酸素や食物が内包する毒性に対する細胞の適応・応答の分子機構の解明

2011 Fiscal Year Annual Research Report

• Project/Area Number: 19GS0312
• Research Institution: Tohoku University
• Principal Investigator: 山本 雅之 東北大学, 大学院・医学系研究科, 教授 (50166823)
• Co-Investigator(Kenkyū-buntansha): 勝岡 史城 東北大学, 大学院・医学系研究科, 准教授 (30447255)
• Keywords: Nrf2 / Keap1 / 酸化ストレス / 低酸素 / エリスロポエチン

Research Abstract

生体は、環境ストレスに適切に応答することで、恒常性を維持している。本研究は、生体がストレスを感知するセンサーの分子機構とストレスによって惹起される生体防御機構の解明を目的としている。
Nrf2-Keap1システムによるストレス感知機構の解析:Nrf2-Keap1によるストレス感知に重要なシステイン残基(Cys)151を含むKeap1 BTBドメインのさらなる構造・機能解析を行うために、Keap1とCul3との相互作用解析を実施した。構造解析に向けて安定なKeap1-Cul3複合体を形成する条件を検討するとともに、様々な親電子性分子が複合体を不安定化することを明らかにした。また、Cys151に変異を導入したKeap1を発現するトランスジェニックマウスを作製・解析することで、ストレス刺激には、その感知にCys151を必須とする刺激とそうでない刺激に分類されることを、マウス個体レベルで実証した。このようなストレス感知における「システインコード」の使い分けは、多様なストレス物質に対応するための分子基盤になっていると考えられる。また、Nrf2活性化モデルマウス、Nrf2活性低下モデルマウスの解析を通して、Nrf2活性の変化は、個体レベルで糖代謝などの様々な経路に影響を与えることを明らかにした。
Epo遺伝子制御機構の解析よる低酸素感知機構の解明:重度の貧血を示すEpo遺伝子改変マウスを作製し、各臓器におけて低酸素誘導性遺伝子群の発現が亢進していることを確認した。本マウスは脂肪肝を呈することから、慢性低酸素が代謝系の異常を誘発することが示された。また、Epo遺伝子の腎臓での発現に重要な1kbの制御領域を同定し、ヒト腎由来Epo産生細胞株(REPC)において低酸素応答活性を有することを明らかにした。今後、同定した領域を更に解析していくことで、腎性貧血の病態解明に繋がると考えられる。

Research Products

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• [Journal Article] Metabolism and tissue distribution of sulforaphane in Nrf2 knockout and wild-type mice (2011)
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• [Journal Article] Specific contribution of the erythropoietin gene 3' enhancer to hepatic erythropoiesis after late embryonic stages (2011)
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• [Journal Article] NRF2 mutation confers malignant potential and resistance to chemoradiation therapy in advanced esophageal squamous cancer (2011)
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• [Journal Article] Nrf2 regulates NGF mRNA induction by carnosic acid in T98G glioblastoma cells and normal human astrocytes (2011)
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• [Journal Article] The novel NRF2-interacting factor KAP1 regulates the susceptibility to oxidative stress by promoting NRF2-mediated cytoprotective response (2011)
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• [Journal Article] Dual Regulation of the Transcriptional Activity of Nrf1 by β-TrCP-and Hrd1-Dependent Degradation Mechanisms (2011)
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• [Journal Article] Association of Keap1 and Nrf2 genetic mutations and polymorphisms with endometrioid endometrial adenocarcinoma survival (2011)
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• [Journal Article] Acceleration of UVB-induced photoageing in nrf2 gene-deficient mice (2011)
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• [Journal Article] Central nervous system-specific deletion of transcription factor Nrf1 causes progressive motor neuronal dysfunction (2011)
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• [Journal Article] Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts lipopolysaccharide-induced ferroportin-1 mRNA suppression in macrophages (2011)
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• [Journal Article] Constitutive activation of nuclear factor-E2-related factor 2 induces biotransformation enzyme and transporter expression in livers of mice with hepatocyte-specific deletion of Kelch-like ECH-associated protein 1 (2011)
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• [Journal Article] Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis (2011)
