakabayashi, Akira Nishiyama, Haruka Sasaki, Wataru Kawase, Naofumi Kaneko, Kyoko Ochiai, Kazuhiko Igarashi, Keiko Ozato, Yutaka Suzuki, Tomohiko Tamura

Cell reports　22　(10)　2628-2641　2018/03/06

DOI： 10.1016/j.celrep.2018.02.048 　

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Monocytes and dendritic cells (DCs), mononuclear phagocytes essential for immune responses, develop from hematopoietic stem cells via monocyte-DC progenitors (MDPs). The molecular basis of their development remains unclear. Because promoter-distal enhancers are key to cell fate decisions, we analyzed enhancer landscapes during mononuclear phagocyte development in vivo. Monocyte- and DC-specific enhancers were gradually established at progenitor stages before the expression of associated genes. Of the transcription factors predicted to bind to these enhancers, IRF8, essential for monocyte and DC development, was found to be required for the establishment of these enhancers, particularly those common to both monocyte and DC lineages. Although Irf8-/- mononuclear phagocyte progenitors, including MDPs, displayed grossly normal gene expression patterns, their enhancer landscapes resembled that of an upstream progenitor population. Our results illustrate the dynamic process by which key transcription factors regulate enhancer formation and, therefore, direct future gene expression to achieve mononuclear phagocyte development.
Individualized doxorubicin sensitivity testing of undifferentiated soft tissue sarcoma (USTS) in a patient-derived orthotopic xenograft (PDOX) model demonstrates large differences between patients Peer-reviewed

Kei Kawaguchi, Kentaro Igarashi, Tasuku Kiyuna, Kentaro Miyake, Masuyo Miyake, Takashi Murakami, Bartosz Chmielowski, Scott D. Nelson, Tara A. Russell, Sarah M. Dry, Yunfeng Li, Arun S. Singh, Michiaki Unno, Fritz C. Eilber, Robert M. Hoffman

Cell Cycle　17　(5)　627-633　2018/03/04
Publisher: Taylor and Francis Inc.
DOI： 10.1080/15384101.2017.1421876 　

ISSN： 1551-4005 1538-4101
Targeting methionine with oral recombinant methioninase (o-rMETase) arrests a patient-derived orthotopic xenograft (PDOX) model of BRAF-V600E mutant melanoma: implications for chronic clinical cancer therapy and prevention Peer-reviewed

Kei Kawaguchi, Qinghong Han, Shukuan Li, Yuying Tan, Kentaro Igarashi, Tasuku Kiyuna, Kentaro Miyake, Masuyo Miyake, Bartosz Chmielowski, Scott D. Nelson, Tara A. Russell, Sarah M. Dry, Yunfeng Li, Arun S. Singh, Mark A. Eckardt, Michiaki Unno, Fritz C. Eilber, Robert M. Hoffman

Cell Cycle　17　(3)　356-361　2018/02/01
Publisher: Taylor and Francis Inc.
DOI： 10.1080/15384101.2017.1405195 　

ISSN： 1551-4005 1538-4101
[Hematopoietic cell differentiation orchestrated by transcription factor network and its related pathogenesis].

Kato H, Igarashi K

[Rinsho ketsueki] The Japanese journal of clinical hematology　2018/01/01

DOI： 10.11406/rinketsu.59.1872 　

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It has long been considered that hematopoietic system development is based on hematopoietic stem cell differentiation with a gradual loss of multipotency. However, recent studies have indicated that hematopoietic stem cells are composed of subsets that exhibit lineage skewing, thereby comprising a heterogeneous population. Therefore, the present hierarchical development model of the hematopoietic system may be reconsidered. Appropriate transcription regulators and epigenetic influences are required for cell differentiation. To this end, transcription factors, such as GATA1 for erythropoiesis and PU.1 for myelopoiesis, have been believed to play key roles at the initiation of hematopoietic cell differentiation. However, the mechanisms controlling the expression of these transcription factors are controlled, and the points at which the lineage commitments occur from hematopoietic stem cells through to progenitor cells are not fully elucidated. As per the findings of this study, we propose that the regulation of transcription and epigenetic factors are central events in hematopoietic cell differentiation.
Recombinant methioninase (rMETase) is an effective therapeutic for BRAF-V600E-negative as well as -positive melanoma in patient-derived orthotopic xenograft (PDOX) mouse models Peer-reviewed

Kei Kawaguchi, Kentaro Igarashi, Shukuan Li, Qinghong Han, Yuying Tan, Kentaro Miyake, Tasuku Kiyuna, Masuyo Miyake, Takashi Murakami, Bartosz Chmielowski, Scott D. Nelson, Tara A. Russell, Sarah M. Dry, Yunfeng Li, Michiaki Unno, Fritz C. Eilber, Robert M. Hoffman

Oncotarget　9　(1)　915-923　2018
Publisher: Impact Journals LLC
DOI： 10.18632/oncotarget.23185 　

ISSN： 1949-2553
Intra-tumor L-methionine level highly correlates with tumor size in both pancreatic cancer and melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse models Peer-reviewed

Kei Kawaguchi, Qinghong Han, Shukuan Li, Yuying Tan, Kentaro Igarashi, Kentaro Miyake, Tasuku Kiyuna, Masuyo Miyake, Bartosz Chemielwski, Scott D. Nelson, Tara A. Russell, Sarah M. Dry, Yunfeng Li, Arun S. Singh, Mark A. Eckardt, Michiaki Unno, Fritz C. Eilber, Robert M. Hoffman

Oncotarget　9　(13)　11119-11125　2018
Publisher: Impact Journals LLC
DOI： 10.18632/oncotarget.24264 　

ISSN： 1949-2553
SUMO modification system facilitates the exchange of histone variant H2A.Z-2 at DNA damage sites International-journal Peer-reviewed

Fukuto, Atsuhiko, Ikura, Masae, Ikura, Tsuyoshi, Sun, Jiying, Horikoshi, Yasunori, Shima, Hiroki, Igarashi, Kazuhiko, Kusakabe, Masayuki, Harata, Masahiko, Horikoshi, Naoki, Kurumizaka, Hitoshi, Kiuchi, Yoshiaki, Tashiro, Satoshi

Nucleus (Austin, Tex.)　9　(1)　87-94　2018/01/01

DOI： 10.1080/19491034.2017.1395543 　

ISSN： 1949-1042

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Histone exchange and histone post-translational modifications play important roles in the regulation of DNA metabolism, by re-organizing the chromatin configuration. We previously demonstrated that the histone variant H2A.Z-2 is rapidly exchanged at damaged sites after DNA double strand break induction in human cells. In yeast, the small ubiquitin-like modifier (SUMO) modification of H2A.Z is involved in the DNA damage response. However, whether the SUMO modification regulates the exchange of human H2A.Z-2 at DNA damage sites remains unclear. Here, we show that H2A.Z-2 is SUMOylated in a damage-dependent manner, and the SUMOylation of H2A.Z-2 is suppressed by the depletion of the SUMO E3 ligase, PIAS4. Moreover, PIAS4 depletion represses the incorporation and eviction of H2A.Z-2 at damaged sites. These findings demonstrate that the PIAS4-mediated SUMOylation regulates the exchange of H2A.Z-2 at DNA damage sites.
SUMO modification system facilitates the exchange of histone variant H2A.Z-2 at DNA damage sites. International-journal Peer-reviewed

Fukuto A, Ikura M, Ikura T, Sun J, Horikoshi Y, Shima H, Igarashi K, Kusakabe M, Harata M, Horikoshi N, Kurumizaka H, Kiuchi Y, Tashiro S

Nucleus (Austin, Tex.)　9　(1)　87-94　2018/01

DOI： 10.1080/19491034.2017.1395543 　

ISSN： 1949-1034

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Histone exchange and histone post-translational modifications play important roles in the regulation of DNA metabolism, by re-organizing the chromatin configuration. We previously demonstrated that the histone variant H2A.Z-2 is rapidly exchanged at damaged sites after DNA double strand break induction in human cells. In yeast, the small ubiquitin-like modifier (SUMO) modification of H2A.Z is involved in the DNA damage response. However, whether the SUMO modification regulates the exchange of human H2A.Z-2 at DNA damage sites remains unclear. Here, we show that H2A.Z-2 is SUMOylated in a damage-dependent manner, and the SUMOylation of H2A.Z-2 is suppressed by the depletion of the SUMO E3 ligase, PIAS4. Moreover, PIAS4 depletion represses the incorporation and eviction of H2A.Z-2 at damaged sites. These findings demonstrate that the PIAS4-mediated SUMOylation regulates the exchange of H2A.Z-2 at DNA damage sites.
The mTOR-Bach2 Cascade Controls Cell Cycle and Class Switch Recombination during B Cell Differentiation Peer-reviewed

Toru Tamahara, Kyoko Ochiai, Akihiko Muto, Yukinari Kato, Nicolas Sax, Mitsuyo Matsumoto, Takeyoshi Koseki, Kazuhiko Igarashi

MOLECULAR AND CELLULAR BIOLOGY　37　(24)　2017/12

DOI： 10.1128/MCB.00418-17 　

ISSN： 0270-7306

eISSN： 1098-5549
Increase in proapoptotic activity of inhibitory PAS domain protein via phosphorylation by MK2 Peer-reviewed

Shuya Kasai, Mary J. E. Richardson, Satoru Torii, Ken-ichi Yasumoto, Hiroki Shima, Kazuhiko Igarashi, Ken Itoh, Kazuhiro Sogawa, Kazutaka Murayama

FEBS JOURNAL　284　(23)　4115-4127　2017/12

DOI： 10.1111/febs.14300 　

ISSN： 1742-464X

eISSN： 1742-4658
S-Adenosylmethionine Synthesis Is Regulated by Selective N-6-Adenosine Methylation and mRNA Degradation Involving METTL16 and YTHDC1 Peer-reviewed

Hiroki Shima, Mitsuyo Matsumoto, Yuma Ishigami, Masayuki Ebina, Akihiko Muto, Yuho Sato, Sayaka Kumagai, Kyoko Ochiai, Tsutomu Suzuki, Kazuhiko Igarashi

CELL REPORTS　21　(12)　3354-3363　2017/12

DOI： 10.1016/j.celrep.2017.11.092 　

ISSN： 2211-1247
Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis Peer-reviewed

Risa Ebina-Shibuya, Mitsuyo Matsumoto, Makoto Kuwahara, Kyoung-Jin Jang, Manabu Sugai, Yoshiaki Ito, Ryo Funayama, Keiko Nakayama, Yuki Sato, Naoto Ishii, Yasunobu Okamura, Kengo Kinoshita, Kohei Kometani, Tomohiro Kurosaki, Akihiko Muto, Masakazu Ichinose, Masakatsu Yamashita, Kazuhiko Igarashi

JOURNAL OF BIOLOGICAL CHEMISTRY　292　(44)　18098-18112　2017/11

DOI： 10.1074/jbc.M117.808535 　

ISSN： 0021-9258

eISSN： 1083-351X
転写因子Bach1及びBach2の環境変化に応じた赤血球-ミエロイド分化制御(Bach1 and Bach2 orchestrate erythro-myeloid differentiation responding to environmental changes)

Kato Hiroki, Itoh Ari, Matsumoto Mitsuyo, Shibuya Risa, Sato Yuki, Kobayashi Masahiro, Muto Akihiko, Fujiwara Tohru, Harigae Hideo, Igarashi Kazuhiko

臨床血液　58　(9)　1489-1489　2017/09
Publisher: (一社)日本血液学会-東京事務局
ISSN： 0485-1439

eISSN： 1882-0824
Reductions in the mitochondrial ABC transporter Abcb10 affect the transcriptional profile of heme biosynthesis genes Peer-reviewed

Alexandra Seguin, Naoko Takahashi-Makise, Yvette Y. Yien, Nicholas C. Huston, Jared C. Whitman, Gabriel Musso, Jared A. Wallace, Thomas Bradley, Hector A. Bergonia, Martin D. Kafina, Mitsuyo Matsumoto, Kazuhiko Igarashi, John D. Phillips, Barry H. Paw, Jerry Kaplan, Diane M. Ward

JOURNAL OF BIOLOGICAL CHEMISTRY　292　(39)　16284-16299　2017/09

DOI： 10.1074/jbc.M117.797415 　

ISSN： 0021-9258

eISSN： 1083-351X
Bach2 represses the AP-1-driven induction of interleukin-2 gene transcription in CD4(+) T cells Peer-reviewed

Eunkyeong Jang, Hye Rim Lee, Geon Hee Lee, Ah-Reum Oh, Ji-Young Cha, Kazuhiko Igarashi, Jeehee Youn

BMB REPORTS　50　(9)　472-477　2017/09

DOI： 10.5483/BMBRep.2017.50.9.124 　

ISSN： 1976-6696

eISSN： 1976-670X
Distinct requirements for energy metabolism in mouse primordial germ cells and their reprogramming to embryonic germ cells Peer-reviewed

Yohei Hayashi, Kei Otsuka, Masayuki Ebina, Kaori Igarashi, Asuka Takehara, Mitsuyo Matsumoto, Akio Kanai, Kazuhiko Igarashi, Tomoyoshi Soga, Yasuhisa Matsui

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　114　(31)　8289-8294　2017/08

DOI： 10.1073/pnas.1620915114 　

ISSN： 0027-8424
BACH transcription factors in innate and adaptive immunity Peer-reviewed

Kazuhiko Igarashi, Tomohiro Kurosaki, Rahul Roychoudhuri

NATURE REVIEWS IMMUNOLOGY　17　(7)　437-450　2017/07

DOI： 10.1038/nri.2017.26 　

ISSN： 1474-1733

eISSN： 1474-1741
Microproteomics with microfluidic-based cell sorting: Application to 1000 and 100 immune cells Peer-reviewed

Kie Kasuga, Yasutake Katoh, Keisuke Nagase, Kazuhiko Igarashi

PROTEOMICS　17　(13-14)　2017/07

DOI： 10.1002/pmic.201600420 　

ISSN： 1615-9853

eISSN： 1615-9861
Genetic ablation of Bach 1 gene enhances recovery from hyperoxic lung injury in newborn mice via transient upregulation of inflammatory genes Peer-reviewed

Masato Ito, Nobuhiko Nagano, Yukio Arai, Ryo Ogawa, Shingo Kobayashi, Yukiko Motojima, Hayato Go, Masanori Tamura, Kazuhiko Igarashi, Phyllis A. Dennery, Fumihiko Namba

PEDIATRIC RESEARCH　81　(6)　926-931　2017/06

DOI： 10.1038/pr.2017.17 　

ISSN： 0031-3998

eISSN： 1530-0447
Glucocorticoid receptor signaling represses the antioxidant response by inhibiting histone acetylation mediated by the transcriptional activator NRF2. International-journal Peer-reviewed

Md Morshedul Alam, Keito Okazaki, Linh Thi Thao Nguyen, Nao Ota, Hiroshi Kitamura, Shohei Murakami, Hiroki Shima, Kazuhiko Igarashi, Hiroki Sekine, Hozumi Motohashi

The Journal of biological chemistry　292　(18)　7519-7530　2017/05/05

DOI： 10.1074/jbc.M116.773960 　

ISSN： 0021-9258

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NRF2 (nuclear factor erythroid 2-related factor 2) is a key transcriptional activator that mediates the inducible expression of antioxidant genes. NRF2 is normally ubiquitinated by KEAP1 (Kelch-like ECH-associated protein 1) and subsequently degraded by proteasomes. Inactivation of KEAP1 by oxidative stress or electrophilic chemicals allows NRF2 to activate transcription through binding to antioxidant response elements (AREs) and recruiting histone acetyltransferase CBP (CREB-binding protein). Whereas KEAP1-dependent regulation is a major determinant of NRF2 activity, NRF2-mediated transcriptional activation varies from context to context, suggesting that other intracellular signaling cascades may impact NRF2 function. To identify a signaling pathway that modifies NRF2 activity, we immunoprecipitated endogenous NRF2 and its interacting proteins from mouse liver and identified glucocorticoid receptor (GR) as a novel NRF2-binding partner. We found that glucocorticoids, dexamethasone and betamethasone, antagonize diethyl maleate-induced activation of NRF2 target genes in a GR-dependent manner. Dexamethasone treatment enhanced GR recruitment to AREs without affecting chromatin binding of NRF2, resulting in the inhibition of CBP recruitment and histone acetylation at AREs. This repressive effect was canceled by the addition of histone deacetylase inhibitors. Thus, GR signaling decreases NRF2 transcriptional activation through reducing the NRF2-dependent histone acetylation. Consistent with these observations, GR signaling blocked NRF2-mediated cytoprotection from oxidative stress. This study suggests that an impaired antioxidant response by NRF2 and a resulting decrease in cellular antioxidant capacity account for the side effects of glucocorticoids, providing a novel viewpoint for the pathogenesis of hypercorticosteroidism.
Frequent downregulation of BTB and CNC homology 2 expression in Epstein-Barr virus-positive diffuse large B-cell lymphoma Peer-reviewed

Mai Noujima-Harada, Katsuyoshi Takata, Tomoko Miyata-Takata, Hiroaki Sakurai, Kazuhiko Igarashi, Etsuro Ito, Keina Nagakita, Kohei Taniguchi, Nobuhiko Ohnishi, Shizuma Omote, Tetsuya Tabata, Yasuharu Sato, Tadashi Yoshino

CANCER SCIENCE　108　(5)　1071-1079　2017/05

DOI： 10.1111/cas.13213 　

ISSN： 1349-7006
Frequent downregulation of BTB and CNC homology 2 expression in Epstein–Barr virus-positive diffuse large B-cell lymphoma Peer-reviewed

Mai Noujima-Harada, Katsuyoshi Takata, Tomoko Miyata-Takata, Hiroaki Sakurai, Kazuhiko Igarashi, Etsuro Ito, Keina Nagakita, Kohei Taniguchi, Nobuhiko Ohnishi, Shizuma Omote, Tetsuya Tabata, Yasuharu Sato, Tadashi Yoshino

Cancer Science　108　(5)　1071-1079　2017/05/01
Publisher: Blackwell Publishing Ltd
DOI： 10.1111/cas.13213 　

ISSN： 1349-7006 1347-9032

eISSN： 1349-7006
Regulatory signatures of liver regeneration distilled by integrative analysis of mRNA, histone methylation, and proteomics Peer-reviewed

Yoshihiro Sato, Yasutake Katoh, Mitsuyo Matsumoto, Masaki Sato, Masayuki Ebina, Ari Itoh-Nakadai, Ryo Funayama, Keiko Nakayama, Michiaki Unno, Kazuhiko Igarashi

JOURNAL OF BIOLOGICAL CHEMISTRY　292　(19)　8019-+　2017/05

DOI： 10.1074/jbc.M116.774547 　

ISSN： 0021-9258

eISSN： 1083-351X
Iron-heme-Bach1 axis is involved in erythroblast adaptation to iron deficiency Peer-reviewed

Masahiro Kobayashi, Hiroki Kato, Hiroshi Hada, Ari Itoh-Nakadai, Tohru Fujiwara, Akihiko Muto, Yukihiro Inoguchi, Kenji Ichiyanagi, Wataru Hojo, Naohisa Tomosugi, Hiroyuki Sasaki, Hideo Harigae, Kazuhiko Igarashi

HAEMATOLOGICA　102　(3)　454-465　2017/03

DOI： 10.3324/haematol.2016.151043 　

ISSN： 0390-6078
Bach2 Controls Homeostasis of Eosinophils by Restricting the Type-2 Helper Function of T Cells Peer-reviewed

Yuki Sato, Hiroki Kato, Risa Ebina-Shibuya, Ari Itoh-Nakadai, Ryuhei Okuyama, Kazuhiko Igarashi

TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE　241　(3)　175-182　2017/03

DOI： 10.1620/tjem.241.175 　

ISSN： 0040-8727

eISSN： 1349-3329
A Bach2-Cebp Gene Regulatory Network for the Commitment of Multipotent Hematopoietic Progenitors Peer-reviewed

Ari Itoh-Nakadai, Mitsuyo Matsumoto, Hiroki Kato, Junichi Sasaki, Yukihiro Uehara, Yuki Sato, Risa Ebina-Shibuya, Mizuho Morooka, Ryo Funayama, Keiko Nakayama, Kyoko Ochiai, Akihiko Muto, Kazuhiko Igarashi

CELL REPORTS　18　(10)　2401-2414　2017/03

DOI： 10.1016/j.celrep.2017.02.029 　

ISSN： 2211-1247
Ubiquitylation of Ku80 by RNF126 Promotes Completion of Nonhomologous End Joining-Mediated DNA Repair Peer-reviewed

Noriko Ishida, Tadashi Nakagawa, Shun-Ichiro Iemura, Akira Yasui, Hiroki Shima, Yasutake Katoh, Yuko Nagasawa, Toru Natsume, Kazuhiko Igarashi, Keiko Nakayama

MOLECULAR AND CELLULAR BIOLOGY　37　(4)　2017/02

DOI： 10.1128/MCB.00347-16 　

ISSN： 0270-7306

eISSN： 1098-5549
Actin Family Proteins in the Human IN080 Chromatin Remodeling Complex Exhibit Functional Roles in the Induction of Heme Oxygenase-1 with Hemin Peer-reviewed

Yuichiro Takahashi, Hirokazu Murakami, Yusuke Akiyama, Yasutake Katoh, Yukako Oma, Hitoshi Nishijima, Kei-ichi Shibahara, Kazuhiko Igarashi, Masahiko Harata

FRONTIERS IN GENETICS　8　17　2017/02

DOI： 10.3389/fgene.2017.00017 　

ISSN： 1664-8021
The double knockout of Bach1 and Bach2 in mice reveals shared compensatory mechanisms in regulating alveolar macrophage function and lung surfactant homeostasis Peer-reviewed

Risa Ebina-Shibuya, Miki Watanabe-Matsui, Mitsuyo Matsumoto, Ari Itoh-Nakadai, Ryo Funayama, Keiko Nakayama, Akihiko Muto, Kazuhiko Igarashi

JOURNAL OF BIOCHEMISTRY　160　(6)　333-344　2016/12

DOI： 10.1093/jb/mvw041 　

ISSN： 0021-924X

eISSN： 1756-2651
Charge-state-distribution analysis of Bach2 intrinsically disordered heme binding region Peer-reviewed

Tomoji Suenaga, Miki Watanabe-Matsui, Tamami Uejima, Hiroki Shima, Toshitaka Matsui, Masao Ikeda-Saito, Mikako Shirouzu, Kazuhiko Igarashi, Kazutaka Murayama

JOURNAL OF BIOCHEMISTRY　160　(5)　291-298　2016/11

DOI： 10.1093/jb/mvw035 　

ISSN： 0021-924X

eISSN： 1756-2651
The Tohoku Medical Megabank Project: Design and Mission Peer-reviewed

Shinichi Kuriyama, Nobuo Yaegashi, Fuji Nagami, Tomohiko Arai, Yoshio Kawaguchi, Noriko Osumi, Masaki Sakaida, Yoichi Suzuki, Keiko Nakayama, Hiroaki Hashizume, Gen Tamiya, Hiroshi Kawame, Kichiya Suzuki, Atsushi Hozawa, Naoki Nakaya, Masahiro Kikuya, Hirohito Metoki, Ichiro Tsuji, Nobuo Fuse, Hideyasu Kiyomoto, Junichi Sugawara, Akito Tsuboi, Shinichi Egawa, Kiyoshi Ito, Koichi Chida, Tadashi Ishii, Hiroaki Tomita, Yasuyuki Taki, Naoko Minegishi, Naoto Ishii, Jun Yasuda, Kazuhiko Igarashi, Ritsuko Shimizu, Masao Nagasaki, Seizo Koshiba, Kengo Kinoshita, Soichi Ogishima, Takako Takai-Igarashi, Teiji Tominaga, Osamu Tanabe, Noriaki Ohuchi, Toru Shimosegawa, Shigeo Kure, Hiroshi Tanaka, Sadayoshi Ito, Jiro Hitomi, Kozo Tanno, Motoyuki Nakamura, Kuniaki Ogasawara, Seiichiro Kobayashi, Kiyomi Sakata, Mamoru Satoh, Atsushi Shimizu, Makoto Sasaki, Ryujin Endo, Kenji Sobue, Masayuki Yamamoto

JOURNAL OF EPIDEMIOLOGY　26　(9)　493-511　2016/09

DOI： 10.2188/jea.JE20150268 　

ISSN： 0917-5040
MiR-196a regulates heme oxygenase-1 by silencing Bach1 in the neonatal mouse lung Peer-reviewed

Hayato Go, Ping La, Fumihiko Namba, Masato Ito, Guang Yang, Andrey Brydun, Kazuhiko Igarashi, Phyllis A. Dennery

AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY　311　(2)　L400-L411　2016/08

DOI： 10.1152/ajplung.00428.2015 　

ISSN： 1040-0605

eISSN： 1522-1504
BACH2 regulates CD8(+) T cell differentiation by controlling access of AP-1 factors to enhancers Peer-reviewed

Rahul Roychoudhuri, David Clever, Peng Li, Yoshiyuki Wakabayashi, Kylie M. Quinn, Christopher A. Klebanoff, Yun Ji, Madhusudhanan Sukumar, Robert L. Eil, Zhiya Yu, Rosanne Spolski, Douglas C. Palmer, Jenny H. Pan, Shashank J. Patel, Derek C. Macallan, Giulia Fabozzi, Han-Yu Shih, Yuka Kanno, Akihiko Muto, Jun Zhu, Luca Gattinoni, John J. O'Shea, Klaus Okkenhaug, Kazuhiko Igarashi, Warren J. Leonard, Nicholas P. Restifo

NATURE IMMUNOLOGY　17　(7)　851-+　2016/07

DOI： 10.1038/ni.3441 　

ISSN： 1529-2908

eISSN： 1529-2916
Genomewide approaches for BACH1 target genes in mouse embryonic fibroblasts showed BACH1-Pparg pathway in adipogenesis Peer-reviewed

Mitsuyo Matsumoto, Keiichi Kondo, Takuma Shiraki, Andrey Brydun, Ryo Funayama, Keiko Nakayama, Nobuo Yaegashi, Hideki Katagiri, Kazuhiko Igarashi

GENES TO CELLS　21　(6)　553-567　2016/06

DOI： 10.1111/gtc.12365 　

ISSN： 1356-9597

eISSN： 1365-2443
NRF2 Intensifies Host Defense Systems to Prevent Lung Carcinogenesis, but After Tumor Initiation Accelerates Malignant Cell Growth Peer-reviewed

Hironori Satoh, Takashi Moriguchi, Daisuke Saigusa, Liam Baird, Lei Yu, Hirofumi Rokutan, Keiko Igarashi, Masahito Ebina, Tatsuhiro Shibata, Masayuki Yamamoto

CANCER RESEARCH　76　(10)　3088-3096　2016/05

DOI： 10.1158/0008-5472.CAN-15-1584 　

ISSN： 0008-5472

eISSN： 1538-7445
Orchestration of B lymphoid cells and their inner myeloid by Bach Peer-reviewed

Kazuhiko Igarashi, Ari Itoh-Nakadai

CURRENT OPINION IN IMMUNOLOGY　39　136-142　2016/04

DOI： 10.1016/j.coi.2016.01.012 　

ISSN： 0952-7915

eISSN： 1879-0372
Multifunctional human transcriptional coactivator protein PC4 is a substrate of Aurora kinases and activates the Aurora enzymes Peer-reviewed

Karthigeyan Dhanasekaran, Sujata Kumari, Ramachandran Boopathi, Hiroki Shima, Amrutha Swaminathan, Mahesh Bachu, Udaykumar Ranga, Kazuhiko Igarashi, Tapas K. Kundu

FEBS JOURNAL　283　(6)　968-985　2016/03

DOI： 10.1111/febs.13653 　

ISSN： 1742-464X

eISSN： 1742-4658
Epigenetic Regulation of the Blimp-1 Gene (Prdm1) in B Cells Involves Bach2 and Histone Deacetylase 3 Peer-reviewed

Hiromu Tanaka, Akihiko Muto, Hiroki Shima, Yasutake Katoh, Nicolas Sax, Shinya Tajima, Andrey Brydun, Tsuyoshi Ikura, Naoko Yoshizawa, Hisao Masai, Yutaka Hoshikawa, Tetsuo Noda, Masaki Nio, Kyoko Ochiai, Kazuhiko Igarashi

JOURNAL OF BIOLOGICAL CHEMISTRY　291　(12)　6316-6330　2016/03

DOI： 10.1074/jbc.M116.713842 　

ISSN： 0021-9258

eISSN： 1083-351X
The Mediator Subunit MED16 Transduces NRF2-Activating Signals into Antioxidant Gene Expression. International-journal Peer-reviewed

Hiroki Sekine, Keito Okazaki, Nao Ota, Hiroki Shima, Yasutake Katoh, Norio Suzuki, Kazuhiko Igarashi, Mitsuhiro Ito, Hozumi Motohashi, Masayuki Yamamoto

Molecular and cellular biology　36　(3)　407-20　2016/02/01

DOI： 10.1128/MCB.00785-15 　

ISSN： 0270-7306

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The KEAP1-NRF2 system plays a central role in cytoprotection. NRF2 is stabilized in response to electrophiles and activates transcription of antioxidant genes. Although robust induction of NRF2 target genes confers resistance to oxidative insults, how NRF2 triggers transcriptional activation after binding to DNA has not been elucidated. To decipher the molecular mechanisms underlying NRF2-dependent transcriptional activation, we purified the NRF2 nuclear protein complex and identified the Mediator subunits as NRF2 cofactors. Among them, MED16 directly associated with NRF2. Disruption of Med16 significantly attenuated the electrophile-induced expression of NRF2 target genes but did not affect hypoxia-induced gene expression, suggesting a specific requirement for MED16 in NRF2-dependent transcription. Importantly, we found that 75% of NRF2-activated genes exhibited blunted inductions by electrophiles in Med16-deficient cells compared to wild-type cells, which strongly argues that MED16 is a major contributor supporting NRF2-dependent transcriptional activation. NRF2-dependent phosphorylation of the RNA polymerase II C-terminal domain was absent in Med16-deficient cells, suggesting that MED16 serves as a conduit to transmit NRF2-activating signals to RNA polymerase II. MED16 indeed turned out to be essential for cytoprotection against oxidative insults. Thus, the KEAP1-NRF2-MED16 axis has emerged as a new regulatory pathway mediating the antioxidant response through the robust activation of NRF2 target genes.
Mechanism governing heme synthesis reveals a GATA factor/heme circuit that controls differentiation Peer-reviewed

Nobuyuki Tanimura, Eli Miller, Kazuhiko Igarashi, David Yang, Judith N. Burstyn, Colin N. Dewey, Emery H. Bresnick

EMBO REPORTS　17　(2)　249-265　2016/02

DOI： 10.15252/embr.201541465 　

ISSN： 1469-221X

eISSN： 1469-3178
Genetic complementation analysis showed distinct contributions of the N-terminal tail of H2A.Z to epigenetic regulations Peer-reviewed

Masayuki Kusakabe, Hiroyuki Oku, Ryo Matsuda, Tetsuya Hori, Akihiko Muto, Kazuhiko Igarashi, Tatsuo Fukagawa, Masahiko Harata

GENES TO CELLS　21　(2)　122-135　2016/02

DOI： 10.1111/gtc.12327 　

ISSN： 1356-9597

eISSN： 1365-2443
[Extensive analysis of protein phosphorylation: An example of transcription factor Bach2]. Peer-reviewed

Kazuhiko Igarashi

Seikagaku. The Journal of Japanese Biochemical Society　88　(1)　31-35　2016/02

ISSN： 0037-1017
High Fractional Occupancy of a Tandem Maf Recognition Element and Its Role in Long-Range beta-Globin Gene Regulation Peer-reviewed

Jared R. Stees, Mir A. Hossain, Tomoki Sunose, Yasushi Kudo, Carolina E. Pardo, Nancy H. Nabilsi, Russell P. Darst, Rosha Poudyal, Kazuhiko Igarashi, Suming Huang, Michael P. Kladde, Joerg Bungert

MOLECULAR AND CELLULAR BIOLOGY　36　(2)　238-250　2016/01

DOI： 10.1128/MCB.00723-15 　

ISSN： 0270-7306

eISSN： 1098-5549
Genetic heterogeneity in 26 infants with a hypomyelinating leukodystrophy Peer-reviewed

Natsuko Arai-Ichinoi, Mitsugu Uematsu, Ryo Sato, Tasuku Suzuki, Hiroki Kudo, Atsuo Kikuchi, Naomi Hino-Fukuyo, Mitsuyo Matsumoto, Kazuhiko Igarashi, Kazuhiro Haginoya, Shigeo Kure

HUMAN GENETICS　135　(1)　89-98　2016/01

DOI： 10.1007/s00439-015-1617-7 　

ISSN： 0340-6717

eISSN： 1432-1203
The Transcription Factor Bach2 Is Phosphorylated at Multiple Sites in Murine B Cells but a Single Site Prevents Its Nuclear Localization Peer-reviewed

Ryo Ando, Hiroki Shima, Toru Tamahara, Yoshihiro Sato, Miki Watanabe-Matsui, Hiroki Kato, Nicolas Sax, Hozumi Motohashi, Keiko Taguchi, Masayuki Yamamoto, Masaki Nio, Tatsuya Maeda, Kyoko Ochiai, Akihiko Muto, Kazuhiko Igarashi

JOURNAL OF BIOLOGICAL CHEMISTRY　291　(4)　1826-1840　2016/01

DOI： 10.1074/jbc.M115.661702 　

ISSN： 0021-9258

eISSN： 1083-351X
Collagen V Is a Potential Substrate for Clostridial Collagenase G in Pancreatic Islet Isolation Peer-reviewed

Hiroki Shima, Akiko Inagaki, Takehiro Imura, Youhei Yamagata, Kimiko Watanabe, Kazuhiko Igarashi, Masafumi Goto, Kazutaka Murayama

JOURNAL OF DIABETES RESEARCH　2016　4396756　2016

DOI： 10.1155/2016/4396756 　

ISSN： 2314-6745

eISSN： 2314-6753
NRF2-MED16を介した抗酸化遺伝子群の転写活性化機構 Peer-reviewed

岡崎慶斗, 関根弘樹, 鈴木教郎, 加藤恭丈, 五十嵐和彦, 伊藤光宏, 本橋ほづみ, 山本雅之

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[4T14L-01(3P0701)]　2015/12
Publisher: (公社)日本生化学会
The artificial loss of Runx1 reduces the expression of quiescence-associated transcription factors in CD4(+) T lymphocytes Peer-reviewed

Won Fen Wong, Kazuyoshi Kohu, Takeshi Nagashima, Ryo Funayama, Mitsuyo Matsumoto, Elaheh Movahed, Grace Min Yi Tan, Tee Cian Yeow, Chung Yeng Looi, Mineo Kurokawa, Motomi Osato, Kazuhiko Igarashi, Keiko Nakayama, Masanobu Satake

MOLECULAR IMMUNOLOGY　68　(2)　223-233　2015/12

DOI： 10.1016/j.molimm.2015.08.012 　

ISSN： 0161-5890
Bach1 deficiency reduces severity of osteoarthritis through upregulation of heme oxygenase-1 Peer-reviewed

Tsuyoshi Takada, Shigeru Miyaki, Hiroyuki Ishitobi, Yuya Hirai, Tomoyuki Nakasa, Kazuhiko Igarashi, Martin K. Lotz, Mitsuo Ochi

ARTHRITIS RESEARCH & THERAPY　17　285　2015/10

DOI： 10.1186/s13075-015-0792-1 　

ISSN： 1478-6354

eISSN： 1478-6362
Synergistic Effect of Neutral Protease and Clostripain on Rat Pancreatic Islet Isolation Peer-reviewed

Mami Dendo, Hiroshi Maeda, Youhei Yamagata, Kazutaka Murayama, Kimiko Watanabe, Takehiro Imura, Akiko Inagaki, Yasuhiro Igarashi, Yasutake Katoh, Masayuki Ebina, Keisei Fujimori, Kazuhiko Igarashi, Noriaki Ohuchi, Susumu Satomi, Masafumi Goto

TRANSPLANTATION　99　(7)　1349-1355　2015/07

DOI： 10.1097/TP.0000000000000662 　

ISSN： 0041-1337

eISSN： 1534-6080
Mitochondrial function provides instructive signals for activation-induced B-cell fates Peer-reviewed

Kyoung-Jin Jang, Hiroto Mano, Koji Aoki, Tatsunari Hayashi, Akihiko Muto, Yukiko Nambu, Katsu Takahashi, Katsuhiko Itoh, Shigeru Taketani, Stephen L. Nutt, Kazuhiko Igarashi, Akira Shimizu, Manabu Sugai

NATURE COMMUNICATIONS　6　6750　2015/04

DOI： 10.1038/ncomms7750 　

ISSN： 2041-1723
Heme binds to an intrinsically disordered region of Bach2 and alters its conformation Peer-reviewed

Miki Watanabe-Matsui, Takashi Matsumoto, Toshitaka Matsui, Masao Ikeda-Saito, Akihiko Muto, Kazutaka Murayama, Kazuhiko Igarashi

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS　565　25-31　2015/01

DOI： 10.1016/j.abb.2014.11.005 　

ISSN： 0003-9861

eISSN： 1096-0384
The transcription repressors Bach2 and Bach1 promote B cell development by repressing the myeloid program Peer-reviewed

Ari Itoh-Nakadai, Reina Hikota, Akihiko Muto, Kohei Kometani, Miki Watanabe-Matsui, Yuki Sato, Masahiro Kobayashi, Atsushi Nakamura, Yuichi Miura, Yoko Yano, Satoshi Tashiro, Jiying Sun, Tomokatsu Ikawa, Kyoko Ochiai, Tomohiro Kurosaki, Kazuhiko Igarashi

NATURE IMMUNOLOGY　15　(12)　1171-1180　2014/12

DOI： 10.1038/ni.3024 　

ISSN： 1529-2908

eISSN： 1529-2916
The transcription repressors Bach2 and Bach1 promote B cell development by repressing the myeloid program

Ari Itoh-Nakadai, Reina Hikota, Akihiko Muto, Kohei Kometani, Miki Watanabe-Matsui, Yuki Sato, Masahiro Kobayashi, Atsushi Nakamura, Yuichi Miura, Yoko Yano, Satoshi Tashiro, Jiying Sun, Tomokatsu Ikawa, Kyoko Ochiai, Tomohiro Kurosaki, Kazuhiko Igarashi

Nature Immunology　15　(12)　1171-1180　2014/11/18
Publisher: Nature Publishing Group
DOI： 10.1038/ni.3024 　

ISSN： 1529-2916 1529-2908
The C113D Mutation in Human Pin1 Causes Allosteric Structural Changes in the Phosphate Binding Pocket of the PPIase Domain through the Tug of War in the Dual-Histidine Motif Peer-reviewed

Ning Xu, Naoya Tochio, Jing Wang, Yu Tamari, Jun-ichi Uewaki, Naoko Utsunomiya-Tate, Kazuhiko Igarashi, Takuma Shiraki, Naohiro Kobayashi, Shin-ichi Tate

BIOCHEMISTRY　53　(34)　5568-5578　2014/09

DOI： 10.1021/bi5007817 　

ISSN： 0006-2960
Orchestration of plasma cell differentiation by Bach2 and its gene regulatory network Peer-reviewed

Kazuhiko Igarashi, Kyoko Ochiai, Ari Itoh-Nakadai, Akihiko Muto

IMMUNOLOGICAL REVIEWS　261　(1)　116-125　2014/09

DOI： 10.1111/imr.12201 　

ISSN： 0105-2896

eISSN： 1600-065X
Validation of multiple single nucleotide variation calls by additional exome analysis with a semiconductor sequencer to supplement data of whole-genome sequencing of a human population Peer-reviewed

Ikuko N. Motoike, Mitsuyo Matsumoto, Inaho Danjoh, Fumiki Katsuoka, Kaname Kojima, Naoki Nariai, Yukuto Sato, Yumi Yamaguchi-Kabata, Shin Ito, Hisaaki Kudo, Ichiko Nishijima, Satoshi Nishikawa, Xiaoqing Pan, Rumiko Saito, Sakae Saito, Tomo Saito, Matsuyuki Shirota, Kaoru Tsuda, Junji Yokozawa, Kazuhiko Igarashi, Naoko Minegishi, Osamu Tanabe, Nobuo Fuse, Masao Nagasaki, Kengo Kinoshita, Jun Yasuda, Masayuki Yamamoto

BMC GENOMICS　15　673　2014/08

DOI： 10.1186/1471-2164-15-673 　

ISSN： 1471-2164
Hemopexin-dependent heme uptake via endocytosis regulates the Bach1 transcription repressor and heme oxygenase gene activation Peer-reviewed

Hiroshi Hada, Takuma Shiraki, Miki Watanabe-Matsui, Kazuhiko Igarashi

BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS　1840　(7)　2351-2360　2014/07

DOI： 10.1016/j.bbagen.2014.02.029 　

ISSN： 0304-4165

eISSN： 1872-8006
Hemopexin-dependent heme uptake via endocytosis regulates the Bach1 transcription repressor and heme oxygenase gene activation Peer-reviewed

Hada, H., Shiraki, T., Watanabe-Matsui, M., Igarashi, K.

