ストレス応答性転写因子による代謝・病態制御

2013 Fiscal Year Annual Research Report

• Project/Area Number: 24249015
• Research Institution: Tohoku University
• Principal Investigator: 山本 雅之 東北大学, 医学(系)研究科(研究院), 教授 (50166823)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 酸化ストレス / 細胞分化 / 病態代謝

Research Abstract

本研究では、酸化ストレス応答において中心的な役割を担う転写因子Nrf2について、ストレス応答系以外の代謝制御や病態制御との関わりについて研究を進めている。
本年度は、糖尿病モデルとしてiNOS-Tgマウスを用いて、酸化ストレス応答性転写因子Nrf2が膵β細胞の保護や多臓器間の代謝制御ネットワークに深く関与していることを見いだした。また、腎臓におけるNrf2の役割を検討したところ、炎症環境において尿細管および糸球体を保護していることを見いだした。腎炎においてマクロファージの集積が認められたので、炎症促進性のマクロファージにおいけるNrf2の役割を検討した。その結果、IL-1β、IL-1α、IL-6などのサイトカイン遺伝子の発現をNrf2が抑制することを明らかにした。これまでの研究では、Nrf2は転写活性化因子としての機能が知られていたが、本研究によって転写抑制能も有することが示唆された。
次に、細胞運命決定におけるNrf2の役割を検討するために、Nrf2およびKeap1（Nrf2抑制因子）の欠損マウスを用いて骨髄造血細胞の解析を行った。その結果、Nrf2は 造血幹細胞を分化の方向に動員させ、造血前駆細胞を増加させる性質を持つことを明らかとした。また、骨髄球系への選択的な分化を誘導することも見いだした。このように、非ストレス環境下でもNrf2は細胞運命決定において必須であることを示すことができた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

膵β細胞の保護や糖尿病、肥満等の病態におけるストレス応答性転写因子Nrf2の機能について明らかにし、論文発表することができた。また、非ストレス環境下におけるNrf2の役割として、造血細胞の運命決定に必須であることを明らかにした。Nrf2の条件付き欠損マウスの解析系の確率や転写因子複合体解析も順調に進んでいる。

Strategy for Future Research Activity

ストレス応答性転写因子Nrf2の腫瘍免疫系における役割を検証する。解析にはNrf2およびKeap1遺伝子の条件付き欠損マウスを用いる。同様に、様々な病態モデル（腎臓病、動脈硬化、肺炎など）を利用して、病態とNrf2の関係を明らかにする。Nrf2およびKeap1と結合するタンパク質の同定を行っており、同定された因子の機能解析を代謝制御系との関連を中心に進める。
これまでにNrf2のDNA結合ドメインに変異を導入したマウスの樹立に成功しており、今後は活性化したNrf2がDnAを認識する分子メカニズムを個体レベルで明らかにする。この研究の成果は、Nrf2を中心とした転写制御ネットワークの理解につながる。

Research Products

• [Journal Article] Hematopoietic stem and progenitor cell activation during chronic dermatitis provoked by constitutively active aryl-hydrocarbon receptor driven by Keratin 14 promoter (2014)
  • Author(s): Murakami S, Yamamoto M, and Motohashi H.
  • Journal Title: Toxicol Sci Volume: 138 Pages: 47-58
  • DOI: 10.1093/toxsci/kft273
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Nrf2 protects pancreatic β-cells from oxidative and nitrosative stress in diabetic model mice (2014)
  • Author(s): Yagishita Y, Fukutomi T, Sugawara A, Kawamura H, Takahashi T, Pi J, Uruno A, and Yamamoto M.