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• [Journal Article] Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells (2011)
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• [Journal Article] Nrf2 degron-fused reporter system ; a new tool for specific evaluation of Nrf2 inducers (2011)
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• [Journal Article] Initial response and cellular protection through the Keap1/Nrf2 system during exposure of primary mouse hepatocytes to 1,2-naphthoquinone (2011)
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• [Journal Article] Isothiocyanates reduce mercury accumulation via an Nrf2-dependent mechanism during exposure of mice to methylmercury (2011)
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• [Journal Article] Antioxidant signaling via Nrf2 counteracts lipopolysaccharide-mediated inflammatory responses in foam cell macrophages (2011)
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• [Journal Article] Role of Nrf2 in host defense against influenza virus in cigarette smoke-exposed mice (2011)
  • Author(s): Yageta Y, Ishii Y, Morishima Y, Masuko H, Ano S, Yamadori T, Itoh K, Takeuchi K, Yamamoto M, Hizawa N
  • Journal Title: J Virol Volume: 85 Pages: 4679-4690
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• [Journal Article] Electrophilic nitro-fatty acids activate NRF2 by a KEAP1 Cysteine 151-independent mechanism (2011)
  • Author(s): Kansanen E, Bonacci G, Schopfer FJ, Kuosmanen SM, Tong KI, Leinonen H, Woodcock SR, Yamamoto M, Carlberg C, Yla-Herttuala S, Freeman BA, Levonen AL
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• [Journal Article] Acute erythropoietin cardioprotection is mediated by endothelial response (2011)
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  • Journal Title: Basic Res Cardiol Volume: 106 Pages: 343-354
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• [Journal Article] Up-regulation of p27kip1 contributes to Nrf2-mediated protection against angiotensin II-induced cardiac hypertrophy (2011)
  • Author(s): Li J, Zhang C, Xing Y, Janicki JS, Yamamoto M, Wang XL, Tang DQ, Cui T
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• [Journal Article] Transcription factor Nrf2 maintains the basa1 expression of Mdm2 : An implication of the regulation of p53 signaling by Nrf2 (2011)
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• [Journal Article] Inducible disruption of autophagy in the lung causes airway hyper-responsiveness (2011)
  • Author(s): Inoue D, Kubo H, Taguchi K, Suzuki T, Komatsu M, Motohashi H, Yamamoto M
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• [Journal Article] Nrf2 and selenoproteins are essential for maintaining oxidative homeostasis in erythrocytes and protecting against hemolytic anemia (2011)
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• [Journal Article] Molecular determinants for small Maf protein control of platelet production (2011)
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• [Journal Article] Nitro-fatty acids and cyclopentenone prostaglandins share strategies to activate the Keap1-Nrf2 system : a study using green fluorescent protein transgenic zebrafish (2011)
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• [Journal Article] Possible involvement of oxidative stress in 5-fluorouracil-mediated myelosuppression in mice (2011)
  • Author(s): Numazawa S, Sugihara K, Miyake S, Tomiyama H, Hida A, Hatsuno M, Yamamoto M, Yoshida T
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• [Journal Article] Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution (2011)