Biochimica et Biophysica Acta - General Subjects　1840　(7)　2351-2360　2014/07

DOI： 10.1016/j.bbagen.2014.02.029 　

ISSN： 0006-3002
【ストレス応答性転写因子:その新機能とがん、免疫・代謝・変性疾患との関係】転写因子Bach2による肺胞マクロファージの機能成熟と肺恒常性維持機構

渋谷里紗, 五十嵐和彦

細胞工学　33　(7)　745-750　2014/06
Publisher: (株)学研メディカル秀潤社
ISSN： 0287-3796
Association between BACH2 expression and clinical prognosis in diffuse large B-cell lymphoma Peer-reviewed

Satoshi Ichikawa, Noriko Fukuhara, Hiroki Katsushima, Taro Takahashi, Joji Yamamoto, Hisayuki Yokoyama, Osamu Sasaki, Osamu Fukuhara, Jun Nomura, Kenichi Ishizawa, Ryo Ichinohasama, Akihiko Muto, Kazuhiko Igarashi, Hideo Harigae

CANCER SCIENCE　105　(4)　437-444　2014/04

DOI： 10.1111/cas.12361 　

ISSN： 1347-9032

eISSN： 1349-7006
Wearing Red for Signaling: The Heme-Bach Axis in Heme Metabolism, Oxidative Stress Response and Iron Immunology Peer-reviewed

Kazuhiko Igarashi, Miki Watanabe-Matsui

TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE　232　(4)　229-253　2014/04

DOI： 10.1620/tjem.232.229 　

ISSN： 0040-8727

eISSN： 1349-3329
Heme-Mediated SPI-C Induction Promotes Monocyte Differentiation into Iron-Recycling Macrophages Peer-reviewed

Malay Haldar, Masako Kohyama, Alex Yick-Lun So, K. C. Wumesh, Xiaodi Wu, Carlos G. Briseno, Ansuman T. Satpathy, Nicole M. Kretzer, Hisashi Arase, Namakkal S. Rajasekaran, Li Wang, Takeshi Egawa, Kazuhiko Igarashi, David Baltimore, Theresa L. Murphy, Kenneth M. Murphy

CELL　156　(6)　1223-1234　2014/03

DOI： 10.1016/j.cell.2014.01.069 　

ISSN： 0092-8674

eISSN： 1097-4172
Examination of the Cause of Changing Solution Color by Mixing Aminophylline and Dopamine, the Compatibility of Which Was Indicated by the Supplier Peer-reviewed

Kazuhiko Igarashi, Masami Kawahara

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN　134　(2)　293-298　2014/02

DOI： 10.1248/yakushi.13-00211 　

ISSN： 0031-6903
Collagenase H Is Crucial for Isolation of Rat Pancreatic Islets Peer-reviewed

Atsushi Fujio, Kazutaka Murayama, Youhei Yamagata, Kimiko Watanabe, Takehiro Imura, Akiko Inagaki, Naomi Ohbayashi, Hiroki Shima, Satoshi Sekiguchi, Keisei Fujimori, Kazuhiko Igarashi, Noriaki Ohuchi, Susumu Satomi, Masafumi Goto

CELL TRANSPLANTATION　23　(10)　1187-1198　2014

DOI： 10.3727/096368913X668654 　

ISSN： 0963-6897

eISSN： 1555-3892
Bach1 Deficiency and Accompanying Overexpression of Heme Oxygenase-1 Do Not Influence Aging or Tumorigenesis in Mice Peer-reviewed

Kazushige Ota, Andrey Brydun, Ari Itoh-Nakadai, Jiying Sun, Kazuhiko Igarashi

OXIDATIVE MEDICINE AND CELLULAR LONGEVITY　2014　757901　2014

DOI： 10.1155/2014/757901 　

ISSN： 1942-0900

eISSN： 1942-0994
Suppression of indomethacin-induced apoptosis in the small intestine due to Bach1 deficiency (vol 45, pg 717, 2011) Peer-reviewed

Akihito Harusato, Yuji Naito, Tomohisa Takagi, Kazuhiko Uchiyama, Katsura Mizushima, Yasuko Hirai, Shinya Yamada, Toshifumi Tuji, Hiroyuki Yoriki, Ryusuke Horie, Ken Inoue, Kohei Fukumoto, Osamu Handa, Takeshi Ishikawa, Satoshi Kokura, Yukiko Minamiyama, Hiroshi Ichikawa, Akihiko Muto, Kazuhiko Igarashi, Toshikazu Yoshikawa

FREE RADICAL RESEARCH　47　(12)　1088-1088　2013/12

DOI： 10.3109/10715762.2013.836313 　

ISSN： 1071-5762

eISSN： 1029-2470
Activation of the SUMO modification system is required for the accumulation of RAD51 at sites of DNA damage

Hiroki Shima, Hidekazu Suzuki, Jiying Sun, Kazuteru Kono, Lin Shi, Aiko Kinomura, Yasunori Horikoshi, Tsuyoshi Ikura, Masae Ikura, Roland Kanaar, Kazuhiko Igarashi, Hisato Saitoh, Hitoshi Kurumizaka, Satoshi Tashiro

Journal of Cell Science　126　(22)　5284-5292　2013/11/15

DOI： 10.1242/jcs.133744 　

ISSN： 0021-9533 1477-9137

eISSN： 1477-9137
Activation of the SUMO modification system is required for the accumulation of RAD51 at sites of DNA damage Peer-reviewed

Hiroki Shima, Hidekazu Suzuki, Jiying Sun, Kazuteru Kono, Lin Shi, Aiko Kinomura, Yasunori Horikoshi, Tsuyoshi Ikura, Masae Ikura, Roland Kanaar, Kazuhiko Igarashi, Hisato Saitoh, Hitoshi Kurumizaka, Satoshi Tashiro

JOURNAL OF CELL SCIENCE　126　(22)　5284-5292　2013/11

DOI： 10.1242/jcs.133744 　

ISSN： 0021-9533

eISSN： 1477-9137
Transcription repressor Bach2 is required for pulmonary surfactant homeostasis and alveolar macrophage function. International-journal Peer-reviewed

Atsushi Nakamura, Risa Ebina-Shibuya, Ari Itoh-Nakadai, Akihiko Muto, Hiroki Shima, Daisuke Saigusa, Junken Aoki, Masahito Ebina, Toshihiro Nukiwa, Kazuhiko Igarashi

The Journal of experimental medicine　210　(11)　2191-204　2013/10/21

DOI： 10.1084/jem.20130028 　

ISSN： 0022-1007

More details Close

Pulmonary alveolar proteinosis (PAP) results from a dysfunction of alveolar macrophages (AMs), chiefly due to disruptions in the signaling of granulocyte macrophage colony-stimulating factor (GM-CSF). We found that mice deficient for the B lymphoid transcription repressor BTB and CNC homology 2 (Bach2) developed PAP-like accumulation of surfactant proteins in the lungs. Bach2 was expressed in AMs, and Bach2-deficient AMs showed alterations in lipid handling in comparison with wild-type (WT) cells. Although Bach2-deficient AMs showed a normal expression of the genes involved in the GM-CSF signaling, they showed an altered expression of the genes involved in chemotaxis, lipid metabolism, and alternative M2 macrophage activation with increased expression of Ym1 and arginase-1, and the M2 regulator Irf4. Peritoneal Bach2-deficient macrophages showed increased Ym1 expression when stimulated with interleukin-4. More eosinophils were present in the lung and peritoneal cavity of Bach2-deficient mice compared with WT mice. The PAP-like lesions in Bach2-deficient mice were relieved by WT bone marrow transplantation even after their development, confirming the hematopoietic origin of the lesions. These results indicate that Bach2 is required for the functional maturation of AMs and pulmonary homeostasis, independently of the GM-CSF signaling.
Collagenase H is Crucial for Isolation of Rat Pancreatic Islets Peer-reviewed

Atsushi Fujio, Kazutaka Murayama, Youhei Yamagata, Kimiko Watanabe, Takehiro Imura, Akiko Inagaki, Naomi Ohbayashi, Hiroki Shima, Satoshi Sekiguchi, Keisei Fujimori, Kazuhiko Igarashi, Noriaki Ohuchi, Susumu Satomi, Masafumi Goto

TRANSPLANTATION　96　(6)　S141-S142　2013/09

ISSN： 0041-1337

eISSN： 1534-6080
Bach1 deficiency protects pancreatic beta-cells from oxidative stress injury Peer-reviewed

Keiichi Kondo, Yasushi Ishigaki, Junhong Gao, Tetsuya Yamada, Junta Imai, Shojiro Sawada, Akihiko Muto, Yoshitomo Oka, Kazuhiko Igarashi, Hideki Katagiri

AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM　305　(5)　E641-E648　2013/09

DOI： 10.1152/ajpendo.00120.2013 　

ISSN： 0193-1849
BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint Peer-reviewed

Srividya Swaminathan, Chuanxin Huang, Huimin Geng, Zhengshan Chen, Richard Harvey, Huining Kang, Carina Ng, Bjoern Titz, Christian Hurtz, Mohammed Firas Sadiyah, Daniel Nowak, Gabriela B. Thoennissen, Vikki Rand, Thomas G. Graeber, H. Phillip Koeffler, William L. Carroll, Cheryl L. Willman, Andrew G. Hall, Kazuhiko Igarashi, Ari Melnick, Markus Mueschen

NATURE MEDICINE　19　(8)　1014-+　2013/08

DOI： 10.1038/nm.3247 　

ISSN： 1078-8956
Bach1 is critical for the transformation of mouse embryonic fibroblasts by Ras(V12) and maintains ERK signaling Peer-reviewed

A. Nakanome, A. Brydun, M. Matsumoto, K. Ota, R. Funayama, K. Nakayama, M. Ono, K. Shiga, T. Kobayashi, K. Igarashi

ONCOGENE　32　(27)　3231-3245　2013/07

DOI： 10.1038/onc.2012.336 　

ISSN： 0950-9232
Transforming Growth Factor-beta Induces Transcription Factors MafK and Bach1 to Suppress Expression of the Heme Oxygenase-1 Gene Peer-reviewed

Yukari Okita, Atsushi Kamoshida, Hiroyuki Suzuki, Ken Itoh, Hozumi Motohashi, Kazuhiko Igarashi, Masayuki Yamamoto, Tomohiro Ogami, Daizo Koinuma, Mitsuyasu Kato

JOURNAL OF BIOLOGICAL CHEMISTRY　288　(28)　20658-20667　2013/07

DOI： 10.1074/jbc.M113.450478 　

ISSN： 0021-9258
Over-expression of BACH2 is related to ongoing somatic hypermutation of the immunoglobulin heavy chain gene variable region of de novo diffuse large B-cell lymphoma Peer-reviewed

Tomoki Kikuchi, Mami Tokunaka, Yara Yukie Kikuti, Joaquim Carreras, Go Ogura, Susumu Takekoshi, Minoru Kojima, Kiyoshi Ando, Yuko Hashimoto, Masafumi Abe, Katsuyoshi Takata, Tadashi Yoshino, Akihiko Muto, Kazuhiko Igarashi, Naoya Nakamura

Pathology International　63　(7)　339-344　2013/07

DOI： 10.1111/pin.12076 　

ISSN： 1320-5463 1440-1827
Bach2 maintains T cells in a naive state by suppressing effector memory-related genes Peer-reviewed

Shin-Ichi Tsukumo, Midori Unno, Akihiko Muto, Arata Takeuchi, Kohei Kometani, Tomohiro Kurosaki, Kazuhiko Igarashi, Takashi Saito

Proceedings of the National Academy of Sciences of the United States of America　110　(26)　10735-10740　2013/06/25

DOI： 10.1073/pnas.1306691110 　

ISSN： 0027-8424 1091-6490
BACH2 represses effector programs to stabilize T-reg-mediated immune homeostasis Peer-reviewed

Rahul Roychoudhuri, Kiyoshi Hirahara, Kambiz Mousavi, David Clever, Christopher A. Klebanoff, Michael Bonelli, Giuseppe Sciume, Hossein Zare, Golnaz Vahedi, Barbara Dema, Zhiya Yu, Hui Liu, Hayato Takahashi, Mahadev Rao, Pawel Muranski, Joseph G. Crompton, George Punkosdy, Davide Bedognetti, Ena Wang, Victoria Hoffmann, Juan Rivera, Francesco M. Marincola, Atsushi Nakamura, Vittorio Sartorelli, Yuka Kanno, Luca Gattinoni, Akihiko Muto, Kazuhiko Igarashi, John J. O'Shea, Nicholas P. Restifo

NATURE　498　(7455)　506-+　2013/06

DOI： 10.1038/nature12199 　

ISSN： 0028-0836

eISSN： 1476-4687
Methionine Adenosyltransferase II-dependent Histone H3K9 Methylation at the COX-2 Gene Locus Peer-reviewed

Yohei Kera, Yasutake Katoh, Mineto Ohta, Mitsuyo Matsumoto, Teruko Takano-Yamamoto, Kazuhiko Igarashi

JOURNAL OF BIOLOGICAL CHEMISTRY　288　(19)　13592-13601　2013/05

DOI： 10.1074/jbc.M112.429738 　

ISSN： 0021-9258

eISSN： 1083-351X
Solution Structure of Clostridial Collagenase H and Its Calcium-Dependent Global Conformation Change Peer-reviewed

Naomi Ohbayashi, Takashi Matsumoto, Hiroki Shima, Masafumi Goto, Kimiko Watanabe, Akihito Yamano, Yasutake Katoh, Kazuhiko Igarashi, Youhei Yamagata, Kazutaka Murayama

BIOPHYSICAL JOURNAL　104　(7)　1538-1545　2013/04

DOI： 10.1016/j.bpj.2013.02.022 　

ISSN： 0006-3495

eISSN： 1542-0086
BTB and CNC Homolog 1 (Bach1) Deficiency Ameliorates TNBS Colitis in Mice: Role of M2 Macrophages and Heme Oxygenase-1 Peer-reviewed

Akihito Harusato, Yuji Naito, Tomohisa Takagi, Kazuhiko Uchiyama, Katsura Mizushima, Yasuko Hirai, Yasuki Higashimura, Kazuhiro Katada, Osamu Handa, Takeshi Ishikawa, Nobuaki Yagi, Satoshi Kokura, Hiroshi Ichikawa, Akihiko Muto, Kazuhiko Igarashi, Toshikazu Yoshikawa

INFLAMMATORY BOWEL DISEASES　19　(4)　740-753　2013/03

DOI： 10.1097/MIB.0b013e3182802968 　

ISSN： 1078-0998
Transcriptional suppression of BACH2 by the Bcr-Abl oncoprotein is mediated by PAX5 Peer-reviewed

D. A. Casolari, M. Makri, C. Yoshida, A. Muto, K. Igarashi, J. V. Melo

LEUKEMIA　27　(2)　409-415　2013/02

DOI： 10.1038/leu.2012.220 　

ISSN： 0887-6924
2P093 Heme binding region of Bach2 as intrinsically disordered protein(02. Heme proteins,Poster)

Murayama Kazutaka, Matsui Miki, Igarashi Kazuhiko

Seibutsu Butsuri　53　(1)　S174　2013
Publisher: The Biophysical Society of Japan General Incorporated Association
DOI： 10.2142/biophys.53.S174_3 　
Duodenal follicular lymphoma lacks AID but expresses BACH2 and has memory B-cell characteristics Peer-reviewed

Katsuyoshi Takata, Yasuharu Sato, Naoya Nakamura, Mami Tokunaka, Yukari Miki, Yara Yukie Kikuti, Kazuhiko Igarashi, Etsuro Ito, Hideo Harigae, Seiichi Kato, Eiko Hayashi, Takashi Oka, Yoshinobu Hoshii, Akira Tari, Hiroyuki Okada, Abd Alkader Lamia Mohamad, Yoshinobu Maeda, Mitsune Tanimoto, Tomohiro Kinoshita, Tadashi Yoshino

Modern Pathology　26　(1)　22-31　2013/01

DOI： 10.1038/modpathol.2012.127 　

ISSN： 0893-3952 1530-0285
Metabolic aspects of epigenome: Coupling of S-adenosylmethionine synthesis and gene regulation on chromatin by SAMIT module Peer-reviewed

Kazuhiko Igarashi, Yasutake Katoh

Sub-Cellular Biochemistry　61　105-118　2013
Publisher: Springer New York
DOI： 10.1007/978-94-007-4525-4_5 　

ISSN： 0306-0225
Bach1 as a regulator of mitosis, beyond its transcriptional function Peer-reviewed

Jie Li, Takuma Shiraki, Kazuhiko Igarashi

Communicative and Integrative Biology　5　(5)　477-479　2012/09

DOI： 10.4161/cib.21149 　

ISSN： 1942-0889

eISSN： 1942-0889
Role of BTB and CNC Homolog 1 (BACH1) in Ischemia-Reperfusion-Challenged Intestinal Inflammation in Mice Peer-reviewed

Takaya Iida, Yuji Naito, Tomohisa Takagi, Kazuhiro Katada, Katsura Mizushima, Kazuhiro Kamada, Kazuhiko Uchiyama, Osamu Handa, Hiroshi Ichikawa, Akihiko Muto, Kazuhiko Igarashi, Toshikazu Yoshikawa

GASTROENTEROLOGY　142　(5)　S365-S365　2012/05

ISSN： 0016-5085
Adoptive Transfer of Heme Oxygenase-1 Highly Expressed Macrophage Ameliorated TNBS-Induced Colitis in Mice Peer-reviewed

Akihito Harusato, Yuji Naito, Tomohisa Takagi, Kazuhiko Uchiyama, Katsura Mizushima, Yasuko Hirai, Toshifumi Tsuji, Wataru Fukuda, Hiroyuki Yoriki, Munehiro Kugai, Ryusuke Horie, Akifumi Fukui, Takaya Iida, Kazuhiro Katada, Osamu Handa, Hiroshi Ichikawa, Akihiko Muto, Kazuhiko Igarashi, Toshikazu Yoshikawa

GASTROENTEROLOGY　142　(5)　S883-S883　2012/05

ISSN： 0016-5085
Bach1 regulates osteoclastogenesis in a mouse model via both heme oxygenase 1-dependent and heme oxygenase 1-independent pathways Peer-reviewed

Maasa Hama, Yohei Kirino, Mitsuhiro Takeno, Kaoru Takase, Takuya Miyazaki, Ryusuke Yoshimi, Atsuhisa Ueda, Ari Itoh-Nakadai, Akihiko Muto, Kazuhiko Igarashi, Yoshiaki Ishigatsubo

ARTHRITIS AND RHEUMATISM　64　(5)　1518-1528　2012/05

DOI： 10.1002/art.33497 　

ISSN： 0004-3591

eISSN： 1529-0131
Bach1-mediated suppression of p53 is inhibited by p19ARF independently of MDM2 Peer-reviewed

Hironari Nishizawa, Kazushige Ota, Yoshihiro Dohi, Tsuyoshi Ikura, Kazuhiko Igarashi

CANCER SCIENCE　103　(5)　897-903　2012/05

DOI： 10.1111/j.1349-7006.2012.02244.x 　

ISSN： 1347-9032
Transcription-independent role of Bach1 in mitosis through a nuclear exporter Crm1-dependent mechanism Peer-reviewed

Jie Li, Takuma Shiraki, Kazuhiko Igarashi

FEBS LETTERS　586　(4)　448-454　2012/02

DOI： 10.1016/j.febslet.2012.01.028 　

ISSN： 0014-5793

eISSN： 1873-3468
Nuclear function of methionine adenosyltransferase II in oxidative stress response

IGARASHI Kazuhiko, KERA Yohei, KATOH Yasutake

Annual Meeting of the Japanese Society of Toxicology　39　S1-3　2012
Publisher: The Japanese Society of Toxicology
DOI： 10.14869/toxpt.39.1.0.S1-3.0 　
Identification of Senescence-Associated Genes and Their Networks Under Oxidative Stress by the Analysis of Bach1 Peer-reviewed

Kazushige Ota, Yoshihiro Dohi, Andrey Brydun, Ayako Nakanome, Sadayoshi Ito, Kazuhiko Igarashi

ANTIOXIDANTS & REDOX SIGNALING　14　(12)　2441-2451　2011/06

DOI： 10.1089/ars.2010.3574 　

ISSN： 1523-0864

eISSN： 1557-7716
Suppression of indomethacin-induced apoptosis in the small intestine due to Bach1 deficiency Peer-reviewed

Akihito Harusato, Yuji Naito, Tomohisa Takagi, Kazuhiko Uchiyama, Katsura Mizushima, Yasuko Hirai, Shinya Yamada, Toshifumi Tuji, Hiroyuki Yoriki, Ryusuke Horie, Ken Inoue, Kohei Fukumoto, Osamu Handa, Takeshi Ishikawa, Satoshi Kokura, Yukiko Minamiyama, Hiroshi Ichikawa, Akihiko Muto, Kazuhiko Igarashi, Toshikazu Yoshikawa

FREE RADICAL RESEARCH　45　(6)　717-727　2011/06

DOI： 10.3109/10715762.2011.574287 　

ISSN： 1071-5762
[Structure and dynamics of gene regulatory network for humoral immune response]. Peer-reviewed

Muto, A., Itoh-Nakadai, A., Igarashi, K.

[Rinshō ketsueki] The Japanese journal of clinical hematology　52　(6)　376-386　2011/06

DOI： 10.11406/rinketsu.52.376 　

ISSN： 0485-1439
Deficiency of BACHI Ameliorates TNBS-Induced Colitis in Mice Thorough the Anti-Inflammatory Function of HO-I Highly Expressed Macrophages Peer-reviewed

Akihito Harusato, Yuji Naito, Tomohisa Takagi, Kazuhiko Uchiyama, Katsura Mizushima, Yasuko Hirai, Toshifumi Tsuji, Hiroyuki Yoriki, Munehiro Kugai, Ryusuke Horie, Ken Inoue, Kohei Fukumoto, Shinya Yamada, Osamu Handa, Satoshi Kokura, Hiroshi Ichikawa, Akihiko Muto, Kazuhiko Igarashi, Toshikazu Yoshikawa

GASTROENTEROLOGY　140　(5)　S649-S649　2011/05

ISSN： 0016-5085
Heme regulates B-cell differentiation, antibody class switch, and heme oxygenase-1 expression in B cells as a ligand of Bach2 Peer-reviewed

Miki Watanabe-Matsui, Akihiko Muto, Toshitaka Matsui, Ari Itoh-Nakadai, Osamu Nakajima, Kazutaka Murayama, Masayuki Yamamoto, Masao Ikeda-Saito, Kazuhiko Igarashi

BLOOD　117　(20)　5438-5448　2011/05

DOI： 10.1182/blood-2010-07-296483 　

ISSN： 0006-4971
Bach1 gene ablation reduces steatohepatitis in mouse MCD diet model Peer-reviewed

Motoki Inoue, Susumu Tazuma, Keishi Kanno, Hideyuki Hyogo, Kazuhiko Igarashi, Kazuaki Chayama

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION　48　(2)　161-166　2011/03

DOI： 10.3164/jcbn.09-122GFR 　

ISSN： 0912-0009

eISSN： 1880-5086
Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch Peer-reviewed

Akihiko Muto, Kyoko Ochiai, Yoshitaka Kimura, Ari Itoh-Nakadai, Kathryn L. Calame, Dai Ikebe, Satoshi Tashiro, Kazuhiko Igarashi

EMBO JOURNAL　29　(23)　4048-4061　2010/12

DOI： 10.1038/emboj.2010.257 　

ISSN： 0261-4189
Bach1 Deficiency Leads to the Suppression of TNBS-Induced Colitis in Mice Peer-reviewed

Akihito Harusato, Yuji Naito, Tomohisa Takagi, Katsura Mizushima, Shinya Yamada, Ryusuke Horie, Ken Inoue, Kohei Fukumoto, Kazuhiko Uchiyama, Osamu Handa, Satoshi Kokura, Hiroshi Ichikawa, Akihiko Muto, Kazuhiko Igarashi, Toshikazu Yoshikawa

DIGESTIVE DISEASES AND SCIENCES　55　(10)　2703-2703　2010/10

ISSN： 0163-2116
MafB as a type I interferon rheostat Peer-reviewed

Hozumi Motohashi, Kazuhiko Igarashi

NATURE IMMUNOLOGY　11　(8)　695-696　2010/08

DOI： 10.1038/ni0810-695 　

ISSN： 1529-2908
Bach1-dependent and -independent Regulation of Heme Oxygenase-1 in Keratinocytes Peer-reviewed

Shuko Okada, Akihiko Muto, Eisaku Ogawa, Ayako Nakanome, Yasutake Katoh, Shuntaro Ikawa, Setsuya Aiba, Kazuhiko Igarashi, Ryuhei Okuyama

JOURNAL OF BIOLOGICAL CHEMISTRY　285　(31)　23581-23589　2010/07

DOI： 10.1074/jbc.M109.068197 　

ISSN： 0021-9258

eISSN： 1083-351X
The Role of BACH1 in Dextran Sodium Sulfate (DSS)-Induced Colitis in Mice Peer-reviewed

Takagi Tomohisa, Naito Yuji, Harusato Akihito, Yamada Shinya, Fukumoto Kohei, Inoue Ken, Horie Ryusuke, Mizushima Katsura, Omatsu Tatsushi, Hirata Ikuhiro, Yoshida Naohisa, Uchiyama Kazuhiko, Ishikawa Takeshi, Handa Osamu, Konishi Hideyuki, Wakabayashi Naoki, Yagi Nobuaki, Kokura Satoshi, Ichikawa Hiroshi, Muto Akihiko, Igarashi Kazuhiko, Yoshikawa Toshikazu

GASTROENTEROLOGY　138　(5)　S263　2010/05

ISSN： 0016-5085
PO-123 B細胞終末分化におけるエピジェネティック制御の解明(小児外科基礎研究,ポスターセッション,病気の子供達に笑顔小児外科に夢そして革新を,第47回日本小児外科学会学術集会)

田中拡, 武藤哲彦, 落合恭子, 和田基, 佐々木英之, 風間理郎, 西功太郎, 工藤博典, 安藤亮, 五十嵐和彦, 仁尾正記

日本小児外科学会雑誌　46　(3)　660-660　2010
Publisher: 特定非営利活動法人日本小児外科学会
DOI： 10.11164/jjsps.46.3_660_1 　
3P108 Spectoroscopic analyses of heme-acceptor region of Bach2 protein(Heme proteins,The 48th Annual Meeting of the Biophysical Society of Japan)

Murayama Kazutaka, Watamabe-Matsui Miki, Matsui Toshitaka, Ikeda-Saito Masao, Igarashi Kazuhiko

Seibutsu Butsuri　50　(2)　S163　2010
Publisher: The Biophysical Society of Japan General Incorporated Association
DOI： 10.2142/biophys.50.S163_5 　
Indirect- and direct-acting mutagenicity of diesel, coal and wood burning-derived particulates and contribution of polycyclic aromatic hydrocarbons and nitropolycyclic aromatic hydrocarbons. Peer-reviewed

Yang XY, Igarashi K, Tang N, Lin JM, Wang W, Kameda T, Toriba A, Hayakawa K

Mutation research　695　(1-2)　29-34　2010/01

DOI： 10.1016/j.mrgentox.2009.10.010 　

ISSN： 0027-5107
Proline cis/trans-Isomerase Pin1 Regulates Peroxisome Proliferator-activated Receptor gamma Activity through the Direct Binding to the Activation Function-1 Domain Peer-reviewed

Yoshito Fujimoto, Takuma Shiraki, Yuji Horiuchi, Tsuyoshi Waku, Akira Shigenaga, Akira Otaka, Tsuyoshi Ikura, Kazuhiko Igarashi, Saburo Aimoto, Shin-ichi Tate, Kosuke Morikawa

JOURNAL OF BIOLOGICAL CHEMISTRY　285　(5)　3126-3132　2010/01

DOI： 10.1074/jbc.M109.055095 　

ISSN： 0021-9258

eISSN： 1083-351X
Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: demonstration that the KEAP1-NRF2 pathway, and not the BACH1-NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compounds Peer-reviewed

A. Kenneth MacLeod, Michael McMahon, Simon M. Plummer, Larry G. Higgins, Trevor M. Penning, Kazuhiko Igarashi, John D. Hayes

CARCINOGENESIS　30　(9)　1571-1580　2009/09

DOI： 10.1093/carcin/bgp176 　

ISSN： 0143-3334

eISSN： 1460-2180
タンパク質修飾による遺伝子発現制御のクロストークメチオニン・アデノシル基転移酵素(MATII)による転写制御(Methionine adenosyltransferase II serves as a transcriptional corepressor of Maf oncoprotein)

加藤恭丈, 星川裕, 井倉毅, 田代聡, 太田嶺人, 野田哲生, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　82回　(5)　1S11p-3　2009/09

DOI： 10.1016/j.molcel.2011.02.018 　

ISSN： 1097-2765
Regulation of cellular senescence by Bach1 Peer-reviewed

Igarashi, K., Ota, K., Nakame, A.

Nippon rinsho. Japanese journal of clinical medicine　67　(7)　1423-1428　2009/07

ISSN： 0047-1852
Genetic ablation of the Bach1 gene reduces hyperoxic lung injury in mice: Role of IL-6 Peer-reviewed

Takuya Tanimoto, Noboru Hattori, Tadashi Senoo, Makoto Furonaka, Nobuhisa Ishikawa, Kazunori Fujitaka, Yoshinori Haruta, Akihito Yokoyama, Kazuhiko Igarashi, Nobuoki Kohno

FREE RADICAL BIOLOGY AND MEDICINE　46　(8)　1119-1126　2009/04

DOI： 10.1016/j.freeradbiomed.2009.01.017 　

ISSN： 0891-5849
Bach1 Deficiency Ameliorates Hepatic Injury in a Mouse Model Peer-reviewed

Akio Iida, Koji Inagaki, Akira Miyazaki, Fumihiko Yonemori, Etsuro Ito, Kazuhiko Igarashi

TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE　217　(3)　223-229　2009/03

DOI： 10.1620/tjem.217.223 　

ISSN： 0040-8727

eISSN： 1349-3329
Crystal structure of the Bach1 BTB domain and its regulation of homodimerization Peer-reviewed

Nobutoshi Ito, Miki Watanabe-Matsui, Kazuhiko Igarashi, Kazutaka Murayama

GENES TO CELLS　14　(2)　167-178　2009/02

DOI： 10.1111/j.1365-2443.2008.01259.x 　

ISSN： 1356-9597
Bach1 Modulates Heme Oxygenase-1 Expression in the Neonatal Mouse Lung Peer-reviewed

Sacha Kassovska-Bratinova, Guang Yang, Kazuhiko Igarashi, Phyllis A. Dennery

PEDIATRIC RESEARCH　65　(2)　145-149　2009/02

DOI： 10.1203/PDR.0b013e318191eedc 　

ISSN： 0031-3998
Inhibition of Bach1 ameliorates indomethacin-induced intestinal injury in mice.

A. Harusato, Y. Naito, T. Takagi, S. Yamada, K. Mizushima, Y. Hirai, R. Horie, K. Inoue, K. Fukumoto, I. Hirata, T. Omatsu, E. Kishimoto, K. Uchiyama, O. Handa, T. Ishikawa, S. Kokura, H. Ichikawa, A. Muto, K. Igarashi, T. Yoshikawa

Journal of physiology and pharmacology : an official journal of the Polish Physiological Society　60　149-154　2009

ISSN： 1899-1505
Genetic Ablation of Transcription Repressor Bach1 Reduces Neural Tissue Damage and Improves Locomotor Function after Spinal Cord Injury in Mice Peer-reviewed

Haruo Kanno, Hiroshi Ozawa, Yoshihiro Dohi, Akira Sekiguchi, Kazuhiko Igarashi, Eiji Itoi

JOURNAL OF NEUROTRAUMA　26　(1)　31-39　2009/01

DOI： 10.1089/neu.2008.0667 　

ISSN： 0897-7151
Transcriptional regulation of cellular senescence Peer-reviewed

Kazuhiko Igarashi, Yoshihiro Dohi

Seikagaku　81　(6)　502-510　2009

ISSN： 0037-1017
Bach1 inhibits oxidative stress-induced cellular senescence by impeding p53 function on chromatin Peer-reviewed

Yoshihiro Dohi, Tsuyoshi Ikura, Yutaka Hoshikawa, Yasutake Katoh, Kazushige Ota, Ayako Nakanome, Akihiko Muto, Shinji Omura, Tsutomu Ohta, Akihiro Ito, Minoru Yoshida, Tetsuo Noda, Kazuhiko Igarashi

NATURE STRUCTURAL & MOLECULAR BIOLOGY　15　(12)　1246-1254　2008/12

DOI： 10.1038/nsmb.1516 　

ISSN： 1545-9985

eISSN： 1545-9985
Bach1 inhibits oxidative stress-induced cellular senescence by impeding p53 function on chromatin Peer-reviewed

Yoshihiro Dohi, Tsuyoshi Ikura, Yutaka Hoshikawa, Yasutake Katoh, Kazushige Ota, Ayako Nakanome, Akihiko Muto, Shinji Omura, Tsutomu Ohta, Akihiro Ito, Minoru Yoshida, Tetsuo Noda, Kazuhiko Igarashi

Nature Structural and Molecular Biology　15　(12)　1246-1254　2008/12

DOI： 10.1038/nsmb.1516 　

ISSN： 1545-9993 1545-9985
Regulation of heme oxygenase-1 by transcription factor Bach1 in the mouse brain Peer-reviewed

Eiichirou Sakoda, Kazuhiko Igarashi, Jiying Sun, Kaoru Kurisu, Satoshi Tashiro

NEUROSCIENCE LETTERS　440　(2)　160-165　2008/08

DOI： 10.1016/j.neulet.2008.04.082 　

ISSN： 0304-3940
Myocardial protection against pressure overload in mice lacking Bach1, a transcriptional repressor of heme oxygenase-1 Peer-reviewed

Shinji Mito, Ryoji Ozono, Tetsuya Oshima, Yoko Yano, Yuichiro Watari, Yoshiyuki Yamamoto, Andrei Brydun, Kazuhiko Igarashi, Masao Yoshizumi

HYPERTENSION　51　(6)　1570-1577　2008/06

DOI： 10.1161/HYPERTENSIONAHA.107.102566 　

ISSN： 0194-911X
Oxidative stress reaction in the meniscus of Bach 1 deficient mice: Potential prevention of meniscal degeneration Peer-reviewed

Satoshi Ochiai, Toshiyuki Mizuno, Masataka Deie, Kazuhiko Igarashi, Yoshiki Hamada, Mitsuo Ochi

JOURNAL OF ORTHOPAEDIC RESEARCH　26　(6)　894-898　2008/06

DOI： 10.1002/jor.20579 　

ISSN： 0736-0266
Ablation of the Bach1 gene leads to the suppression of atherosclerosis in Bach1 and apolipoprotein E double knockout mice Peer-reviewed

Yuichiro Watari, Yoshiyuki Yamamoto, Andrei Brydun, Takafumi Ishida, Shinji Mito, Masao Yoshizumi, Kazuhiko Igarashi, Kazuaki Chayama, Tetsuya Ohshima, Ryoji Ozono

HYPERTENSION RESEARCH　31　(4)　783-792　2008/04

DOI： 10.1291/hypres.31.783 　

ISSN： 0916-9636
Regulation of the plasma cell transcription factor Blimp-1 gene by Bach2 and Bcl6 Peer-reviewed

Kyoko Ochiai, Akihiko Muto, Hiromu Tanaka, Shinichiro Takahashi, Kazuhiko Igarashi

INTERNATIONAL IMMUNOLOGY　20　(3)　453-460　2008/03

DOI： 10.1093/intimm/dxn005 　

ISSN： 0953-8178
Regulation of the plasma cell transcription factor Blimp-1 gene by Bach2 and Bcl6. Peer-reviewed

Ochiai K Muto, A, Tanaka, H, Takahashi, S, Igarashi K

Int Immunol.　20　(3)　453-4560　2008/03

DOI： 10.1093/intimm/dxn005 　

ISSN： 0953-8178
The mobility of Bach2 nuclear foci is regulated by SUMO-1 modification. International-journal Peer-reviewed

Kazuteru Kono, Yumi Harano, Hideto Hoshino, Masao Kobayashi, David P Bazett-Jones, Akihiko Muto, Kazuhiko Igarashi, Satoshi Tashiro

Experimental cell research　314　(4)　903-13　2008/02/15

DOI： 10.1016/j.yexcr.2007.12.013 　

ISSN： 0014-4827

eISSN： 1090-2422
The mobility of Bach2 nuclear foci is regulated by SUMO-1 modification Peer-reviewed

Kazuteru Kono, Yumi Harano, Hideto Hoshino, Masao Kobayashi, David P. Bazett-Jones, Akihiko Muto, Kazuhiko Igarashi, Satoshi Tashiro

EXPERIMENTAL CELL RESEARCH　314　(4)　903-913　2008/02

DOI： 10.1016/j.yexcr.2007.12.013 　

ISSN： 0014-4827

eISSN： 1090-2422
Modulation of the secondary injury process after spinal cord injury in Bach1-deficient mice by heme oxygenase-1: Laboratory investigation

Yamada, K., Tanaka, N., Nakanishi, K., Kamei, N., Ishikawa, M., Mizuno, T., Igarashi, K., Ochi, M.