  • Journal Title: Diabetes Volume: 63 Pages: 605-618
  • DOI: 10.2337/db13-0909
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Critical role of Nrf2 in oxidative stress-induced retinal ganglion cell death (2014)
  • Author(s): Himori N, Yamamoto K, Maruyama K, Ryu M, Taguchi K, Yamamoto M, and Nakazawa T. “
  • Journal Title: J Neurochem Volume: 127 Pages: 669-680
  • DOI: 10.1111/jnc.12325
  • Peer Reviewed
• [Journal Article] Nrf2 enhances cholangiocyte expansion in Pten-deficient livers (2014)
  • Author(s): Taguchi K, Hirano I, Itoh T, Tanaka M, Miyajima A, Suzuki A, Motohashi H, Yamamoto M
  • Journal Title: Mol Cell Biol Volume: 34 Pages: 900-913
  • DOI: 10.1128/MCB.01384-13
  • Peer Reviewed
• [Journal Article] Kinetic, Thermodynamic and Structural Characterizations of Association between Nrf2-DLGex Degron and Keap1 (2014)
  • Author(s): Fukutomi T, Takagi K, Mizushima T, Ohuchi N, Yamamoto M
  • Journal Title: Mol Cell Biol Volume: 34 Pages: 832-846
  • DOI: 10.1128/MCB.01191-13
  • Peer Reviewed
• [Journal Article] Possible involvementof nuclear factor erythroid 2-related factor 2in the gene expression of Cyp2b10and Cyp2a5 (2014)
  • Author(s): Ashino T, Ohkubo-Morita H, Yamamoto M, Yoshida T, Numazawa S
  • Journal Title: Redox Biology Volume: 10 Pages: 284-288
  • DOI: 10.1016/j.redox.2013.12.025
  • Peer Reviewed
• [Journal Article] Keap1-Nrf2 system regulates cell fate determination of hematopoietic stem cells (2014)
  • Author(s): Murakami S, Shimizu R, Romeo P-H, Yamamoto M, Motohashi H
  • Journal Title: Genes Cells Volume: 19 Pages: 239-253
  • DOI: 10.1111/gtc.12126
  • Peer Reviewed
• [Journal Article] NRF2 immunolocalization in human breast cancer patients as a prognostic factor (2014)
  • Author(s): Onodera Y, Motohashi H, Takagi K, Miki Y, Shibahara Y, Watanabe M, Ishida T, Hirakawa H, Sasano H, Yamamoto M, Suzuki T
  • Journal Title: Endocr Relat Cancer Volume: 21 Pages: 241-252
  • DOI: 10.1530/ERC-13-0234
  • Peer Reviewed
• [Journal Article] Notch-Nrf2 axis: Regulation of Nrf2 gene expression and cytoprotection by Notch signaling (2014)
  • Author(s): Wakabayashi N, Skoko JJ, Chartoumpekis DV, Kimura S, Slocum SL, Noda K, Palliyaguru DL, Fujimuro M, Boley PA, Tanaka Y, Shigemura N, Biswal S, Yamamoto M, Kensler TW
  • Journal Title: Mol Cell Biol Volume: 34 Pages: 653-663
  • DOI: 10.1128/MCB.01408-13
  • Peer Reviewed
• [Journal Article] Does Nrf2 gene transfer facilitate recovery after contusion spinal cord injury? (2014)
  • Author(s): Pomeshchik Y, Kidin I, Savchenko E, Rolova T, Yamamoto M, Levonen AL, Yla-Herttuala S, Kanninen K, Malm T, Koistinaho J
  • Journal Title: Antioxid Redox Signal Volume: 20 Pages: 1313-1323
  • DOI: 10.1089/ars.2013.5453
  • Peer Reviewed
• [Journal Article] Keap1-Nrf2系と腎臓病 (2014)
  • Author(s): 祢津昌広・相馬友和・山本雅之
  • Journal Title: Annual Review腎臓 Volume: 2014 Pages: 89-96
