Pathogenesis by disrupting the cytoprotective system

• Project/Area Number: 22790127
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Environmental pharmacy
• Research Institution: Tohoku University
• Principal Investigator: TAGUCHI Keiko 東北大学, 大学院・医学系研究科, 助教 (20466527)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2010: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 転写因子 / 蛋白質分解 / 肝臓 / オートファジー / Nrf2 / Keap1 / タンパク質分解 / がん

Research Abstract

Pathogenesis by disrupting the cytoprotective system
Keap1-Nrf2 system regulates a battery of cytoprotective genes in response to both endogenous and exogenous stimuli. Constitutive Nrf2 activation by Keap1 deletion leads to hyperkeratosis in the upper digestive tract. In this study, we examined impaired autophagy activates Nrf2 to cause liver injury. The results indicate that Nrf2 activation needs properly regulation by Keap1.

Research Products

• [Journal Article] Nrf2 inhibits hepatic iron accumulation and counteracts oxidative stress-induced liver injury in nutritional steatohepatitis (2012)
  • Author(s): Okada K, Warabi E, Sugimoto H, Horie M, Tokushige K, Ueda T, Harada N, Taguchi K, Hashimoto E, Itoh K, Ishii T, Utsunomiya H, Yamamoto M, Shoda J
  • Journal Title: J Gastroenterol Volume: (in press)
  • NAID: 10031051379
  • Peer Reviewed
• [Journal Article] Nrf2 inhibits hepatic iron accumulation and counteracts oxidative stress-induced liver injury in nutritional steatohepatitis (2012)
  • Author(s): Okada K, Warabi E, Sugimoto H, Horie M, Tokushige K, Ueda T, Harada N, Taguchi K, Hashimoto E, Itoh K, Ishii T, Utsunomiya H, Yamamoto M, Shoda J
  • Journal Title: J.Gastroenterol Volume: (印刷中) Issue: 8 Pages: 924-935
  • DOI: 10.1007/s00535-012-0552-9
  • NAID: 10031051379
  • Peer Reviewed
• [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)
  • Author(s): Cheng Q, Taguchi K, Aleksunes LM, Manautou JE, Cherrington NJ, Yamamoto M, Slitt AL
  • Journal Title: J Biochem Mol Toxicol Volume: 25 Pages: 320-329
  • Peer Reviewed
• [Journal Article] Initial response and cellular protection through the Keap1/Nrf2 system during exposure of primary mouse hepatocytes to 1, 2-naphthoquinone (2011)
  • Author(s): Miura T, Shinkai Y, Jiang HY, Iwamoto N, Sumi D, Taguchi K, Yamamoto M, Jinno H, Tanaka-Kagawa T, Cho AK, Kumagai Y
  • Journal Title: Chem Res Toxicol Volume: 24 Pages: 559-567
  • Peer Reviewed
• [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
  • Journal Title: Biochem Biophys Res Commun Volume: 405 Pages: 13-18
  • Peer Reviewed
• [Journal Article] Two-electron quinone reductase (AKR1C isozyme)augments the oxidative DNA damage induced by quinones in diesel exhaust particles by accelerating redox cycling (2011)
  • Author(s): Yamano S, Shibata M, Kita H, Matsusue K, Narimatsu S, Taguchi K, Kumagai Y
  • Journal Title: J Health Sci Volume: 57 Pages: 107-114
  • Peer Reviewed
• [Journal Article] Nrf2-Keap1生体防御システムの機能とその破綻による病態の解明 (2011)
  • Author(s): 田口恵子
  • Journal Title: 東北醫學雑誌 Volume: 123 Pages: 51-45
• [Journal Article] Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution (2011)
  • Author(s): Taguchi K, Motohashi H, Yamamoto M
  • Journal Title: Genes Cells Volume: 16 Pages: 123-140
  • Peer Reviewed
• [Journal Article] Initial response and cellular protection through the Keap1/Nrf2 system during exposure of primary mouse hepatocytes to 1,2-naphthoquinone (2011)
  • Author(s): Miura T, Shinkai Y, Jiang HY, Iwamoto N, Sumi D, Taguchi K, Yamamoto M, Jinno H, Tanaka-Kagawa T, Cho AK, Kumagai Y