Journal of Neurosurgery: Spine　9　(6)　2008

DOI： 10.3171/SPI.2008.10.08488 　
Bach1 repression of ferritin and thioredoxin reductase1 is heme-sensitive in cells and in vitro and coordinates expression with heme oxygenase1, beta-globin, and NADP(H) quinone (oxido) reductase1 Peer-reviewed

Korry J. Hintze, Yasutake Katoh, Kazuhiko Igarashi, Elizabeth C. Theil

JOURNAL OF BIOLOGICAL CHEMISTRY　282　(47)　34365-34371　2007/11

DOI： 10.1074/jbc.M700254200 　

ISSN： 0021-9258
Bach1 repression of ferritin and thioredoxin reductase1 is heme-sensitive in cells and in vitro and coordinates expression with heme oxygenase1, beta-globin, and NADP(H) quinone (oxido) reductase1 Peer-reviewed

Korry J. Hintze, Yasutake Katoh, Kazuhiko Igarashi, Elizabeth C. Theil

JOURNAL OF BIOLOGICAL CHEMISTRY　282　(47)　34365-34371　2007/11

DOI： 10.1074/jbc.M700254200 　

ISSN： 0021-9258
Heme induces ubiquitination and degradation of the transcription factor bach1 Peer-reviewed

Yukari Zenke-Kawasaki, Yoshihiro Dohi, Yasutake Katoh, Tsuyoshi Ikura, Masae Ikura, Toshimasa Asahara, Furninori Tokunaga, Kazuhiro Iwai, Kazuhiko Igarashi

MOLECULAR AND CELLULAR BIOLOGY　27　(19)　6962-6971　2007/10

DOI： 10.1128/MCB.0241-06 　

ISSN： 0270-7306

eISSN： 1098-5549
DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics Peer-reviewed

Tsuyoshi Ikura, Satoshi Tashiro, Akemi Kakino, Hiroki Shima, Naduparambil Jacob, Ravindra Amunugarna, Kristine Yoder, Shunsuke Izumi, Isao Kuraoka, Kiyoji Tanaka, Hiroshi Kimura, Masae Tkura, Shuichi Nishikubo, Takashi Ito, Akihiko Muto, Kiyoshi Miyagawa, Shunichi Takeda, Richard Fishel, Kazuhiko Igarashi, Kenji Kamiya

MOLECULAR AND CELLULAR BIOLOGY　27　(20)　7028-7040　2007/10

DOI： 10.1128/MCB.00579-07 　

ISSN： 0270-7306
Architecture and dynamics of the transcription factor network that regulates B-to-plasma cell differentiation Peer-reviewed

Kazuhiko Igarashi, Kyoko Ochiai, Akihiko Muto

JOURNAL OF BIOCHEMISTRY　141　(6)　783-789　2007/06

DOI： 10.1093/jb/mvm106 　

ISSN： 0021-924X
Co-repressor SMRT and class II histone deacetylases promote Bach2 nuclear retention and formation of nuclear foci that are responsible for local transcriptional repression. International-journal Peer-reviewed

Hideto Hoshino, Tomonori George Nishino, Satoshi Tashiro, Masaya Miyazaki, Yoshihiro Ohmiya, Kazuhiko Igarashi, Sueharu Horinouchi, Minoru Yoshida

Journal of biochemistry　141　(5)　719-27　2007/05

DOI： 10.1093/jb/mvm073 　

ISSN： 0021-924X
Bcr-Abl signaling through the PI-3/S6 kinase pathway inhibits nuclear translocation of the transcription factor Bach2, which represses the antiapoptotic factor heme oxygenase-1 Peer-reviewed

Chikashi Yoshida, Fumiko Yoshida, Daniel E. Sears, Stephen M. Hart, Dai Ikebe, Akihiko Muto, Subham Basu, Kazuhiko Igarashi, Junia V. Melo

BLOOD　109　(3)　1211-1219　2007/02

DOI： 10.1182/blood-2005-12-040972 　

ISSN： 0006-4971
Nuclear positioning of the BACH2 gene in BCR-ABL positive leukemic cells Peer-reviewed

Atsushi Ono, Kazuteru Kono, Dai Ikebe, Akihiko Muto, Jiying Sun, Masao Kobayashi, Kazuhiro Ueda, Junia V. Melo, Kazuhiko Igarashi, Satoshi Tashiro

GENES CHROMOSOMES & CANCER　46　(1)　67-74　2007/01

DOI： 10.1002/gcc.20390 　

ISSN： 1045-2257
Bach1, a heme-dependent transcription factor, reveals presence of multiple heme binding sites with distinct coordination structure Peer-reviewed

Shusuke Hira, Takeshi Tomita, Toshitaka Matsui, Kazuhiko Igarashi, Masao Ikeda-Saito

IUBMB LIFE　59　(8-9)　542-551　2007

DOI： 10.1080/15216540701225941 　

ISSN： 1521-6543
Plasmacytic transcription factor Blimp-1 is repressed by Bach2 in B cells Peer-reviewed

Kyoko Ochiai, Yasutake Katoh, Tsuyoshi Ikura, Yutaka Hoshikawa, Tetsuo Noda, Hajime Karasuyama, Satoshi Tashiro, Akihiko Muto, Kazuhiko Igarashi

JOURNAL OF BIOLOGICAL CHEMISTRY　281　(50)　38226-38234　2006/12

DOI： 10.1074/jbc.M607592200 　

ISSN： 0021-9258
Down-regulation of heme oxygenase-2 is associated with the increased expression of heme oxygenase-1 in human cell lines Peer-reviewed

Yuanying Ding, Yong Z. Zhang, Kazumichi Furuyama, Kazuhiro Ogawa, Kazuhiko Igarashi, Shigeki Shibahara

FEBS JOURNAL　273　(23)　5333-5346　2006/12

DOI： 10.1111/j.1742-4658.2006.05526.x 　

ISSN： 1742-464X
Transcription on chromatin: overview Peer-reviewed

Igarashi, K.

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme　51　(14 Suppl)　2067-2068　2006/11

ISSN： 0039-9450
Genetic ablation of the transcription repressor Bach1 leads to myocardial protection against ischemia/reperfusion in mice Peer-reviewed

Y Yano, R Ozono, Y Oishi, M Kambe, M Yoshizumi, T Ishida, S Omura, T Oshima, K Igarashi

GENES TO CELLS　11　(7)　791-803　2006/07

DOI： 10.1111/j.1365-2443.2006.00979.x 　

ISSN： 1356-9597
beta-carotene and cigarette smoke condensate regulate heme oxygenase-1 and its repressor factor Bach 1: Relationship with cell growth Peer-reviewed

Paola Palozza, Simona Serini, Diego Curro, Gabriella Calviello, Kazuhiko Igarashi, Cesare Mancuso

ANTIOXIDANTS & REDOX SIGNALING　8　(5-6)　1069-1080　2006/05

DOI： 10.1089/ars.2006.8.1069 　

ISSN： 1523-0864

eISSN： 1557-7716
Differential gene expression profiling between wild-type and ALAS2-null erythroblasts: Identification of novel heme-regulated genes Peer-reviewed

T Fujiwara, H Harigae, S Takahashi, K Furuyama, O Nakajima, JY Sun, K Igarashi, M Yamamoto, S Sassa, M Kaku, T Sasaki

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　340　(1)　105-110　2006/02

DOI： 10.1016/j.bbrc.2005.11.163 　

ISSN： 0006-291X
Heme oxygenase-1 gene enhancer manifests silencing activity in a chromatin environment prior to oxidative stress Peer-reviewed

Yoshihiro Dohi, Jawed Alam, Masao Yoshizumi, Jiying Sun, Kazuhiko Igarashi

Antioxidants and Redox Signaling　8　(1-2)　60-67　2006/01

DOI： 10.1089/ars.2006.8.60 　

ISSN： 1523-0864
Molecular mechanisms of oxidative stress response and implications in diseases Peer-reviewed

Igarashi, K., Dohi, Y.

Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology.　103　(1)　7-14　2006/01

ISSN： 0446-6586
Heme oxygenase-1 gene enhancer manifests silencing activity in a chromatin environment prior to oxidative stress Peer-reviewed

Y Dohl, J Alam, M Yoshizumi, JY Sun, K Igarashi

ANTIOXIDANTS & REDOX SIGNALING　8　(1-2)　60-67　2006/01

DOI： 10.1089/ars.2006.8.60 　

ISSN： 1523-0864

eISSN： 1557-7716
The heme-Bach1 pathway in the regulation of oxidative stress response and erythroid differentiation Peer-reviewed

K Igarashi, JY Sun

ANTIOXIDANTS & REDOX SIGNALING　8　(1-2)　107-118　2006/01

DOI： 10.1089/ars.2006.8.107 　

ISSN： 1523-0864

eISSN： 1557-7716
The superoxide-producing NAD(P)H oxidase Nox4 in the nucleus of human vascular endothelial cells Peer-reviewed

J Kuroda, K Nakagawa, T Yamasaki, K Nakamura, R Takeya, F Kuribayashi, S Imajoh-Ohmi, K Igarashi, Y Shibata, K Sueishi, H Sumimoto

GENES TO CELLS　10　(12)　1139-1151　2005/12

DOI： 10.1111/j.1365-2443.2005.00907.x 　

ISSN： 1356-9597
Prognostic significance of BACH2 expression in diffuse large B-cell lymhomna: A study of the Osaka Lymphoma Study Group Peer-reviewed

E Sakane-Ishikawa, S Nakatsuka, Y Tomita, S Fujita, Nakamichi, I, T Takakuwa, H Sugiyama, S Fukuhara, M Hino, A Kanamaru, T Soma, M Tsukaguchi, K Igarashi, Y Kanakura, K Aozasa

JOURNAL OF CLINICAL ONCOLOGY　23　(31)　8012-8017　2005/11

DOI： 10.1200/JCO.2005.02.1626 　

ISSN： 0732-183X
Transgenic expression of BACH1 transcription factor results in megakaryocytic impairment Peer-reviewed

T Toki, F Katsuoka, F Kanezaki, G Xu, H Kurotaki, JY Sun, T Kamio, S Watanabe, S Tandai, K Terui, S Yagihashi, N Komatsu, K Igarashi, M Yamamoto, E Ito

BLOOD　105　(8)　3100-3108　2005/04

DOI： 10.1182/blood-2004-07-2826 　

ISSN： 0006-4971
Cancer and epigenetics - basic research and clinical implications: Joint Meeting of the Fourteenth International Symposium of the Hiroshima Cancer Seminar and the Eighth Meeting of the Tottori Bioscience Promotion Foundation, October 2004 Peer-reviewed

W Yasui, M Oshimura, K Igarashi, H Ito, E Tahara

CANCER SCIENCE　96　(4)　245-248　2005/04

DOI： 10.1111/j.1349-7006.2005.00034.x 　

ISSN： 1347-9032
Dynamic cytoplasmic anchoring of the transcription factor Bach1 by intracellular hyaluronic acid binding protein IHABP Peer-reviewed

C Yamasaki, S Tashiro, Y Nishito, T Sueda, K Igarashi

JOURNAL OF BIOCHEMISTRY　137　(3)　287-296　2005/03

DOI： 10.1093/jb/mvi031 　

ISSN： 0021-924X
Effects of genetic ablation of bach1 upon smooth muscle cell proliferation and atherosclerosis after cuff injury Peer-reviewed

S Omura, H Suzuki, M Toyofuku, R Ozono, N Kohno, K Igarashi

GENES TO CELLS　10　(3)　277-285　2005/03

DOI： 10.1111/j.1365-2443.2005.00832.x 　

ISSN： 1356-9597
Polycomb group gene mel-18 regulates early T progenitor expansion by maintaining the expression of Hes-1, a target of the notch pathway Peer-reviewed

M Miyazaki, H Kawamoto, Y Kato, M Itoi, K Miyazaki, K Masuda, S Tashiro, H Ishihara, K Igarashi, T Amagai, R Kanno, M Kanno

JOURNAL OF IMMUNOLOGY　174　(5)　2507-2516　2005/03

ISSN： 0022-1767
Dynamic cytoplasmic anchoring of the transcription factor Bach1 by intracellular hyaluronic acid binding protein IHABP Peer-reviewed

C Yamasaki, S Tashiro, Y Nishito, T Sueda, K Igarashi

JOURNAL OF BIOCHEMISTRY　137　(3)　287-296　2005/03

DOI： 10.1093/jb/mvi031 　

ISSN： 0021-924X
Polycomb group gene mel-18 regulates early T progenitor expansion by maintaining the expression of Hes-1, a target of the notch pathway Peer-reviewed

M Miyazaki, H Kawamoto, Y Kato, M Itoi, K Miyazaki, K Masuda, S Tashiro, H Ishihara, K Igarashi, T Amagai, R Kanno, M Kanno

JOURNAL OF IMMUNOLOGY　174　(5)　2507-2516　2005/03

ISSN： 0022-1767
Prognostic significance of BACH2 expression in diffuse large B-cell lymphoma: A study of the Osaka Lymphoma Study Group Peer-reviewed

Emiko Sakane-Ishikawa, Shin-Ichi Nakatsuka, Yasuhiko Tomita, Shigeki Fujita, Itsuko Nakamichi, Tetsuya Takakuwa, Haruo Sugiyama, Shirou Fukuhara, Masayuki Hino, Akihisa Kanamaru, Toshihiro Soma, Machiko Tsukaguchi, Kazuhiko Igarashi, Yuzuru Kanakura, Katsuyuki Aozasa

Journal of Clinical Oncology　23　(31)　8012-8017　2005

DOI： 10.1200/JCO.2005.02.1626 　

ISSN： 0732-183X
Transgenic expression of BACH1 transcription factor results in down-regulation of the p45 target genes in megakaryocytic lineage cells. Peer-reviewed

T Toki, F Katsuoka, R Kanezaki, S Watanabe, T Kamio, S Tandai, H Kurotaki, S Yagihashi, JY Sun, N Komatsu, K Igarashi, M Yamamoto, E Ito

BLOOD　104　(11)　447A-447A　2004/11

ISSN： 0006-4971
Heme-dependent up-regulation of the alpha-globin gene expression by transcriptional repressor Bach1 in erythroid cells Peer-reviewed

T Tahara, JY Sun, K Igarashi, S Taketani

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　324　(1)　77-85　2004/11

DOI： 10.1016/j.bbrc.2004.09.022 　

ISSN： 0006-291X
Regulation of heme oxygenase-1 gene transcription: Recent advances and highlights from the International Conference (Uppsala, 2003) on heme oxygenase Peer-reviewed

J Alam, K Igarashi, S Immenschuh, S Shibahara, RM Tyrrell

ANTIOXIDANTS & REDOX SIGNALING　6　(5)　924-933　2004/10

DOI： 10.1089/ars.2004.6.924 　

ISSN： 1523-0864

eISSN： 1557-7716
Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate for proteasomal degradation of Nrf2 Peer-reviewed

A Kobayashi, MI Kang, H Okawa, M Ohtsuji, Y Zenke, T Chiba, K Igarashi, M Yamamoto

MOLECULAR AND CELLULAR BIOLOGY　24　(16)　7130-7139　2004/08

DOI： 10.1128/MCB.24.16.7130-7139.2004 　

ISSN： 0270-7306
Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1 Peer-reviewed

H Suzuki, S Tashiro, S Hira, JY Sun, C Yamazaki, Y Zenke, M Ikeda-Saito, M Yoshida, K Igarashi

EMBO JOURNAL　23　(13)　2544-2553　2004/07

DOI： 10.1038/sj.emboj.7600248 　

ISSN： 0261-4189
The transcriptional programme of antibody class switching involves the repressor Bach2. International-journal Peer-reviewed

Akihiko Muto, Satoshi Tashiro, Osamu Nakajima, Hideto Hoshino, Satoru Takahashi, Eiichirou Sakoda, Dai Ikebe, Masayuki Yamamoto, Kazuhiko Igarashi

Nature　429　(6991)　566-71　2004/06/03

DOI： 10.1038/nature02596 　

ISSN： 0028-0836

eISSN： 1476-4687
Repression of PML nuclear body-associated transcription by oxidative stress-activated Bach2. International-journal Peer-reviewed

Satoshi Tashiro, Akihiko Muto, Keiji Tanimoto, Haruka Tsuchiya, Hiroshi Suzuki, Hideto Hoshino, Minoru Yoshida, Joachim Walter, Kazuhiko Igarashi

Molecular and cellular biology　24　(8)　3473-84　2004/04

DOI： 10.1128/MCB.24.8.3473-3484.2004 　

ISSN： 0270-7306

eISSN： 1098-5549
Heme regulates the dynamic exchange of Bach1 and NF-E2-related factors in the Maf transcription factor network Peer-reviewed

JY Sun, M Brand, Y Zenke, S Tashiro, M Groudine, K Igarashi

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　101　(6)　1461-1466　2004/02

DOI： 10.1073/pnas.0308083100 　

ISSN： 0027-8424
Heme positively regulates the expression of beta-globin at the locus control region via the transcriptional factor Bach1 in erythroid cells Peer-reviewed

T Tahara, JY Sun, K Nakanishi, M Yamamoto, H Mori, T Saito, H Fujita, K Igarashi, S Taketani

JOURNAL OF BIOLOGICAL CHEMISTRY　279　(7)　5480-5487　2004/02

DOI： 10.1074/jbc.M302733200 　

ISSN： 0021-9258
Dynamic changes in transcription factor complexes during erythroid differentiation revealed by quantitative proteomics Peer-reviewed

Marjorie Brand, Jeffrey A. Ranish, Nicolas T. Kummer, Joan Hamilton, Kazuhiko Igarashi, Claire Francastel, Tian H. Chi, Gerald R. Crabtree, Ruedi Aebersold, Mark Groudine

Nature Structural and Molecular Biology　11　(1)　73-80　2004/01

DOI： 10.1038/nsmb713 　

ISSN： 1545-9993
Cadmium induces nuclear export of Bach1, a transcriptional repressor of heme oxygenase-1 gene Peer-reviewed

H Suzuki, S Tashiro, JY Sun, H Doi, S Satomi, K Igarashi

JOURNAL OF BIOLOGICAL CHEMISTRY　278　(49)　49246-49253　2003/12

DOI： 10.1074/jbc.M306764200 　

ISSN： 0021-9258
B-cell-specific transcription factor BACH2 modifies the cytotoxic effects of anticancer drugs Peer-reviewed

T Kamio, T Toki, R Kanezaki, S Sasaki, S Tandai, K Terui, D Ikebe, K Igarashi, E Ito

BLOOD　102　(9)　3317-3322　2003/11

DOI： 10.1182/blood-2002-12-3656 　

ISSN： 0006-4971
The B cell-specific transcription factor BACH2 modifies the cytotoxic effects of anticancer drugs. Peer-reviewed

E Ito, T Kamio, T Toki, R Kanezaki, S Sasaki, S Tandai, K Terui, D Ikebe, K Igarashi

BLOOD　102　(11)　592A-592A　2003/11

DOI： 10.1182/blood-2002-12-3656 　

ISSN： 0006-4971
Targeted gene delivery to human osteosarcoma cells with magnetic cationic liposomes under a magnetic field Peer-reviewed

K Hirao, T Sugita, T Kubo, K Igarashi, K Tanimoto, T Murakami, Y Yasunaga, M Ochi

INTERNATIONAL JOURNAL OF ONCOLOGY　22　(5)　1065-1071　2003/05

ISSN： 1019-6439
Bach1 functions as a hypoxia-inducible repressor for the heme oxygenase-1 gene in human cells Peer-reviewed

T Kitamuro, K Takahashi, K Ogawa, R Udono-Fujimori, K Takeda, K Furuyama, M Nakayama, JY Sun, H Fujita, W Hida, T Hattori, K Shirato, K Igarashi, S Shibahara

JOURNAL OF BIOLOGICAL CHEMISTRY　278　(11)　9125-9133　2003/03

DOI： 10.1074/jbc.M209939200 　

ISSN： 0021-9258
Small Maf compound mutants display central nervous system neuronal degeneration, aberrant transcription, and Bach protein mislocalization coincident with myoclonus and abnormal startle response Peer-reviewed

F Katsuoka, H Motohashi, Y Tamagawa, S Kure, K Igarashi, JD Engel, M Yamamoto

MOLECULAR AND CELLULAR BIOLOGY　23　(4)　1163-1174　2003/02

DOI： 10.1128/MCB.23.4.1163-1174.2003 　

ISSN： 0270-7306

eISSN： 1098-5549
Oxidative stress protection by heme Peer-reviewed

Igarashi, K., Sun, H.

Masui. The Japanese journal of anesthesiology　51 Suppl　S16-25　2002/12

ISSN： 0021-4892
Transgenic expression of BACH1 results in megakaryocytic linage impairement. Peer-reviewed

T Toki, F Katsuoka, R Kanezaki, T Kamio, S Tandai, H Kurotaki, S Yagihashi, K Igarashi, M Yamamoto, E Ito

BLOOD　100　(11)　721A-721A　2002/11

ISSN： 0006-4971
Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene Peer-reviewed

JY Sun, H Hoshino, K Takaku, O Nakajima, A Muto, H Suzuki, S Tashiro, S Takahashi, S Shibahara, J Alam, MM Taketo, M Yamamoto, K Igarashi

EMBO JOURNAL　21　(19)　5216-5224　2002/10

DOI： 10.1093/emboj/cdf516 　

ISSN： 0261-4189
Expression of the oxidative stress-regulated transcription factor bach2 in differentiating neuronal cells. International-journal Peer-reviewed

Hideto Hoshino, Kazuhiko Igarashi

Journal of biochemistry　132　(3)　427-31　2002/09

DOI： 10.1093/oxfordjournals.jbchem.a003239 　

ISSN： 0021-924X
Activation of Maf/AP-1 repressor Bach2 by oxidative stress promotes apoptosis and its interaction with promyelocytic leukemia nuclear bodies Peer-reviewed

A Muto, S Tashiro, H Tsuchiya, A Kume, M Kanno, E Ito, M Yamamoto, K Igarashi

JOURNAL OF BIOLOGICAL CHEMISTRY　277　(23)　20724-20733　2002/06

DOI： 10.1074/jbc.M112003200 　

ISSN： 0021-9258

eISSN： 1083-351X
Interaction and cooperation of mi transcription factor (MITF) and myc-associated zinc-finger protein-related factor (MAZR) for transcription of mouse mast cell protease 6 gene Peer-reviewed

E Morii, K Oboki, TR Kataoka, K Igarashi, Y Kitamura

JOURNAL OF BIOLOGICAL CHEMISTRY　277　(10)　8566-8571　2002/03

DOI： 10.1074/jbc.M110392200 　

ISSN： 0021-9258
Chromatin and cancer: The eleventh international symposium of the hiroshima cancer seminar, November 2001 Peer-reviewed

Wataru Yasui, Kazuhiko Igarashi, Masamoto Kanno, Eiichi Tahara

Japanese Journal of Cancer Research　93　(4)　467-469　2002
Publisher: Japanese Cancer Association
DOI： 10.1111/j.1349-7006.2002.tb01279.x 　

ISSN： 0910-5050
The promoter of mouse transcription repressor bach1 is regulated by Sp1 and trans-activated by Bach1. International-journal Peer-reviewed

J Sun, A Muto, H Hoshino, A Kobayashi, S Nishimura, M Yamamoto, N Hayashi, E Ito, K Igarashi

Journal of biochemistry　130　(3)　385-92　2001/09

DOI： 10.1093/oxfordjournals.jbchem.a002997 　

ISSN： 0021-924X
Activation of beta-major globin gene transcription is associated with recruitment of NF-E2 to the beta-globin LCR and gene promoter Peer-reviewed

T Sawado, K Igarashi, M Groudine

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　98　(18)　10226-10231　2001/08

ISSN： 0027-8424
Fission yeast homologues of the B ' subunit of protein phosphatase 2A: multiple roles in mitotic cell division and functional interaction with calcineurin Peer-reviewed

O Tanabe, D Hirata, H Usui, Y Nishito, T Miyakawa, K Igarashi, M Takeda

GENES TO CELLS　6　(5)　455-473　2001/05

DOI： 10.1046/j.1365-2443.2001.00429.x 　

ISSN： 1356-9597

eISSN： 1365-2443
Transcription factor BACH1 is recruited to the nucleus by its novel alternative spliced isoform Peer-reviewed

R Kanezaki, T Toki, M Yokoyama, K Yomogida, K Sugiyama, M Yamamoto, K Igarashi, E Ito

JOURNAL OF BIOLOGICAL CHEMISTRY　276　(10)　7278-7284　2001/03

DOI： 10.1074/jbc.M004227200 　

ISSN： 0021-9258
Reconstitution of human β-globin locus control region hypersensitive sites in the absence of chromatin assembly

Leach, K.M., Nightingale, K., Igarashi, K., Levings, P.P., Engel, J.D., Becker, P.B., Bungert, J.

Molecular and Cellular Biology　21　(8)　2001

DOI： 10.1128/MCB.21.8.2629-2640.2001 　
Suppression of rat thromboxane synthase gene transcription by peroxisome proliferator-activated receptor gamma in macrophages via an interaction with NRF2 Peer-reviewed

Y Ikeda, A Sugawara, Y Taniyama, A Uruno, K Igarashi, S Arima, S Ito, K Takeuchi

JOURNAL OF BIOLOGICAL CHEMISTRY　275　(42)　33142-33150　2000/10

DOI： 10.1074/jbc.M002319200 　

ISSN： 0021-9258
Cloning and expression of human B cell-specific transcription factor BACH2 mapped to chromosome 6q15 Peer-reviewed

S Sasaki, E Ito, T Toki, T Maekawa, R Kanezaki, T Umenai, A Muto, H Nagai, T Kinoshita, M Yamamoto, J Inazawa, MM Taketo, T Nakahata, K Igarashi, M Yokoyama

ONCOGENE　19　(33)　3739-3749　2000/08

DOI： 10.1038/sj.onc.1203716 　

ISSN： 0950-9232
The mouse L-histidine decarboxylase gene: Structure and transcriptional regulation by CpG methylation in the promoter region Peer-reviewed

Satsuki Suzuki-Ishigaki, Keiko Numayama-Tsuruta, Atsuo Kuramasu, Eiko Sakurai, Yoko Makabe, Sanae Shimura, Kunio Shirato, Kazuhiko Igarashi, Takehiko Watanabe, Hiroshi Ohtsu

Nucleic Acids Research　28　(14)　2627-2633　2000/07/15

ISSN： 0305-1048
Cloning of a coproporphyrinogen oxidase promoter regulatory element binding protein Peer-reviewed

S Takahashi, K Furuyama, A Kobayashi, S Taketani, H Harigae, M Yamamoto, K Igarashi, T Sasaki, N Hayashi

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　273　(2)　596-602　2000/07

DOI： 10.1006/bbrc.2000.2991 　

ISSN： 0006-291X
Oxidative stress abolishes leptomycin B-sensitive nuclear export of transcription repressor Bach2 that counteracts activation of Maf recognition element. International-journal Peer-reviewed

H Hoshino, A Kobayashi, M Yoshida, N Kudo, T Oyake, H Motohashi, N Hayashi, M Yamamoto, K Igarashi

The Journal of biological chemistry　275　(20)　15370-6　2000/05/19

DOI： 10.1074/jbc.275.20.15370 　

ISSN： 0021-9258
Oxidative stress abolishes Crm1/Exportin1-dependent nuclear export of Maf-interacting transcription repressor Bach2. Peer-reviewed

J. Biol. Chem.　275　15370-15376　2000/05

DOI： 10.1074/jbc.275.20.15370 　
Function of NF-E2-related transcription factors

K. Igarashi

Seikagaku　72　(4)　257-268　2000/04
Publisher:
ISSN： 0037-1017
A combinatorial code for gene expression generated by transcription factor Bach2 and MAZR (MAZ-related factor) through the BTB/POZ domain. International-journal Peer-reviewed

A Kobayashi, H Yamagiwa, H Hoshino, A Muto, K Sato, M Morita, N Hayashi, M Yamamoto, K Igarashi

Molecular and cellular biology　20　(5)　1733-46　2000/03

DOI： 10.1128/MCB.20.5.1733-1746.2000 　

ISSN： 0270-7306
Regulation of transcription by locus control regions

Igarashi, K., Kobayashi, A.

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme　45　(9 Suppl)　2000
Atomic force microscopy proposes a 'kiss and pull' mechanism for enhancer function Peer-reviewed

Shige H. Yoshimura, Chikashi Yoshida, Kazuhiko Igarashi, Kunio Takeyasu

Journal of Electron Microscopy　49　(3)　407-413　2000
Publisher: Oxford University Press
DOI： 10.1093/oxfordjournals.jmicro.a023822 　

ISSN： 0022-0744
Generation of molecular probes for hematopoietic cell purification Peer-reviewed

S Takahashi, N Minegishi, K Igarashi, M Yamamoto

TISSUE ENGINEERING FOR THERAPEUTIC USE 4　1198　131-140　2000

ISSN： 0531-5131
Long range interaction of cis-DNA elements mediated by architectural transcription factor Bach1 Peer-reviewed

C Yoshida, F Tokumasu, KI Hohmura, J Bungert, N Hayashi, T Nagasawa, JD Engel, M Yamamoto, K Takeyasu, K Igarashi

GENES TO CELLS　4　(11)　643-655　1999/11

DOI： 10.1046/j.1365-2443.1999.00291.x 　

ISSN： 1356-9597
Molecular cloning and functional characterization of a new Cap'n' collar family transcription factor Nrf3 Peer-reviewed

A Kobayashi, E Ito, T Toki, K Kogame, S Takahashi, K Igarashi, N Hayashi, M Yamamoto

JOURNAL OF BIOLOGICAL CHEMISTRY　274　(10)　6443-6452　1999/03

DOI： 10.1074/jbc.274.10.6443 　

ISSN： 0021-9258

eISSN： 1083-351X
Posttranscriptional regulation of U(s)11 in cells infected with a herpes simplex virus 1 recombinant lacking both 222-bp domains containing S- component origins of DNA synthesis

McCormick, L., Igarashi, K., Roizman, B.

Virology　259　(2)　1999

DOI： 10.1006/viro.1999.9790 　
BTB/POZ domain proteins in nuclear structure and DNA loop formation

Yoshida, C., Igarashi, K.

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme　44　(12 Suppl)　1999
Identification of Bach2 as a B-cell-specific partner for small maf proteins that negatively regulate the immunoglobulin heavy chain gene 3' enhancer. International-journal Peer-reviewed

A Muto, H Hoshino, L Madisen, N Yanai, M Obinata, H Karasuyama, N Hayashi, H Nakauchi, M Yamamoto, M Groudine, K Igarashi

The EMBO journal　17　(19)　5734-43　1998/10/01

DOI： 10.1093/emboj/17.19.5734 　

ISSN： 0261-4189

eISSN： 1460-2075
Multivalent DNA binding complex generated by small Maf and Bach1 as a possible biochemical basis for beta-globin locus control region complex. International-journal Peer-reviewed

K Igarashi, H Hoshino, A Muto, N Suwabe, S Nishikawa, H Nakauchi, M Yamamoto

The Journal of biological chemistry　273　(19)　11783-90　1998/05/08

DOI： 10.1074/jbc.273.19.11783 　

ISSN： 0021-9258
Function of LCR-binding protein Bach1 as an architectural transcription factor

K. Igarashi

Seikagaku　70　(2)　114-118　1998/02
Publisher:
ISSN： 0037-1017
Regulation of NF-E2 activity in erythroleukemia cell differentiation Peer-reviewed

T Nagai, K Igarashi, J Akasaka, K Furuyama, H Fujita, N Hayashi, M Yamamoto, S Sassa

JOURNAL OF BIOLOGICAL CHEMISTRY　273　(9)　5358-5365　1998/02

DOI： 10.1074/jbc.273.9.5358 　

ISSN： 0021-9258
Cloning of human Bach1 transcription factor which regulates transcription through NF-E2 site with small Maf proteins. Peer-reviewed

T Toki, R Kanezaki, K Arai, M Yokoyama, K Igarashi, M Yamamoto, E Ito

BLOOD　90　(10)　196-196　1997/11

ISSN： 0006-4971
An Nrf2 small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements Peer-reviewed

K Itoh, T Chiba, S Takahashi, T Ishii, K Igarashi, Y Katoh, T Oyake, N Hayashi, K Satoh, Hatayama, I, M Yamamoto, Y Nabeshima

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　236　(2)　313-322　1997/07

DOI： 10.1006/bbrc.1997.6943 　

ISSN： 0006-291X
Human small Maf proteins form heterodimers with CNC family transcription factors and recognize the NF-E2 motif Peer-reviewed

T Toki, J Itoh, J Kitazawa, K Arai, K Hatakeyama, J Akasaka, K Igarashi, N Nomura, M Yokoyama, M Yamamoto, E Ito

ONCOGENE　14　(16)　1901-1910　1997/04

DOI： 10.1038/sj.onc.1201024 　

ISSN： 0950-9232
Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site. International-journal Peer-reviewed

T Oyake, K Itoh, H Motohashi, N Hayashi, H Hoshino, M Nishizawa, M Yamamoto, K Igarashi

Molecular and cellular biology　16　(11)　6083-95　1996/11

ISSN： 0270-7306
Abundant expression of erythroid transcription factor P45 NF-E2 mRNA in human peripheral granulocytes Peer-reviewed

T Toki, J Itoh, K Arai, J Kitazawa, M Yokoyama, K Igarashi, M Yamamoto, E Ito

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　219　(3)　760-765　1996/02

DOI： 10.1006/bbrc.1996.0307 　

ISSN： 0006-291X
Mesodermal- vs neuronal-specific expression of MafK is elicited by different promoters Peer-reviewed

H Motohashi, K Igarashi, K Onodera, S Takahashi, H Ohtani, M Nakafuku, M Nishizawa, JD Engel, M Yamamoto

GENES TO CELLS　1　(2)　223-238　1996/02

ISSN： 1356-9597
Histidine decarboxylase expression in mouse mast cell line P815 is induced by mouse peritoneal cavity incubation Peer-reviewed

Ohtsu, H, Kuramasu, A, Suzuki, S, Igarashi, K, Ohuchi, Y, Sato, M, Tanaka, S, Nakagawa, S, Shirato, K, Yamamoto, M, Ichikawa, A, Watanabe, T

Journal of Biological Chemistry　271　(45)　1996
CLONING AND CHARACTERIZATION OF A NOVEL ERYTHROID CELL-DERIVED CNC FAMILY TRANSCRIPTION FACTOR HETERODIMERIZING WITH THE SMALL MAF FAMILY PROTEINS Peer-reviewed

K ITOH, K IGARASHI, N HAYASHI, M NISHIZAWA, M YAMAMOTO

MOLECULAR AND CELLULAR BIOLOGY　15　(8)　4184-4193　1995/08

ISSN： 0270-7306

eISSN： 1098-5549
CONDITIONAL EXPRESSION OF THE UBIQUITOUS TRANSCRIPTION FACTOR MAFK INDUCES ERYTHROLEUKEMIA CELL-DIFFERENTIATION Peer-reviewed

K IGARASHI, K ITOH, N HAYASHI, M NISHIZAWA, M YAMAMOTO

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　92　(16)　7445-7449　1995/08

DOI： 10.1073/pnas.92.16.7445 　

ISSN： 0027-8424
THE ROLE OF THE ERYTHROID-SPECIFIC DELTA-AMINOLEVULINATE SYNTHASE GENE-EXPRESSION IN ERYTHROID HEME-SYNTHESIS Peer-reviewed

K MEGURO, K IGARASHI, M YAMAMOTO, H FUJITA, S SASSA

BLOOD　86　(3)　940-948　1995/08

ISSN： 0006-4971
SMALL MAF PROTEINS HETERODIMERIZE WITH FOS AND MAY ACT AS COMPETITIVE REPRESSORS OF THE NF-E2 TRANSCRIPTION FACTOR Peer-reviewed

K KATAOKA, K IGARASHI, K ITOH, KT FUJIWARA, M NODA, M YAMAMOTO, M NISHIZAWA

MOLECULAR AND CELLULAR BIOLOGY　15　(4)　2180-2190　1995/04

ISSN： 0270-7306
ACTIVITY AND EXPRESSION OF MURINE SMALL MAF FAMILY PROTEIN MAFK Peer-reviewed

K IGARASHI, K ITOH, H MOTOHASHI, N HAYASHI, Y MATUZAKI, H NAKAUCHI, M NISHIZAWA, M YAMAMOTO

JOURNAL OF BIOLOGICAL CHEMISTRY　270　(13)　7615-7624　1995/03

DOI： 10.1074/jbc.270.13.7615 　

ISSN： 0021-9258

eISSN： 1083-351X
Erratum: Small Maf proteins heterodimerize with fos and may act as competitive repressors of the NF-E2 transcription factor (Molecular and Cellular Biology (1995) 15:5 (2188))

Kataoka, K., Igarashi, K., Itoh, K., Fujiwara, K.T., Noda, M., Yamamoto, M., Nishizawa, M.

Molecular and Cellular Biology　15　(6)　1995
Combinatorial functioning of hematopoietic transcription factors and regulation of hematopoietic cell differentiation

Igarashi, K., Yamamoto, M.

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme　40　(11)　1995
Effect of repeated cold stress on mouse stomach histidine decarboxylase

Tanaka, S., Funakoshi, E., Kawahara, A., Nemoto, K., Fukui, T., Suzuki, T., Igarashi, K., Ichikawa, A.

Methods and Findings in Experimental and Clinical Pharmacology　17　(SUPPL. C)　1995
Epitope mapping and functional characterization of monoclonal antibodies specific for the α subunit of Escherichia coli RNA polymerase Peer-reviewed

Karim A. Sharif, Noboyuki Fujita, Ruzhong Jin, Kazuhiko Igarashi, Akira Ishihama, Joseph S. Krakow

Journal of Biological Chemistry　269　(38)　23655-23660　1994/09/23

ISSN： 0021-9258
REGULATION OF TRANSCRIPTION BY DIMERIZATION OF ERYTHROID FACTOR NF-E2 P45 WITH SMALL MAF PROTEINS Peer-reviewed

K IGARASHI, K KATAOKA, K ITOH, N HAYASHI, M NISHIZAWA, M YAMAMOTO

NATURE　367　(6463)　568-572　1994/02

DOI： 10.1038/367568a0 　

ISSN： 0028-0836
The Ada protein is a class I transcription factor of Escherichia coli. International-journal Peer-reviewed

K Sakumi, K Igarashi, M Sekiguchi, A Ishihama

Journal of bacteriology　175　(8)　2455-7　1993/04

ISSN： 0021-9193

More details Close

The methylated Ada protein of Escherichia coli, a regulatory protein for the adaptive response, binds to a target DNA from positions -62 to -31 upstream of the ada gene and facilitates the binding of RNA polymerase to the promoter. Mutant RNA polymerases consisting of C-terminal-deleted alpha subunits are virtually inactive in response to activation by the Ada protein. Thus, we conclude that the Ada protein is a class I transcription factor which requires the C-terminal region of the RNA polymerase alpha subunit for transcription activation.
E.coli RNA polymerase, deleted in the C-terminal part of its α-subunit, interacts differently with the cAMP-CRP complex at the lacP1 and at the gaP1 promoter Peer-reviewed

Annie Kolb, Kazuhiko Igarashi, Akira Ishihama, Marc Lavigne, Malcolm Buckle, Henri Buc

Nucleic Acids Research　21　(2)　319-326　1993/01/25

DOI： 10.1093/nar/21.2.319 　

ISSN： 0305-1048
Construction and properties of a recombinant herpes simplex virus 1 lacking both S-component origins of DNA synthesis

Igarashi, K., Fawl, R., Roller, R.J., Roizman, B.