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• [Presentation] 4NQO誘発舌がんにおけるKeap1-Nrf2系の役割 (2012)
  • Author(s): 大越明、鈴木隆史、小林俊光、山本雅之
  • Organizer: 第147回日本耳鼻咽喉科学会宮城県地方部会学術講演会
  • Place of Presentation: 仙台
  • Year and Date: 2012-03-18
• [Presentation] 環境ストレス応答の分子基盤と病態 (2012)
  • Author(s): 山本雅之
  • Organizer: 都医学研セミナー
  • Place of Presentation: 東京
  • Year and Date: 2012-02-28
• [Presentation] Nrf2 activates the pentose phosphate pathway and glutamine consumption in metabolic reprogramming (2012)
  • Author(s): Mitsuishi Y, Taguchi K, Aburatani H, Yamamoto M, Motohashi H
  • Organizer: Keystone Symposium on Cancer and Metabolism
  • Place of Presentation: アルバータ、カナダ
  • Year and Date: 2012-02-12
• [Presentation] Hypoxia-inducible and tissue-specific erythropoietin gene regulation (2012)
  • Author(s): Masayuki Yamamoto
  • Organizer: Keystone Symposia ; Advances in Hypoxic Signaling
  • Place of Presentation: アルバータ、カナダ(招待講演)
  • Year and Date: 2012-02-12
• [Presentation] Nrf2-sMaf2量体のDNA結合配列指向性と転写制御機構のゲノムワイド解析 (2012)
  • Author(s): 弘津陽介、勝岡史城、長嶋剛史、西田有一郎、舟山亮、中山啓子、山本雅之
  • Organizer: 新学術領域研究「転写代謝システム」と転写研究会若手ワークショップ
  • Place of Presentation: 湯河原
  • Year and Date: 2012-02-09
• [Presentation] マウス遺伝学と環境応答研究 (2012)
  • Author(s): 山本雅之
  • Organizer: 筑波大学生命科学動物資源センター10周年記念シンポジウム
  • Place of Presentation: つくば(招待講演)
  • Year and Date: 2012-02-07
• [Presentation] Keap1-Nrf2システムとPten-PI3K-Aktシグナルのクロストークは肝臓における細胞増殖と分化を制御する (2012)
  • Author(s): 田口恵子、本橋ほづみ、山本雅之
  • Organizer: GCOE冬の合宿2012
  • Place of Presentation: 秋保
  • Year and Date: 2012-02-04
• [Presentation] 生体防御システムを支える転写因子Nrf2-MafGのゲノムワイド解析 (2012)
  • Author(s): 弘津陽介、勝岡史城、西田有一郎、舟山亮、中山啓子、山本雅之
  • Organizer: NM-GCOE第5回リトリード
  • Place of Presentation: 仙台
  • Year and Date: 2012-01-21
• [Presentation] 環境応答の分子基盤 (2012)
  • Author(s): 山本雅之
  • Organizer: ERATO研究成果報告会
  • Place of Presentation: 埼玉
  • Year and Date: 2012-01-18
• [Presentation] Nrf2ノックアウトマウスはウレタン投与による肺癌形成が阻害され、形成されたNrf2欠損癌結節はNudeマウスへの著しい生着不全を示す (2012)
  • Author(s): 佐藤大希、森口尚、守田匡伸、海老名雅仁、山本雅之
  • Organizer: 平成23年度「個体レベルでのがん研究支援活動」ワークショップ
  • Place of Presentation: 滋賀
  • Year and Date: 2012-01-18
• [Presentation] 慢性腎臓病における繊維化と腎性貧血を担う細胞の同定およびその制御法の開発 (2011)
  • Author(s): 高瀬昌幸、浅田礼光、中村仁、小口綾貴子、浅田美咲子、鈴木教郎、山村研一、名越慈人、芝田晋介、Tata Rao Nagaswara、Hans Fehling Joerg、深津敦司、峯岸直子、北徹、木村剛、岡野栄之、山本雅之、柳田素子
  • Organizer: 第34回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-13
• [Presentation] 含セレン蛋白質とNrf2による酸化ストレス防御機構の脳発達時期における役割 (2011)
  • Author(s): 大越明、鈴木隆史、西島維知子、山本雅之
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-13
• [Presentation] HIF-HRE系によるエリスロポエチン遺伝子の低酸素誘導的・組織特異的転写制御機構 (2011)
  • Author(s): 鈴木教郎、潘小青、山本雅之
  • Organizer: 第9回がんとハイポキシア研究会
  • Place of Presentation: 東京
  • Year and Date: 2011-11-26
• [Presentation] Transcription factor Nrf2 drives the pentose phosphate pathway and glutamine consumption in proliferating cells (2011)
  • Author(s): Yoichiro Mitsuishi, Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto
  • Organizer: Discovery on Target ; Cancer Cell Metabolism as Drug Target
  • Place of Presentation: Boston, USA
  • Year and Date: 2011-11-02
• [Presentation] 転写因子Nrf2の活性制御タンパク質Keap1の分解と合成 (2011)
  • Author(s): 田口恵子, 藤川奈々子、本橋ほづみ, 山本雅之
  • Organizer: フォーラム2011:衛生薬学・環境トキシコロジー
  • Place of Presentation: 金沢
  • Year and Date: 2011-10-27
• [Presentation] Keap1 degradation by autophagy for the maintenance of redox homeostasis (2011)
  • Author(s): Fujikawa N, Taguchi K, Motohashi H, Yamamoto M