• [Journal Article] Adipose deficiency of Nrf2 in ob/ob mice results in severe metabolic syndrome (2013)
  • Author(s): Xue P, Hou Y, Chen Y, Yang B, Fu J, Zheng H, Yarborough K, Woods CG, Liu D, Yamamoto M, Zhang Q, Andersen ME, Pi J
  • Journal Title: Diabetes Volume: 62 Pages: 845-854
  • DOI: 10.2337/db12-0584
  • Peer Reviewed
• [Journal Article] Roles of Keap1-Nrf2 system in upper aerodigestive tract carcinogenesis (2013)
  • Author(s): Ohkoshi A, Suzuki T, Ono M, Kobayashi T, Yamamoto M
  • Journal Title: Cancer Prev Res Volume: 6 Pages: 149-159
  • DOI: 10.1158/1940-6207
  • Peer Reviewed
• [Journal Article] Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling (2013)
  • Author(s): Guiu J, Shimizu R, D'Altri T, Fraser ST, Hatakeyama J, Bresnick EH, Kageyama R, Dzierzak E, Yamamoto M, Espinosa L, Bigas A
  • Journal Title: J Exp Med Volume: 210 Pages: 71-84
  • DOI: 10.1084/jem.20120993
  • Peer Reviewed
• [Journal Article] The absence of macrophage Nrf2 promotes early atherogenesis (2013)
  • Author(s): Ruotsalainen AK, Inkala M, Partanen ME, Lappalainen JP, Kansanen E, Makinen PI, Heinonen SE, Laitinen HM, Heikkila, Vatanen T, Horkko S, Yamamoto M, Yla-Herttuala S, Jauhiainen M, Levonen AL
  • Journal Title: Cardiovasc Res Volume: 98 Pages: 107-115
  • DOI: 10.1093/cvr/cvt008
  • Peer Reviewed
• [Journal Article] Redox-sensitive transcription factor nrf2 regulates vascular smooth muscle cell migration and neointimal hyperplasia (2013)
  • Author(s): Ashino T, Yamamoto M, Yoshida T, Numazawa S
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 33 Pages: 760-768
  • DOI: 10.1161/ATVBAHA.112.300614
  • Peer Reviewed
• [Journal Article] Disruption of the Hbsl1-Myb locus causes hereditary persistence of fetal hemoglobin in mouse (2013)
  • Author(s): Suzuki M, Yamazaki H, Mukai HY, Motohashi H, Shi L, Tanabe O, Engel JD, Yamamoto M
  • Journal Title: Mol Cell Biol Volume: 33 Pages: 1687-1695
  • DOI: 10.1128/MCB.01617-12
  • Peer Reviewed
• [Journal Article] Naturally occurring oncogenic GATA1 mutants with internal deletions in transient abnormal myelopoiesis in Down syndrome (2013)
  • Author(s): Toki T, Kanezaki R, Kobayashi E, Kaneko H, Suzuki M, Wang R, Terui K, Kanegane H, Maeda M, Endo M, Mizuochi T, Adachi S, Hayashi Y, Yamamoto M, Shimizu R, Ito E
  • Journal Title: Blood Volume: 121 Pages: 3181-3194
  • DOI: 10.1182/blood-2012-01-405746
  • Peer Reviewed
• [Journal Article] Erythropoietin contributes to slow oxidative muscle fiber specification via PGC-1a and AMPK activation (2013)
  • Author(s): Wang L, Jia Y, Rogers H, Suzuki N, Gassmann M, Wang Q, McPherron AC, Kopp J, Yamamoto M, Noguchi CT
  • Journal Title: Int J Biochem Cell Biol Volume: 45 Pages: 1155-1164
  • DOI: 10.1016/j.biocel.2013.03.007
  • Peer Reviewed
• [Journal Article] The Keap1-Nrf2 system prevents onset of diabetes mellitus (2013)