Journal of Virology　67　(4)　1993
A third recognition element in bacterial promoters: DNA binding by the α subunit of RNA polymerase Peer-reviewed

Wilma Ross, Khoosheh K. Gosink, Julia Salomon, Kazuhiko Igarashi, Chao Zou, Akira Ishihama, Konstantin Severinov, Richard L. Gourse

Science　262　(5138)　1407-1413　1993

DOI： 10.1126/science.8248780 　

ISSN： 0036-8075
Stimulation of the phage λ pL promoter by integration host factor requires the carboxy terminus of the α-subunit of RNA polymerase Peer-reviewed

Hilla Giladi, Kazuhiko Igarashi, Akira Ishihama, Amos B. Oppenheim

Journal of Molecular Biology　227　(4)　985-990　1992/10/20

DOI： 10.1016/0022-2836(92)90514-K 　

ISSN： 0022-2836
Activation defects caused by mutations in Escherichia coli rpoA are promoter specific. International-journal Peer-reviewed

G N Gussin, C Olson, K Igarashi, A Ishihama

Journal of bacteriology　174　(15)　5156-60　1992/08

ISSN： 0021-9193

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Escherichia coli RNA polymerases containing mutated alpha subunits were tested for their ability to respond to three different positive regulators (activators) in vitro. The two alpha (rpoA) mutants, alpha-256 and alpha-235, have deletions of the C-terminal 73 and 94 amino acids, respectively. In runoff transcription assays catalyzed by reconstituted holoenzyme, the effects of the mutations on each of three promoters tested were different: activation of the lambda pRM promoter by cI protein (repressor) was nearly normal, activation of the lambda pRE promoter by cII protein was reduced approximately fivefold, and direct activation of the trpPB promoter of Pseudomonas aeruginosa was completely inhibited. We also found that the reconstituted mutant enzyme was defective in recognition of trpPI in the absence of activator. The differential responses of the three promoters to their activators in the presence of the mutant enzymes indicate that the location of an activator-binding site does not by itself determine the region of RNA polymerase with which the activator interacts.
Mapping the cAMP receptor protein contact site on the α subunit of Escherichia coli RNA polymerase Peer-reviewed

Chao Zou, Nobuyuki Fujita, Kazuhiko Igarashi, Akira Ishihama

Molecular Microbiology　6　(18)　2599-2605　1992

DOI： 10.1111/j.1365-2958.1992.tb01437.x 　

ISSN： 1365-2958 0950-382X
Functional specialization within the α-subunit of Escherichia coli RNA polymerase Peer-reviewed

Richard S. Hayward, Kazuhiko Igarashi, Akira Ishihama

Journal of Molecular Biology　221　(1)　23-29　1991/09/05

DOI： 10.1016/0022-2836(91)80197-3 　

ISSN： 0022-2836
Bipartite functional map of the E. coli RNA polymerase α subunit: Involvement of the C-terminal region in transcription activation by cAMP-CRP Peer-reviewed

Kazuhiko Igarashi, Akira Ishihama

Cell　65　(6)　1015-1022　1991/06/14

DOI： 10.1016/0092-8674(91)90553-B 　

ISSN： 0092-8674
Identification of a subunit assembly domain in the alpha subunit of Escherichia coli RNA polymerase Peer-reviewed

Kazuhiko Igarashi, Nobuyuki Fujita, Akira Ishihama

Journal of Molecular Biology　218　(1)　1-6　1991/03/05

DOI： 10.1016/0022-2836(91)90865-4 　

ISSN： 0022-2836
Functional map of the α subunit of Escherichia coli RNA polymerase: Two modes of transcription activation by positive factors Peer-reviewed

K. Igarashi, A. Hanamura, K. Makino, H. Aiba, H. Aiba, T. Mizuno, A. Nakata, A. Ishihama

Proceedings of the National Academy of Sciences of the United States of America　88　(20)　8958-8962　1991

DOI： 10.1073/pnas.88.20.8958 　

ISSN： 0027-8424
Sequence analysis of two temperature-sensitive mutations in the alpha subunit gene (rpoA) of Escherichia coli RNA polymerase. International-journal Peer-reviewed

K Igarashi, N Fujita, A Ishihama

Nucleic acids research　18　(20)　5945-8　1990/10/25

ISSN： 0305-1048

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The rpoA gene of Escherichia coli encodes the alpha subunit of the DNA-dependent RNA polymerase. Two mutant alleles, rpoA101 and rpoA112, both of which produce RNA polymerase with altered thermostability and reduced fidelity of transcription in vitro (Ishihama et al. (1980) J. Mol. Biol. 137, 137-150), have been analyzed in details. The mutations were found to be responsible for the temperature-sensitive growth by complementation test using a rpoA-expression plasmid. Each mutant allele was amplified from total cell DNA by PCR (polymerase chain reaction) and directly sequenced. Both the mutant rpoA genes were found to carry a single base transition which leads to a substitution of Cys for Arg at the position 191 (rpoA101) or 45 (rpoA112), respectively. Since the rpoA112 mutation causes the defect in RNA polymerase assembly (Kawakami & Ishihama (1980) Biochemistry 19, 3491-3495), the amino-terminal region of alpha including the position 45 was considered to play an important role in subunit assembly.
Promoter selectivity of Escherichia coli RNA polymerase: omega factor is responsible for the ppGpp sensitivity. International-journal Peer-reviewed

K Igarashi, N Fujita, A Ishihama

Nucleic acids research　17　(21)　8755-65　1989/11/11

ISSN： 0305-1048

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Transcription in vitro of stringently controlled Escherichia coli genes by purified RNA polymerase holoenzyme is inhibited by guanosine tetraphosphate (ppGpp). In order to examine possible role of omega factor in this ppGpp sensitivity, RNA polymerases with or without the omega factor were reconstituted and tested for their ppGpp sensitivity using an in vitro mixed transcription system. RNA polymerase lacking the omega factor was found virtually insensitive to ppGpp but the addition of a purified omega factor restored the ppGpp sensitivity of this omega-free RNA polymerase. These results raise a possibility that the omega factor is a regulatory protein of RNA polymerase and is involved in the ppGpp-mediated alteration of the promoter selectivity.
Expression of the insulinoma gene rig during liver regeneration and in primary cultured hepatocytes Peer-reviewed

Chiyoko Inoue, Kazuhiko Igarashi, Motoo Kitagawa, Kimio Terazono, Shin Takasawa, Ken-ichi Obata, Kazushi Iwata, Hiroshi Yamamoto, Hiroshi Okamoto

Biochemical and Biophysical Research Communications　150　(3)　1302-1308　1988/02/15

DOI： 10.1016/0006-291X(88)90771-1 　

ISSN： 1090-2104 0006-291X

Show all ︎Show first 5

Misc. 328

Intracellular iron metabolism by the transcription factor BACH1 and iron-deficient cell death in head and neck cancer

中村和樹, 中村和樹, 松本光代, 松本光代, 遠藤緋理, 六郷正博, 六郷正博, 西澤弘成, 香取幸夫, 五十嵐和彦, 五十嵐和彦

日本癌学会学術総会抄録集(Web)　83rd　2024
BACH1 and TBK1 synergistically promote epithelial-mesenchymal transition via iron

松本光代, 松本光代, 劉亮, 田中美帆, PANG Jingyao, 林秀一郎, 島弘季, 五十嵐和彦, 五十嵐和彦

日本癌学会学術総会抄録集(Web)　83rd　2024
BACH1遺伝子ネットワークによる鉄流通と抗老化フェロトーシスシグナルの制御

五十嵐和彦, 西澤弘成, 中村和樹, 松本光代

日本分子生物学会年会プログラム・要旨集(Web)　47th　2024
Construction and Evaluation of Cancer Cell Selective Drug Delivery System: III: Development pancreatic cancer of a selective drug delivery system to suppress the malignant progression

加藤ひらり, 東亮太, 荒木保幸, 西嶋政樹, 松本光代, 松本光代, 山吉麻子, 五十嵐和彦, 大村美香, 中瀬生彦, 和田健彦

日本化学会春季年会講演予稿集(Web)　104th　2024
A Construction of Chimeric Artificial Nucleic Acids (CANA) forward Inhibition of Pancreatic Cancer Transcription Factor BACH1: IV:-Effects of Junction Position on Complex Stability and Cleavage Efficiency-

五十嵐優希, 堀内結翔, 松本光代, 松本光代, 荒木保幸, 西嶋政樹, 三瓶悠, 山吉麻子, 五十嵐和彦, 和田健彦

日本化学会春季年会講演予稿集(Web)　104th　2024
Construction of Chimeric Artificial Nucleic Acids (CANA) toward Pancreatic Cancer Treatments by Inhibition of Transcription Factor BACH1: III: Establishment of Molecular Design Strategy Based on In Vitro Analysis

堀内結翔, 石渡望, 藤田一寿, 西嶋政樹, 三瓶悠, 荒木保幸, 松本光代, 松本光代, 山吉麻子, 五十嵐和彦, 和田健彦

日本化学会春季年会講演予稿集(Web)　104th　2024
Construction of Chimeric Artificial Nucleic Acids (CANA) toward Pancreatic Cancer Treatments by Inhibition of Transcription Factor BACH 1: IV: Establishment of Molecular Design Strategy Based on In vitro and in vivo Analysis

和田健彦, 堀内結翔, 加藤ひらり, 五十嵐優希, 町田光翼, 藤田一寿, 松本光代, 松本光代, 荒木保幸, 三瓶悠, 三瓶悠, 山吉麻子, 山吉麻子, 五十嵐和彦

日本核酸医薬学会年会講演要旨集(CD-ROM)　9th　2024
Mutation related to MECOM-associated syndrome reduces hematopoietic stem and progenitor cells in mice

新堀哲也, 永井康貴, 武藤哲彦, 林慶和, 阿部太紀, 五十嵐和彦, 青木洋子

日本小児科学会雑誌　128　(2)　2024

ISSN： 0001-6543
BACH1 promotes metastasis of pancreatic cancer

佐藤正規, 大塚英郎, 水間正道, 松本光代, 斎木由利子, 大沼忍, 中川圭, 亀井尚, 五十嵐和彦, 海野倫明

日本がん転移学会学術集会・総会プログラム抄録集　32nd　2023
Functional analysis of transcription factor NRF3 as a novel tumor growth factor in pancreatic cancer

佐藤克哉, 道原琢登, 山元康平, 佐藤健, 松本光代, 五十嵐和彦, 和久剛, 小林聡

日本分子生物学会年会プログラム・要旨集(Web)　46th　2023
B細胞におけるBACH転写因子のタンパク質量比による転写調節機構の解明

倉澤岳志, 武藤哲彦, 松本光代, 落合恭子, 村山和隆, 五十嵐和彦, 五十嵐和彦

日本生化学会大会(Web)　96th　2023
The avoidance of cell death by BACH1 in head and neck cancer cells

遠藤緋理, 松本光代, 松本光代, 六郷正博, 六郷正博, 落合恭子, 西澤弘成, 五十嵐和彦, 五十嵐和彦

日本分子生物学会年会プログラム・要旨集(Web)　45th　2022
Insights into the mechanism of epithelial-mesenchymal transition regulated by the TBK1-BACH1 axis in pancreatic cancer cell

松本光代, 松本光代, LIU Liang, 田中美帆, 島弘季, 五十嵐和彦, 五十嵐和彦

日本分子生物学会年会プログラム・要旨集(Web)　45th　2022
Regulatory mechanisms of iron metabolism in B cell immune responses by the transcription factor BACH2

倉澤岳志, 武藤哲彦, 松本光代, 松本光代, 落合恭子, 五十嵐和彦, 五十嵐和彦

日本分子生物学会年会プログラム・要旨集(Web)　45th　2022
核内受容体新規転写共役因子の探索

横山敦, 纐纈拓海, 尾坪優李, 沢津橋俊, 島弘季, 佐藤郁郎, 川村貞文, 鈴木貴, 五十嵐和彦, 菅原明

日本アンドロロジー学会総会記事　41st　2022

ISSN： 0918-6239
アンドロゲン受容体新規転写共役因子の探索

横山敦, 纐纈拓海, 尾坪優李, 沢津橋俊, 島弘季, 佐藤郁郎, 川村貞文, 鈴木貴, 五十嵐和彦, 菅原明

日本アンドロロジー学会総会記事　41st　2022

ISSN： 0918-6239
BACH1による鉄代謝と上皮間葉転換のクロストーク

五十嵐和彦, 西澤弘成, 松本光代

日本酸化ストレス学会学術集会プログラム・抄録集　74th (CD-ROM)　2021
Methionine metabolism controls erythropoiesis by epigenetic regulation

加藤浩貴, 加藤浩貴, 加藤浩貴, NGUYEN Long, 石井悠翔, 石井悠翔, 松本光代, 三枝大輔, 舟山亮, 岡江寛明, 藤原亨, 武藤哲彦, 中山啓子, 有馬隆博, SCADDEN David, 五十嵐和彦, 張替秀郎

日本血液学会学術集会抄録(Web)　83rd　2021
Elucidation of the role of FAM210B in mitochondrial metabolism in erythroblasts

鈴木千恵, 鈴木千恵, 藤原亨, 藤原亨, 島弘季, 小野浩弥, 齋藤慧, 加藤浩貴, 小野寺晃一, 市川聡, 福原規子, 大西康, 横山寿行, 中村幸夫, 五十嵐和彦, 張替秀郎

日本血液学会学術集会抄録(Web)　83rd　2021
環境変化に応じた造血系の恒常性維持におけるBach因子群の役割

加藤浩貴, 五十嵐和彦

臨床免疫・アレルギー科　72　(5)　535-540　2019/11
Publisher: (有)科学評論社
ISSN： 1881-1930
Bach1欠損に伴う大腸粘液分泌亢進における分子機序の解析

谷川潤, 高木智久, 水島かつら, 平井泰子, 武藤哲彦, 五十嵐和彦, 内藤裕二, 東村泰希

日本補完代替医療学会学術集会プログラム・抄録集　22回　22-22　2019/11
Publisher: 日本補完代替医療学会
血液内科学 Bach因子群と赤血球造血

加藤浩貴, 五十嵐和彦

医学のあゆみ　270　(11)　1079-1080　2019/09
Publisher: 医歯薬出版(株)
ISSN： 0039-2359
肝臓におけるHnf4αを介した糖新生遺伝子の転写メカニズムの解明

門間里奈, 横山敦, 島弘季, 五十嵐和彦, 菅原明

日本生化学会大会プログラム・講演要旨集　92回　[1T13a-06]　2019/09
Publisher: (公社)日本生化学会
細胞内SAM濃度レポーターに基づいたスクリーニング系による新規MAT2A阻害剤の同定

奈良和樹, 石井悠翔, 加藤浩貴, 島弘季, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　92回　[2T13m-06]　2019/09
Publisher: (公社)日本生化学会
ヘムシグナルによる転写因子BACH2のリン酸化と相互作用因子の制御

松井美紀, 角屋駿, 島弘季, 武藤哲彦, 松本光代, 白水美香子, 村山和隆, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　92回　[3T15m-03]　2019/09
Publisher: (公社)日本生化学会
膵β細胞におけるグルコース応答性転写因子ChREBPの機能制御因子の探索

横山敦, 野呂英理香, 松澤拓郎, 吉川雄朗, 島弘季, 五十嵐和彦, 菅原明

日本生化学会大会プログラム・講演要旨集　92回　[3T15m-04]　2019/09
Publisher: (公社)日本生化学会
膵癌におけるBACH1の機能

佐藤正規, 大塚英郎, 松本光代, 齋木由利子, 三浦孝之, 有明恭平, 益田邦洋, 石田晶玄, 水間正道, 林洋毅, 森川孝則, 中川圭, 元井冬彦, 内藤剛, 石田孝宣, 亀井尚, 五十嵐和彦, 海野倫明

日本外科学会定期学術集会抄録集　119回　SF-065　2019/04
Publisher: (一社)日本外科学会
膵癌細胞株における放射線照射によるdCK活性増加を介したGEM感受性亢進作用の解明

高橋裕季, 大塚英郎, 三浦孝之, 有明恭平, 益田邦洋, 石田晶玄, 水間正道, 林洋毅, 森川孝則, 中川圭, 元井冬彦, 内藤剛, 石田孝宣, 亀井尚, 五十嵐和彦, 海野倫明

日本外科学会定期学術集会抄録集　119回　PS-065　2019/04
Publisher: (一社)日本外科学会
膵癌におけるBACH1の機能

佐藤正規, 大塚英郎, 松本光代, 齋木由利子, 三浦孝之, 有明恭平, 益田邦洋, 石田晶玄, 水間正道, 林洋毅, 森川孝則, 中川圭, 元井冬彦, 内藤剛, 石田孝宣, 亀井尚, 五十嵐和彦, 海野倫明

日本外科学会定期学術集会抄録集　119回　SF-8　2019/04
Publisher: (一社)日本外科学会
膵癌間質プロテオミクスによる新規リンパ節転移関連因子ヘモペキシンの発見

鈴木ゆき恵, 高館達之, 水間正道, 島弘季, 鈴木貴, 橘知睦, 志村充広, 畠達夫, 伊関雅裕, 川口桂, 青木豪, 林洋毅, 森川孝則, 中川圭, 元井冬彦, 内藤剛, 石田孝宣, 亀井尚, 五十嵐和彦, 海野倫明

日本外科学会定期学術集会抄録集　119回　PS-5　2019/04
Publisher: (一社)日本外科学会
膵癌細胞株における放射線照射によるdCK活性増加を介したGEM感受性亢進作用の解明

高橋裕季, 大塚英郎, 三浦孝之, 有明恭平, 益田邦洋, 石田晶玄, 水間正道, 林洋毅, 森川孝則, 中川圭, 元井冬彦, 内藤剛, 石田孝宣, 亀井尚, 五十嵐和彦, 海野倫明

日本外科学会定期学術集会抄録集　119回　PS-5　2019/04
Publisher: (一社)日本外科学会
アルドステロン合成酵素の転写制御因子の同定

野呂英理香, 横山敦, 小林真, 島田洋樹, 西澤翔輝, 門間里奈, 鈴木歩, 島弘季, 五十嵐和彦, 菅原明

日本内分泌学会雑誌　95　(1)　439-439　2019/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
膵癌間質プロテオミクスによる新規リンパ節転移関連因子ヘモペキシンの発見

鈴木ゆき恵, 高館達之, 水間正道, 島弘季, 鈴木貴, 橘知睦, 志村充広, 畠達夫, 伊関雅裕, 川口桂, 青木豪, 林洋毅, 森川孝則, 中川圭, 元井冬彦, 内藤剛, 石田孝宣, 亀井尚, 五十嵐和彦, 海野倫明

日本外科学会定期学術集会抄録集　119回　PS-063　2019/04
Publisher: (一社)日本外科学会
【RNAが修飾される!エピトランスクリプトームによる生命機能と疾患の制御】RNA修飾研究の新展開遺伝子発現制御に隠されたシステムエピトランスクリプトーム

深水昭吉, 五十嵐和彦

実験医学　36　(19)　3200-3204　2018/12
Publisher: (株)羊土社
ISSN： 0288-5514
【RNAが修飾される!エピトランスクリプトームによる生命機能と疾患の制御】RNAメチル化によるSAM代謝制御

島弘季, 五十嵐和彦

実験医学　36　(19)　3217-3221　2018/12
Publisher: (株)羊土社
ISSN： 0288-5514
転写因子ネットワークによる血液細胞分化の調節とその病態

加藤浩貴, 五十嵐和彦

臨床血液　59　(10)　1872-1879　2018/10
Publisher: (一社)日本血液学会-東京事務局
ISSN： 0485-1439

eISSN： 1882-0824
ドナー膵の細胞外マトリックス組成に対応する膵島分離の実現に向けた試み

宮崎勇希, 猪村武弘, 村山和隆, 稲垣明子, 宮城重人, 島弘季, 五十嵐和彦, 海野倫明, 亀井尚, 後藤昌史

Organ Biology　25　(3)　94-94　2018/10
Publisher: (一社)日本臓器保存生物医学会
ISSN： 1340-5152

eISSN： 2188-0204
ドナー膵組織の細胞外マトリックス組成に対応する膵島分離酵素の至適化に向けた試み

宮崎勇希, 猪村武弘, 村山和隆, Fathi Ibrahim, 山形洋平, 前田浩, 渡邉君子, 稲垣明子, 宮城重人, 島弘季, 五十嵐和彦, 海野倫明, 亀井尚, 後藤昌史

移植　53　(総会臨時)　523-523　2018/09
Publisher: (一社)日本移植学会
ISSN： 0578-7947

eISSN： 2188-0034
TBK1による転写抑制因子Bach2の調節機構の解明

角屋駿, 松井美紀[渡部], 武藤哲彦, 島弘季, 松本光代, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　91回　[1T12e-236)]　2018/09
Publisher: (公社)日本生化学会
生体金属のMagical Powerとその研究最前線形質細胞分化におけるヘムシグナルと天然変性タンパク質Bach2

松井美紀, 角屋駿, 島弘季, 武藤哲彦, 松本光代, 白水美香子, 村山和隆, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　91回　[3S09m-03]　2018/09
Publisher: (公社)日本生化学会
RNAのメチル化恒常性:Methylstat RNAメチル化によるS-アデノシルメチオニン量の制御機構とその意義

島弘季, 松本光代, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　91回　[3S06a-02]　2018/09
Publisher: (公社)日本生化学会
Bach1は筋芽細胞を活性化し筋の再生を促進する

鈴木一史, 松本光代, 加藤恭丈, 永富良一, 奥野洋史, 井樋栄二, 五十嵐和彦

日本整形外科学会雑誌　92　(8)　S1742-S1742　2018/08
Publisher: (公社)日本整形外科学会
ISSN： 0021-5325
Correction: Distinct requirements for energy metabolism in mouse primordial germ cells and their reprogramming to embryonic germ cells (Proceedings of the National Academy of Sciences of the United States of America (2017) 114 (8289-8294) DOI: 10.1073/pna

Hayashi Y, Otsuka K, Ebina M, Igarashi K, Takehara A, Matsumoto M, Kanai A, Igarashi K, Soga T, Matsui Y

Proceedings of the National Academy of Sciences of the United States of America　115　(30)　2018/07/24
Publisher: Proceedings of the National Academy of Sciences of the United States of America
DOI： 10.1073/pnas.1811451115 　

ISSN： 0027-8424

More details Close

© 2018 National Academy of Sciences. All rights reserved. Correction to Supporting Information for “Distinct requirements for energy metabolism in mouse primordial germ cells and their reprogramming to embryonic germ cells,” by Yohei Hayashi, Kei Otsuka, Masayuki Ebina, Kaori Igarashi, Asuka Takehara, Mitsuyo Matsumoto, Akio Kanai, Kazuhiko Igarashi, Tomoyoshi Soga, and Yasuhisa Matsui, which was first published July 17, 2017; 10.1073/pnas.1620915114 (Proc Natl Acad Sci USA 114: 8289–8294). The authors note that, in the SI Appendix, the units "fmol/mm3" in the Fig. S2 legend, Fig. S4, Fig. S5, and Dataset S1 should have instead appeared as "nmol/mm3." The authors also note that in Fig. S4A, row 3, column 2, the tick marks along the vertical axis appeared incorrectly. The SI Appendix has been corrected online.
膵β細胞におけるグルコース応答性転写因子ChREBPの機能制御因子のRIME法を用いた探索

野呂英理香, 横山敦, 小暮直敬, 鈴木歩, 清水恭子, 島弘季, 五十嵐和彦, 菅原明

日本内分泌学会雑誌　94　(1)　360-360　2018/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
Estimating frequency of pathogenic variants in a Japanese population by using the whole-genome reference panel of ToMMo

Yumi Yamaguchi-Kabata, Jun Yasuda, Osamu Tanabe, Yoichi Suzuki, Hiroshi Kawame, Nobuo Fuse, Masao Nagasaki, Yosuke Kawai, Kaname Kojima, Fumiki Katsuoka, Sakae Saito, Inaho Danjoh, Ikuko N. Motoike, Riu Yamashita, Seizo Koshiba, Daisuke Saigusa, Gen Tamiya, Shigeo Kure, Nobuo Yaegashi, Yoshio Kawaguchi, Fuji Nagami, Shinichi Kuriyama, Junichi Sugawara, Naoko Minegishi, Atsushi Hozawa, Soichi Ogishima, Hideyasu Kiyomoto, Takako Takai-Igarashi, Kengo Kinoshita, Masayuki Yamamoto

HUMAN GENOMICS　12　2018/03

ISSN： 1473-9542

eISSN： 1479-7364
相同組換え修復時の相同的対合は特徴的な核内区画で起こる

堀越保則, 島弘季, 島弘季, 孫継英, 小林航, 松田俊, 木野村愛子, 落合博, 落合博, 時林, 福戸敦彦, 松田知成, 胡桃坂仁志, 井倉毅, 楯真一, 五十嵐和彦, 五十嵐和彦, 田代聡

日本分子生物学会年会プログラム・要旨集(Web)　41st　2018
細胞内メチル化恒常性の維持機構とその異常

五十嵐和彦

上原記念生命科学財団研究報告集　31　1-4　2017/12
Publisher: (公財)上原記念生命科学財団
eISSN： 2433-3441
転写因子Bach1による酸化ストレス依存メラノーマ細胞増殖抑制機序

松本光代, ブリドン・アンドレイ, 熊谷さやか, 五十嵐和彦

生命科学系学会合同年次大会　2017年度　[1P-1046]　2017/12
Publisher: 生命科学系学会合同年次大会運営事務局
全能性獲得と消失の分子機構の理解に向けてマウス始原生殖細胞の発生分化における代謝特性変換の制御機構の解析

林陽平, 大塚慧, 蝦名真行, 五十嵐香織, 竹原雅子花, 松本光代, 金井昭夫, 五十嵐和彦, 曽我朋義, 松居靖久

生命科学系学会合同年次大会　2017年度　[3PW22-3]　2017/12
Publisher: 生命科学系学会合同年次大会運営事務局
Bach1によるフェロトーシス誘導と細胞老化抑制による細胞運命の二極化

西澤弘成, 松本光代, 進藤智彦, 三枝大輔, 蝦名真行, 下川宏明, 五十嵐和彦

生命科学系学会合同年次大会　2017年度　[3PT19-0396)]　2017/12
Publisher: 生命科学系学会合同年次大会運営事務局
RNA修飾によるエピトランスクリプトーム制御の新展開エピジェネティックな代謝産物、S-adenosylmethionineは選択的mRNAメチル化依存的分解により自身の合成を調節する(Epigenetic metabolite S-adenosylmethionine regulates its own synthesis by selective mRNA methylation-dependent degradation)

五十嵐和彦, 島弘季

生命科学系学会合同年次大会　2017年度　[4PS09-2]　2017/12
Publisher: 生命科学系学会合同年次大会運営事務局
ヘムシグナルによる天然変性タンパク質Bach2の制御機構と生理学的意義の解明

松井美紀, 島弘季, 武藤哲彦, 松本光代, 村山和隆, 五十嵐和彦

生命科学系学会合同年次大会　2017年度　[4P2T15-0632)]　2017/12
Publisher: 生命科学系学会合同年次大会運営事務局
卵母細胞に高発現するBasonuclin1のSUMO化はPias4によって促進される

井原基公, 坂本雅弘, 立花眞仁, 八重樫伸生, 加藤恭丈, 五十嵐和彦, Tseng Hung, Schultz Richard M

日本生殖医学会雑誌　62　(3)　149-149　2017/07
Publisher: (一社)日本生殖医学会
ISSN： 1881-0098
【エピジェネティクスと環境科学】エピジェネティック代謝物の地産地消

五十嵐和彦, 井倉毅

最新医学　72　(5)　685-692　2017/05
Publisher: (株)最新医学社
ISSN： 0370-8241
代謝経路とエピジェネティクス制御系のクロストークとストレス応答

五十嵐和彦

心身医学　57　(4)　343-349　2017/04
Publisher: (一社)日本心身医学会
ISSN： 0385-0307
グルコース応答性転写因子ChREBPの機能制御因子の探索

野呂英理香, 横山敦, 小暮直敬, 鈴木歩, 清水恭子, 島弘季, 五十嵐和彦, 菅原明

日本内分泌学会雑誌　93　(1)　363-363　2017/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
肝再生を考慮した肝切除基礎から臨床へ多層的オミックス解析による門脈塞栓後代償性肝肥大の分子メカニズムの解明

佐藤好宏, 大塚英郎, 深瀬耕二, 加藤恭丈, 松本光代, 蝦名真行, 有明恭平, 益田邦洋, 水間正道, 坂田直昭, 中川圭, 林洋毅, 森川孝則, 元井冬彦, 内藤剛, 五十嵐和彦, 海野倫明

日本外科学会定期学術集会抄録集　117回　WS-6　2017/04
Publisher: (一社)日本外科学会
Transcription Factor Bach1 and Bach2 Operate Erythro-Myeloid Competitive Differentiation By Responding to Environmental Changes

Hiroki Kato, Ari Itoh-Nakadai, Mitsuyo Matsumoto, Risa Ebina-Shibuya, Yuki Sato, Masahiro Kobayashi, Akihiko Muto, Tohru Fujiwara, Hideo Harigae, Kazuhiko Igarashi

BLOOD　128　(22)　2016/12

ISSN： 0006-4971

eISSN： 1528-0020
卵母細胞に高発現するBasonuclin1のSUMO化はPias4によって促進される

井原基公, 坂本雅弘, 加藤恭丈, 星野由美, Tseng Hung, Schultz Richard, 五十嵐和彦, 立花眞仁, 八重樫伸生

日本生殖医学会雑誌　61　(4)　432-432　2016/10
Publisher: (一社)日本生殖医学会
ISSN： 1881-0098
【遺伝子制御の新たな主役栄養シグナル糖、脂質、アミノ酸による転写調節・生体恒常性機構と疾患をつなぐニュートリゲノミクス】(第1章)新たに見えてきた、栄養・代謝物シグナルによる遺伝子制御メカニズム鉄代謝と遺伝子制御

松井美紀[渡部], 五十嵐和彦

実験医学　34　(15)　2475-2480　2016/09
Publisher: (株)羊土社
ISSN： 0288-5514
S-アデノシルメチオニン合成酵素MAT2Aの発現は3'UTRアデニンメチル化が介するmRNA安定性により制御される

島弘季, 松本光代, 蝦名真行, 武藤哲彦, 熊谷さやか, 五十嵐和彦, CREST、AMED

日本生化学会大会プログラム・講演要旨集　89回　[1T15-254)]　2016/09
Publisher: (公社)日本生化学会
核内受容体PPARγに対する赤芽球由来新規内在性リガンドの同定

白井友理, 栃尾尚哉, 五十嵐和彦, 楯真一, 白木琢磨

日本生化学会大会プログラム・講演要旨集　89回　[1P-191]　2016/09
Publisher: (公社)日本生化学会
転写因子Bach1によるフェロトーシスの促進機能

西澤弘成, 松本光代, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　89回　[2T05-035)]　2016/09
Publisher: (公社)日本生化学会
INO80クロマチンリモデリング複合体によるHO-1発現制御アクチンファミリーの機能解析と人為的操作の試み

秋山祐亮, 高橋裕一朗, 村上寛和, Heinis Christian, 加藤恭丈, 五十嵐和彦, 原田昌彦

日本生化学会大会プログラム・講演要旨集　89回　[2T15-272)]　2016/09
Publisher: (公社)日本生化学会
ヘムによる転写因子Bach2天然変性領域の制御機構の解明

松井美紀[渡部], 島弘季, 上島珠美, 白水美香子, 村山和隆, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　89回　[2T15-274)]　2016/09
Publisher: (公社)日本生化学会
活性化B細胞の遺伝子ネットワークのシングルセル解析

武藤哲彦, Sax Nicolas, 松本光代, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　89回　[2T16-372)]　2016/09
Publisher: (公社)日本生化学会
細胞外環境を転写とエピゲノムへ統合する分子機構 Inner Myeloidの遺伝子制御ネットワークとその環境応答機構

五十嵐和彦, 加藤浩貴, 張替秀郎, 武藤哲彦, 松本光代, 伊藤亜里, AMED-CREST

日本生化学会大会プログラム・講演要旨集　89回　[2S01-2]　2016/09
Publisher: (公社)日本生化学会
細胞のロバストネスを規定するタンパク質複合体のダイナミクス活性型PI3K-AKTシグナル伝達の存在下と非存在下における内因性NRF2複合体の精製と分析(Purification and analysis of endogenous NRF2 complex in the presence and absence of active PI3K-AKT signaling)

本橋ほづみ, 太田奈緒, 島弘季, 五十嵐和彦, 関根弘樹

日本生化学会大会プログラム・講演要旨集　89回　[2S12-5]　2016/09
Publisher: (公社)日本生化学会
卵母細胞に高発現するBasonuclin1のSUMO化はPias4によって促進される

井原基公, 坂本雅弘, 加藤恭丈, ソン・ハン, シュルツ・リチャード, 五十嵐和彦, 立花眞仁, 八重樫伸生

日本生化学会大会プログラム・講演要旨集　89回　[1P-385]　2016/09
Publisher: (公社)日本生化学会
門脈結紮後代償性肝肥大における細胞周期関連遺伝子の発現制御機構と、転写因子FOXM1の機能解析

佐藤好宏, 大塚英郎, 深瀬耕二, 加藤恭丈, 松本光代, 元井冬彦, 内藤剛, 江川新一, 五十嵐和彦, 海野倫明

日本消化器外科学会総会　71回　P1-3　2016/07
Publisher: (一社)日本消化器外科学会
代謝経路とエピジェネティクス制御系のクロストークとストレス応答

五十嵐和彦

心身医学　56　(6)　568-568　2016/06
Publisher: (一社)日本心身医学会
ISSN： 0385-0307
門脈結紮後の代償性肝肥大における、FOXM1による細胞周期関連遺伝子の活性化の意義

佐藤好宏, 大塚英郎, 加藤恭丈, 松本光代, 蝦名真行, 前田晋平, 有明恭平, 川口桂, 益田邦洋, 石田晶玄, 深瀬耕二, 水間正道, 坂田直昭, 中川圭, 林洋毅, 森川孝則, 元井冬彦, 内藤剛, 五十嵐和彦, 海野倫明

日本外科学会定期学術集会抄録集　116回　PS-4　2016/04
Publisher: (一社)日本外科学会
メタボライトとエピゲノム S-アデノシルメチオニン(SAM)の地産地消機構とその意義

五十嵐和彦, 蝦名真行, 島弘季, 加藤恭丈

日本薬学会年会要旨集　136年会　(1)　210-210　2016/03
Publisher: (公社)日本薬学会
ISSN： 0918-9823
ビッグデータから読み解く生命現象単一タンパク質の徹底的リン酸化解析と機能特定:転写因子Bach2を例に

島弘季, 安藤亮, 玉原亨, 五十嵐和彦

生化学　88　(1)　31-35　2016/02
Publisher: (公社)日本生化学会
DOI： 10.14952/SEIKAGAKU.2016.880031 　

ISSN： 0037-1017
マルチオミクス解析を通したマウス始原生殖細胞の代謝特性の解析

林陽平, 林陽平, 林陽平, 蝦名真行, 五十嵐香織, 大塚慧, 竹原雅子花, 松本光代, 五十嵐和彦, 金井昭夫, 曽我朋義, 松居靖久, 松居靖久, 松居靖久

日本分子生物学会年会プログラム・要旨集(Web)　39th　2016
RAD51による相同組換え修復の制御機構

堀越保則, 堀越保則, 島弘季, 島弘季, 河野一輝, 鈴木秀和, 松田俊, SCHMID Volker J, 福戸敦彦, 木野村愛子, 孫継英, 松田知成, 井倉毅, 楯真一, 楯真一, 五十嵐和彦, 五十嵐和彦, CREMER Marion, CREMER Thomas, 田代聡, 田代聡

日本分子生物学会年会プログラム・要旨集(Web)　39th　ROMBUNNO.1P‐0263 (WEB ONLY)　2016
真核生物における細胞分化と遺伝子発現の連携した制御メカニズム S-アデノシルメチオニン地産地消機構によるクロマチンなどのメチル化とその調節

五十嵐和彦, 蝦名真行, 島弘季, 加藤恭丈

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[1W4-6]　2015/12
Publisher: (公社)日本生化学会
ミトコンドリアによる活性化B細胞運命決定機構の解析

蒋景眞, 眞野浩人, Aoki Koji, 林達成, 武藤哲彦, 南部由希子, Takahashi Katsu, Itoh Katsuhiko, Taketani Shigeru, Nutt Stephen L., 五十嵐和彦, Shimizu Akira, Sugai Manabu

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[1P1350]-[1P1350]　2015/12
Publisher: (公社)日本生化学会
転写因子による細胞分化・増殖抑制転写因子IRF4が支配する胚中心B細胞および形質細胞分化誘導の遺伝子発現ネットワーク

落合恭子, 近藤晴香, 岡村容伸, 木下賢吾, 五十嵐和彦

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[2W9-6]　2015/12
Publisher: (公社)日本生化学会
核局在MATIIalphaのセントロメア領域における役割

蝦名真行, 加藤恭丈, 池田真教, 田中耕三, 五十嵐和彦

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[2T25-13(2P0648)]　2015/12
Publisher: (公社)日本生化学会
酸化ストレス応答遺伝子HO-1発現へのINO80クロマチンリモデリング複合体の関与遺伝子欠損細胞とbicyclic peptideを用いた解析

秋山祐亮, 高橋裕一郎, 村上寛和, Heinis Christian, 加藤恭丈, 五十嵐和彦, 原田昌彦

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[2P0626]-[2P0626]　2015/12
Publisher: (公社)日本生化学会
S-アデノシルメチオニン合成酵素MAT2Aの発現は3'UTRアデニンメチル化が介するmRNA安定性により制御される

島弘季, 松本光代, 武藤哲彦, 熊谷さやか, 五十嵐和彦

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[3T25-13(3P0747)]　2015/12
Publisher: (公社)日本生化学会
多層的オミックス解析による肝再生分子メカニズムの解明

佐藤好宏, 加藤恭丈, 松本光代, 蝦名貴行, 海野倫明, 五十嵐和彦

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[3P1029]-[3P1029]　2015/12
Publisher: (公社)日本生化学会
グルコース応答性転写因子ChREBPの機能制御因子の探索

野呂英理香, 横山敦, 小暮直敬, 清水恭子, 島弘季, 五十嵐和彦, 菅原明

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[3LBA034]-[3LBA034]　2015/12
Publisher: (公社)日本生化学会
生体金属の最前線ヘムによる新たなタンパク質制御機構とその生理学的意義

松井美紀[渡部], 島弘季, 村山和隆, 五十嵐和彦

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[4W8-5]　2015/12
Publisher: (公社)日本生化学会
Mechanism Governing Heme Synthesis Reveals a GATA Factor-Heme Circuit That Controls Differentiation

Emery H. Bresnick, Nobuyuki Tanimura, Eli Miller, Kazuhiko Igarashi, David T. Yang, Judith Burstyn, Colin Dewey

BLOOD　126　(23)　2015/12

ISSN： 0006-4971

eISSN： 1528-0020
Transcription Factor Bach1 and Bach2 Control Common Myeloid Progenitor Cell Differentiation Under Infectious Stimuli

Hiroki Kato, Ari Itoh-Nakadai, Risa Ebina-Shibuya, Masahiro Kobayashi, Mitsuyo Matsumoto, Akihiko Muto, Tohru Fujiwara, Hideo Harigae, Kazuhiko Igarashi

BLOOD　126　(23)　2015/12

ISSN： 0006-4971

eISSN： 1528-0020
多層的オミックス解析による肝再生分子メカニズムの解明

佐藤好宏, 加藤恭丈, 松本光代, 蝦名真行, 海野倫明, 五十嵐和彦

Organ Biology　22　(3)　74-74　2015/10
Publisher: (一社)日本臓器保存生物医学会
ISSN： 1340-5152

eISSN： 2188-0204
【自己免疫疾患の病態解明の新展開】リンパ球系とミエロイド系の遺伝子制御ネットワークの拮抗による細胞運命決定機構

伊藤亜里, 五十嵐和彦

臨床免疫・アレルギー科　64　(3)　244-249　2015/09
Publisher: (有)科学評論社
ISSN： 1881-1930
LINKING HEME BIOSYNTHESIS WITH A GATA FACTOR-REGULATED GENETIC NETWORK THAT CONTROLS CELLULAR DIFFERENTIATION

Nobuyuki Tanimura, Eli Miller, Kazuhiko Igarashi, Judith N. Burstyn, Colin N. Dewey, Emery H. Bresnick

EXPERIMENTAL HEMATOLOGY　43　(9)　S99-S99　2015/09

ISSN： 0301-472X

eISSN： 1873-2399
Secondary Publication 膵島分離におけるコラゲナーゼHの作用機序に関する研究

藤尾淳, 村山和隆, 山形洋平, 渡邉君子, 猪村武弘, 稲垣明子, 大林尚美, 島弘季, 関口悟, 藤盛啓成, 五十嵐和彦, 大内憲明, 里見進, 後藤昌史

移植　50　(2-3)　216-228　2015/08
Publisher: (一社)日本移植学会
ISSN： 0578-7947

eISSN： 2188-0034
Bach1ノックアウトマウスは加齢性および実験的変形性関節症の症状を軽減する

石飛博之, 味八木茂, 高田剛志, 中佐智幸, 五十嵐和彦, 越智光夫

日本抗加齢医学会総会プログラム・抄録集　15回　229-229　2015/05
Publisher: (一社)日本抗加齢医学会
Heme Oxygease-1 (HO-1) Prevents Intestinal Ischemia-Reperfusion Injury (IRI) Through Its Regulation of the Inflammasome

Yusuke Horii, Kazuhiko Uchiyama, Yuma Hotta, Atsushi Majima, Toshifumi Doi, Makoto Tanaka, Yuriko Onozawa, Kentaro Suzuki, Yukiko Uehara, Hideki Horie, Osamu Dohi, Tetsuya Okayama, Naohisa Yoshida, Kazuhiro Katada, Kazuhiro Kamada, Takeshi Ishikawa, Osamu Handa, Tomohisa Takagi, Hideyuki Konishi, Yuji Naito, Akihiko Muto, Kazuhiko Igarashi, Yoshito Itoh

GASTROENTEROLOGY　148　(4)　S548-S548　2015/04

ISSN： 0016-5085

eISSN： 1528-0012
鉄過剰症の病態と治療

加藤浩貴, 五十嵐和彦

日本医事新報　(4743)　53-53　2015/03
Publisher: (株)日本医事新報社
ISSN： 0385-9215
(Secondary Publication) Collagenase H is crucial for isolation of rat pancreatic islets

藤尾淳, 村山和隆, 山形洋平, 渡邉君子, 猪村武弘, 稲垣明子, 大林尚美, 大林尚美, 島弘季, 関口悟, 藤盛啓成, 五十嵐和彦, 大内憲明, 里見進, 後藤昌史, 後藤昌史

移植(Web)　50　(2-3)　2015

ISSN： 2188-0034
Plasma proteome analysis for a large-scale population-based cohort study