  • Journal Title: Chem Res Toxicol Volume: 24 Issue: 4 Pages: 559-567
  • DOI: 10.1021/tx100427p
  • Peer Reviewed
• [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)
  • Author(s): Cheng Q, Taguchi K, Aleksunes LM, Manautou JE, Cherrington NJ, Yamamoto M, Slitt AL
  • Journal Title: J Biochem Mol Toxicol Volume: 25 Issue: 5 Pages: 320-329
  • DOI: 10.1002/jbt.20392
  • Peer Reviewed
• [Journal Article] Two-electron quinone reductase (AKR1C isozyme) augments the oxidative DNA damage induced by quinones in diesel exhaust particles by accelerating redox cycling (2011)
  • Author(s): Yamano S, Shibata M, Kita H, Matsusue K, Narimatsu S, Taguchi K, et al.
  • Journal Title: Journal of Health Science Volume: 57 Pages: 107-114
  • Peer Reviewed
• [Journal Article] Inducible disruption of autophagy in the lung causes airway hyper-responsiveness (2011)
  • Author(s): Inoue D, Kubo H, Taguchi K, et al.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 405 Pages: 13-18
  • Peer Reviewed
• [Journal Article] Initial response and cellular protection through the Keap1/Nrf2 system during exposure of primary mouse hepatocytes to 1,2-naphthoquinone (2011)
  • Author(s): Miura T, Shinkai Y, Jiang HY, Iwamoto N, Sumi D, Taguchi K, et al.
  • Journal Title: Chemical Research in Toxicology Volume: (未定 印刷中)
  • Peer Reviewed
• [Journal Article] Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution (2011)
  • Author(s): Taguchi K, Motohashi H, Yamamoto M
  • Journal Title: Genes to Cells Volume: 16 Pages: 123-140
  • Peer Reviewed
• [Journal Article] The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1 (2010)
  • Author(s): Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou YS, Ueno I, Sakamoto A, Tong KI, Kim M, Nishito Y, Iemura S, Natsume T, Ueno T, Kominami E, Motohashi H, Tanaka K, Yamamoto M
  • Journal Title: Nat Cell Biol Volume: 12 Pages: 213-223
  • Peer Reviewed
• [Journal Article] Genetic Analysis of Cytoprotective Functions Supported by Graded Expression of Keap1 (2010)
  • Author(s): Taguchi K, Maher JM, Suzuki T, Kawatani Y, Motohashi H, Yamamoto M
  • Journal Title: Mol Cell Biol Volume: 30 Pages: 3016-3026
  • Peer Reviewed
• [Journal Article] Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway : a potential role for protein aggregation in autophagic substrate selection (2010)
  • Author(s): Riley BE, Kaiser SE, Shaler TA, Ng AC, Hara T, Hipp MS, Lage K, Xavier RJ, Ryu KY, Taguchi K, Yamamoto M, Tanaka K, Mizushima N, Komatsu M, Kopito RR
  • Journal Title: J Cell Biol Volume: 191 Pages: 537-552
  • Peer Reviewed
• [Journal Article] Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung (2010)
  • Author(s): Satoh H, Moriguchi T, Taguchi K, Takai J, Maher JM, Suzuki T, Winnard PT Jr, Raman V, Ebina M, Nukiwa T, Yamamoto M
  • Journal Title: Carcinogenesis Volume: 31 Pages: 1833-1843
  • Peer Reviewed
• [Journal Article] The transcriptome of Nrf2-/-mice provides evidence for impaired cell cycle progression in the development of cigarette-smoke-induced emphysematous changes (2010)
  • Author(s): Gebel S, Diehl S, Pype J, Friedrichs B, Weiler H, Schuller J, Xu H, Taguchi K, Yamamoto M, Muller T
  • Journal Title: Toxicol Sci Volume: 115 Pages: 238-252
  • Peer Reviewed
• [Journal Article] Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice (2010)
  • Author(s): Sugimoto H, Okada K, Shoda J, Warabi E, Ishige K, Ueda T, Taguchi K, Yanagawa T, Nakahara A, Hyodo I, Ishii T, Yamamoto M