  • Organizer: 16th World Congress on Advances in Oncology and 14th International Symposium on Molecular Medicine
  • Place of Presentation: Rhodes Island, Greece
  • Year and Date: 2011-10-16
• [Presentation] Select heterozygous Keap1 mutations have a dominant-negative effect on wild-type Keap1 in vivo (2011)
  • Author(s): Takafumi Suzuki, Jonathan Maher, Masayuki Yamamoto
  • Organizer: 16th World Congress on Advances in Oncology and 14th International Symposium on Molecular Medicine
  • Place of Presentation: Rhodes Island, Greece
  • Year and Date: 2011-10-06
• [Presentation] Nrf2 activates the pentose phosphate pathway and glutamine consumption in proliferating cells (2011)
  • Author(s): Yoichiro Mitsuishi, Keiko Taguchi, Masayuki Yamamoto, Hozumi Motohashi
  • Organizer: 16th World Congress on Advances in Oncology and 14th International Symposium on Molecular Medicine
  • Place of Presentation: Rhodes Island, Greece
  • Year and Date: 2011-10-06
• [Presentation] マウス遺伝学解析に基盤とするKeap1-Nrf2システムの解明 (2011)
  • Author(s): 山本雅之、鈴木隆史、田口恵子、本橋ほづみ
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋(招待講演)
  • Year and Date: 2011-10-03
• [Presentation] 転写因子Nrf2欠損はウレタン誘導性肺発癌を減少させ、Nrf2欠損癌組織は免疫不全マウスで著しい生着不全と増殖能低下をきたす (2011)
  • Author(s): 佐藤大希、森口尚、田口恵子、海老名雅仁、貫和敏博、山本雅之
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-03
• [Presentation] 胎仔期神経細胞、神経堤細胞によるエリスロポエチン産生 (2011)
  • Author(s): 平野育生, 鈴木教郎, 潘小青, 山嵜瞬, 峯岸直子, 山本雅之
  • Organizer: 新学術領域「細胞運命制御」総括班主催「若手の会」
  • Place of Presentation: 軽井沢
  • Year and Date: 2011-09-23
• [Presentation] エリスロポエチン欠損マウスの部分レスキューによる遺伝性超貧血マウスの樹立 (2011)
  • Author(s): 山嵜瞬, 峯岸直子, 鈴木教郎, 山本雅之
  • Organizer: 新学術領域「細胞運命制御」総括班主催「若手の会」
  • Place of Presentation: 軽井沢
  • Year and Date: 2011-09-23
• [Presentation] 腎臓Erythropoietin産生細胞の単離と遺伝子発現様式の解析 (2011)
  • Author(s): 潘小青、鈴木教郎、平野育生、山嵜瞬、峯岸直子、山本雅之
  • Organizer: 新学術領域「細胞運命制御」総括班主催「若手の会」
  • Place of Presentation: 軽井沢
  • Year and Date: 2011-09-23
• [Presentation] CNC因子と小Maf因子のヘテロ二量体による生体防御遺伝子の発現制御の意義 (2011)
  • Author(s): 勝岡史城、山嵜博未、山本雅之
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-21
• [Presentation] Keap1による多様なストレス感知機構の実証 (2011)
  • Author(s): 高屋快、鈴木隆史、山本雅之
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-21
• [Presentation] 転写因子Nrf2はペントースリン酸経路とグルタミン代謝を制御して細胞増殖に貢献する (2011)
  • Author(s): 光石陽一郎、田口恵子、油谷浩幸、貫和敏博、本橋ほづみ、山本雅之
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-21
• [Presentation] 転写因子NF-E2 p45による血小板機能制御メカニズムの解明 (2011)
  • Author(s): 藤田理恵、辻本昌理子、油谷浩幸、本橋ほづみ、山本雅之
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-21
• [Presentation] レドックス恒常性維持に重要なKeap1分解機構の解明 (2011)
  • Author(s): 藤川奈々子、田口恵子、本橋ほづみ、山本雅之
  • Organizer: 平成23年度がん若手ワークショップ
  • Place of Presentation: 蓼科
  • Year and Date: 2011-08-31
• [Presentation] Keap1-Nrf2システムとAktシグナルの相互作用と肝疾患 (2011)
  • Author(s): 田口恵子, 本橋ほづみ, 山本雅之
  • Organizer: 新学術領域研究「修飾シグナル病」領域推進会議
  • Place of Presentation: 東京
  • Year and Date: 2011-07-01
• [Presentation] Keap1による多様なストレス感知機構 (2011)
  • Author(s): 高屋快、鈴木隆史、本橋ほづみ、山本雅之
  • Organizer: 新学術領域研究「活性酸素シグナル」第6回班会議
  • Place of Presentation: 東京
  • Year and Date: 2011-05-14
• [Book] Oxidative Stress in Vertebrates and Invertebrates : Molecular Aspects of Cell Signaling, 5 Survival Strategy and Disease Pathogenesis According to the Nrf2-Small Maf Heterodimer (2012)
  • Author(s): Morita M, Motohashi H
  • Total Pages: 63-82
  • Publisher: Wiley-Blackwell
• [Patent(Industrial Property Rights)] うつ病の予防または治療剤 (2011)
  • Inventor(s): 山本雅之、村松裕行
  • Industrial Property Rights Holder: 山本雅之、村松裕行
  • Industrial Property Number: 特許、特願2011-283379
  • Filing Date: 2011-12-09