Katoh Yasutake, Koshiba Seizo, Igarashi Kazuhiko, Yamamoto Masayuki, Tanabe Osamu, Ebina Masayuki, Shirota Matsuyuki, Motoike Ikuko, Kinoshita Kengo, Kudo Hisaaki, Nobukuni Takahiro, Minegishi Naoko, Saigusa Daisuke

Abstracts for Annual Meeting of Japanese Proteomics Society　2015　(0)　62-62　2015
Publisher: Japanese Proteomics Society (Japan Human Proteome Organisation)
DOI： 10.14889/jhupo.2015.0.62.0 　
BACH2 promotes Lineage-Specific Fate Decisions in BCR-ABL1-Driven Leukemia

Eugene Park, Srividya Swaminathan, Mohammed Firas Sadiyah, Kazuhiko Igarashi, Ari Melnick, Markus Muschen

BLOOD　124　(21)　2014/12

ISSN： 0006-4971

eISSN： 1528-0020
鉄生化学の新しい潮流ヘム-Bach1経路は鉄欠乏下での適応的な赤血球新生を調節する(The heme-Bach1 pathway regulates the adaptive erythropoiesis under iron deficiency)

五十嵐和彦, 小林匡洋, 加藤浩貴, 伊藤亜里

日本生化学会大会プログラム・講演要旨集　87回　[2S12a-1]　2014/10
Publisher: (公社)日本生化学会
ミトコンドリアによる活性化B細胞運命決定機構の解析ヘム合成能制御による分化決定

蒋景眞, 眞野浩人, 青木耕史, 林達成, 武藤哲彦, 南部由希子, 原恵理, 高橋克, 伊藤克彦, 竹谷茂, 五十嵐和彦, 清水章, 菅井学

日本生化学会大会プログラム・講演要旨集　87回　[4T14a-10]　2014/10
Publisher: (公社)日本生化学会
ヘムによる天然変性タンパク質Bach2の制御

渡部美紀, 村山和隆, 松井敏高, 齋藤正男, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　87回　[3P-341]　2014/10
Publisher: (公社)日本生化学会
大規模住民コホート研究のためのLC‐MS/MS血漿プロテオーム解析の標準化

加藤恭丈, 蝦名真行, 城田松之, 木下賢吾, 五十嵐和彦, 田邉修, 山本雅之

日本生化学会大会(Web)　87回　[3P-505]　2014/10
Publisher: (公社)日本生化学会
小腸虚血再灌流傷害におけるBTB and CNC homolog1(Bach1)を介するinflammasomeの制御

堀居雄介, 内山和彦, 小野澤由里子, 鈴木建太朗, 上原有紀子, 堀江秀樹, 福居顕文, 堅田和弘, 鎌田和浩, 半田修, 高木智久, 内藤裕二, 武藤哲彦, 五十嵐和彦, 伊藤義人

日本酸化ストレス学会学術集会プログラム・抄録集　67th　66　2014/08/29
Bach1ノックアウトマウスは加齢性および実験的変形性関節症の症状を軽減する

高田剛志, 味八木茂, 石飛博之, 中佐智幸, 五十嵐和彦, 越智光夫

日本整形外科学会雑誌　88　(8)　S1617-S1617　2014/08
Publisher: (公社)日本整形外科学会
ISSN： 0021-5325
Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1 (vol 23, pg 2544, 2004)

Hiroshi Suzuki, Satoshi Tashiro, Shusuke Hira, Jiying Sun, Chikara Yamazaki, Yukari Zenke, Masao Ikeda-Saito, Minoru Yoshida, Kazuhiko Igarashi

EMBO JOURNAL　33　(15)　1727-1727　2014/08

DOI： 10.15252/embj.201489414 　

ISSN： 0261-4189

eISSN： 1460-2075
Heme regulates unstructured region of transcription factor Bach2

M. Matsui, K. Igarashi, K. Murayama, T. Matsui, M. Ikeda-Saito, T. Matsumoto

JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY　19　S243-S243　2014/03

ISSN： 0949-8257

eISSN： 1432-1327
小腸虚血再灌流傷害におけるBTB and CNC homolog1(Bach1)を介したinflammasomeの制御

堀居雄介, 内山和彦, 小野澤由里子, 鈴木建太朗, 上原有紀子, 堀江秀樹, 稲田裕, 福田亘, 飯田貴弥, 福居顕文, 堅田和弘, 鎌田和浩, 半田修, 高木智久, 八木信明, 内藤裕二, 武藤哲彦, 五十嵐和彦, 伊藤義人

日本潰瘍学会プログラム・抄録集　111　(臨増総会)　A264-A264　2014/03
Publisher: (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
眼疾患と遺伝子緑内障のゲノム解析次世代医療・個別化医療に向けて

布施昇男, 清水愛, 木村雅恵, 高野良真, 石棟, 宮澤晃子, 国松志保, 劉孟林, 渡邉亮, 安田正幸, 横山悠, 檜森紀子, 津田聡, 山本耕太郎, 中澤徹, 安田純, 勝岡史城, 小島要, 成相直樹, 松本光代, 元池育子, 長崎正朗, 木下賢吾, 五十嵐和彦, 山本雅之, 新堀哲也, 青木洋子, 松原洋一, 舟山亮, 長嶋剛史, 中山啓子, 眞島行彦, 船山智代, 田中光一, 原田高幸, 阿部春樹, 福地健郎, 安田典子, 出田秀尚, 鄭暁東, 白石敦, 大橋裕一, 石田誠夫, 原岳, 金森章泰, 山田裕子, 中村誠, 酒井寛, Richards Julia E

日本眼科学会雑誌　118　(3)　216-240　2014/03
Publisher: (公財)日本眼科学会
ISSN： 0029-0203
エピゲノム制御における地産地消機構

五十嵐和彦

広島大学原爆放射線医科学研究所年報　(54)　161-161　2014/01
Publisher: 広島大学原爆放射線医科学研究所
ISSN： 1348-3765
転写因子Bach2はmTORによって制御される

玉原亨, 佐藤好宏, 落合恭子, 五十嵐和彦

日本分子生物学会年会プログラム・要旨集(Web)　37th　2P-0731 (WEB ONLY)　2014
The standardization of parameters for plasma proteome samples in a large clinical cohort

Katoh Yasutake, Ebina Masayuki, Shirota Matsuyuki, Kinoshita Kengo, Igarashi Kazuhiko, Tanabe Osamu

Abstracts for Annual Meeting of Japanese Proteomics Society　2014　(0)　111-111　2014
Publisher: Japanese Proteomics Society (Japan Human Proteome Organisation)
DOI： 10.14889/jhupo.2014.0.111.0 　
Plasma proteome for the large-scale cohort study

Ebina Masayuki, Katoh Yasutake, Tanabe Osamu, Igarashi Kazuhiko

Abstracts for Annual Meeting of Japanese Proteomics Society　2014　(0)　110-110　2014
Publisher: Japanese Proteomics Society (Japan Human Proteome Organisation)
DOI： 10.14889/jhupo.2014.0.110.0 　
ヘム-Bach2経路によるヘムトランスポーターHRG1の発現制御

松井美紀, 伊藤亜里, 武藤哲彦, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　86回　2P-141　2013/09
Publisher: (公社)日本生化学会
酸化ストレス条件におけるヒトINO80複合体の遺伝子発現制御への関与の解析

高橋裕一朗, 松田涼, 加藤恭丈, 五十嵐和彦, 西嶋仁, 柴原慶一, 原田昌彦

日本生化学会大会プログラム・講演要旨集　86回　3T14a-05　2013/09
Publisher: (公社)日本生化学会
十二指腸濾胞性リンパ腫はAIDの発現を欠くがBACH2の発現を有しmemory B細胞としての性質を有する

高田尚良, 佐藤康晴, 中村直哉, 徳中摩美, 三木由香里, 菊池イアーラ幸江, 五十嵐和彦, 伊藤悦郎, 張替秀雄, 加藤省一, 林詠子, 岡剛史, 星井嘉信, 田利晶, 岡田裕之, Mohamad Abd Alkader Lamia, 前田嘉信, 谷本光音, 木下朝博, 吉野正

岡山医学会雑誌　125　(2)　103-107　2013/08
Publisher: 岡山医学会
ISSN： 0030-1558

eISSN： 1882-4528
Bach1ノックアウトマウスはHO-1の発現により変形性膝関節症の進行を予防する

高田剛志, 味八木茂, 石飛博之, 中邑祥博, 加藤智弘, 五十嵐和彦, 越智光夫

日本整形外科学会雑誌　87　(8)　S1398-S1398　2013/08
Publisher: (公社)日本整形外科学会
ISSN： 0021-5325
Duodenal follicular lymphoma lacks AID but expresses BACH2 and has memory B-cell characteristics (vol 26, pg 22, 2013)

Katsuyoshi Takata, Yasuharu Sato, Naoya Nakamura, Mami Tokunaka, Yukari Miki, Yara Yukie Kikuti, Kazuhiko Igarashi, Etsuro Ito, Hideo Harigae, Seiichi Kato, Eiko Hayashi, Takashi Oka, Yoshinobu Hoshii, Akira Tari, Hiroyuki Okada, Lamia Abd Al-Kader, Yoshinobu Maeda, Mitsune Tanimoto, Tomohiro Kinoshita, Tadashi Yoshino

MODERN PATHOLOGY　26　(8)　1152-1152　2013/08

DOI： 10.1038/modpathol.2013.118 　

ISSN： 0893-3952
小腸虚血再灌流傷害におけるBTB and CNC homolog1(Bach1)を介した炎症制御

堅田和弘, 内藤裕二, 高木智久, 飯田貴弥, 水島かつら, 鎌田和浩, 内山和彦, 石川剛, 半田修, 小西秀幸, 八木信明, 市川寛, 武藤哲彦, 五十嵐和彦, 吉川敏一

日本消化器病学会雑誌　110　(臨増総会)　A204-A204　2013/02
Publisher: (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
Bach1の細胞分裂期におけるヒアルロン酸受容体と共役して分裂軸を制御するメカニズムの解明

李ショウ, 白木琢磨, 島弘季, 五十嵐和彦

日本分子生物学会年会プログラム・要旨集(Web)　36th　2013
Hemopexin-dependent heme uptake through endocytosis regulates Bach1 transcriptional activity of cellular stress responses

羽田浩士, 白木琢磨, 松井美紀, 五十嵐和彦

日本生化学会大会(Web)　86th　2013
膵島分離におけるコラゲナーゼHの作用機序の解明および対象マトリックスの検討

藤尾淳, 村山和隆, 山形洋平, 渡邉君子, 猪村武弘, 稲垣明子, 大林尚美, 大林尚美, 島弘季, 関口悟, 藤盛啓成, 五十嵐和彦, 大内憲明, 里見進, 後藤昌史, 後藤昌史

日本膵・膵島移植研究会プログラム・抄録集　40th　2013
全身性炎症反応症候群による小腸遠隔障害の制御:ヘムオキシゲナーゼと一酸化炭素

堅田和弘, 内藤裕二, 高木智久, 飯田貴弥, 水島かつら, 鎌田和浩, 内山和彦, 半田修, 石川剛, 八木信明, 市川寛, 武藤哲彦, 五十嵐和彦, 吉川敏一

日本消化管学会総会学術集会プログラム・抄録集　9th　268　2013

ISSN： 2189-9037
生体遷移金属のパラダイムシフト生体内シグナル分子としての機能ヘムによる天然変性タンパク質の制御

渡部美紀, 村山和隆, 松井敏高, 齋藤正男, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　85回　2S13-8　2012/12
Publisher: (公社)日本生化学会
組換えヘモペキシンを用いた細胞外ヘムによる遺伝子制御機構の解明

羽田浩士, 白木琢磨, 松井美紀, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　85回　3T12-07　2012/12
Publisher: (公社)日本生化学会
Bach1-Deficient Macrophages that Highly Express Heme Oxygenase-1 Play a Key Role in Protection Against Murine TNBS-Induced Colitis

Akihito Harusato, Yuji Naito, Tomohisa Takagi, Kazuhiko Uchiyama, Katsura Mizushima, Akihiko Muto, Kazuhiko Igarashi, Toshikazu Yoshikawa

DIGESTIVE DISEASES AND SCIENCES　57　(11)　2730-2731　2012/11

ISSN： 0163-2116
BACH2 Is Required for Pre-B Cell Receptor Checkpoint Control and p53-Dependent Tumor Surveillance

Srividya Swaminathan, Huining Kang, Richard C. Harvey, Chuanxin Huang, Maike Buchner, Zhengshan Chen, Huimin Geng, Andrew Hall, Kazuhiko Igarashi, William L. Carroll, Cheryl L. Willman, Ari Melnick, Markus Muschen

BLOOD　120　(21)　2012/11

ISSN： 0006-4971
Bach1 deficiency protects pancreatic beta cells from oxidative stress injury

K. Kondo, Y. Ishigaki, J. Gao, T. Yamada, J. Imai, S. Sawada, A. Muto, Y. Oka, K. Igarashi, H. Katagiri

DIABETOLOGIA　55　S65-S65　2012/10

ISSN： 0012-186X

eISSN： 1432-0428
INFLAMMATORY REGULATION IN ISCHEMIA-REPERFUSION-CHALLENGED INTESTINAL INJURY : ROLE OF BTB AND CNC HOMOLOG1 (BACH1)

KATADA Kazuhiro, NAITO Yuji, TAKAGI Tomohisa, IIDA Takaya, YORIKI Hiroyuki, MIZUSHIMA Katsura, TSUJI Toshifumi, FUKUI Akifumi, UCHIYAMA Kazuhiko, ISHIKAWA Takeshi, HANDA Osamu, YAGI Nobuaki, KOKURA Satoshi, ICHIKAWA Hiroshi, MUTO Akihiko, IGARASHI Kazuhiko, YOSHIKAWA Toshikazu

潰瘍　39　(2)　148-152　2012/09/20

ISSN： 0916-3301
MATIIによるエピジェネティックなCox2遺伝子抑制機構

解良洋平, 加藤恭丈, 五十嵐和彦, 山本照子

日本矯正歯科学会大会プログラム・抄録集　71回　178-178　2012/09
Publisher: (公社)日本矯正歯科学会
Transcription-independent role of Bachl in mitosis through a nuclear exporter Crm1-dependent mechanism (vol 586, pg 448, 2012)

Jie Li, Takuma Shiraki, Kazuhiko Igarashi

FEBS LETTERS　586　(19)　3537-3537　2012/09

DOI： 10.1016/j.febslet.2012.07.006 　

ISSN： 0014-5793
小腸虚血再灌流傷害における炎症制御:BTB and CNC homolog 1(Bach1)の役割

堅田和弘, 内藤裕二, 高木智久, 飯田貴弥, 寄木浩行, 水島かつら, 辻俊史, 福居顕文, 内山和彦, 石川剛, 半田修, 八木信明, 古倉聡, 市川寛, 武藤哲彦, 五十嵐和彦, 吉川敏一

潰瘍　39　(2)　148-152　2012/09
Publisher: (一社)日本潰瘍学会
ISSN： 2189-7956
最新の医学論文を読みこなそう!(第11回) 遺伝情報発現制御機構とその病態(その2)

五十嵐和彦, 落合恭子

THE LUNG-perspectives　20　(3)　318-322　2012/08
Publisher: (株)メディカルレビュー社
ISSN： 0919-5742
エピジェネティクスから捉えた毒作用発現ストレス応答性遺伝子発現におけるS-アデノシルメチオニン合成酵素の核内機能

五十嵐和彦, 解良洋平, 加藤恭丈

The Journal of Toxicological Sciences　37　(Suppl.1)　S26-S26　2012/07
Publisher: (一社)日本毒性学会
ISSN： 0388-1350

eISSN： 1880-3989
最新の医学論文を読みこなそう!(第10回) 遺伝情報発現制御機構とその病態(その1)

五十嵐和彦, 落合恭子, Brydun Andrey

THE LUNG-perspectives　20　(2)　192-197　2012/05
Publisher: (株)メディカルレビュー社
ISSN： 0919-5742
BTB and CNC homology 1(Bach1)欠損による膵β細胞保護効果

近藤敬一, 石垣泰, 高俊弘, 澤田正二郎, 山田哲也, 今井淳太, 鈴木亨, 本間緑, 武藤哲彦, 五十嵐和彦, 岡芳知, 片桐秀樹

糖尿病　55　(Suppl.1)　S-349　2012/04
Publisher: (一社)日本糖尿病学会
ISSN： 0021-437X

eISSN： 1881-588X
Bach 2遺伝子欠損マウスにおける肺胞蛋白症発症機構の解明

中村敦, 貫和敏博, 五十嵐和彦

日本呼吸器学会誌　1　(増刊)　278-278　2012/03
Publisher: (一社)日本呼吸器学会
ISSN： 2186-5876

eISSN： 2186-5884
小腸虚血再灌流傷害におけるHeme Oxygenase(HO)の転写調節による炎症制御機構

飯田貴弥, 高木智久, 堅田和弘, 水島かつら, 寄木浩行, 辻俊史, 福居顕文, 久貝宗弘, 鎌田和浩, 内山和彦, 石川剛, 半田修, 小西英幸, 八木信明, 古倉聡, 市川寛, 武藤哲彦, 五十嵐和彦, 内藤裕二, 吉川敏一

日本消化器病学会雑誌　109　(臨増総会)　A276-A276　2012/03
Publisher: (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
Heme oxygenase‐1発現制御性転写因子Bach1の抑制は腸管炎症を改善する

高木智久, 内藤裕二, 春里暁人, 辻俊史, 寄木浩行, 福居顕文, 堀江隆介, 内山和彦, 堅田和弘, 水島かつら, 平井泰子, 半田修, 小西英幸, 八木信明, 市川寛, 武藤哲彦, 五十嵐和彦, 吉川敏一

消化器と免疫　(48)　16-19　2012/03
Publisher: 日本消化器免疫学会
Bach1によるPparγ遺伝子発現抑制を介した脂肪細胞分化阻害

松本光代, 松本光代, 白木琢磨, BURYDUN Andrey, 舟山亮, 西田有一郎, 中山啓子, 八重樫伸生, 五十嵐和彦

日本分子生物学会年会プログラム・要旨集(Web)　35th　2012
C.histolyticum由来コラゲナーゼHの溶液構造の解析

大林尚美, 大林尚美, 松本崇, 島弘季, 後藤昌史, 後藤昌史, 渡邉君子, 五十嵐和彦, 山形洋平, 村山和隆

日本薬学会年会要旨集　132nd　(4)　2012

ISSN： 0918-9823
The role of chromatin dynamics in DNA damage-induced checkpoint activation Peer-reviewed

Masae Ikura, Satoshi Tashiro, Hiroki Shima, Kazuhiko Igarashi, Tsuyoshi Ikura

広島大学原爆放射線医科学研究所創立50 周年記念国際シンポジウム 2012 年2 月20-21 日　2012
小腸虚血再灌流傷害におけるNF‐E2‐related factor2(Nrf2)およびBTB and CNC homolog1(Bach1)を介した炎症制御機構

堅田和弘, 内藤裕二, 高木智久, 飯田貴弥, 寄木浩行, 水島かつら, 福田亘, 稲田裕, 辻俊史, 久貝宗弘, 福居顕文, 内山和彦, 石川剛, 半田修, 八木信明, 古倉聡, 市川寛, 武藤哲彦, 五十嵐和彦, 吉川敏一

日本消化管学会総会学術集会プログラム・抄録集　8th　248　2012

ISSN： 2189-9037
SAMIT複合体によるヒストンメチル化の制御とストレス応答

五十嵐和彦

広島大学原爆放射線医科学研究所年報　(52)　176-176　2011/11
Publisher: 広島大学原爆放射線医科学研究所
ISSN： 1348-3765
BACH2 Mediates Early B Cell Differentiation and Oncogene-Induced Senescence in Acute Lymphoblastic Leukemia

Srividya Swaminathan, Chuanxin Huang, Bjorn Titz, Maike Buchner, Huimin Geng, Thomas G. Graeber, Cheryl L. Willman, Kazuhiko Igarashi, Ari Melnick, Markus Muschen

BLOOD　118　(21)　258-259　2011/11

ISSN： 0006-4971
Bach1 Regulates Osteoclastogenesis Via Heme Oxgenase-1 Dependent and Independent Pathways

Maasa Hama, Yohei Kirino, Mitsuhiro Takeno, Kaoru Takase, Ryusuke Yoshimi, Atsuhisa Ueda, Akihiko Muto, Kazuhiko Igarashi, Yoshiaki Ishigatsubo

ARTHRITIS AND RHEUMATISM　63　(10)　S436-S436　2011/10

ISSN： 0004-3591

eISSN： 1529-0131
【世代を超えて伝わる代謝エピジェネティクス】エピゲノム系の代謝的側面をS-アデノシルメチオニンから考える

加藤恭丈, 五十嵐和彦

実験医学　29　(14)　2241-2245　2011/09
Publisher: (株)羊土社
ISSN： 0288-5514
転写抑制因子Bach2におけるヘム制御ドメインの解析

松井美紀, 村山和隆, 松井敏高, 齋藤正男, 武藤哲彦, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　84回　3P-0443　2011/09
Publisher: (公社)日本生化学会
組み換えヘモペキシンを用いたヘム-ヘモペキシン複合体の調製と外来ヘムによる遺伝子制御機構の解明

羽田浩士, 白木琢磨, 松井美紀, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　84回　3P-0444　2011/09
Publisher: (公社)日本生化学会
SAMIT核内モジュールによるSAM合成とヒストンメチル化の共役

五十嵐和彦, 解良洋平, 森野杏子, 加藤恭丈

日本生化学会大会プログラム・講演要旨集　84回　2S1p-4　2011/09
Publisher: (公社)日本生化学会
核内受容体PPARγの機能解析分子生物学的アプローチと生化学的アプローチ

白木琢磨, 五十嵐和彦, 森川耿右

日本生化学会大会プログラム・講演要旨集　84回　3S1p-2　2011/09
Publisher: (公社)日本生化学会
インドメタシン小腸粘膜傷害におけるheme oxygenase‐1の治療標的分子としての可能性

寄木浩行, 内藤裕二, 高木智久, 春里暁人, 辻俊史, 久貝宗弘, 堀江隆介, 吉田直久, 堅田和弘, 内山和彦, 半田修, 石川剛, 八木信明, 古倉聡, 市川寛, 武藤哲彦, 五十嵐和彦, 吉川敏一

日本消化器病学会雑誌　108　(臨増大会)　A827-A827　2011/09
Publisher: (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
腸管炎症病態におけるBach1の役割

春里暁人, 内藤裕二, 高木智久, 内山和彦, 辻俊史, 水島かつら, 石川剛, 半田修, 南山幸子, 古倉聡, 市川寛, 武藤哲彦, 五十嵐和彦, 吉川敏一

G.I. Research　19　(4)　398-399　2011/08
Publisher: (株)先端医学社
ISSN： 0918-9408
当大学医学部における過去33年間の留年者の原因とアウトカム

亀岡淳一, 小野栄夫, 五十嵐和彦, 石井誠一, 金塚完

医学教育　42　(Suppl.)　73-73　2011/07
Publisher: (一社)日本医学教育学会
ISSN： 0386-9644
インドメタシン小腸粘膜障害に対するHO‐1の防御的効果

寄木浩行, 内藤裕二, 高木智久, 春里暁人, 辻俊史, 久貝宗弘, 堀江隆介, 堅田和弘, 内山和彦, 半田修, 八木信明, 市川寛, 武藤哲彦, 五十嵐和彦, 吉川敏一

日本酸化ストレス学会学術集会プログラム・抄録集　64th　76　2011/06/27
Double translocation lymphoma(DTL)の免疫学的および分子生物学的解析

菊地智樹, 菊池イアーラ幸江, 小島稔, 安藤潔, 橋本優子, 阿部正文, 高田尚良, 吉野正, 富田直人, 武藤哲彦, 五十嵐和彦, 中村直哉

日本リンパ網内系学会会誌　51　80-80　2011/06
Publisher: (一社)日本リンパ網内系学会
ISSN： 1342-9248

eISSN： 1883-681X
赤血球造血におけるシグナルと転写制御液性免疫応答における遺伝子制御ネットワーク

武藤哲彦, 伊藤亜里, 五十嵐和彦

臨床血液　52　(6)　376-386　2011/06
Publisher: (一社)日本血液学会-東京事務局
ISSN： 0485-1439

eISSN： 1882-0824
インドメタシン小腸粘膜傷害におけるheme oxygenase‐1発現制御性転写因子Nrf‐2,Bach1の役割

春里暁人, 内藤裕二, 高木智久, 内山和彦, 寄木浩行, 山田真也, 辻俊史, 久貝宗弘, 堀江隆介, 福居顕文, 井上健, 福本晃平, 吉田直久, 半田修, 石川剛, 古倉聡, 市川寛, 武藤哲彦, 五十嵐和彦, 吉川敏一

潰瘍　38　(1)　30-33　2011/05/20

ISSN： 0916-3301
インドメタシン小腸粘膜傷害におけるheme oxygenase‐1発現制御性転写因子Nrf‐2,Bach1の役割

春里暁人, 内藤裕二, 高木智久, 内山和彦, 寄木浩行, 山田真也, 辻俊史, 久貝宗弘, 堀江隆介, 福居顕文, 井上健, 福本晃平, 吉田直久, 半田修, 石川剛, 古倉聡, 市川寛, 武藤哲彦, 五十嵐和彦, 吉川敏一

潰瘍　38　(1)　30-33　2011/05
Publisher: (一社)日本潰瘍学会
ISSN： 2189-7956
Bach1の転写制御標的遺伝子の同定

松本光代, 松本光代, BRYDUN Andrey, 中目亜矢子, 舟山亮, 西田有一郎, 中山啓子, 八重樫伸生, 五十嵐和彦

日本分子生物学会年会プログラム・要旨集(Web)　34th　2011
「The role of histone H2AX eviction in DNA damage-induced checkpoint activation」 Peer-reviewed

井倉正枝, 松浦嘉奈子, 田代聡, 島弘季, 松田涼, 五十嵐和彦, 井倉毅

第34 回日本分子生物学会年会ワークショップ 2011 年12 月15 日横浜　2011
「DNA 損傷応答シグナルにおけるヒストン H2AX のダイナミクス」 Peer-reviewed

井倉毅, 松浦嘉奈子, 島弘季, 田代聡, 五十嵐和彦, 井倉正枝

第7 回宮崎サイエンスキャンプ平成23 年2 月　2011
インドメタシン小腸粘膜傷害におけるheme oxygenase‐1発現制御性転写因子Nrf‐2,Bach1の役割

寄木浩行, 内藤裕二, 高木智久, 春里暁人, 山田真也, 辻俊史, 久貝宗弘, 堀江隆介, 井上健, 福本晃平, 吉田直久, 内山和彦, 半田修, 石川剛, 八木信明, 古倉聡, 市川寛, 武藤哲彦, 五十嵐和彦, 吉川俊一

日本消化管学会総会学術集会プログラム・抄録集　7th　296　2011

ISSN： 2189-9037
Bach1を標的とした腸管炎症制御

春里暁人, 内藤裕二, 高木智久, 内山和彦, 辻俊史, 寄木浩行, 久貝宗弘, 堀江隆介, 福居顕文, 井上健, 福本晃平, 山田真也, 半田修, 石川剛, 古倉聡, 市川寛, 武藤哲彦, 五十嵐和彦, 吉川敏一

日本消化管学会総会学術集会プログラム・抄録集　7th　295　2011

ISSN： 2189-9037
エピゲノム情報のリーディングと制御 SAMITはS-アデノシルメチオニン合成と転写制御を結びつける(Reading and regulation of epigenome information SAMIT connects S-adenosylmethionine synthesis and transcription regulation)

五十嵐和彦, 解良洋平, 太田嶺人, 加藤恭丈

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　83回・33回　2S3-1　2010/12
Publisher: (公社)日本生化学会
レドックス制御のケミカルバイオロジー核内受容体PPARγに対する内在性リガンドのケミカルバイオロジー

白木琢磨, 和久剛, 五十嵐和彦, 森川耿右

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　83回・33回　2W15-2　2010/12
Publisher: (公社)日本生化学会
転写因子Bach1によるMDM2非依存的p19ARF-p53経路の制御機構

太田一成, 西澤弘成, 土肥由裕, 五十嵐和彦

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　83回・33回　1T2-5　2010/12
Publisher: (公社)日本生化学会
メチオニン・アデノシル転移酵素(MATII)複合体の機能解析

加藤恭丈, 太田嶺人, 解良洋平, 五十嵐和彦

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　83回・33回　2T8-7　2010/12
Publisher: (公社)日本生化学会
核内受容体PPARγのリガンドタイプ依存的活性化機構の構造基盤

和久剛, 白木琢磨, 塩生くらら, 五十嵐和彦, 白井剛, 森川耿右

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　83回・33回　1P-0361　2010/12
Publisher: (公社)日本生化学会
メチオニン・アデノシル転移酵素(MATII)によるクロマチン構造と遺伝子発現の制御機構

解良洋平, 加藤恭丈, 太田嶺人, 高野照子[山本], 五十嵐和彦

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　83回・33回　3P-0684　2010/12
Publisher: (公社)日本生化学会
メチオニン・アデノシル転移酵素IIによるBMP6遺伝子制御と鉄代謝への関与

太田嶺人, 加藤恭丈, 解良洋平, 五十嵐和彦

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　83回・33回　3P-0685　2010/12
Publisher: (公社)日本生化学会
BACH1 DEFCIENCY AMELIORATES DEXTRAN SULPHATE SODIUM-INDUCED COLITIS IN MICE

HARUSATO Akihito, NAITO Yuji, TAKAGI Tomohisa, YAMADA Shinya, INOUE Ken, FUKUMOTO Kohei, HIRATA Ikuhiro, OMATSU Tatsushi, KISHIMOTO Etsuko, UCHIYAMA Kazuhiko, HANDA Osamu, ICHIKAWA Hiroshi, MUTO Akihiko, IGARASHI Kazuhiko, YOSHIKAWA Toshikazu

37　(2)　164-164　2010/09/20

ISSN： 0916-3301
赤血球造血におけるシグナルと転写制御ヘム結合転写因子Bachによる赤血球分化およびリンパ球系細胞分化の制御

伊藤亜里, 渡部美紀, 武藤哲彦, 五十嵐和彦

臨床血液　51　(9)　886-886　2010/09
Publisher: (一社)日本血液学会-東京事務局
ISSN： 0485-1439

eISSN： 1882-0824
Bach2の過剰発現はDLBCLにおけるIgH-V遺伝子のongoing mutationと関連する(Over-expression of Bach2 is related to ongoing somatic hypermutation of the IgH-V gene of DLBCL)

菊地智樹, 小倉豪, 竹腰進, 小島稔, 安藤潔, 橋本優子, 阿部正文, 高田尚良, 吉野正, 武藤哲彦, 五十嵐和彦, 中村直哉

日本癌学会総会記事　69回　163-163　2010/08
Publisher: 日本癌学会
ISSN： 0546-0476
びまん性大細胞型B細胞リンパ腫における免疫グロブリン重鎖遺伝子のongoing mutationとBACH2の発現

徳中摩実, 菊池イアーラ幸江, 千木良浩志, 竹腰進, 高田尚良, 吉野正, 橋本優子, 阿部正文, 武藤哲彦, 五十嵐和彦, 小島稔, 安藤潔, 中村直哉

日本リンパ網内系学会会誌　50　91　2010/05/31

ISSN： 1342-9248
びまん性大細胞型B細胞リンパ腫における免疫グロブリン重鎖遺伝子のongoing mutationとBACH2の発現

徳中摩実, 菊池イアーラ幸江, 千木良浩志, 竹腰進, 高田尚良, 吉野正, 橋本優子, 阿部正文, 武藤哲彦, 五十嵐和彦, 小島稔, 安藤潔, 中村直哉

日本リンパ網内系学会会誌　50　121　2010/05/31

ISSN： 1342-9248
B細胞終末分化におけるエピジェネティック制御の解明

田中拡, 武藤哲彦, 落合恭子, 和田基, 佐々木英之, 風間理郎, 西功太郎, 工藤博典, 安藤亮, 五十嵐和彦, 仁尾正記

日本小児外科学会雑誌　46　(3)　660-660　2010/05
Publisher: (NPO)日本小児外科学会
ISSN： 0288-609X

eISSN： 2187-4247
DLBCLにおける免疫グロブリン遺伝子ongoing mutationとBACH2の発現

徳中摩実, 菊池幸江, 千木良浩志, 加戸伸明, 平林華子, 竹腰進, 中村直哉, 長村義之, 高田尚良, 吉野正, 橋本優子, 安部正文, 武藤哲彦, 五十嵐和彦

日本病理学会会誌　99　(1)　277　2010/03/26

ISSN： 0300-9181
遺伝情報デコードによる生体調節核内メチル化反応を支えるタンパク質ネットワーク

加藤恭丈, 解良洋平, 太田嶺人, 五十嵐和彦

日本薬学会年会要旨集　130年会　(1)　374-374　2010/03
Publisher: (公社)日本薬学会
ISSN： 0918-9823
Bach1欠損マウスにおけるインドメタシン小腸粘膜傷害の検討

春里暁人, 内藤裕二, 高木智久, 山田真也, 平田育大, 尾松達司, 岸本悦子, 井上健, 福本晃平, 堀江隆介, 内山和彦, 半田修, 石川剛, 八木信明, 古倉聡, 市川寛, 武藤哲彦, 五十嵐和彦, 吉川敏一

日本消化器病学会雑誌　107　(臨増総会)　A238-A238　2010/03
Publisher: (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
損傷クロマチンの動的変化がもたらすDNA 損傷応答シグナルの活性化メカニズム Peer-reviewed

井倉正枝, 島弘季, 田代聡, 五十嵐和彦, 井倉毅

文部科学省科学研究費補助金、特定領域研究「染色体サイクルの制御ネットワーク」最終領域会議、2010年3月、鹿児島県霧島市　2010
「DNA 損傷応答におけるヒストン化学修飾のダイナミクス」 Peer-reviewed

井倉正枝, 松浦嘉奈子, 田代聡, 五十嵐和彦, 井倉毅

第33 回日本分子生物学会年会第83 回目本生化学会大会合同大会 2010 年12 月　2010
マウスインドメタシン小腸粘膜傷害モデルにおけるBach1の役割に関する検討

春里暁人, 内藤裕二, 高木智久, 山田真也, 平田育大, 尾松達司, 井上健, 福本晃平, 堀江隆介, 内山和彦, 半田修, 石川剛, 古倉聡, 市川寛, 武藤哲彦, 五十嵐和彦, 吉川敏一

日本消化管学会総会学術集会プログラム・抄録集　6th　246　2010

ISSN： 2189-9037
Bach1‐Heme oxygenase系を標的とした新規炎症性腸疾患治療の基磁的検討

高木智久, 内藤裕二, 春里暁人, 平田育大, 尾松達司, 山田真也, 福本晃平, 井上健, 堀江隆介, 水島かつら, 林奈津子, 平井泰子, 内山和彦, 石川剛, 半田修, 古倉聡, 市川寛, 武藤哲彦, 五十嵐和彦, 吉川敏一

日本消化管学会総会学術集会プログラム・抄録集　6th　136　2010

ISSN： 2189-9037
インドメタシン小腸粘膜傷害におけるheme oxygenase‐1(HO‐1),ならびに,HO‐1発現調節転写因子Nrf‐2,Bach1の役割

春里暁人, 内藤裕二, 高木智久, 内山和彦, 寄木浩行, 山田真也, 辻俊史, 久貝宗弘, 堀江隆介, 福居顕文, 井上健, 福本晃平, 吉田直久, 半田修, 石川剛, 古倉聡, 市川寛, 武藤哲彦, 五十嵐和彦, 吉川敏一

日本潰瘍学会プログラム・抄録集　38th　37　2010
INHIBITION OF BACH1 AMELIORATES INDOMETHACIN-INDUCED INTESTINAL INJURY IN MICE

A. Harusato, Y. Naito, T. Takagi, S. Yamada, K. Mizushima, Y. Hirai, R. Horie, K. Inoue, K. Fukumoto, I. Hirata, T. Omatsu, E. Kishimoto, K. Uchiyama, O. Handa, T. Ishikawa, S. Kokura, H. Ichikawa, A. Muto, K. Igarashi, T. Yoshikawa

JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY　60　149-154　2009/12

ISSN： 0867-5910
金属・小分子ネットワークによる遺伝情報発現制御ヘム関連代謝物による核内受容体PPARγの活性調節

白木琢磨, 森川耿右, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　82回　2S3a-1　2009/09
Publisher: (公社)日本生化学会
MATIIを介したヒストンメチル化とクロマチン構造の調節機構

解良洋平, 加藤恭丈, 山本照子, 五十嵐和彦

日本生化学会大会プログラム・講演要旨集　82回　3P-534　2009/09
Publisher: (公社)日本生化学会
Bach1による細胞老化の制御機構 (日本臨床)

五十嵐和彦, 太田一成, 中目亜矢子

日本臨床　67　(7)　1423-1428　2009/07
Publisher: (株)日本臨床社
ISSN： 0047-1852
細胞老化の酸化ストレス応答性：Bach1による指揮 (生化学)

五十嵐和彦, 土肥由裕

生化学　81　(6)　502-510　2009/06
Publisher: (公社)日本生化学会
ISSN： 0037-1017
DNA 損傷応答におけるクロマチン構造変換の分子機構とその役割 Invited

井倉毅, 井倉正枝, 島弘季, 田代聡, 五十嵐和彦

文部科学省科学研究費補助金、特定領域研究「染色体サイクルの制御ネットワーク」第5 回領域会議、2009 年6 月静岡市　2009
マウス実験腸炎におけるBach1の役割に関する検討

春里暁人, 内藤裕二, 高木智久, 山田真也, 平田育大, 尾松達司, 井上健, 堀江隆介, 内山和彦, 半田修, 石川剛, 古倉聡, 市川寛, 武藤哲彦, 五十嵐和彦, 吉川敏一

日本潰瘍学会プログラム・抄録集　37th　97　2009
ヒストンコード仮説と生命現象現状と将来 DNA損傷応答におけるヒストンコードの解明

井倉毅, 茂野裕子, 井倉正枝, 田代聡, 五十嵐和彦

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　81回・31回　1S4-2　2008/11
Publisher: (公社)日本生化学会
生体のホメオスタシスの維持におけるヘムの役割ヘムの新機能ヘムはB細胞分化・免疫応答に関与する

松井美紀[渡部], 武藤哲彦, 松井敏高, 齋藤正男, 五十嵐和彦

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　81回・31回　2S15-6　2008/11
Publisher: (公社)日本生化学会
転写シグナリングと複合体ダイナミクスの新展開クロマチンにおける転写抑制とメチオニン代謝のカップリング(Coupling of transcription repression and methionine metabolism on chromatin)

加藤恭丈, 太田嶺人, 井倉毅, 五十嵐和彦

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　81回・31回　3S11-3　2008/11
Publisher: (公社)日本生化学会
濾胞性リンパ腫における転写抑制因子BACH2の発現(Expression of BACH2, a transcription repressor, in follicular lymphoma)

山本譲司, 石澤賢一, 五十嵐和彦, 一迫玲, 張替秀郎

日本癌学会総会記事　67回　317-317　2008/09
Publisher: 日本癌学会
ISSN： 0546-0476
Bach1によるヘムオキシゲナーゼ-1(HO-1)制御が非アルコール性脂肪性肝炎に与える影響

井上基樹, 田妻進, 兵庫秀幸, 菅野啓司, 野中裕広, 鍋島由宝, 岩本慶子, 石飛朋和, 五十嵐和彦, 茶山一彰

G.I.Research　16　(4)　368-369　2008/08
Publisher: (株)先端医学社
ISSN： 0918-9408
がん抑制蛋白質p19ARFのBach1を介した新機能

西澤弘成, 土肥由裕, 井倉毅, 五十嵐和彦

生化学　80　(6)　593-593　2008/06
Publisher: (公社)日本生化学会
ISSN： 0037-1017
ユビキチン化を介した損傷クロマチンのダイナミクスとその意義

井倉毅, 田代聡, 井倉正枝, 島弘季, 五十嵐和彦

生化学　80　(6)　595-595　2008/06
Publisher: (公社)日本生化学会
ISSN： 0037-1017
Ras^V12による形質転換における転写因子Bach1の機能解析