  • Author(s): Uruno A, Furusawa Y, Yagishita Y, Fukutomi T, Muramatsu H, Negishi T, Sugawara A, Kensler TW, Yamamoto M
  • Journal Title: Mol Cell Biol Volume: 33 Pages: 2996-3010
  • DOI: 10.1128/MCB.00225-13
  • Peer Reviewed
• [Journal Article] A mouse model of adult-onset anaemia due to erythropoietin deficiency (2013)
  • Author(s): Yamazaki S, Souma T, Hirano I, Pan XQ, Minegishi N, Suzuki N, Yamamoto M
  • Journal Title: Nature Commun Volume: 4 Pages: 1950
  • DOI: 10.1038/ncomms2950
  • Peer Reviewed
• [Journal Article] Transforming growth factor-β Induces transcription factors MafK and Bach1 to suppress expression of the heme oxygenase-1 gene (2013)
  • Author(s): Okita Y, Kamoshida A, Suzuki H, Itoh K, Motohashi H, Igarashi K, Yamamoto M, Ogami T, Koinuma D, Kato M
  • Journal Title: J Biol Chem Volume: 288 Pages: 20658-20667
  • DOI: 10.1074/jbc.M113.450478
  • Peer Reviewed
• [Journal Article] Plasticity of renal erythropoietin-producing cells governs fibrosis (2013)
  • Author(s): Souma T, Yamazaki S, Moriguchi T, Suzuki N, Hirano I, Pan X, Minegishi N, Abe M, Kiyomoto H, Ito S, Yamamoto M
  • Journal Title: J Am Soc Nephrol Volume: 24 Pages: 1599-1616
  • DOI: 10.1681/ASN.2013010030
  • Peer Reviewed
• [Journal Article] Keap1-Nrf2 complex in ischemia-induced hepatocellular damage of mouse liver transplants (2013)
  • Author(s): Ke B, Shen XD, Zhang Y, Ji H, Gao F, Yue S, Kamo N, Zhai Y, Yamamoto M, Busuttil RW, Kupiec-Weglinski JW
  • Journal Title: J Hepatol Volume: 59 Pages: 1200-1207
  • DOI: 10.1016/j.jhep.2013.07.016
  • Peer Reviewed
• [Journal Article] Keap1 knockdown increases markers of metabolic syndrome after long-term high fat diet feeding (2013)
  • Author(s): More VR, Xu J, Shimpi PC, Belgrave C, Luyendyk JP, Yamamoto M, Slitt AL
  • Journal Title: Free Radic Biol Med Volume: 61C Pages: 85-94
  • DOI: 10.1016/j.freeradbiomed.2013.03.007
  • Peer Reviewed
• [Journal Article] Regulatory nexus of synthesis and degradation deciphers cellular Nrf2 expression levels (2013)
  • Author(s): Suzuki T, Shibata T, Takaya K, Shiraishi K, Kohno T, Kunitoh H, Tsuta K, Furuta K, Goto K, Hosoda F, Sakamoto H, Motohashi H, Yamamoto M
  • Journal Title: Mol Cell Biol Volume: 33 Pages: 2402-2412
  • DOI: 10.1128/MCB.00065-13
  • Peer Reviewed
• [Journal Article] The role of the Nrf2-mediated defense system in corneal epithelial wound healing (2013)
  • Author(s): Hayashi R, Himori N, Taguchi K, Ishikawa Y, Uesugi K, Ito M, Duncan T, Tsujikawa M, Nakazawa T, Yamamoto M, Nishida K
  • Journal Title: Free Radic Biol Med Volume: 61C Pages: 333-342
  • DOI: 10.1016/j.freeradbiomed.2013.04.008
  • Peer Reviewed
• [Journal Article] The nuclear factor erythroid 2-related factor 2 activator oltipraz attenuates chronic hypoxia-induced cardiopulmonary alterations in mice (2013)
  • Author(s): Eba S, Hoshikawa Y, Moriguchi T, Mitsuishi Y, Satoh H, Ishida K, Watanabe T, Shimizu T, Shimokawa H, Okada Y, Yamamoto M, Kondo T
  • Journal Title: Am J Respir Cell Mol Biol Volume: 49 Pages: 324-333
  • DOI: 1165/rcmb.2011-0396OC
  • Peer Reviewed
• [Journal Article] Nrf2 prevents initiation but accelerates progression through the Kras signaling pathway during lung carcinogenesis (2013)
  • Author(s): Satoh H, Moriguchi T, Takai J, Ebina M, Yamamoto M
  • Journal Title: Cancer Res Volume: 73 Pages: 4158-4168
  • DOI: 10.1158/0008-5472.CAN-12-4499
  • Peer Reviewed
• [Journal Article] NF-E2 p45 is important for establishing normal function of platelets (2013)
  • Author(s): Fujita R, Takayama-Tsujimoto M, Satoh H, Gutierrez L, Aburatani H, Fujii S, Sarai A, Bresnick EH, Yamamoto M, Motohashi H
  • Journal Title: Mol Cell Biol Volume: 33 Pages: 2659-2670
  • DOI: 10.1128/MCB.01274-12
  • Peer Reviewed
• [Journal Article] Establishment of erythroleukemic GAK14 cells and characterization of GATA1 N-terminal domain (2013)
  • Author(s): Mukai HY, Suzuki M, Nagano M, Ohmori S, Otsuki A, Tsuchida K, Moriguchi T, Ohneda K, Shimizu R, Ohneda O, Yamamoto M,
  • Journal Title: Genes Cells Volume: 18 Pages: 886-898
  • DOI: 10.1111/gtc.12084
  • Peer Reviewed
• [Journal Article] Nrf2 deficiency leads to behavioral, neurochemical and transcriptional changes in mice (2013)
  • Author(s): Muramatsu H, Katsuoka F, Toide K, Shimizu Y, Furusako S, Yamamoto M
  • Journal Title: Genes Cells Volume: 18 Pages: 899-908
  • DOI: 10.1111/gtc.12083
  • Peer Reviewed
• [Journal Article] GATA factor switching from GATA2 to GATA1 contributes to erythroid differentiation (2013)
  • Author(s): Suzuki M, Kobayashi-Osaki M, Tsutsumi S, Pan X, Ohmori S, Takai J, Moriguchi T, Ohneda O, Ohneda K, Shimizu R, Kanki Y, Kodama T, Aburatani H, Yamamoto M
  • Journal Title: Genes Cells Volume: 18 Pages: 921-933
  • DOI: 10.1111/gtc.12086
  • Peer Reviewed
• [Journal Article] 4-Hydroxy hexenal derived from docosahexaenoic acid protects endothelial cells via Nrf2 activation (2013)
  • Author(s): Ishikado A, Morino K, Nishio Y, Nakagawa F, Mukose A, Sono Y, Yoshioka N, Kondo K, Sekine O, Yoshizaki T, Ugi S, Uzu T, Kawai H, Makino T, Okamura T, Yamamoto M, Kashiwagi A, Maegawa H
  • Journal Title: PLoS One Volume: 8 Pages: e69415
  • DOI: 10.1371/journal.pone.0069415
  • Peer Reviewed
• [Journal Article] Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration (2013)
  • Author(s): Holmstrom KM, Baird L, Zhang Y, Hargreaves I, Chalasani A, Land JM, Stanyer L, Yamamoto M, Dinkova-Kostova AT, Abramov AY
  • Journal Title: Biol Open Volume: 2 Pages: 761-770
  • DOI: 10.1242/bio.20134853
  • Peer Reviewed
• [Journal Article] Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy (2013)