中目亜矢子, 中目亜矢子, 太田一成, 加藤恭丈, 井倉毅, 志賀清人, 小林俊光, 五十嵐和彦

生化学　2008

ISSN： 0037-1017
転写因子Bach1-p53複合体によって制御される細胞老化の転写ネットワークの解明

太田一成, 中目亜矢子, BRYDUN Andrey, 井倉毅, 五十嵐和彦

生化学　2008

ISSN： 0037-1017
転写因子ネットワークによるBリンパ球分化制御とその病態

五十嵐和彦

小児がん　44　(プログラム・総会号)　99-99　2007/12
Publisher: (NPO)日本小児がん学会
ISSN： 0389-4525
Bach1複合体はp53依存性細胞老化を阻害する(The Bach1 complex impedes p53-dependent cellular senescence)

土肥由裕, 井倉毅, 五十嵐和彦

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　80回・30回　1S17-3　2007/11
Publisher: (公社)日本生化学会
Analyses of heme-regulated genes during erythoid differentiation Peer-reviewed

Tohru Fujiwara, Yoko Okitsu, Tsuyoshi Ikura, Shinichiro Takahashi, Kazumichi Furuyama, Kazuhiko Igarashi, Masayuki Yamamoto, Shigeru Sassa, Hideo Harigae

BLOOD　110　(11)　782A-782A　2007/11

ISSN： 0006-4971
Bach 1遺伝子欠損によるヘムオキシゲナーゼ-1(HO-1)活性化が非アルコール性脂肪性肝炎に与える影響

井上基樹, 田妻進, 兵庫秀幸, 菅野啓司, 野中裕広, 鍋島由宝, 岩本慶子, 石飛朋和, 五十嵐和彦, 茶山一彰

肝臓　48　(Suppl.2)　A473-A473　2007/09
Publisher: (一社)日本肝臓学会
ISSN： 0451-4203

eISSN： 1881-3593
DNA損傷応答におけるTIP60ヒストンアセチル化酵素の役割

井倉正枝, 井倉毅, 田代聡, 五十嵐和彦

生化学　79　(7)　718-718　2007/07
Publisher: (公社)日本生化学会
ISSN： 0037-1017
Architecture and dynamics of the transcription factor network that regulates B-to-plasma cell differentiation. (J. Biochem. )

Igarashi K, Ochiai K, Muto A

J. Biochem.　141　783-789　2007/07

DOI： 10.1093/jb/mvm106 　
【転写因子による生命現象解明の最前線クロマチン制御機構・エピジェネティクスと転写因子複合体ネットワークの包括的解明】転写因子ネットワーク液性免疫応答を制御するBach2転写因子ネットワーク

五十嵐和彦, 武藤哲彦, 落合恭子

実験医学　25　(10)　1562-1567　2007/06
Publisher: (株)羊土社
ISSN： 0288-5514
【転写因子による生命現象解明の最前線クロマチン制御機構・エピジェネティクスと転写因子複合体ネットワークの包括的解明】転写研究の古くて新しい諸問題について (実験医学)

五十嵐和彦, 山本雅之

実験医学　25　(10)　1418-1430　2007/06
Publisher: (株)羊土社
ISSN： 0288-5514
ヘムオキシゲナーゼ-1(HO-1)制御が非アルコール性脂肪性肝炎(NASH)の病期進展に与える影響について

井上基樹, 田妻進, 兵庫秀幸, 野中裕広, 鍋島由宝, 岩本慶子, 石飛朋和, 五十嵐和彦, 茶山一彰

肝臓　48　(Suppl.1)　A99-A99　2007/04
Publisher: (一社)日本肝臓学会
ISSN： 0451-4203

eISSN： 1881-3593
Heme oxygenase-1 (HO-1), a physiological anti-oxidant, uniquely prevents lipid accumulation in the liver. A novel aspect on the pathogenic role of oxidative stress in nonalcoholic steatohepatitis (NASH)

Motoki Inoue, Susumu Tazuma, Hideyuki Hyogo, Michihiro Nonaka, Keiko Iwamoto, Yashitaka Nabeshima, Tomokazu Ishitobi, Kazuhiko Igarashi, Kazuaki Chayama

GASTROENTEROLOGY　132　(4)　A820-A820　2007/04

ISSN： 0016-5085
転写因子から生命現象を考える

五十嵐和彦

東北医学雑誌　118　(2)　123-124　2006/12
Publisher: 東北医学会
ISSN： 0040-8700
The effect of gene-targetting of transcriptional factor Bach1 on atherosclerosis

Yuichiro Watari, Ryoji Ozono, Yoshiyuki Yamamoto, Adrei Brydun, Koichiro Okuhara, Kazuaki Chayama, Kazuhiko Igarashi, Tetsuya Oshima

JOURNAL OF HYPERTENSION　24　55-55　2006/12

ISSN： 0263-6352
B細胞-形質細胞分化における転写因子Bach2の機能 (遺伝子医学MOOK6)

落合恭子, 武藤哲彦, 五十嵐和彦

遺伝子医学MOOK6　(6)　75-79　2006/12
Publisher: (株)メディカルドゥ
ISSN： 1349-2527
オーバービュー (細胞核の世界--ダイナミクスから病態まで) -- (クロマチンリモデリングと転写)

五十嵐和彦

蛋白質核酸酵素　51　(14)　2067-2068,1916　2006/11
Publisher: 共立出版
ISSN： 0039-9450
転写抑制因子Bachが形成する抗体応答制御遺伝子プログラムの解明

五十嵐和彦

上原記念生命科学財団研究報告集　20　131-133　2006/11
Publisher: (公財)上原記念生命科学財団
eISSN： 2433-3441
ヘム結合転写因子Bach1によるヘム応答性遺伝子制御の解析

孫継英, 田代聡, 五十嵐和彦

広島大学原爆放射線医科学研究所年報　(47)　92-92　2006/10
Publisher: 広島大学原爆放射線医科学研究所
ISSN： 1348-3765
Gene ablation Bach-1 leads to suppression of atherosclerosis in apolipoprotein-E (Apo-E) and Bach1 double knockout mice (ApoE(-I-)Bach1(-I-))

Yulchiro Watari, Ryoji Ozono, Yoshiyuki Yamamoto, Yoko Yano, Andorei Brydun, Tetsuya Oshima, Kazuaki Chayama, Masao Yoshizumi, Kazuhiko Igarashi

CIRCULATION　114　(18)　227-227　2006/10

ISSN： 0009-7322
Effects of genetic ablation of Bach1 on an animal model of nonalcoholic steatohepatitis

Motoki Inoue, Hideyuki Hyogo, Michihiro Nonaka, Keiko Iwamoto, Yoshitaka Nabeshima, Tomokazu Ishitobi, Kazuhiko Igarashi, Susumu Tazuma, Kazuaki Chayama

HEPATOLOGY　44　(4)　669A-669A　2006/10

ISSN： 0270-9139
Gene ablation Bach-1 leads to suppression of atherosclerosis in apolipoprotein-E and Bach1 double knockout mice

Yuichiro Watari, Ryoji Ozonic, Yoshiyuki Yamamoto, Yoko Yano, Andorei Brydun, Tetsuya Oshima, Kazualki Chayama, Kazuhiko Igarashi

HYPERTENSION　48　(4)　E93-E93　2006/10

ISSN： 0194-911X
Reduced capacity of heme oxygenese-1 induction in patients with coronary artery disease

Andrei Brydun, Ryoji Ozono, Koichim Okuhara, Fujilko Kohno, Tetsuya Oshima, Yuichiro Watari, Kazualki Chayama, Kazuhiko Igarashi

HYPERTENSION　48　(4)　E63-E63　2006/10

ISSN： 0194-911X
肝疾患における酸化ストレス非アルコール性脂肪性肝炎(NASH)動物モデルにおける酸化ストレス応答の意義ヘムオキシゲナーゼ-1(HO-1)による病期進展抑制効果

井上基樹, 五十嵐和彦, 田妻進

肝臓　47　(Suppl.2)　A370-A370　2006/09
Publisher: (一社)日本肝臓学会
ISSN： 0451-4203

eISSN： 1881-3593
日本学術振興会賞を受賞して

五十嵐和彦

東北医学雑誌　118　(1)　71-73　2006/06/25

ISSN： 0040-8700
The heme-Bach1 pathway in the regulation of oxidative stress response and erythroid differentiation. (Antioxid. Redox. Signal. )

Igarashi K, Sun J

Antioxid. Redox. Signal.　8　107-118　2006/06

DOI： 10.1089/ars.2006.8.107 　
【酸化ストレスと消化器・肝疾患】酸化ストレス応答の分子機構と病態

五十嵐和彦, 土肥由裕

日本消化器病学会雑誌　103　(1)　7-14　2006/01
Publisher: (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【細胞分化を制御する遺伝情報デコードシステム転写因子・クロマチン制御・non-coding RNA】序細胞分化を支えるDECODEシステム

五十嵐和彦

細胞工学　25　(1)　10-12　2005/12
Publisher: (株)学研メディカル秀潤社
ISSN： 0287-3796
Transcriptional regulation of the Bach2 B-cell differentiation and apoptotic factor by the Bcr-Abl oncoprotein.

M Makri, C Yoshida, A Muto, K Igarashi, JV Melo

BLOOD　106　(11)　838A-838A　2005/11

ISSN： 0006-4971
Genetic ablation of Bach1, a critical transcriptional repressor of heme oxygenase-1, prevents left ventricular remodeling after myocardial infarction in mice

Y Yano, R Ozono, M Kambe, K Igarashi, T Oshima

CIRCULATION　112　(17)　U217-U217　2005/10

ISSN： 0009-7322
SUMO修飾による転写因子Bach2の局在および機能制御

田代聡, 河野和輝, 原野由美, 武藤哲彦, 星野英人, 吉田稔, 五十嵐和彦

日本血液学会・日本臨床血液学会総会プログラム・抄録集　67回・47回　755-755　2005/09
Publisher: 日本臨床血液学会
【血液疾患 state of arts】病態生理に関する基礎的・臨床的研究最近の進歩基礎研究 Bach(BTB and CNC homology)転写因子の造血系細胞における機能

五十嵐和彦, 武藤哲彦

医学のあゆみ　別冊　(血液疾患-state of arts Ver.3)　67-69　2005/09
Publisher: 医歯薬出版(株)
ISSN： 0039-2359
抗ストレス防御因子ヘムオキシゲネース 1の遺伝子誘導能と冠動脈疾患重症度の関連

Brydun Andorei, 小園亮次, 矢野陽子, 奥原宏一郎, 五十嵐和彦, 末田泰二郎, 神辺眞之, 大島哲也

日本高血圧学会総会プログラム・抄録集　28回　72-72　2005/09
Publisher: (NPO)日本高血圧学会
ヘムに制御される赤血球特異的遺伝子群の発現制御機構と新規Histone Acetyltransferaseの同定

藤原亨, 張替秀郎, 高橋伸一郎, 五十嵐和彦, 賀来満夫, 佐々木毅

日本血液学会・日本臨床血液学会回総会プログラム・抄録集　67回・47回　(67回47回)　796-796　2005/09
Publisher: 日本臨床血液学会
【転写制御と疾患遺伝子のon-offと病態】転写制御研究に基づいて病態の理解を深める試み

五十嵐和彦

Molecular Medicine　42　(9)　962-965　2005/08
Publisher: (株)中山書店
ISSN： 0918-6557
【転写制御と疾患遺伝子のon-offと病態】動脈硬化における酸化ストレス応答と転写制御

土肥由裕, 五十嵐和彦

Molecular Medicine　42　(9)　982-988　2005/08
Publisher: (株)中山書店
ISSN： 0918-6557
Transgenic expression of BACH1 transcription factor results in megakaryocytic impairment

T Toki, F Katsuoka, F Kanezaki, G Xu, H Kurotaki, JY Sun, T Kamio, S Watanabe, S Tandai, K Terui, S Yagihashi, N Komatsu, K Igarashi, M Yamamoto, E Ito

BLOOD　105　(8)　3100-3108　2005/04

DOI： 10.1182/blood-2004-07-2826 　

ISSN： 0006-4971
Effects of Genetic Ablation of Bach1 upon Smooth Muscle Cell Proliferation and Atherosclerosis after Cuff Injury(Molecular Biology, Vascular 1 (H), The 69th Annual Scientific Meeting of the Japanese Circulation Society)

Omura Shinji, Dohi Yoshihiro, Yano Yoko, Yoshizumi Masao, Ozono Ryoji, Igarashi Kazuhiko

Circulation journal : official journal of the Japanese Circulation Society　69　156-156　2005/03/01
Publisher: Japanese Circulation Society
ISSN： 1346-9843
Dynamic changes in transcription factor complexes during erythroid differentiation revealed by quantitative proteomics.

M Brand, JA Ranish, K Igarashi, R Aebersold, M Groudine

BLOOD CELLS MOLECULES AND DISEASES　34　(2)　78-79　2005/03

ISSN： 1079-9796
Effects of genetic ablation of Bach1 upon smooth muscle cell proliferation and atherosclerosis after cuff injury

S Omura, Y Dohl, K Igarashi

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY　45　(3)　406A-406A　2005/02

ISSN： 0735-1097
ヒト肺細胞におけるヘムオキシゲナーゼの発現調節

小川和宏, 五十嵐和彦, 藤田博美, 柴原茂樹, 柳澤輝行

日本薬理学雑誌　125　(1)　8P-8P　2005/01
Publisher: (公社)日本薬理学会
ISSN： 0015-5691

eISSN： 1347-8397
Bach1 is a key repressor of heme oxygenase-1 and regulates cell proliferation

S Omura, Y Dohi, K Igarashi

CIRCULATION　110　(17)　277-277　2004/10

ISSN： 0009-7322
DNA修復,細胞死と核内ドメイン

田代聡, 宮川清, 五十嵐和彦

日本癌学会総会記事　63回　242-242　2004/09
Publisher: 日本癌学会
ISSN： 0546-0476
Bachオーケストラの新展開 Bach2による形質細胞分化の調節

武藤哲彦, 五十嵐和彦

細胞工学　23　(7)　818-819　2004/06
Publisher: (株)学研メディカル秀潤社
ISSN： 0287-3796
The transcriptional programme of antibody class switching involves the repressor Bach2

A Muto, S Tashiro, O Nakajima, H Hoshino, S Takahashi, E Sakoda, D Ikebe, M Yamamoto, K Igarashi

NATURE　429　(6991)　566-571　2004/06

DOI： 10.1038/nature02596 　

ISSN： 0028-0836
酸化ストレス防御酵素ヘムオキシゲナーゼ1の発現調節と病態への関与

五十嵐和彦

Organ Biology　11　(2)　148-148　2004/05
Publisher: (一社)日本臓器保存生物医学会
ISSN： 1340-5152

eISSN： 2188-0204
Repression of PML nuclear body-associated transcription by oxidative stress-activated Bach2

S Tashiro, A Muto, K Tanimoto, H Tsuchiya, H Suzuki, H Hoshino, M Yoshida, J Walter, K Igarashi

MOLECULAR AND CELLULAR BIOLOGY　24　(8)　3473-3484　2004/04

DOI： 10.1128/MCB.24.8.3473-3484.2004 　

ISSN： 0270-7306

eISSN： 1098-5549
OJ-172 Inactivation of Bach1 Promotes Macrophage-phagocytosis through the Induction of Heme Oxygenase-1 (HO-1) and Monocyte Chemoattachment Protein-1 (MCP-1)(Infection/Inflammation/Immunity 1 (H) : OJ20)(Oral Presentation (Japanese))

Omura Shinji, Yano Yoko, Igarashi Kazuhiko

Circulation journal : official journal of the Japanese Circulation Society　68　272-272　2004/03/01
Publisher: Japanese Circulation Society
ISSN： 1346-9843
PE-317 Bach1 Is a Key-repressor of Heme Oxygenase-1 (HO-1) and Regulates Cell Proliferation(Atherosclerosis, Basic 4 (IHD) : PE54)(Poster Session (English))

Omura Shinji, Yano Yoko, Igarashi Kazuhiko

Circulation journal : official journal of the Japanese Circulation Society　68　439-439　2004/03/01
Publisher: Japanese Circulation Society
ISSN： 1346-9843
FRS-163 Genetic ablation of Bach1, a critical transcriptional repressor of heme oxygenase-1, leads to myocardial protection against ischemia/reperfusion injury in mice(Coronary Heart Disease : Basic Science (IHD) : FRS20)(Featured Research Session (English))

Yano Yoko, Ozono Ryoji, Oishi Yoshihiko, Kambe Masayuki, Omura Shinji, Igarashi Kazuhiko, Oshima Tetsuya

Circulation journal : official journal of the Japanese Circulation Society　68　132-132　2004/03/01
Publisher: Japanese Circulation Society
ISSN： 1346-9843
Bach1 is a key-repressor of heme oxygenase-1 and regulates cell proliferation

S Omura, JY Sun, H Suzuki, K Igarashi

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY　43　(5)　506A-506A　2004/03

ISSN： 0735-1097
Myocarial protection against ischemic stress by induction of heme oxygenqenase-1 in mice lacking Bach1 gene

Y Yano, R Ozono, K Igarashi, T Oshima

FASEB JOURNAL　18　(4)　A390-A390　2004/03

ISSN： 0892-6638
Genetic ablation of Bach1, a transcriptional repressor of heme oxygenase-1, leads to myocardial protection against ischemia/reperfusion injury in mice

R Ozono, Y Oishi, M Kambe, K Igarashi, T Oshima, Y Yano

JOURNAL OF HYPERTENSION　22　S84-S84　2004/02

ISSN： 0263-6352
Dynamic changes in transcription factor complexes during erythroid differentiation revealed by quantitative proteomics

M Brand, JA Ranish, NT Kummer, J Hamilton, K Igarashi, C Francastel, TH Chi, GR Crabtree, R Aebersold, M Groudine

NATURE STRUCTURAL & MOLECULAR BIOLOGY　11　(1)　73-80　2004/01

DOI： 10.1038/nsmb713 　

ISSN： 1545-9985
Bach1によるHeme Oxygenase-1(HO-1)の発現調節と臨床的意義

五十嵐和彦, 大村真司

ファルマシア　39　(12)　1152-1156　2003/12
Publisher: (公社)日本薬学会
ISSN： 0014-8601

eISSN： 2189-7026
The transcription factor Bach2 is phosphorylated via PI-3 kinase by Bcr-Abl.

C Yoshida, F Yoshida, SA Vieira, M Makri, A Muto, K Igarashi, JM Goldman, JV Melo

BLOOD　102　(11)　578A-579A　2003/11

ISSN： 0006-4971
抗酸化作用を有するヘムオキシゲナーゼ1遺伝子はBach1による転写抑制の解除により誘導される

大村真司, 孫継英, 山崎力, 五十嵐和彦

Circulation Journal　67　(Suppl.III)　994-994　2003/10
Publisher: (一社)日本循環器学会
ISSN： 1346-9843

eISSN： 1347-4820
Bach1-inhibition promotes macrophage-phagocytosis through the induction of heme oxygenase-1 and monocyte chemoattachment protein-1

S Omura, JY Sun, H Suzuki, K Igarashi

CIRCULATION　108　(17)　103-103　2003/10

ISSN： 0009-7322
Bach1 is a key-repressor of heme oxygenase-1 and regulates cell proliferation

S Omura, JY Sun, H Suzuki, K Igarashi

CIRCULATION　108　(17)　291-291　2003/10

ISSN： 0009-7322
Deletion of Bach1, a critical transcriptional repressor of heme oxygenase-1, leads to myocardial protection agaist ischemia reperfusion in mice

Y Yano, R Ozono, Y Oishi, H Nakashima, M Kambe, S Omura, K Igarashi, T Oshima

CIRCULATION　108　(17)　157-157　2003/10

ISSN： 0009-7322
【臨床遺伝子学'03 がんのジェネティクス】発がんと化学予防におけるAP-1系転写因子の機能

五十嵐和彦

最新医学　58　(9月増刊)　2214-2222　2003/09
Publisher: (株)最新医学社
ISSN： 0370-8241
Bach1, a transcriptional repressor of heme oxygenase-1, is a novel therapeutic target for ischemic myocardial injury

Y Yano, R Ozono, Y Oishi, M Kambe, S Omura, K Igarashi, T Oshima

HYPERTENSION　42　(3)　390-390　2003/09

ISSN： 0194-911X
B細胞特異的転写抑制因子Bach2による細胞死誘導機構の解析

田代聡, 武藤哲彦, 池部大, 小野厚, 五十嵐和彦

臨床血液　44　(8)　686-686　2003/08
Publisher: (一社)日本血液学会-東京事務局
ISSN： 0485-1439

eISSN： 1882-0824
転写調節機構と核高次構造

田代聡, 五十嵐和彦

日本癌学会総会記事　62回　257-257　2003/08
Publisher: 日本癌学会
ISSN： 0546-0476
Hemoprotein BACH1 regulates enhancer accessibility of heme oxygenase-1 gene.

JY Sun, A Muto, H Suzuki, O Nakajima, M Yamamoto, K Igarashi

BLOOD CELLS MOLECULES AND DISEASES　31　(1)　146-147　2003/07

ISSN： 1079-9796
【発生・細胞分化を決定するエピジェネティクスと遺伝子発現機構クロマチン構造の変化,転写制御から疾患とのかかわりまで】クロマチン制御とエピジェネティクスエピジェネティクスと遺伝子発現制御機構グロビン遺伝子の発現制御機構

五十嵐和彦, 田邉修

実験医学　21　(11)　1469-1477　2003/07
Publisher: (株)羊土社
ISSN： 0288-5514
Heme oxygenase-1 is repressed by Bach1: A novel heme-binding transcriptional repressor in smooth muscle cells and macrophages

S Omura, JY Sun, H Suzuki, M Toyofuku, K Igarashi

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY　41　(6)　314A-314A　2003/03

ISSN： 0735-1097
ヘムは酸化ストレスを防御するか?

五十嵐和彦, 孫継英

麻酔　51　(増刊)　S16-S25　2002/12
Publisher: 克誠堂出版(株)
ISSN： 0021-4892
ヘムオキシゲナーゼ1遺伝子発現における基質誘導の分子機構

孫継英, 鈴木洋, 五十嵐和彦

生化学　74　(11)　1413-1413　2002/11
Publisher: (公社)日本生化学会
ISSN： 0037-1017
転写因子MITFとMAZRによるマウス・マスト細胞プロテアーゼ6遺伝子発現における協調作用

森井英一, 五十嵐和彦, 北村幸彦

日本癌学会総会記事　61回　85-85　2002/10
Publisher: 日本癌学会
ISSN： 0546-0476
転写調節機構と核高次構造

田代聡, 五十嵐和彦

日本癌学会総会記事　61回　85-85　2002/10
Publisher: 日本癌学会
ISSN： 0546-0476
【細胞核再発見解明が進む機能ドメインとその役割】核高次構造と核機能:染色体領域-クロマチン間領域モデルを中心として

田代聡, 小野厚, 五十嵐和彦

細胞工学　21　(10)　1154-1156　2002/09
Publisher: (株)学研メディカル秀潤社
ISSN： 0287-3796
核基盤構造の機能とダイナミクス核機能可視化技術を用いた核高次構造の解析

田代聡, Thomas Cremer, 五十嵐和彦

生化学　74　(8)　682-682　2002/08
Publisher: (公社)日本生化学会
ISSN： 0037-1017
転写制御複合体の形成とその生物機能構造転写因子Bach1による標的遺伝子の選択

五十嵐和彦, 孫継英, 鈴木洋, 大村真司, 田代聡, 武藤哲彦

生化学　74　(8)　690-690　2002/08
Publisher: (公社)日本生化学会
ISSN： 0037-1017
ヘムオキシゲナーゼ1遺伝子はBach1による転写抑制の解除により誘導される

大村真司, 孫継英, 鈴木洋, 豊福守, 五十嵐和彦

生化学　74　(8)　1073-1073　2002/08
Publisher: (公社)日本生化学会
ISSN： 0037-1017
転写制御因子Bach1のヘム配位構造

平就介, 富田毅, 五十嵐和彦, 齋藤正男

生化学　74　(8)　1002-1002　2002/08
Publisher: (公社)日本生化学会
ISSN： 0037-1017
ヘム結合性転写因子Bach1によるヘムオキシゲナーゼ-1遺伝子制御機構の解析

孫継英, 中島修, 鈴木洋, 武藤哲彦, 田代聡, 柴原茂樹, 武藤誠, 山本雅之, 五十嵐和彦

生化学　74　(8)　1002-1002　2002/08
Publisher: (公社)日本生化学会
ISSN： 0037-1017
NOドナーによる転写抑制因子Bach1のDNA結合調節

小川和宏, 五十嵐和彦, 竹谷茂, 西谷千明, 柴原茂樹, 藤田博美

生化学　74　(8)　1002-1002　2002/08
Publisher: (公社)日本生化学会
ISSN： 0037-1017
B細胞特異的転写因子BACH2によるBCL-2関連遺伝子A1の発現抑制機構

丹代諭, 山田, 佐藤秀子, 金崎里香, 土岐力, 五十嵐和彦, 伊藤悦朗

弘前医学　54　(1)　8-20　2002/07
Publisher: 弘前大学大学院医学研究科・弘前医学会
ISSN： 0439-1721
Heme-regulated transcription factor Bach1

K Ogawa, K Igarashi, C Nishitani, S Shibahara, H Fujita

JOURNAL OF HEALTH SCIENCE　48　(1)　1-6　2002/02

DOI： 10.1248/jhs.48.1 　

ISSN： 1344-9702
DNA修復機構と核高次構造

田代聡, 五十嵐和彦, 宮川清

日本癌学会総会記事　60回　72-72　2001/09
Publisher: 日本癌学会
ISSN： 0546-0476
AP-1系転写抑制因子Bach2による酸化ストレス応答性細胞死の制御

五十嵐和彦, 田代聡

日本癌学会総会記事　60回　129-129　2001/09
Publisher: 日本癌学会
ISSN： 0546-0476
Bach1によるヘムオキシゲナーゼ1遺伝子発現制御機構の解析

孫継英, Alam Jawed, 柴原茂樹, 五十嵐和彦

生化学　73　(8)　715-715　2001/08
Publisher: (公社)日本生化学会
ISSN： 0037-1017
ヘムによる転写抑制因子Bach1の活性調節

小川和宏, 孫継英, 西谷千明, 柴原茂樹, 藤田博美, 五十嵐和彦

生化学　73　(8)　719-719　2001/08
Publisher: (公社)日本生化学会
ISSN： 0037-1017
Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1. International-journal Peer-reviewed

K Ogawa, J Sun, S Taketani, O Nakajima, C Nishitani, S Sassa, N Hayashi, M Yamamoto, S Shibahara, H Fujita, K Igarashi

The EMBO journal　20　(11)　2835-43　2001/06/01

DOI： 10.1093/emboj/20.11.2835 　

ISSN： 0261-4189
ヘムによる転写因子Bach1の調節機構

小川和宏, 五十嵐和彦, 西谷千明, 竹谷茂, 柴原茂樹, 藤田博美

日本薬学会年会要旨集　121年会　(4)　48-48　2001/03
Publisher: (公社)日本薬学会
ISSN： 0918-9823
転写因子Bach2を介した酸化ストレス情報伝達経路の機能

星野英人, 吉田稔, 武藤哲彦, 伊藤悦朗, 山本雅之, 五十嵐和彦

生化学　73　(2)　143-143　2001/02
Publisher: (公社)日本生化学会
ISSN： 0037-1017

eISSN： 2189-0544
Cloning of a coproporphyrinogen oxidase promoter regulatory element binding protein.

S Takahashi, K Furuyama, A Kobayashi, S Taketani, H Harigae, M Yamamoto, K Igarashi, H Yokoyama, Ishikawa, I, O Sasaki, J Kameoka, K Miyamura, K Meguro, N Hayashi, T Sasaki

BLOOD　96　(11)　285A-285A　2000/11

ISSN： 0006-4971
Contribution of small maf transcription factors to erythropoiesis.

D Engel, K Igarashi, F Katsuoka, H Motohashi, K Onodera, J Shavit, N Suwabe, M Yamamato

BLOOD CELLS MOLECULES AND DISEASES　26　(5)　494-495　2000/10

ISSN： 1079-9796
MAZ関連転写因子MAZRによるc-mycプロモーターの活性化

五十嵐和彦, 小林聡

日本癌学会総会記事　59回　493-493　2000/09
Publisher: 日本癌学会
ISSN： 0546-0476
遺伝子の収納と発現の基本メカニズム DNAを折り畳む転写因子群の機能

五十嵐和彦, 孫継英, 小林聡

生化学　72　(8)　684-684　2000/08
Publisher: (公社)日本生化学会
ISSN： 0037-1017
転写因子Bach 1のヘム結合モチーフ

小川和宏, 五十嵐和彦, 西谷千明, 竹谷茂, 中島修, 山本雅之, 柴原茂樹, 林典夫, 藤田博美

生化学　72　(8)　978-978　2000/08
Publisher: (公社)日本生化学会
ISSN： 0037-1017
c-Yesのユニーク領域内自己リン酸化の酵素活性に及ぼす影響

清水雅裕, 碓井裕史, 田邉修, 西藤泰昌, 五十嵐和彦

生化学　72　(8)　996-996　2000/08
Publisher: (公社)日本生化学会
ISSN： 0037-1017
ヒストン修飾酵素と転写制御複合体形成 locus control regionによる転写制御

五十嵐和彦, 小林聡

蛋白質・核酸・酵素　45　(9)　1436-1445　2000/06
Publisher: 共立出版(株)
ISSN： 0039-9450
酸素ストレスによる赤血球分化機序の検討

永井正, 大嶺謙, 樽本高壽, 今川重彦, 小松則男, 五十嵐和彦, 山本雅之, 佐々茂, 小澤敬也

International Journal of Hematology　71　(Suppl.1)　192-192　2000/04
Publisher: (一社)日本血液学会
ISSN： 0925-5710

eISSN： 1865-3774
B細胞特異的転写因子Bach2の機能解析

伊藤悦朗, 土岐力, 佐々木伸也, 五十嵐和彦, 横山碓

International Journal of Hematology　71　(Suppl.1)　108-108　2000/04
Publisher: (一社)日本血液学会
ISSN： 0925-5710

eISSN： 1865-3774
【細胞核研究の最先端】核機能の発現にかかわる蛋白質分子複合体核内構造とBTB/POZドメイン BACH1によるDNAのループ構造の形成

吉田近思, 五十嵐和彦

蛋白質・核酸・酵素　44　(12)　1771-1779　1999/09
Publisher: 共立出版(株)
ISSN： 0039-9450
p45 NF-E2関連転写因子Bach1の精巣特異的アイソフォームの単離

土岐力, 金崎里香, 伊藤悦朗, 横山碓, 五十嵐和彦, 山本雅之

臨床血液　40　(9)　1033-1033　1999/09
Publisher: (一社)日本血液学会-東京事務局
ISSN： 0485-1439

eISSN： 1882-0824
ヘムによる転写因子Bach1の活性調節

小川和宏, 五十嵐和彦, 竹谷茂, 吉田近思, 中島修, 山本雅之, 柴原茂樹, 林典夫, 藤田博美

生化学　71　(8)　948-948　1999/08
Publisher: (公社)日本生化学会
ISSN： 0037-1017
新たなNF-E2関連因子Nrf3の単離と機能解析 (生化学)

小林聡, 伊藤悦朗, 土岐力, 小亀圭司, 五十嵐和彦, 山本雅之, 林典夫

生化学　71　(8)　947-947　1999/08
Publisher: (公社)日本生化学会
ISSN： 0037-1017
マウスbach1遺伝子の構造解析 (生化学)

孫継英, 五十嵐和彦, 小林聡, 星野英人, 西村滋子, 山本雅之, 林典夫

生化学　71　(8)　814-814　1999/08
Publisher: (公社)日本生化学会
ISSN： 0037-1017

eISSN： 2189-0544
クロマチン機能の制御グロビン遺伝子LCRと抗体重鎖遺伝子LCRの結合因子群 (生化学)

五十嵐和彦, 小林聡, 吉田近思, 武藤哲彦, 星野英人, 竹安邦夫, 山本雅之, 林典夫

生化学　71　(8)　608-608　1999/08
Publisher: (公社)日本生化学会
ISSN： 0037-1017

eISSN： 2189-0544
【ゲノム・オペレーティングシステム】LCR クロマチン構造を制御するDNA配列

星野英人, 五十嵐和彦

細胞工学　18　(7)　963-967　1999/07
Publisher: (株)学研メディカル秀潤社
ISSN： 0287-3796
造血幹細胞をめぐる研究の新展開'99-2000 造血幹細胞の分化血球分化における転写因子の役割 B細胞転写因子Bach2と抗体重鎖遺伝子LCR

五十嵐和彦, 武藤哲彦, 小林聡

実験医学　17　(9)　1149-1153　1999/06
Publisher: (株)羊土社
ISSN： 0288-5514
Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain

Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J.D., Yamamoto, M.

Genes and Development　13　(1)　76-86　1999

DOI： 10.1101/gad.13.17.2328 　

ISSN： 0890-9369
Functional analyses of Bach2-associated factor FOB

KOBAYASHI Akira, YAMAGIWA Hironori, MUTO Akihiko, MOCHITA Miyuki, HOSHINO Hideto, YAMAMOTO Masayuki, HAYASHI Norio, IGARASHI Kazuhiko

21　406-406　1998/12/01
Structure of Mouse bach2 Gene

TAKAHASHI S., HOSHINO H., MUTO A., ITO E., YAMAMOTO M., KOBAYASHI A., IGARASHI K., HAYASHI N.

21　405-405　1998/12/01
Funetion of BTB domain of FOB, a friend of Bach

MOCHITA Miyuki, KOBAYASHI Akira, YAMAGIWA Hironori, YAMAMOTO Masayuki, HAYASHI Norio, IGARASHI Kazuhiko

21　406-406　1998/12/01
Regulation of IgH gene expression by Bach2 and samll Maf

MUTO A., HOSHINO H., MADISEN L., YAMAMOTO M., GROUDINE M., HAYASHI N., IGARASHI K.

21　406-406　1998/12/01
Visualization of β-globin LCR/Bach1complex by Atomic Force Microscopy

YOSHIDA Cikashi, TOKUMASU Fuyuki, HOUMURA Kenichi, HAYASHI Norio, NAGASAWA Toshiro, YAMAMOTO Masayuki, TAKEYASU Kunio, IGARASHI Kazuhiko

21　419-419　1998/12/01
グロビン遺伝子LCRに作用する転写因子群の機能の解析

五十嵐和彦

生化学　70　(8)　594-594　1998/08
Publisher: (公社)日本生化学会
ISSN： 0037-1017
bZip型転写因子Bachファミリーと癌原遺伝子産物との相互作用

五十嵐和彦

日本癌学会総会記事　56回　348-348　1997/08
Publisher: 日本癌学会
ISSN： 0546-0476
The world according to Maf Invited Peer-reviewed

H Motohashi, JA Shavit, K Igarashi, M Yamamoto, JD Engel

NUCLEIC ACIDS RESEARCH　25　(15)　2953-2959　1997/08

DOI： 10.1093/nar/25.15.2953 　

ISSN： 0305-1048
LCR結合因子Bach1の多量体形成能の解析

五十嵐和彦

生化学　69　(7)　699-699　1997/07
Publisher: (公社)日本生化学会
ISSN： 0037-1017
Human small Maf proteins form heterodimers with CNC family transcription factors and recognize NF-E2 motif.

E Ito, T Toki, K Arai, J Kitazawa, K Igarashi, K Hatakeyama, M Yamamoto, M Yokoyama

BLOOD　88　(10)　758-758　1996/11

ISSN： 0006-4971
Activation of the erythroid transcription factor NF-E2, in MEL cell differentiation.

T Nagai, K Igarashi, K Furuyama, H Fujita, N Hayashi, M Yamamoto, S Sassa

BLOOD　88　(10)　757-757　1996/11

ISSN： 0006-4971
マウスmafK遺伝子の神経組織における発現と神経特異的なプロモーターによる発現調節

本橋ほづみ, 五十嵐和彦, 中福雅人, 山本雅之

日本分子生物学会年会プログラム・講演要旨集　19　438-438　1996/08/01
赤血球型δ-アミノレブリン酸合成酵素欠損ES細胞の分化

張替秀郎, 諏訪部徳芳, 山本雅之, 五十嵐和彦, 藤田博美, 佐々茂

日本分子生物学会年会プログラム・講演要旨集　19　826-826　1996/08/01
転写因子ECHのドメイン解析と細胞質-核移行による機能制御

伊東健, 小宅達也, 林典夫, 五十嵐和彦, 山本雅之

日本分子生物学会年会プログラム・講演要旨集　19　603-603　1996/08/01
新しい転写因子Bachファミリーの解析

小宅達也, 伊東健, 林典夫, 西澤誠, 本橋ほづみ, 山本雅之, 五十嵐和彦

日本分子生物学会年会プログラム・講演要旨集　19　603-603　1996/08/01
Upregulation of the erythroid transcription factor, NF-E2, by DMSO and hemin: Distinctive mechanisms.

T Nagai, K Igarashi, K Furuyama, H Fujita, N Hayashi, M Yamamoto, S Sassa

BLOOD　86　(10)　2693-2693　1995/11

ISSN： 0006-4971
Structure and regulation of the genes encoding GATA factors and NF-E2.