  • Author(s): Ichimura Y, Waguri S, Sou Y-S, Kageyama S, Hasegawa J, Ishimura R, Saito T, Yang Y, Kouno T, Fukutomi T, Hoshii T, Hirao A, Takagi K, Mizushima T, Motohashi H, Lee M-S, Yoshimori T, Tanaka K, Yamamoto M, Komatsu M
  • Journal Title: Mol Cell Volume: 51 Pages: 618-631
  • DOI: 10.1016/j.molcel.2013.08.003
  • Peer Reviewed
• [Journal Article] The Gata1 5' region harbors distinct cis-regulatory modules that direct gene activation in erythroid cells and gene inactivation in HSCs (2013)
  • Author(s): Takai J, Moriguchi T, Suzuki M, Yu L, Ohneda K, Yamamoto M
  • Journal Title: Blood Volume: 122 Pages: 3450-3460
  • DOI: 10.1182/blood-2013-01-476911
  • Peer Reviewed
• [Journal Article] Verification of the in vivo activity of three distinct cis-acting elements within the Gata1 gene promoter-proximal enhancer in mice (2013)
  • Author(s): Shimizu R, Hasegawa A, Ottolenghi S, Ronchi A, Yamamoto M
  • Journal Title: Genes Cells Volume: 18 Pages: 1032-1041
  • DOI: 10.1111/gtc.12096
  • Peer Reviewed
• [Journal Article] Loss of a Rho-regulated actin nucleator, mDia2, impairs cytokinesis during mouse fetal erythropoiesis (2013)
  • Author(s): Watanabe S, Zan TD, Ishizaki T, Yasuda S, Kamijyo H, Yamada D, Aoki T, Kiyonari H, Kaneko H, Shimizu R, Yamamoto M, Goshima G, Narumiya S
  • Journal Title: Cell Reports Volume: 5 Pages: 926-932
  • DOI: 10.1016/j.celrep.2013.10.021
  • Peer Reviewed
• [Journal Article] Erythropoietin production in neuroepithelial and euralcrest cells during primitive erythropoiesis (2013)
  • Author(s): Suzuki N, Hirano I, Pan X, Minegishi N, Yamamoto M
  • Journal Title: Nature Commun Volume: 4 Pages: 2902
  • DOI: 10.1038/ncomms3902
  • Peer Reviewed
• [Journal Article] 酸化ストレス応答の新展開 (2013)
  • Author(s): 福富俊明、山本雅之
  • Journal Title: 医学のあゆみ Volume: 247 Pages: 731-736
• [Presentation] 肝毒性物質による肝肥大における転写因子Nrf2の役割 (2013)
  • Author(s): 田口恵子、本橋ほづみ、伊藤暢、田中稔、宮島篤、山本雅之
  • Organizer: フォーラム2013：衛生薬学・環境トキシコロジー
  • Place of Presentation: 九州大学
  • Year and Date: 20130911-20130913
• [Presentation] 酸化ストレス応答の分子メカニズムと病態
  • Author(s): 山本雅之
  • Organizer: 第50回日本臨床分子医学会学術集会
  • Place of Presentation: 東京国際フォーラム
  • Invited
• [Presentation] エリスロポエチン遺伝子の発現制御メカニズム
  • Author(s): 山本雅之
  • Organizer: 第86回日本内分泌学会学術集会
  • Place of Presentation: 仙台国際センター
  • Invited
• [Presentation] 赤血球系転写因子の発現制御とエピジェネティクス機構
  • Author(s): 山本雅之
  • Organizer: 第7回日本エピジェネティクス研究会年会
  • Place of Presentation: 奈良県新公会堂
  • Invited
• [Presentation] Molecular Basis of Environmental Response by Keap1-Nrf2 System
  • Author(s): Yamamoto M
  • Organizer: RCCH symposium
  • Place of Presentation: Seoul, Korea
  • Invited
• [Presentation] 抗酸化ストレス転写因子Nrf2欠損マウス由来肺腫瘍はKras経路の抑制と肺腺癌特異的な遺伝子発現低下をきたす
  • Author(s): 佐藤大希、森口尚、海老名雅仁、山本雅之
  • Organizer: 第53回日本呼吸器学会学術総会
  • Place of Presentation: 東京国際フォーラム
• [Presentation] 門脈枝結紮による代償性肝肥大におけるNrf2の役割
  • Author(s): 白崎圭一、田口恵子、本橋ほづみ、海野倫明、山本雅之
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