YAMAMOTO MASAYUKI, MOTOHASHI HOZUMI, ONODERA KO, TAKAHASHI SATOSHI, MINEGISHI NAOKO, ITO KEN, YOMOGIDA KENTARO, IGARASHI KAZUHIKO

日本分子生物学会年会プログラム・講演要旨集　18th　169　1995/11
血球系転写因子群の協調的機能発現と血液細胞の分化制御

五十嵐和彦, 山本雅之

蛋白質・核酸・酵素　40　(11)　1721-1730　1995/08
Publisher: 共立出版(株)
ISSN： 0039-9450
SMALL MAF PROTEINS HETERODIMERIZE WITH FOS AND MAY ACT AS COMPETITIVE REPRESSORS OF THE NF-E2 TRANSCRIPTION FACTOR (VOL 15, PG 2188, 1995)

K KATAOKA, K IGARASHI, K ITOH, KT FUJIWARA, M NODA, M YAMAMOTO, M NISHIZAWA

MOLECULAR AND CELLULAR BIOLOGY　15　(6)　3461-3461　1995/06

ISSN： 0270-7306
赤血球分化の分子生物学 NF-E2とGATA因子による赤血球特異的遺伝制御

五十嵐和彦, 山本雅之

血液・腫瘍科　30　(1)　1-9　1995/01
Publisher: (有)科学評論社
ISSN： 0915-8529
TPA-MEDIATED INHIBITION OF ERYTHROID-DIFFERENTIATION INVOLVES DOWN-REGULATION OF THE ERYTHROID-SPECIFIC TRANSCRIPTION FACTOR NF-E2

T NAGAI, K IGARASHI, H FUJITA, N HAYASHI, M YAMAMOTO, S SASSA

BLOOD　84　(10)　A15-A15　1994/11

ISSN： 0006-4971
赤血球分化と転写制御 GATA因子群とNF-E2の機能

五十嵐和彦

International Journal of Hematology　59　(Suppl.1)　78-78　1994/04
Publisher: (一社)日本血液学会
ISSN： 0925-5710

eISSN： 1865-3774
第8回朝霧シンポジウム「転写制御」

五十嵐和彦

蛋白質核酸酵素　39　(3)　p293-295　1994/03
Publisher: 共立出版
ISSN： 0039-9450
GATAおよびNF‐E2転写因子と赤血球分化

山本雅之, 五十嵐和彦, 石原元, 伊藤健, 蓬田健太郎, 片岡浩介, 西沢誠

日本分子生物学会年会プログラム・講演要旨集　16th　154　1993/11
トリ赤血球特異的転写因子NF‐E2の構造解析

伊東健, 五十嵐和彦, 山本雅之, 片岡浩介, 西沢誠

日本分子生物学会年会プログラム・講演要旨集　16th　269　1993/11
maf関連遺伝子群による赤血球特異的転写因子NF‐E2の機能変換

五十嵐和彦, 伊東健, 山本雅之, 片岡浩介, 西沢誠

日本分子生物学会年会プログラム・講演要旨集　16th　270　1993/11
RNAポリメラーゼωサブユニットの生理機能緊縮制御の調節因子

五十嵐和彦

生化学　61　(9)　863-863　1989/09
Publisher: (公社)日本生化学会
ISSN： 0037-1017

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Books and Other Publications 8

特集RNAが修飾される! : エピトランスクリプトームによる生命機能と疾患の制御

五十嵐, 和彦, 深水, 昭吉

羊土社　2018/12

ISBN: 9784758125147
シンプル生化学

野口, 正人, 五十嵐, 和彦, 林, 典夫, 廣野, 治子

南江堂　2014/03

ISBN: 9784524268078
イラストレイテッドハーパー・生化学

Harper, Harold Anthony, Murray, Robert K., Bender, David A., Botham, Kathleen M., Kennelly, Peter J., Rodwell, Victor W., Weil, P. Anthony, 清水, 孝雄, 五十嵐, 和彦

丸善出版　2013/10

ISBN: 9784621087282
遺伝情報の発現制御 : 転写機構からエピジェネティクスまで

Latchman, David S., 五十嵐, 和彦, 深水, 昭吉, 山本, 雅之

メディカル・サイエンス・インターナショナル　2012/02

ISBN: 9784895926973
遺伝情報発現におけるDECODEシステム解明 : 研究成果報告書

五十嵐, 和彦

[五十嵐和彦]　2011/03
転写因子による生命現象解明の最前線 : クロマチン制御機構・エピジェネティクスと転写因子複合体ネットワークの包括的解明

五十嵐, 和彦, 深水, 昭吉, 大熊, 芳明, 山本, 雅之

羊土社　2007/06

ISBN: 9784758102834
ヘム結合性転写因子Bach1による細胞増殖分化の制御機構

五十嵐, 和彦

[五十嵐和彦]　2007/05
新しい転写因子Bachファミリーによる細胞分化調節機構の解析

五十嵐, 和彦

[五十嵐和彦]　1999/03

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Research Projects 62

Elucidation of mechanisms in iron-driven pancreatic cancer cell metastasis

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

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

Institution: Tohoku University

2022/04/01 - 2025/03/31
Development of anti-cancer strategy by exploiting BACH1 addiction

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 (B))

Institution: Tohoku University

2020/10/27 - 2025/03/31
Elucidation of epigenetic regulation of erythropoiesis and translation to therapeutic strategy

IGARASHI Kazuhiko

Offer Organization: Japan Society for the Promotion of Science

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

Category: Challenging Research (Pioneering)

Institution: Tohoku University

2018/06/29 - 2021/03/31

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We aimed to understand the roles of MAT2, which synthesizes S-adenosylmethionine (SAM), in red blood cell (RBC) development including the effect of SAM in their epigenome. We found that the expression of MAT2A, the catalytic subunit of MAT2, is gradually decreased along RBD differentiation with concomitant decrease in SAM. The reduction of SAM led to global alterations in the epigenome of precursor cells (erythroid cells) including DNA methylation and histone methylation. As MAT2A expression is maintained by a feedback regulation involving SAM in other types of cells like Hela cells, our results suggest that erythroid cells lack the feedback regulation, enabling them to use the reduction of SAM as a signal to drive RBC differentiation.
Age-related alterations of hematopoietic stem and progenitor cells due to failure of Bach transcription factors

IGARASHI Kazuhiko

Offer Organization: Japan Society for the Promotion of Science

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

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

Institution: Tohoku University

2018/04/01 - 2021/03/31

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We aimed to understand the functions of BACH1 and BACH2 in the regulation of hematopoietic cell differentiation. By generating and analyzing mice lacking both of these genes, we found that these mice showed reduced differentiation of red blood cells and lymphoid cells, which were similar to alterations observed in myelodysplastic syndrome (MDS). By analyzing gene expression of the bone marrow cells of patients of MDS, we found that the expression of BACH2 was reduced along the progression of the disease, suggesting that a reduction in the function of BACH2 is involved in the disease progress including anemia and immunodeficiency. BACH1 and BACH2 were found to promote differentiation of erythroid cells and lymphoid cells by repressing the expression of genes important for the differentiation and/or function of myeloid cells.
The effects of Bach 1 on skeletal muscle damage

Okuno Hiroshi

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

2017/04/01 - 2020/03/31

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The regenerative potential after skeletal muscle damage was lower in Bach1-deficient mice than wild-type ones. The knockdown of the Bach1 gene caused the deterioration of the myoblast growth and differentiation and the expression of myogenin gene in C2C12 myoblasts. The expression of HO-1 increased and the expression of Smad 2/3 and FoxO1 decreased in Bach1-deficient mice and Bach1-silenced C2C12 myoblasts. These results suggested Bach1 encourages the recovery from skeletal muscle damage by increasing the myogenin expression through Smad 2/3 and FoxO1 pathways.
The effect of BACH1 on malignant transformation of tumor

Matsumoto Mitsuyo, SATO masaki, IGARASHI kazuhiko

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

2016/04/01 - 2019/03/31

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BTB and CNC homolog 1 (BACH1) promotes transformation, cell proliferation and tumor formation in a model of activated RAS transfected-mouse embryonic fibroblasts (MEFs). We focused on the role of BACH1 in the pancreatic ductal adenocarcinoma (PDAC) more than 90% of which has KRAS mutation. Although BACH1 did not affect cell proliferation and tumor growth, but promoted migration ability and invasion ability in vitro and metastasis in vivo. We revealed that BACH1 repressed directly the expression of multiple epithelial-related genes as its mechanism. We showed also BACH1 is a poor prognostic factor on PDAC.
Development of a new strategy for tumor immunity activation

IGARASHI Kazuhiko

Offer Organization: Japan Society for the Promotion of Science

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

Category: Grant-in-Aid for Challenging Exploratory Research

Institution: Tohoku University

2016/04/01 - 2018/03/31

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Cytotoxic T cells play critical roles in eliminating tumor cells with tumor-specific antigens. Although this tumor surveillance is effective during initial phases of tumorgenesis, it eventually fail to restrict tumor progression due to exhaustion of cytotoxic T cells. In addition, regulatory T cells and suppressor myeloid cells also inhibit the cytotoxic T cell activities. Based on our previous findings that the transcription factor Bach2 is essential for the differentiation of regulatory T cells, restricting cytotoxic T cell differentiation, this study was carried out to understand potential roles of Bach2 in the process of the T cell exhaustion and to develop a new strategy to activate tumor immunity. We found that Bach2-deficient T cells showed enhanced cytotoxic T cell differentiation and activity in vitro. Furthermore, many of the genes involved in T cell activation and cytotoxic activity were more highly expressed in Bach2-deficient T cells than in wild-type cells.
Regulation of erythropoiesis and macrophages by the heme signal

IGARASHI Kazuhiko, MATSUI Miki, SAIGUSA Daisuke

Offer Organization: Japan Society for the Promotion of Science

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

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

Institution: Tohoku University

2015/04/01 - 2018/03/31

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We reported previously that heme binds to the transcription factors Bach1 and Bach2 to regulate gene expression. In this study, we have successfully established the regulatory roles and biological significances of the heme-mediated regulation of these transcription factors. We found that, unlike known heme-binding proteins, the heme-binding region of Bach2 is structurally disordered, and that this region remained disordered even in the presence of heme. Nonetheless, heme induced an interaction of Bach2 and protein kinase, which then phosphorylated Bach2. We also found that Bach1 was critical for adaptation of erythroid cells to iron deficiency. Bach1 kept expression of key erythroid transcription factor genes under such conditions. In stem and progenitor cells, Bach2 and Bach1 were found to promote lymphoid cell differentiation by restricting the expression of myeloid transcription factors as well as their target genes important for myeloid cell differentiation.
Novel molecular mechanism collaborating stem neural stem cell mainteinance and differentiation

Katsuyama Yu, IGARASHI Kazuhiko, OBAYASHI Takeshi

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)

2014/04/01 - 2017/03/31

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We prepared polyclonal antibodies against Sbno1 protein, Western blot analysis using these antibodies detected different band pattern, suggesting that Sbno1 protein is regulated by cleavage. Sbno1 knockout mice showed premature neuronal differentiation, extinction of the neural stem cells, and apoptosis. Yeast two hybrid screening identified several molecules interacting with Sbno1. Our analyses suggested that one of these is transcription factor regulating cell differentiation, some of these are involved in regulation of cell cycle, and rest of these is deubiquitination enzyme which downregulates apoptosis. These findings suggest that Sbno1 function is regulated after protein translation, probably by protein cleavage mechanisms. Sbno1 can bind to multiple factors of different function, such as regulation of cell differentiation, cell cycle, and apoptosis. Thus, Sbno1 is a molecule which integrates these cellular processes.
Methods rewriting epigenome as the target of methyonine adenosyltransferase II

KATOH Yasutake, MORITA Masanobu, NAGASHIMA Takeshi, SAIGUSA Daisuke, MATSUMOTO Mitsuyo, IGARASHI Kazuhiko

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

2013/04/01 - 2016/03/31

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Methionine adenosyltransferase (MAT) catalyzes S-adenosylmethionine (SAM) synthesis, which is utilized as a methyl donor in transmethylation reactions. MATII, a MAT isozyme, is composed of the catalytic α and regulatory β subunits. Both of the subunits are recruited to a subset of target genes of Bach1 and MafK to facilitate their repression. However, it has been unclear how the nuclear accumulation of MATII subunits is regulated. Using overexpression and bimolecular fluorescence complementation, we found that MATIIβ promoted the nuclear localization of the α subunit and that resulting heterooligomer was present predominantly in nuclear compartment. A single serine residue of α subunit was required for its interaction with β subunit and efficient nuclear accumulation.These results suggest that β subunit defines nulcear-specific MAT isozyme by facilitating nuclear import of its catalytic subunit.
Crosstalk of transcriptional control and energy pathways by hub metabolites

FUKAMIZU Akiyoshi, IGARASHI Kazuhiko, NAKAO Mitsuyoshi, SUGASAWA Kaoru, MOTOHASHI Hozumi, YAHAGI Naoya, SHIMIZU Toshiyuki, SASAKI Hiroyuki, YONEDA Yoshihiro, KASUGA Masato

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: University of Tsukuba

2011/04/01 - 2016/03/31

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Our research project aimed to explore the crosstalk between the transcriptional status and energy metabolism. As the organizing group of this project, we held the annual meetings of the research groups and promoted the interaction and collaboration among the members, for example, by setting up “Collaboration Proposal Meeting”. We also supported the workshops organized by graduate students and young scientists, and “Transcription-Metabolism Seminars” held 58 times all over the country. Furthermore, we spread information on a website, held public lectures and announced our achievements to the people through mass media.
Coupring mechanism of methionine metabolism and epigenome

IGARASHI Kazuhiko

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: Tohoku University

2011/04/01 - 2016/03/31

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Regulation of epigenome relies on methylation of DNA and histones, which utilizes S-adenosyl-L-methoinine (SAM) as a sole methyl donor. SAM is synthesized by methionine adenosyltransferase (MAT) using methionine and ATP as substrates. In this research project, we discovered the molecular mechanism for the nuclear accumulation of MATII, one of the isozyme of MAT in higher eukaryotes. We also found that nuclear MATII interacted with various chromatin and transcription regulators, promoted histone H3 lysine 9 trimethylation of its target genes, and thus repress their expression. MATII also promoted formation of heterochromatin structure of certain chromatin subregions. These observations support our original contention that SAM is synthesized in nuclei for chromatin and gene expression (“local synthesis of SAM for local consumption” model). Next important step will be to understand how the activity of nuclear SAM is regulated during cell differentiation and/or proliferation.
Profiling of proteins associated with cell differentiation based on changes in relative abundance and post-translational modification.

IGARASHI KAZUHIKO, SHIMA Hiroki

Offer Organization: Japan Society for the Promotion of Science

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

Category: Grant-in-Aid for Challenging Exploratory Research

Institution: Tohoku University

2013/04/01 - 2015/03/31

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Cell differentiation is mainly regulated by a concerted action of transcription factors and chromatin factors. Since these categories of proteins are relatively scarce in their amounts, identification of critical regulators has been challenging. In this project, we have tried to use mass spectrometry to compare relative levels of nuclear and chromatin proteins between B lymphoid cells and plasma cells. We also tried to compare post-translational modifications of proteins. The reproducibility of the protocols we established was confirmed via many rounds of repetition. The feasibility of the protocols were confirmed by comparing known regulators of B cells and plasma cells, such as Pax5, Bach2 and Irf4. We found several, uncharacterized transcription factors and chromatin factors whose expression was much higher in plasma cells. We are now carrying out functional analyses of these proteins.
Regulation of immune cells by heme and its receptors Bach1 and Bach2

IGARAHI KAZUHIKO

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

2012/04/01 - 2015/03/31

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Based on our recent findings that Bach1 and Bach2 are critical regulators of immune cells and that they are receptors of heme, we have tried to investigate the possible regulation of immune cells by heme. First, we established a system to express and to purify hemopexin from HeLa cells. Using a complex of the recombinant hemopexin and heme, we showed that hemopexin-bound heme regulates the protein level of Bach1. Therefore, heme within the blood can affect gene expression by altering the function of Bach1 and possibly Bach2. Using extensive gene expression profiling and chromatin immunoprecipitation-sequencing analysis, we identified candidate target genes of Bach2 in pro-B cells. The list included genes involved in cell cycle regulation, apoptosis, cytokine and chemokines and their receptors, and iron-related genes. We also found a critical function of Bach1 in the regulation of iron-metabolizing macrophages.
Regulation of nuclear receptor activity by intracellular signals and ligands

SHIRAKI Takuma, IGARASHI Kazuhiko

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: Kinki University

2011 - 2013

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According to our previous findings of endogenous ligands for PPARg, we hypothesized that extracellular signaling molecules regulate PPARg activity through not only their intracellular metabolites acting as ligands, but also intracellular signals evoked by membrane associated receptors. To analyze the temporal and spatial regulation of PPARg activity, we developed novel reporter system, by which six independent transcriptional activities were simultaneously detected. We found that expression of phosphorylation induced stabilization of PPARg proteins by itself and blocked nuclear export of PPARg protein only in the presence of SDP-1. We also analyzed the effects of PPARg mutation identified in German obese subjects on the phoshphorylation-dependent regulation, and found that P85Q mutation blocked the effects of SDP-1. Thus, we conclude that phosphorylation signal regulates PPARg activity in the distinct mechanism from that of ligands.
Elucidation of the transcription factor network that regulates cancer-stroma interaction

IGARASHI Kazuhiko

Offer Organization: Japan Society for the Promotion of Science

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

Category: Grant-in-Aid for Challenging Exploratory Research

Institution: Tohoku University

2011 - 2012

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Interaction between stroma and cancer cells appears critical for the development of cancer. However, little is known about how the functions of stroma cells are regulated at the level of gene expression. In this project, we focused on the transcription factor Bach1 on which we had several preliminary observations suggesting its important roles in the cancer-stroma interaction. We found that Bach1 is critical for tumor formation in several mouse model systems. We identified downstream genes of Bach1 which appeared to be critical for the stroma function. We also studied the regulation of BACH1 in human stroma cells. These results will be an important foundation for future studies on the cancer-stroma interaction.
Regulation of immune cell responses by heme

IGARASHI Kazuhiko, MOTOHASHI Hozumi, MUTO Akihiko, KATOH Yasutake, MURAYAMA Kazutaka

Offer Organization: Japan Society for the Promotion of Science

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

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

Institution: Tohoku University

2009 - 2011

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The transcription factor Bach2 is required in B cells for the antibody class switch DNA recombination and somatic hypermutation. In this project, we have established that the prosthetic group heme binds directly to Bach2 to inhibits its DNA binding activity and to induce rapid turnover within cells. We also identified a domain-like structure within Bach2 that mediates the regulation by heme. Three cysteine residues within this domain were critical for the heme-Bach2 interaction. These results suggest that heme functions as a signaling molecule in B cells to regulate immune responses.
Promotion of Studies on the DECODE System in the Genetic Information Expression

IGARASHI Kazuhiko, FUKAMIZU Akiyoshi, OGATA Kazuhiro

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Priority Areas

Category: Grant-in-Aid for Scientific Research on Priority Areas

2004 - 2010
ES細胞を用いた細胞記憶の改変技術の開発

五十嵐和彦, 加藤恭丈

Offer Organization: 日本学術振興会

System: 科学研究費助成事業挑戦的萌芽研究

Category: 挑戦的萌芽研究

Institution: 東北大学

2008 - 2009

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メチオニン・アデノシル基転移酵素(MAT)は、S-アデノシルメチオニン(SAM)の生合成に必須の酵素である。合成されたSAMはメチル基転移酵素(MT)の基質として利用され、そのメチル基はDNA中のシトシンやヒストンのリジン残基などへ転移され、クロマチンレベルでの細胞記憶を支配する。本研究の主題は、MATに着目してヒストンやDNAのメチル化を包括的に低下させる方法を開拓し、細胞記憶を消去することによりクロマチンと細胞の可塑性を高める技術を開発することにある。まず、MATのアイソザイムの一つMATIIを様々な培養細胞でノックダウンを行い、ヘテロクロマチン構造やヒストンメチル化状態の変化を調べた。さらに、MATII結合因子をプロテオミクス技術を駆使して特定し、MATII以外の標的分子の探索を行った。肝臓細胞株、マクロファージ株で効率よくMATIIをノックダウンする条件を決めた。このノックダウン下ではヘテロクロマチン構造により抑制されている遺伝子発現が亢進すること、また、ヘテロクロマチン構造に重要なヒストンメチル化やユビキチン化が低下することを見いだした。同様の実験をES細胞で行うために、種々条件検討を行ったが、肝臓細胞株等と同等のノックダウン効率を達成することはできていない。現在、効率改善の検討、および、この不完全なノックダウン下でもヘテロクロマチン構造が変化する可能性を検討している。最終的には転写因子とMATIIノックダウンを組み合わせることによりES細胞分化能を変換させることを目指したが、ここまでは到達できなかった。しかし、その基盤技術開発には成功しており、今後も発展を目指したい。また、MATII結合因子の探索よりヘテロクロマチン化への関与が予想される新規因子を複数見いだしており、これらも細胞記憶改変の標的となる可能性があり、さらに研究を継続する。
Comparative Analysis of the DECODE Systems in Hematopoiesis and Oxidative Stress Response

IGARASHI Kazuhiko, MUTO Akihiko

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Priority Areas

Category: Grant-in-Aid for Scientific Research on Priority Areas

Institution: Tohoku University

2005 - 2009

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DECODE complexes of Bach1, Bach2, and MafK were purified and characterized by using mass spectrometry analysis. Bach1 was found to interact with the tumor suppressor p53 and to inhibit cellular senescence induced by oxidative stress. Bach1 recruits histone deacetylase 1 to some of the p53 target genes and promotes histone deacetylation. In addition, a DECODE gene circuit for the class switch recombination of antibody genes has been identified.
Regulation of the tumor suppressor p53 by Bach1

IGARASHI Kazuhiko

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

2007 - 2008
Genetic ablation of transcription repressor Bach1 reduces neural tissue damage after spinal cord injury in mice

OZAWA Hiroshi, IGARASHI Kazuhiko, KANNO Haruo

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

2007 - 2008
Control of cell proliferation and differentiation by heme bindiny transcription factor Bachl

IGARASHI Kazuhiko, MUTO Akihiko, IKURA Tsuyoshi

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

2005 - 2006

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The transcription repressor Bach1 is a sensor and an effecter of heme that regulates the expression of heme oxygenase-1 and globin genes. Heme binds to Bachl, inhibiting its DNA binding activity and inducing its nuclear export. We found that hemin further induced the degradation of endogenous Bachl in NIH3T3 cells, murine embryonic fibroblasts, and murine erythroleukemia cells. In contrast, succinylacetone, an inhibitor of heme synthesis, caused accumulation of Bachl in murine embryonic fibroblasts, indicating that physiological levels of heme regulated the Bachl turnover. Poly-ubiquitination and rapid degradation of overexpressed Bachl were induced by hemin treatment. HOIL-1, an ubiquitin-protein ligase which recognizes heme-bound, oxidized iron regulatory protein 2, was found to bind with Bachl when both were overexpressed in NIH3T3 cells. HOIL-1 stimulated the poly-ubiquitination of Bachl in a purified in vitro ubiquitination system depending on the intact heme binding motifs of Bachl. Expression of dominant negative HOIL-1 in murine erythroleukemia cells resulted in higher stability of endogenous Bachl, raising the possibility that the heme-regulated degradation involved HOIL-1 in murine erythroleukemia. cells. These results suggest that heme within a cell regulates the poly-ubiquitination and degradation of Bachl. In addition, we found in this study that Bachl inhibits oxidative stress-induced cellular senescence. Bachl-deficient murine embryonic fibroblasts (MEFs) showed profound cellular senescence in response to oxygen in vitro as compared to wild-type control MEFs. Expression profiling of Bachl-deficient MEFs suggested that overexpression of several genes might be responsible for the oxygen-induced cellular senescence.
Regulation of hematopoiesis by the transcription factors Bach1 and Bach2

IGARASHI Kazuhiko, TASHIRO Satoshi, MUTO Akihiko

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: Hiroshima University

2003 - 2004

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For the sake of clarity, I shall give a summary of the analysis of B cell system below. Activated B cells differentiate to plasma cells to secrete immunoglobulin MI (IgM) or, after undergoing class switch recombination (CSR), to secrete other classes of immunoglobulins. Diversification of antibody function by CSR is important for humoral immunity. However, it remains unclear how the decision for the bifurcation is made. Bach2 is a B cell-specific transcription repressor interacting with the small Maf proteins whose expression is high only prior to plasma cell stage. Here we report that Bach2 is critical for CSR and somatic hypermutation (SHM) of immunoglobulin genes. Genetic ablation of bach2 in mice revealed that Bach2 was required for both T cell-independent and -dependent IgG responses and SHM. When stimulated in vitro, Bach2-deficient B cells produced IgM as did wild-type cells and expressed abundantly Blimp-1 and XBP-1, critical regulators of the plasmacytic differentiation, suggesting that Bach2 was not required for the plasmacytic differentiation per se. However, they failed to undergo efficient CSR. These findings define Bach2 as a key regulator of antibody response and provide an insight into the orchestration of CSR and SHM during plasma cell differentiation.
Study of the mechanism of apoptosis and drug resistance in leukemic cells

TASHIRO Satoshi, IGARASHI Kazuhiko

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: HIROSHIMA UNIVERSITY

2003 - 2004

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Imatinib is a molecular targeting drug against chronic myelocytic leukemia (CML), and induces apoptosis of leukemic cells. Bach2, a B cell specific transcription factor and a proapoptotic factor, is upregulated by imatinib in CML. To study the mechanism of the induction of apoptosis by imatinib via Bach2 in CML cells, we analyzed the localization and dynamics of Bach2. We found that Bach2 relocated from cytoplasm into cell nucleus and forms nuclear foci around PML body upon oxidative stress. Bach2 selectively repressed transcriptional activity associated with PML body. Furthermore, Bach2 required protein modification for the envelopment of PML body. Since PML is a known pro-apoptotic factor, these results suggest that Bach2 might induce apoptosis through the transcription repression of genes associated with PML body in CML cells after treatment with imatinib.
ヘムオキシゲナーゼ1制御因子を標的とした虚血再潅流病態改善薬探索システムの開発

五十嵐和彦, 田代聡, 武藤哲彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業萌芽研究

Category: 萌芽研究

Institution: 広島大学

2003 - 2004

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酸化ストレスによりヘムオキシゲナーゼ-1(HO-1)が強く誘導される。このHO-1の誘導は細胞保護に重要な役割を担っており,HO-1遺伝子導入により虚血再灌流時の細胞障害が軽減されることも報告されている。転写因子Bach1はHO-1遺伝子の抑制因子であることを発見した(EMBO J.2002,Sun et al.)。このような知見から,もしも薬剤でBach1を阻害することができれば,HO-1の発現を高く誘導し,細胞保護を達成することができると考えられる。そこで本研究は,Bach1活性を生きた細胞の中でモニターするシステムを構築し,様々なHO-1誘導条件下でその活性が低下することを検証することを目指した。さらに,このシステムを予備的なスクリーニング系に供し,ランダムスクリーニングのための最適化も試みることとした。 1.リポーター細胞株の樹立 HO-1リポーター遺伝子を線維芽細胞へ導入し,染色体上に安定に遺伝子導入されたリポーター細胞株を樹立した。さらに,これら細胞株でもHO-1誘導剤に応答してリポータールシフェラーゼ活性が変動することを確認した。また,ヘム応答性核排出リポーターを作製した。 2.予備的スクリーニングの実施前年度までに確立したクロマチン免疫沈降法および一過性リポーターシステムを用いて,共同研究を実施している製薬企業から供与された薬剤候補の効果を検討した。そして,いずれも薬剤作用の検出に利用できることを確認した。しかし,ランダムスクリーニングを行うためにはアッセイ当たり所要時間や費用の点に問題があると判断された。 3.新規アッセイシステムの構築 Bach1の阻害蛋白質としてIHABPを同定し,その相互作用が薬剤の標的となる可能性を示した。
bach1/bach2二重ノックアウトマウスを用いたヘム応答性遺伝子制御システムの解析

五十嵐和彦, 孫継英

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: 広島大学

2002 - 2004

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GST-Bach1融合蛋白質を大腸菌で発現・精製し,ウサギに注射し抗血清を計6種類得た。免疫沈降に使用可能な抗体をスクリーニングし,うち1つは内在性Bach1を免疫沈降できることを確認した。NIH3T3細胞を用いて,ヘミン処理前後のBach1-エンハンサー複合体の動態をクロマチン免疫沈降法で検討した。 NIH3T3細胞では,HO-1の発現はごく低いが,細胞をヘミン(10μM)で処理することにより,2-3時間内にmRNA転写が強く誘導された。この時間経過で,HO-1エンハンサーへのBach1の結合量をクロマチン免疫沈降法で測定したところ,誘導前にはエンハンサーにBach1がMafKとの複合体として結合しているが,ヘミン処理後30分内にBach1がエンハンサーから解離することが明らかになった。この間,MafKはエンハンサーに結合したままであり,Bach1の解離とともに活性化サブユニットNrf2がエンハンサーに結合してくることも判明した。転写抑制や活性化に関わるクロマチン修飾を同様にクロマチン免疫沈降法で検討したところ,Bach1により転写が抑制されている状態でもクロマチンは活性化型の修飾(H3およびH4ヒストンのアセチル化やH3 K4のメチル化)を受けていた。Bach1はエンハンサーに結合し転写を抑制するが,この抑制は活性化の前段階に相当する状況にあること,すなわち,Bach1はエンハンサーやプロモーターにおける転写複合体を途中の段階に留め置くこと(poising)により転写を抑制すると考えられた。さらに,ヘムにBach1を標的としてその活性を変えることにより,エンハンサー上での転写抑制因子と活性化因子の動的変換を誘導することが理解された。すなわち,生命にとって必須の補欠分子ヘムが,核内では転写複合体の動態制御をも行うことが初めて明らかになった。
Regulation of cell proliferation ancl apoptcsis by the nansaiption factois Bach1 and Bach2

IGARASHI Kazuhiko

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Priority Areas

Category: Grant-in-Aid for Scientific Research on Priority Areas

Institution: Hiroshima Univeisity Graduate School of Biomedical Sciences

2001 - 2004

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Several lines of evidence suggest that gene expression is regulated not only by the interaction between transcription factors and DNA but also by the higher order architecture oft the cell nucleus. PML bodies are one of the most prominent nuclear substructures, which have been implicated in transcription regulation during apoptosis and stress responses. Bach2 is a member of the BTB-basic region leucine zipper factor family, and represses transcription activity directed by the 12-0-tetradecanoylphorbol-13-acetate response element, the Maf recognition element and the antioxidant-responsive element. Bach2 forms nuclear foci associated with PML bodies upon oxidative stress and induces apoptosis when overexpressed in NIH3T3 cells and B cell lines. Transcription activity associated with PML bodies is selectively repressed by the recruitment of Bach2 around PML bodies. Fluorescence recovery after photobleaching experiments revealed that Bach2 showed rapid turnover in the nuclear foci. Bach2 N terminal region including the BTB domain is essential for the focus formation. SUMOylation of Bach2 is required for the recruitment of the protein around PML bodies. Bach1 is a transcriptional repressor of heme oxygenase-1 and other heme-related genes some of which are known to be transcriptionally induced by heme. To test the hypothesis that heme regulates the activity of Bach1, we expressed wild-type and mutated versions of Bach1 together with or without its heterodimer partner MafK in human 293T and GMO2063 cells and examined their subcellular localization. Inhibition of heme synthesis enhanced the nuclear accumulation of Bach1 whereas treating cells with hemin resulted in nuclear exclusion of Bach1. While the cadmium-inducible nuclear export signal of Bach1 was dispensable for the heme response, a region containing two of the heme-binding motifs were found to be critical for the heme-induced nuclear exclusion. This region functioned as a heme-regulated nuclear export signal dependent on the exporter Crm1. These results extend the regulatory roles for heme in protein sorting, and suggest that Bach1 transduces metabolic activity into gene expression. By analyzing the proliferation of wild-type and Bach1-knockout smooth muscle cells (SMC) in vitro, we found that Bach1 is involved in the proliferation of SMC. We are currently searching for the down-stream, direct target gene of Bach1 in SMC and fibroblastic cells.
Evaluation of toxicities of porphyrin derivatives and its possible application

FUJITA Hiroyoshi, IGARASHI Kazuhiko, SHIBAHARA Shigeki, SATO Haruo, OGAWA Kazuhiro

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: Hokkaido University

2001 - 2003

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Evaluation of porphyrin derivatives on lives were carried out in the points of effects on cell differentiation as well as on transcription. We, evidenced that Bach1 is the first heme-controlled transcriptional factor in vertebrates. Bach1 is shown to be regulated heme oxygenase-1, which is one of the members of defense system against chemical hazards. Thus, it seems to be possible the evaluation of toxicity via Bach1. In addition, Bach1 also regulates erythroid cell differentiation through globin ge nes. The function of Bach1 can be exchanged by metalloporphyrins other than heme, suggesting some porphyrin derivatives could be applied as drugs to control differentiation.
核内オーファンプロテインネットワークの解明

田代聡, 五十嵐和彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業特定領域研究

Category: 特定領域研究

Institution: 広島大学

2002 - 2002

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1)GFP-RAD51融合タンパク質の過剰発現により可視化された領域は、ICD領域の一部であり、さらに遺伝子転写部位と密接な関連があることが明らかになった。さらに、特定の条件下でGFP-RAD51融合蛋白質が形成するフィラメントが破壊されることが明らかになったため、現在GFP-RAD51と結合し複合体を形成している蛋白質の解析を行っている。 2)ゲノム修復蛋白質動態の解析をより効率的に行うため、市販されている紫外線レーザーを装備した共焦点レーザー顕微鏡を用いて紫外線マイクロ照射法を新たに確立したので報告した。 3)間期核における染色邸領域配置を解析するための三次元マルチカラーFISH法を確立した。これと関連して、ヒト細胞において染色体の複製標識法を用いることにより、個々の染色体領域は細胞分裂時に再配置されることを明らかにしたので報告した。 3)転写抑制因子Bach2と転写部位の関連の検討を行った。その結果、酸化ストレス誘導後、SUMO化されたBach2が形成する核内フォーカスがPML bodyと位置的に密接な関連を示し、さらにPML body内の遺伝子転写が特異的に抑制されることを明らかにした。現在論文投稿中である。現在、Bach2フォーカスに共局在する蛋白質の解析と、リンパ球での内因性Bach2の局在の解析とを進めている。特定の転写因子による遺伝子発現調節と核高次構造の関連を明らかにした報告は国内外になく、ポストゲノムにおける核高次構造研究の重要性を示すことができたと考えられる。
Regulation of gene transcription and nuclear structure by architectural transcription factors

IGARASHI Kazuhiko, TASHIRO Satoshi

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: HIROSHIMA UNIVERSITY

2001 - 2002

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We found : 1. Binding of Bach1 to the globin LCR is regulated by heme, the prothetic group of hemoglobin. 2. Heme oxygenase-1 (HO-1) is another physiological target gene of Bach1. 3. Heme regulates binding of Bach1 to the LCR of HO-1 gene through direct binding to Bach1. The BTB domain of Bach1 is essential for the Bach1 binding to the HO-1 LCR. 4. Bach1 regulates HO-1 gene expression through mechanisms that are distinct from regulation of histone acetylation-deacetylation. 5. Bach2 accumulates within the PML nuclear bodies to repress gene expression there. 6. The BTB domain of Bach2 is essential for the targeting of Bach2 to PML bodies.
Cytogenetically analysis of congenital abnormality and childhood malignancy using multicolor FISH methods

TASHIRO Satoshi, IGARASHI Kazuhiko

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: HIROSHIMA UNIVERSITY

2001 - 2002

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We established Color banding FISH method for the precise cytogenetical analysis, and started collection of clinical sample in 2001. We are testing the ways to transfer clinical sample to Prof. Michael Speeches, a collaborator, for multicolor FISH analysis of these clinical samples in Munich. Clinical samples of childhood leukemia are provided from "Japan Association of Childhood Leukemia Study, J*****. To identify new genes associated with childhood leukemia by the new method combining color banding FISH method and conventional FISH method to detect a specific gene, we have done functional analysis of some candidate genes. Among them, we have revealed that BACH2, a B cell specific transcription regulator, showed induction of apoptosis upon oxidative stress. Furthermore, we also found that Bach2 is expressed not only in B cell but also in brain. We have established a method to study the dynamics of chromosome in living cell to study the mechanism of chromosome translocation with Prof. Thomas Cremer, a Collaborator in Munich, and study the dynamics of chromosome territories using method.
核内オーファンプロテインネットワークの解明

田代聡, 五十嵐和彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業特定領域研究(C)

Category: 特定領域研究(C)

Institution: 広島大学

2001 - 2001

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1)GFP-RAD51融合タンパク質の過剰発現により可視化されたICD領域と遺伝子転写部位、複製部位の可視化を行った。その結果、転写部位はICD領域と密接な関連があることが明らかとなった。また、転写部位、複製部位の核内分布には一定の法則があることが示唆されたため、現在海外共同研究者とともにシミュレーションモデルとの比較による検討を行っている。 2)紫外線マイクロ照射法および通常のX線照射によるゲノム損傷誘導後のゲノム修復関連タンパク質Rad51およびMre11とssDNA形成部位の空間的、時間的関連を解析により、ゲノム損傷部位ではまずMre11ついでRad51の集積が認められることを明らかにした。また、これらのタンパク質複合体は様々なパターンでssDNA形成部位と共局在を示し、ゲノム修復の多様性が示唆された。現在論文投稿準備中である。また、RAD54Bがヒト細胞においてゲノム修復に関わらないゲノム相同組換えに重要であることを明らかにした。 3)転写抑制因子Bach2と転写部位の関連の検討を行った。その結果、酸化ストレス誘導後、Bach2が形成する核内フォーカスがPML bodyと密接な関連を示し、さらにPML body内の遺伝子転写が特異的に抑制されることを明らかにした。現在論文投稿準備中である。特定の転写因子による遺伝子発現調節と核高次構造の関連を明らかにした報告は国内外になく、ポストゲノムにおける核高次構造研究の重要性を示すことができたと考えられる。
転写調節による造血分化制御

仲野徹, 田中信之, 平井久丸, 山本雅之, 五十嵐和彦, 小守寿文, 北村幸彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業特定領域研究(A)

Category: 特定領域研究(A)

Institution: 大阪大学

1998 - 2001

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マウス胚性幹細胞から血液細胞への分化誘導法と、テトラサイクリンによるコンデイショナル遺伝子発現系を組み合わせて、GATA-2の機能解析をおこなった。その結果、GATA-2は未分化な造血前駆細胞の増殖を亢進させること、また赤血球・巨核球への分化を促進することがあきらかになった。また、GATA-1の機能ドメインを解析するために、GATA-1ノックダウンマウスの致死性をGATA-1遺伝子の発現制御領域制御下に種々のGATA-1変異体を発現するトランスジェニックマウスにより相補する実験をおこなった。その結果、Cフィンガー,Nフィンガーは両方とも個体レベルでのGATA-1機能に必須であることがあきらかになった。 mi遺伝子座がコードするbasic-helix-loop-helix leucine zipper型転写因子(MITF)はbasic domainの1アミノ酸の異常では抑制性の機能をもつのに対し、大半のアミノ酸を欠損することであらゆる機能を失った。また、MITFと結合するタンパク質としてzinc finger domainをもつMAZRを単離した。MAZRはマスト細胞で高発現しているプロテアーゼ遺伝子の転写活性をMITFと相乗的に高めていた。また、骨芽細胞分化、破骨細胞分化、骨形成におけるCbfa1の機能およびB細胞分化におけるBach1の機能を明らかにした。 AML1の成体における機能を明らかにするため、AML1のコンディショナル・ノックアウトマウスを作製し、T細胞特異的AML1欠損マウスおよびB細胞特異的AML1欠損マウスの解析を行った。T細胞特異的AML1欠損マウスは著しい胸腺低形成を示し、CD4,8陰性(DN)分画内ではCD25陽性CD44陰性(DN3)分画に細胞が蓄積し、それ以降の分化が抑制されていた。また、B細胞特異的AML1欠損マウスにおいてもB細胞の分化障害を認めた。以上のように、種々の血液細胞系列における転写因子の機能を明らかにすることができた。
Regulation of chromatin structures and hematopoietic cell differentiation by architectural transcription factors Bach1 and Bach2

IGARASHI Kazuhiko

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: HIROSHIMA UNIVERSITY

2000 - 2000

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This study focused on the function of transcription factors Bach1 and Bach2 in regulation of chromatin structures at the molecular levels as well as their roles in hematopoietic cell differentiation. They possess the BTB/POZ domain that has been implicated in regulation of chromatin structures. To understand the biochemical basis for the BTB/POZ domain function, we searched for proteins that interact with the Bach1 BTB/POZ domain by yeast two hybrid sereening. Isolated candidates include a protein that regulates actin structure, transcritional coregulators, and structural proteins. In addition, we found that Bach2 regulates oxidative stress-induced cell death. Thus, further analysis of the interactions may pave a way to understand functional link among regulation of transcription, chromatin structures, and cell differentiation.
Regulation of chromatin structures during hematopoietic cell differentiation

IGARASHI Kazuhiko, KOBAYASHI Akira

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: HIROSHIMA UNIVERSITY

2000 - 2000

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This study focused on the tissu-and cell lineage-specific regulation of chromatin structures in hematopoietic cells. There are several transcription factors that bind to the locus control region of hematopoietic-specific genes. To understand their roles, we generated mutant mice lacking the transcription factor genes bach1 or bach2. Further analysis of the phenotypic changes of these mice may pave a way to understand functional link among regulation of transcription, chromatin structures, and cell differentiation. Along these experiments, we also screened for proteins that interact with Bach1 or Bach2 using yeast two hybrid screen. Isolated candidates include proteins that regulate actin structure, transcritional co-regulators, and structural proteins, suggesting their implication in regulation of chromatin structures.
BTB型転写因子によるクロマチン構造と核内構造の共役

五十嵐和彦, 西藤泰昌, 田邉修

Offer Organization: 日本学術振興会

System: 科学研究費助成事業特定領域研究(A)

Category: 特定領域研究(A)

Institution: 広島大学

2000 - 2000

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BachとMAZRは、BTB/POZドメインを持つLCR(locus Control Region)結合因子群である。そこでBTB/POZドメインにより形成される核内構造体の構成因子を明らかにすることにより、このドメインを有する一群の転写因子の作用機構を明らかにすることをめざした。 1.Bach2とMAZRはそれぞれのBTBドメインを介して多量体を形成する。Bach2は単独では転写抑制因子として作用するのに対して、Bach2/MAZRの複合体はプロモーターコンテクストに依存して転写活性化を示すことが明らかになった。 2.Bach1のBTBドメインを含む断片をベイトとしてtwo hybrid screeningを行い、その結合因子の同定を試みた。現在までにBach1自身に加え、細胞骨格関連因子がいくつか単離された。一方、我々はノックアウトマウスの作成も平行して進めており、今後さらにこの研究を遂行することにより、転写制御、核内構造、そして細胞機能の制御を結びつけて理解することが可能になると期待される。
核内オーファンプロテインネットワークの解明

五十嵐和彦, 西藤泰昌

Offer Organization: 日本学術振興会

System: 科学研究費助成事業特定領域研究(C)

Category: 特定領域研究(C)

Institution: 広島大学

2000 - 2000

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ゲノムプロジェクトは、数多くの機能未知の蛋白質(オーファンプロテイン)の存在を明らかにしつつある。一方、核では複製、修復、転写などの素反応が特定の部位で生じることも明らかになりつつある。そこで本研究では、核内で特徴的な分布を示すオーファンプロテインに着目し、その分布と核内反応部位との関連、そして結合因子を同定することにより、核における新しい蛋白質ネットワークを同定することを目指した。 1.核内の機能部位とオーファンプロテインの相互関係を明らかにするために、修復部位をRad51抗体染色、DNA複製部位をCy3-dUTPパルス標識、RNA合成部位をBrUTPパルス標識で同時に検出するシステムを構築した。このシステムをオーファンプロテイン-EGFP融合因子発現細胞に用いることにより、核内素反応とオーファンプロテインの局在との関連を検討できるものと期待できる。 2.いくつかのBTB/POZ因子に関してEGFP融合蛋白質を発現させ、そのドットと機能部位の関連を検討した。その結果、うち一つに関しては転写部位と一致する分布を示すことが明らかになった。
Bachファミリーによる細胞の増殖と死の制御

五十嵐和彦, 西藤泰昌, 田邉修

Offer Organization: 日本学術振興会

System: 科学研究費助成事業特定領域研究(C)

Category: 特定領域研究(C)

Institution: 広島大学

2000 - 2000

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Bach1およびBach2はMafファミリーとヘテロ二量体を形成し、転写抑制因子として作用する。本研究では、Bach1ならびにBach2がAP-1系の抑制因子として担う生理機能を明らかにすること、そしてその異常が癌化に関わる可能性を検討した。まず、Bach1ならびにBach2が細胞増殖等におよぼす影響を、レトロウィルスを用いた過剰発現系にて検討した。その結果、Bach2はジエチルマレイン酸などの酸化ストレス刺激に応答して核へ集積し、アポトーシスを誘導することを見いだした。したがって、Bach2はストレス応答の経路でpro-apoptotic geneとして作用すると考えられる。一方、Bach1はBach2と同様の機能モチーフを持つにも関わらず、細胞死の誘導活性は認めらなかった。Bachは癌関連因子で見い出されるBTB/POZドメインを有することが特徴であるが、このドメインはBach2の細胞死誘導活性に必須であった。そこでBach2のBTB領域と結合する因子を検索したところ、新規BTB-Znフィンガー型転写因子MAZRを発見した。MAZRはEwing sarcomaでEWSと相互転座をしている例が報告されたことから、癌化への直接的な関与が示唆された。
Nucleosome Structure-Function Relationship : Analyses by using atomic force microscopy

TAKEYASU Kunio, KAZUHIKO Igarashi, GOTO Koji, SATO Masahiko

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: KYOTO UNIVERSITY

1998 - 2000

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We have previously developed the analytical techniques of atomic force microscopy (AFM) for the study of interaction between DNA and DNA-binding proteins. Here we further extended the AFM application to the higher-order structures of DNA/protein complexes. (1) The DNase I-hyper-sensitive sites (HS2-HS4) in the β-globin gene enhancer region (locus control region ; LCR) were found to form a looped-DNA structure as the target of Bach1/MafK heterodimers. Further detailed analyses of the loop formation proposed a novel 'kiss and pull' model for the enhancer/protein interaction : the Bach1/MafK heterodimer preferentially binds to HS2 with highest affinity and to HS3 with lower affinity, resulting in a stay and leave at the HS2 and HS3 sites, respectively, by forming a stable complex of 4 heterodimers (J.Electron Microscopy, 49 : 407-413). (2) The resolutions of AFM have been limited to an inherent property of the technique ; tip effect associated with a large radius of the scanning probe. To overcome this problem, we developed a carbon nanotube probe by attaching a carbon nanotube to a conventional scanning probe under a well-controlled process. Because of the constant and small radius of the tip (2.5-10nm) and the high aspect ratio (1 : 100) of carbon nanotube, the lateral resolutions have been much improved, and enabled us to clearly visualize the subunit organization of multi-subunit proteins (J.Electron Microscopy, 49 : 415-421 ; Proc.Nat'l Acad.Sci.USA, 97 : 14127-14132). (3) DNA supercoiling is known to play an important role in a variety of cellular events, such as transcription, replication and recombination. When a replication initiator protein, RepE54, binds to the specific sequences (iterons) of the negatively supercoiled mini-F plasmid, it induces a dynamic structural transition of the plasmid to a relaxed state without a DNA strand beak, a local melting, nor a DNA wrapping. These data indicate that a local strain imposed by initiator binding can induce a drastic shift of the DNA conformation from a supercoiled to a relaxed state (Biochemistry, 39 : 9139-9145). (4) To address the question of how nuclear histones and DNA interact and form a nucleosome structure, an in vitro reconstituted chromatin system was established in which AFM can be applied to the visualization of a "beads-on-a-string" structure with each nucleosome trapping 150 bp DNA and constant spacing. An addition of histone H1 to the system resulted in a tight compaction of the dinucleosomal structure (FEBS lett., ). A Substitution of H3 for a centromere specific protein CENP-A resulted in the formation of centromere-specific nucleosomes with a well-known beads-on-a-string structure consisted of only about 110bp DNA.Moreover, the volume of centromere-specific nucleosome was significantly smaller (15%) than that of control nucleosome (Proc.Nat'l Acad.Sci.USA, 97 : 7266-7271).
REGULATION OF CELL PROLIFERATION BY CROSS-TALK OF BACH AND AP-1 TRANSCRIPTION FACTORS.

IGARASHI Kazuhiko

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Priority Areas (A)

Category: Grant-in-Aid for Scientific Research on Priority Areas (A)

Institution: HIROSHIMA UNIVERSITY

1999 - 1999

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The mammalian transcription activator Nrf2 plays critical roles in executing oxidative stress response by binding to the regulatory DNA sequence MARE (Maf recognition element). Bach2 is an Nrf2-related transcription repressor and a tissue-specific partner of the Maf oncoprotein family. We show here how Bach2 is regulated by an oxidative stress-sensitive conditional nuclear export. In cultured cells, Bach2 was localized in cytoplasm through its C-terminal evolutionarily conserved cytoplasmic localization signal (CLS). The CLS directed leptomycin B-sensitive nuclear export of reporter proteins, suggesting its dependence on the nuclear exporter Crml/Exportinl. However, the CLS sequence does not bear resemblance to the leucine-rich class of nuclear export signal, and mutagenesis analysis indicated that a stretch of non-hydrophobic amino acids are essential for its activity. Oxidative stressors aborted the CLS activity and induced nuclear accumulation of Bach2. Whereas oxidative stress is known to activate MARE-dependent transcription, overexpression of Bach2 in cultured cells silenced the inducibility of MARE.The results suggest that Bach2 mediates nucleocytoplasmic communication to couple oxidative stress and transcription repression in mammalian cells.
NF-E2関連因子群によるクロマチン構造の制御と造血細胞分化における転写制御機構

小林聡, 五十嵐和彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業特定領域研究(A)

Category: 特定領域研究(A)

Institution: 東北大学

1999 - 1999

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我々が単離したNF-E2関連因子Nrt3,Bach1,Bach2は、発現様式と機能的類似性から、NF-E2と同様に造血細胞分化過程おいて重要な機能を担う転写因子であると予想される。またNF-E2結合配列はβグロビン遺伝子やIgH遺伝子などのLCR(Locus control region)中に存在していることから、NF-E2関連因子がLCRの特徴の一つであるクロマチン構造の制御をもたらしているとも考えられる。そこで本研究ではこれら因子から造血細胞分化とクロマチン構造制御機構の解明を目指し、以下の3点を明らかにした。 (1)新たなNF-E2関連因子Nrf3を単離し、分子進化上一つの共通祖先遺伝子からchromosome duplicationなどにより4つの関連因子に派生した可能性を明らかにした。 (2)Bach2の細胞内局在は、核移行と核外排出機構により拮抗的に制御され、最終的に細胞質に局在していること、そして酸化ストレスにより核に集積することを明らかにした。 (3)Bach2のBTBドメインに結合する因子MAZR(MAZ-related factor)を単離し、造血発生過程においてBach因子と協調的に構造転写因子として機能している可能性を明らかにした。
造血細胞分化におけるNF-E2関連因子群の機能

小林聡, 五十嵐和彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業特定領域研究(A)

Category: 特定領域研究(A)

Institution: 東北大学

1999 - 1999

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我々が単離したNF-E2関連因子Nrf3,Bach1,Bach2は、発現様式と機能的類似性から、NF-E2と同様に造血細胞分化過程おいて重要な機能を担う転写因子であると予想される。またNF-E2結合配列はβグロビン遺伝子やIgH遺伝子などのLCR(Locus control region)中に存在していることから、NF-E2関連因子がLCRの特徴の一つであるクロマチン構造の制御をもたらしているとも考えられる。そこで本研究ではこれら因子から造血細胞分化とクロマチン構造制御機構の解明を目指し、以下の3点を明らかにした。 (1)新たなNF-E2関連因子Nrf3を単離し、分子進化上一つの共通祖先遺伝子からchromosome duplicationなどにより4つの関連因子に派生した可能性を明らかにした。 (2)Bach2の細胞内局在は、核移行と核外排出機構により拮抗的に制御され、最終的に細胞質に局在していること、そして酸化ストレスにより核に集積することを明らかにした。 (3)Bach2のBTBドメインに結合する因子MAZR(MAZ-related factor)を単離し、造血発生過程においてBach因子と協調的に構造転写因子として機能している可能性を明らかにした。
Roles of heme in the regulation of gene expression and cell differentiation of erythroid cells

HAYASHI Norio, IGARASHI Kazuhiko, KOBAYASHI Akira

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

1998 - 1999

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The purpose of this study is to understand the regulatory mechanisms of gene expression promoting erythroid cell differentiation. We examined the gene regulatory mechanisms of coproporphyrinogen (CPO) gene using reporter assays in cultured cells. The CPO gene is specifically active in erythroid cells but not in non-erythroid cells. We identified a novel motif CPRE, which appeared to be important for the differential expression of the gene. We also examined the function of Nrf3 and Bach1, which are members of the CNC transcription factor family. Among the members of this family, NF-E2 p45 is considered as a key transcription factor for erythroid differentiation. Molecular dissection of Nrf3 revealed a novel motif interacting with caspase 9. Biochemical analysis revealed that Bach1 associates with heme. Heme-bound Bach1 lost its DNA binding ability, suggesting that repressor activity of Bach1 is abrogated by heme. Consistently, Bach1-null mice displayed constitutive activation of heme-oxygenase 1 gene, which is a candidate target gene of Bach1. Thus, these data support the contention that Bach1 is a sensor of heme concentration and translates the heme abundance into the gene expression.
BachファミリーとAP-1のクロストークによる細胞増殖・分化の調節機構

五十嵐和彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業特定領域研究(A)

Category: 特定領域研究(A)

Institution: 東北大学

1998 - 1998

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細胞の分化と癌化を理解するためには、遺伝子発現の調節機構とその異常を分子レベルで明らかにすることが必須となる。本研究は、Maf因子群とBach因子群による遺伝子発現と細胞分化の制御機構、およびその失調と癌化の関連を解明することを目的とした。Bachファミリーは、CNC因子群に特徴的なbZipを有し、さらに、リンパ腫や前骨髄性白血病に伴う染色体転座部位に存在するLAZ3/BCL6、PLZF転写因子とホモロジーを示す領域(BTB ドメイン)を有する。そこで、特にBachの分子レベルでの機能とその制御機構に関して研究を進め、以下の興味深い知見を得ることができた。(1)Bach2の細胞内局在が、核移行シグナルならびに核くみ出しシグナルにより制御されること、そしてこの核からのくみ出しは酸化ストレスなどにより特異的に制御されることを見いだした。(2)エンハンサーやサイレンサーとプロモータとが相互作用する過程では、DNAのループ構造が形成されると考えられる。原子間力顕微鏡を用いた解析から、Bach1はそのBTBドメインの作用によりDNAループを形成する転写因子であることを明らかにした。BTBドメインを有する癌関連転写因子はDNAループ形成を担う因子として作用すること、そしてこのようなDNAループ形成反応の異常が癌化に関わることが考えられる。(3)Bach1やBach2のBTB領域に特異的に結合する新規BTBドメイン転写囚子FOBを発見し、この因子がc-mycプロモーターの強い活性化因子として作用することを見いだした。
グロビン遺伝子LCR結合因子によるクロマチン構造調節機構の解析

五十嵐和彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業特定領域研究(A)

Category: 特定領域研究(A)

Institution: 東北大学

1998 - 1998

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グロビン遺伝子のLCRは、染色体構造を赤血球特異的に活性化するという点でユニークな調節領域であり、クロマチン構造と転写調節の共役を解析する上で格好のモデルとなる。LCRにはMafなどの転写因子の結合配列が高頻度で存在する。前年度までの研究により見いだされた転写因子Bachファミリーは、Mafとヘテロ二量体を形成しLCRに結合する。本研究では、LCRの機能発現におけるBachファミリーの役割を細胞レベルならびに個体レベルで明らかにするとともに、その機能機構を生化学的に解明することを目的とした。Bachは、クロマチン構造への関与が考えられるGAGA因子など一連の転写因子と共通の構造(BTB/POZ領域)を有する点に特色があることから、BTBドメインの役割に特に注目して解析を行い、以下の成果を上げることができた。 (1)Bach1はそのBTB領域を介して多量体を形成する。このような多量体とLCR DNAとの相互作用の結果作り出される複合体を、原子間力顕微鏡(AFM)を用いて定量的に可視化することに成功した。(2)相同遺伝子組換え法を用いてBach1ならびにBach2遺伝子を欠損するマウスを作成することを試み、Bach1に関してはヘテロ変異マウスを得ることに成功した。(3)BTB領域に相互作用する蛋白質cDNAを、酵母中での蛋白質相互作用を利用して検索し、新規BTB因子Fob(Friend of Bach)を見いだした。(4)抗体重鎖遺伝子(IgH)のLCRに結合するB細胞特異的因子が、Bach2であることを見いだした。
NF-E2結合配列を介した転写調節機構とその血液細胞分化における役割

小林聡, 五十嵐和彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業特定領域研究(A)

Category: 特定領域研究(A)

Institution: 東北大学

1998 - 1998

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血球細胞特異的な転写因子NF-E2の関連因子として、Bach1,Bach2,Nrf3を単離した。その発現様式と構造的相似性から、これら因子も造血細胞発生過程において機能することが示唆される。現在までに以下の知見を得た。 1 抗体重鎖(IgH)遺伝子のLCR(Locus Control Region)に、複数のMAREを見出した。そのMAREに対し、Bach2は最終分化前のB細胞に発現する転写抑制因子である(EMBO J.(1998)17,5734-43)。一方、Nrf3はB細胞分化の後期に発現する転写活性化因子であることを見出した(J.Biol.Chem.(1999)印刷中)。したがって、Bach2とNrf3とが細胞分化段階に応じて拮抗的にIgH遺伝子発現の調節を行っている可能性が考えられた。 2 BTBドメインは、クロマチン構造の制御や蛋白質間相互作用そして転写抑制に関わることが知られている。そこで、Bach2のBTBドメインと結合する因子を酵母two hybrid systemにより検索したところ、新たなBTB転写因子FOB(Friend of Bach)を単離することができた。その発現は胸腺、胎児肝、骨髄で著しいが、特にBach2と同様に幼弱なpro-B、pre-B細胞で高く発現していた。このことは、IgH鎖遺伝子の発現抑制において、Bach2とFOBが協調的に機能している可能性を示した。今後の方針としては、現在進行中のNrf3、FOB、Bach2ノックアウトマウスの解析を完了する。またBach1については予備的解析を行ったところ、造血細胞分化調節に関与することが示唆された。
GENETIC CONTROL OF HEMATOPOIETIC CELL DOFFERENTIATION

IGARASHI Kazuhiko, PATIENT Roger, ENGEL J.Douglas, YAMAMOTO Masayuki

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research Grant-in-Aid for international Scientific Research

Category: Grant-in-Aid for international Scientific Research

1997 - 1998

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Hematopoiesis is a good model system for analyzing regulation of cell differentiation. Using this system, we tried to identify transcription factors that regulate cell differentiation. We analyzed function of NF-E2 and related factors, and accumulated novel as well as unexpected results. These findings should lead to understanding of molecular and genetic regulation of hematopoiesis. (1) To identify novel NF-E2-related transcription factors, we carried out further homology screening. As a result, we succeeded in identifying sixth member of the NF-E2-related factors which we named Nrf3. Its expression profile suggested that Nrf3 may regulate differentiation of hematopoietic cell differentiation. We are now carrying out gene disruption experiment using mice system, together with Prof.Engel. (2) By making nrf2-knockout mice and analyzing its phenotypic changes, we revealed that Nrf2 is a key essentail regulator of phase II de-toxifying system expression. (3) The BTB domain of Bach1 and Bach2 appears to be involved in regulation of chromatin structure. Using atomic force microscopy, we revealed that Bach1, and possible Bach2, function as a novel type of architectural transcription factor that mediate DNA loop formation. As such, Bach1 may be involved in regulation of the globin gene locus control region.
血球系転写因子NF−E2の活性調節機構の解析

永井正, 五十嵐和彦

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

1997 - 1998

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マウス赤白血病細胞を用いた解析から、p45のN末端側83アミノ酸の領域内に転写活性化ドメインが存在することが明らかになった。そこで、本年度はこのドメインと直接結合しうる補助転写活性化因子の単離をYeast Two Hybridシステムを用いて試みた。まず、スクリーニングに際し標的として用いる領域を決定するため、p45のN末端側83アミノ酸の領域を1-83、1-36および39-83の各アミノ酸領域に分割し、それぞれとpGBT9プラスミドとの融合コンストラクトを作製した。それぞれの融合コンストラクトを酵母HF7cに遺伝子導入したところ、1-36アミノ酸領域を導入した場合のみヒスチジン(-)選択培地上で全くコロニー形成能を示さなかった。この結果から、1-36アミノ酸領域がスクリーニングの標的として最も適していると結論された。そこで次に、1-36アミノ酸領域とpGBT9との融合コンストラクトで形質転換された酵母HF7cを、マウス17日目杯由来cDNAライブラリーでさらに形質転換し、ヒスチジン要求性を指標に相互作用因子のスクリーニングを行った。第1回目のスクリーニングでは標的領域と結合しうる因子を最終的に得ることができなかったため、引き続き二回目のスクリーニングを行った。その結果、当初21個のコロニーがヒスチジン(-)選択培地より単離されたが、LacZ活性などを指標に陽性コロニーを数個まで絞り、現在それぞれのクローンについて塩基配列を決定している。今後は、得られた塩基配列を基に補助転写活性化因子としての可能性が高いと考えられるのを選択し、哺乳類の培養細胞を用いて標的領域との相互作用について確認する予定でいる。
REGULATION OF DIFFERENTIATION BY BACH TRANSCRIPTION FACTORS

IGARASHI Kazuhiko

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)

1997 - 1998

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To understand molecular regulation of cell differentiation, it is essential to reveal regulation of transcription in these processes. Bachi and Bach2 are closely related transcription factors that bind to DNA by forming heterodimers with Maf family of transcription factors. During the past two years supported by this grant, we accumulated results that suggested that Bachi and Bach2 are involved in regulation of hematopoiesis, and that they function as a novel type of architectural transcription fadors. (1) The BTB domain of Bach1 and Bach2 appears to be involved in regulation of chromatin structure. Using atomic force microscopy, we revealed that Bach1, and possible Bach2, fundion as a novel type of architectural transcription factor that mediate DNA loop formation. As such, Bach1 may be involved in regulation of the globin gene locus control region. (2) Expression of Bach2 is specific to B cells among hematopoietic cells. Its expression is high during early stages and down regulated upon maturation to plasmacytes. Bach2 represses 3' enhancer of the immunoglobulin heavy chain gene. Thus Bach2 appears to regulate stage-specific gene expression during B cell differentiation. (3) Using yeast two hybrid screen, we isolated a novel transcription factor, FOB (friend of Bach), as aprotein that binds to the BTB domain of Bach. FOB carries the BTB domain as well as a C2H2-typeZn fingers. Expression profile of FOB suggested that it is a partner of Bach1 and/or Bach2 inhematopoietic cells.
新しい転写因子Bachファミリーと小Maf による細胞増殖分化の調節機構の解析

五十嵐和彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業重点領域研究

Category: 重点領域研究

Institution: 筑波大学

1997 - 1997

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本研究は小Maf因子群とBach因子群による遺伝子発現と細胞分化の制御機構、およびその失調と癌化の関連を解明することを目的とし、本年度は以下の成果を得た。 1.Bach1は血液細胞分化のごく初期から発現する転写因子である。また、赤白血病(MEL)細胞において小Maf因子はBach1とのヘテロニ量体としてDNAに結合する。 2.Bach2は神経細胞およびB細胞において細胞系列および分化段階特異的に発現する。いずれの細胞系列においても、小Maf因子はBach2とのヘテロニ量体として機能する。 3.Bach1やBach2のBTB領域に特異的に結合するロイシンジッパー型新規蛋白質やBTBドメインを有する転写因子を発見した。本研究により、赤血球系細胞、B細胞、そして成熟神経細胞においてBach1あるいはBach2と小Mafとのヘテロニ量体が主要なAP-1様活性を形成することが明らかになった。Bach2が分裂停止した成熟神経細胞で特異的に発現することは、この因子が細胞周期の調節に関与することを示唆する。昨年度の研究からBachファミリーは転写抑制因子として機能することが明らかになっていることから、小MafとBachにより形成されるAP-1様活性は、AP-1系においてユニークな機能を担うことが予想される。今後は、このようなAP-1様活性の細胞分化における機能を明らかにすることが重要となる。
グロビン遺伝子LCR結合因子によるクロマチン構造調節機構の解析

五十嵐和彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業重点領域研究

Category: 重点領域研究

Institution: 筑波大学

1997 - 1997

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NF-E2関連転写因子Bachファミリーは、クロマチン構造に影響することが知られている特徴的構造(BTB領域)を有することから、この因子群はクロマチン構造を介して遺伝子発現調節を行う可能性が考えられる。本年度はこのBachファミリーの構造と機能の解析を進め、以下の知見を得た。 1)胚性幹細胞(ES細胞)を特殊な支持細胞上で培養することにより、効率よく赤血球分化を誘導することができる。この系を用いて赤血球分化過程におけるBach1の発現を解析したところ、ES細胞ではBach1の発現を全く認められないのに対して、分化を誘導することにより血液細胞マーカーの発現に先行してBach1の発現が強く誘導されることが明らかになった。この結果は、LCR領域のクロマチン構造は血液細胞分化の初期段階から既に活性化されているという報告と考え合わせると、非常に興味深い。 2)赤芽球抽出液を用いて、LCR中のNF-E2結合配列に対する結合活性をゲルシフト法を用いて検討した。その結果、赤芽球中にはNF-E2p45と小Mafのヘテロ二量体に加えて、Bach1と小Mafの二量体が存在することが明らかになった。このことは、Bach1がLCRの作用因子であることを強く示唆する。 3)昨年度の研究から、Bach1/MafKヘテロ二量体はBachのBTB領域を介した相互作用によりさらに多量体化することが示された。そこで、原子間力顕微鏡を用いて組み換えBach1とLCRDNAとの相互作用の可視化を試みた。ヒトLCRの12kbDNAとBach1、そしてMafKを反応させたところ、Bach1は多量体を形成して複数のDNA配列に同時に結合し、ループ状のDNA・蛋白質複合体を作り出すことが観察された。この結果から、Bach1はLCR領域の調節複合体の骨格の形成を仲介する因子である可能性が考えられる。
小Maf因子群とCNC転写因子群とによる細胞増殖分化の調節機構の解析

五十嵐和彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業重点領域研究

Category: 重点領域研究

Institution: 筑波大学

1996 - 1996

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我々は昨年度の研究から、小Mafと会合する新規bZip型転写因子Bachファミリー(Bach1,Bach2)を発見した。小Maf因子群による遺伝子発現と細胞分化の制御機構に関してさらに理解を深めるために、本年度はBachファミリーの解析を行い、以下の知見を得た。 1.cDNA構造を解析した結果、Bachファミリーは、CNC因子群に特徴的なbZipに加え、BTBドメインを有することが明らかになった。BTBドメインは、リンパ腫や前骨髄性白血病に伴う染色体転座部位に存在するLAZ3/BCL6、PLZF転写因子、そしてショウジョウバエの発生過程で重要な役割を担う一群の転写因子(GAGA因子やBroad complex、tramtrackなど)に見いだされる。 2.Bachファミリーは、MafKのみならずc-Maf、Jun、Fosなどとも二量体を形成する。これらのヘテロ二量体はAP-1結合配列(TRE)に類似したDNA配列に結合する。BachファミリーはTREに作用して転写抑制因子として機能する。Bach2の発現、およびDNA結合活性は、Jun、Fosなどとは対照的に細胞増殖刺激に依存せずに構成的に認められる。 3.BachファミリーのBTB領域は、bZip領域とは独立に4量体以上の多量体の形成を担う。このことは、bZip領域を介して形成される二量体がさらにBTB領域を介して多量体化すること、そして、Bachが他の癌関連BTB因子との高次複合体を形成する可能性を示唆する。
グロビン遺伝子LCRの結合因子によるクロマチン構造調節機構の解析

五十嵐和彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業重点領域研究

Category: 重点領域研究

Institution: 筑波大学

1996 - 1996

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本研究は、LCRの機能発現における転写因子群(NF-E2、Bach、ECH/Nrf2)の役割を明らかにすることを目的とする。昨年度の研究で発見した新しいNF-E2関連転写因子Bachファミリーは、クロマチン構造に影響することが知られている特徴的構造(BTB領域)を有することから、この因子群はクロマチン構造を介して遺伝子発現調節を行う可能性が考えられる。本年度はこのBachファミリー構造と機能の解析を進め、以下の知見を得た。 1)Bach1は造血幹細胞を含む血液細胞で高い発現を示す。この結果は、LCR領域のクロマチン構造は幹細胞の段階から既に活性化されているという報告と考え会わせると、非常に興味深い。 2)Bach1のBTB領域はホモフィリックな結合を行うことを明らかにした。また、ゲルシフト法や共沈降法を用いた実験により、Bach1/MafKヘテロ二量体はBach1のBTB領域を介した相互作用によりさらに多量体化することが示された。一方、Bachの細胞内局在を一過性過剰発現の系を用いて解析したところ、BTB領域に依存して核内で斑点状の分布を示すことが明らかになった。このようなBTB領域に由来するBachファミリーのユニークな活性は、LCR凝集体形成過程に関与する可能性が考えられた。
新しい赤血球転写因子ECHによる転写制御機構の解析

五十嵐和彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業奨励研究(A)

Category: 奨励研究(A)

Institution: 筑波大学

1996 - 1996

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昨年度に引き続き、ECHのドメイン構造の解析を行い、さらに各ドメインに相互作用する因子を酵母two hybrid法を用いて検索した。その結果、以下の知見を得ることができた。 1)転写活性化領域の同定:ECHの内部に二カ所、転写活性化に必須の領域を同定した。このうち一カ所は直接転写活性化に関与するのに対して、もう一カ所は補助的に作用することが考えられた。 2)活性調節領域の同定:昨年度の研究から、ECHのN末端領域はECHの機能を負に制御することを見い出していた。この領域の機能をさらに詳しく解析した結果、この領域は他の因子と会合することによりECHの機能を制御することを発見した。さらに、two hybrid法を用いてこの領域に結合すると考えられる新しい蛋白質をいくつか同定した。 3)bZip領域に相互作用する因子の同定:昨年度までの研究から、ECHは小Maf群因子と二量体を形成し機能することが明らかとなっている。この二量体ネットワークの全体像を明らかにするために、two hybrid法を用いてbZip領域に結合する因子を系統的に検索した。その結果、小Mafに加えATF4を新しい二量体形成のパートナーとして同定できた。
転写因子群による赤血球特異的な遺伝子発現制御機序の解析

山本雅之, 五十嵐和彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業重点領域研究

Category: 重点領域研究

Institution: 筑波大学

1995 - 1995

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これまでに,GATA配列およびNF-E2結合配列に結合する転写因子群が遺伝子発現の赤血球特異性に重要な貢献を果していることが強く示唆されている.本研究ではこれらの転写因子の発現と機能を以下の三つの観点から検討した. GATA因子群やNF-E2を発現するプラスミドを赤血球系形質を持った培養細胞株に遺伝子導入し,これらの因子を誘導的に過剰発現した際の細胞の表現形質や分化能の変化を検討した.NF-E2の小サブユニットであるMafKをマウス赤白血病(MEL)細胞に過剰発現したところ,同細胞は他の誘導剤の存在の有無に関わらず赤血球に分化した.このことから,MafKは実際に血液細胞の分化に働く転写因子であることが理解される.また,GATA因子群のうちGATA-1とGATA-2をコードする遺伝子の転写制御解析を進めた.GATA-1の精巣型プロモーターには二つのGATA配列が存在し,それらは実際に転写活性化シグナルを媒介することができる配列であった.一方、赤血球型プロモーターの機能をトランスジェニックマウス系を用いて検討したところ,同プロモーターと上流域2.9kbはin vivoで胎児型赤血球特異的な転写活性化を指示することが可能であることが明らかになった.さらに,MafK遺伝子の構造と機能を行い,MafK遺伝子には中胚葉特異的なプロモーター/第一エキソンと神経細胞特異的なそれとが存在することを見出した.マウスGATA-1抗体N6はPFA固定した組織切片中のGATA-1を免疫染色できることから,MEL細胞より核を単離し,PFA固定後N6抗体で免疫沈降する方法でGATA-1の標的遺伝子の単離・同定が可能である.そこで,本方法を用いてGATA-1遺伝子の調節領域にGATA-1自身が結合していることを証明した.
赤血球系転写因子群とMaf関連蛋白質による赤血球分化の制御とその異常の解析

五十嵐和彦, 山本雅之

Offer Organization: 日本学術振興会

System: 科学研究費助成事業重点領域研究

Category: 重点領域研究

Institution: 東北大学

1995 - 1995

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血球系転写活性化因子NF-E2は血球系特異的に発現するp45 NF-E2とより広範な細胞系列で発現する小Maf群因子(MafF,MafG,MafK)とのヘテロ二量体である。本研究は、NF-E2の血球分化調節とその異常である白血病化への関与を明らかにすることを目的とする。本年度はNF-E2サブユニットとその関連転写因子群の機能と機能機構の解析を行い、以下の成果を得た。 1.MafKは他の因子と相互作用することにより積極的に転写を抑制する活性をも有すること、そしてこの活性は二量体組成に依存して抑圧されることを見い出した。 2.昨年度の研究により発見したNF-E2関連転写因子ECHの解析を特に構造機能相関に重点をおいて進めた結果、この因子は非常に強い転写活性化ドメインを有すること、そしてその転写活性化能は他の因子との結合により負に制御されることが明らかになった。この相互作用の解析から、蛋白質間相互作用を司る新しいモチーフが発見された。 3.MafKと会合する因子の検索を酵母中でのtwo hybrid systemを用いて行い、新しいbZip型転写因子遺伝子群を発見した。この遺伝子群は、MafKなど小Maf因子群の機能制御に重要な役割を担う可能性がある。
グロビン遺伝子エンハンサーLCRによる活性化クロマチン構造の誘導機構

五十嵐和彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業重点領域研究

Category: 重点領域研究

Institution: 筑波大学

1995 - 1995

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赤血球特異的に発現するグロビン遺伝子の発現調節領域(Locus Control Region,LCR)は、数多くある組織特異的エンハンサーのなかでも、染色体構造を赤血球特異的に活性化するという点でユニークな調節領域であり、クロマチン構造と転写調節の相互作用を解析する上で格好のモデルとなる。これまで、LCRの機能発現に重要と考えられる転写因子NF-E2とECHの構造と機能の解析を進めてきたが、本年度はこれら蛋白質に関する理解が一段と深まるとともに、新しいNF-E2関連因子が発見された。 1)ECH分子の機能ドメインの解析:ECHは非常に強い転写活性化因子として機能する。種々の欠失変異を作製し、この強い転写活性化を担う機能ドメインを同定した。また、ECHの転写活性化機能を赤血球中で制御する領域を同定した。この領域は、赤血球中に存在する分子と会合することによりECH分子の機能を調節することが考えられた。 2)NF-E2の小サブユニットと会合する分子を酵母でのスクリーニング系を用いて検索したところ、NF-E2大サブユニットと弱い類似性を示し、さらにGAGAなどに見い出されるBTBドメインを有する二種類の分子を発見し、BCH-1,BCH-2と名付けた。これらはいずれもNF-E2小サブユニットと二量体を形成しLCR中の配列に結合することから、LCRの機能発現に関与することが考えられる。 3)クロマチン鋳型を用いた試験管内転写系で各因子の機能を解析することを目的として、ECH,BCH-1,BCH-2そしてNF-E2小サブユニットの大腸菌での過剰発現系を確立した。また、それぞれに対する抗体を調製した。
新しい赤血球特異的転写因子ECHとMaf関連蛋白質との会合による転写制御

五十嵐和彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業奨励研究(A)

Category: 奨励研究(A)

Institution: 筑波大学

1995 - 1995

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bZip構造を有する転写因子ECHは、小Maf群蛋白質とのヘテロ二量体として赤血球特異的遺伝子の調節領域に存在する配列(TGCTGAGTCAT;以下NF-E2配列と称す)に結合する。本研究は、ECHによる転写活性化の分子機構と赤血球分化過程におけるECHの機能を明らかにすることを目的とした。本年度は以下の成果を得た。 1.ECHは他の動物由来転写因子には類を見ない非常に強い転写活性化能を有することが、培養細胞への遺伝子導入実験から明らかになった。そこで種々の欠失変異をcDNA上で作製し、この強い転写活性化能を担う領域を固定した。その結果、ECHのアミノ末端側の二つの領域に転写活性化能を担う領域が局在することが明らかになった。この領域は酸性アミノ酸に富むが、この性状に加え他の構造上の特徴もその強い転写活性化能に重要である可能性が考えられた。 2.種々の変異ECHの機能解析実験から、ECHの強い転写活性化能を負に制御する領域が、転写活性化ドメインやbZipドメインとは独立して存在することが明らかになった。赤芽球系細胞を用いた遺伝子導入実験において、この領域を欠失することによりECHの活性は増強すること、そしてこの領域のみを野性型ECHと共発現することにより、ECHによる転写活性化はトランスに増強されることを観察した。したがって、この領域は他の因子と結合することによりECHの転写活性化能を抑制することが示唆された。このような機能調節系は、外来性シグナルに対する反応性をこの転写因子に付与するものと考えられる。 3.試験管内での赤芽球分化誘導系を用いて、赤芽球分化に伴うECHの発現動態を検証した。その結果、赤芽球分化に際してECHの発現は強く誘導されることが明らかになった。このことは、ECHが赤血球分化過程の調節に関与することを強く示唆する。
転写因子群による赤血球特異的な遺伝子発現調節機序の解析

山本雅之, 五十嵐和彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業重点領域研究

Category: 重点領域研究

Institution: 東北大学

1994 - 1994

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私たちは以前にGATA因子がファミリーを形成していることを明らかにしたが,本研究ではGATA‐1発現が赤血球・巨核球系の分化形質と強く相関するのに対して,GATA‐2発現はさらに未分化な造血細胞にみられることを見出した.この結果は,GATA‐2が造血前駆細胞において機能しているのに対して,GATA‐1はすでに分化がある程度進んだ細胞での形質発現に貢献していることを示唆しており,転写因子群の機能分担を考察するうえで興味深い. NF‐E2を構成する一つのサブユニットであるp45のcDNAクローン化が最近報告され,p45は塩基性領域/ロイシンジッパー構造を持っており,もう一つのサブユニット(p18)とヘテロ二量体を形成してNF‐E2活性を示すことが提唱された.私たちは西澤誠博士と協力して,p18の本体は核内癌遺伝子Mafの関連遺伝子である小Maf群蛋白質であることを発見した.小Mafホモ二量体はNF‐E2配列を介して負の転写抑制を行うのに対して,P45が同時に細胞内に存在してヘテロ二量体を形成するとその分子は同じ配列を通して転写活性化に働く.NF‐E2配列を通して転写活性化と抑制はMafとp45との濃度平衡の変化に応じて行われており,このことから新しい転写制御様式が存在することが強く示唆される.最近,p45はショウジョウバエCNC因子と相同性を持った因子からなるファミリーを構成していることが明らかにされた.このことからNF‐E2は異なるサブユニットの解離・会合を通して多様な遺伝子発現制御を創り出してしることが理解される.造血幹細胞は多様な細胞系列へ分化するが,それぞれの細胞系列の確立の際に転写因子群が重要な貢献をしていることは疑いない.私たちは赤血球特異的な遺伝子発現調節機構の解析を通して血液細胞分化過程の理解を試みているが,それはまた細胞分化機構一般の分子的基盤の理解を進めるものであると思われる.
癌遺伝子mafの関連遺伝子産胸による赤血球系転写因子NF-E2の機能変換

五十嵐和彦, 山本雅之

Offer Organization: 日本学術振興会

System: 科学研究費助成事業重点領域研究

Category: 重点領域研究

Institution: 東北大学

1994 - 1994

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本研究では、赤血球系転写因子であるNF‐E2 p45の機能が、Maf関連蛋白質との会合によりどのように調節されるのか、並びに、赤血球分化におけるMaf関連蛋白質とp45の機能とその作用機作を明らかにすることを目的とした。本年度は以下の成果をあげた。 1.小Maf群蛋白質のうち、MafKをコードするマウスcDNAを単離した。すでに報告されているニワトリMafKとのアミノ酸配列の比較から、機能上重要と考えられる領域が明らかになった。 2.mafK遺伝子の発現様式の詳細な解析を、正常骨髄細胞とマウス胚を材料に用いて行った。その結果、mafK遺伝子は血球細胞の分化に加え、間葉系細胞と神経細胞の分化にも深く関与することが推察された。 3.MafKとp45のcDNAを培養細胞内で発現させ、転写因子としての機能を解析した。その結果、MafKは単独では転写抑制因子として機能すること、そしてp45それ自体のDNA結合活性は非常に低いことが明らかになった。一方、MafKとp45とのヘテロ二重体(NF‐E2)は強くDNAに結合し、転写を活性化することも明らかになった。さらに、NF‐E2による転写活性化に必須の領域を、p45分子上に同定した。 4.マウス赤白血病細胞株を用いて、mafK遺伝子を亜鉛依存性に過剰発現する細胞株を樹立した。この細胞の解析から、MafKは赤血球の分化を促進することが明らかになった。また、MafKとヘテロ二重体を形成する未知の蛋白質の存在が明らかになった。
赤血球特異的転写因子NF-E2とMaf関連蛋白質との会合による転写制御

五十嵐和彦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業奨励研究(A)

Category: 奨励研究(A)

Institution: 東北大学

1994 - 1994

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本研究では、赤血球系転写因子であるNF-E2p45の機能が、Maf関連蛋白質との会合によりどのように調節されるのか、並びに、赤血球分化におけるMaf関連蛋白質とp45の機能とその作用機作を明らかにすることを目的とした。本年度は以下の成果をあげた。 1.小Maf群蛋白質のうち、MafKをコードするマウスcDNAを単離した。すでに報告されているニワトリMafKとのアミノ酸配列の比較から、機能上重要と考えられる領域が明らかになった。 2.mafK遺伝子の発現様式の詳細な解析を、正常骨髄細胞とマウス胚を材料に用いて行った。その結果、mafK遺伝子は血球細胞の分化に加え、間葉系細胞と神経細胞の分化にも深く関与することが推察された。 3.MafKとp45のcDNAを培養細胞内で発現させ、転写因子としての機能を解析した。その結果、MafKは単独では転写抑制因子として機能すること、そしてp45それ自体のDNA結合活性は非常に低いことが明らかになった。一方、MafKとp45とのヘテロ二量体(NF-E2)は強くDNAに結合し、転写を活性化することも明らかになった。さらに、NF-E2による転写活性化に必須の領域を、p45分子上に同定した。 4.マウス赤白血病細胞株を用いて、mafK遺伝子を亜鉛依存性に過剰発現する細胞株を樹立した。この細胞の解析から、MafKは赤血球の分化を促進することが明らかになった。また,MafKとヘテロ二量体を形成する未知の蛋白質の存在が明らかになった。

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