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 298 Pages: 283-294
  • Peer Reviewed
• [Journal Article] Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice (2010)
  • Author(s): Sugimoto H, Okada K, Shoda J, Warabi E, Ishige K, Ueda T, Taguchi K, et al.
  • Journal Title: American Journal of Physiology Gastrointestinal and Liver Physiology Volume: 298
  • Peer Reviewed
• [Journal Article] The transcriptome of Nrf2-/- mice provides evidence for impaired cell cycle progression in the development of cigarette-smoke-induced emphysematous changes (2010)
  • Author(s): Gebel S, Diehl S, Pype J, Friedrichs B, Weiler H, Schuller J, Xu H, Taguchi K, et al.
  • Journal Title: Toxicological Sciences Volume: 115 Pages: 238-252
  • Peer Reviewed
• [Journal Article] The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1 (2010)
  • Author(s): Komatsu M, Kurokawa H, Waguri S, Taguchi K, et al.
  • Journal Title: Nature Cell Biology Volume: 12 Pages: 213-223
  • Peer Reviewed
• [Journal Article] Genetic Analysis of Cytoprotective Functions Supported by Graded Expression of Keap1 (2010)
  • Author(s): Taguchi K, et al.
  • Journal Title: Molecular and Cellular Biology Volume: 30 Pages: 3016-3026
  • Peer Reviewed
• [Journal Article] Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway : a potential role for protein aggregation in autophagic substrate selection (2010)
  • Author(s): Riley BE, Kaiser SE, Shaler TA, Ng AC, Hara T, Hipp MS, Lage K, Xavier RJ, Ryu KY, Taguchi K, et al.
  • Journal Title: Journal of Cell Biology Volume: 191 Pages: 537-552
  • Peer Reviewed
• [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: 秋保温泉
• [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(宮城)
• [Presentation] Co-activation of Nrf2 and Akt causes bile ductal metaplasia (2011)
  • Author(s): Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto
  • Organizer: Tohoku University Global COE for conquest of Signal Transduction Diseases with "Network Medicine" Network Medicine Winter Camp of GCOE
  • Place of Presentation: 宮城県秋保
  • Year and Date: 2011-02-05
• [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: 金沢市
• [Presentation] Keap1 degradation by autophagy for the maintenance of redox homeostasis (2011)
  • Author(s): Nanako Fujikawa, Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto
  • Organizer: 16th World Congress on Advances in Oncology and 14th International Symposium on Molecular Medicine
  • Place of Presentation: Hotel Rodos Palace, Rhodes Island in Greece
• [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: ギリシャ・ロードス島
• [Presentation] 上皮細胞における転写因子Nrf2の活性化 (2010)
  • Author(s): 田口恵子、鈴木隆史、本橋ほづみ、山本雅之
  • Organizer: フォーラム2010:衛生薬学・環境トキシコロジー
  • Place of Presentation: 星薬科大学
  • Year and Date: 2010-09-09
• [Presentation] 上皮細胞における転写因子Nrf2の活性化 (2010)
  • Author(s): 田口恵子、鈴木隆史、本橋ほづみ、山本雅之
  • Organizer: 第76回日本生化学会東北支部会例会
  • Place of Presentation: コラッセ福島
  • Year and Date: 2010-05-08
• [Presentation] Co-activation of Nrf2 and Akt causes bile ductal metaplasia (2010)
  • Author(s): Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto
  • Organizer: Tohoku University Global COE for conquest of Signal Transduction Diseases with"Network Medicine", Network Medicine Winter Camp of GCOE
  • Place of Presentation: Akiu, Miyagi
• [Book] 活性酸素種や親電子性物質によるシグナル伝達実験医学2012増刊号「シグナル伝達研究の最前線 2012-2013」 (2012)
  • Author(s): 田口恵子、山本雅之
  • Publisher: 羊土社
• [Book] 実験医学2012増刊号「シグナル伝達研究の最前線2012-2013」7.活性酸素種や親電子性物質によるシグナル伝達 (2012)
  • Author(s): 田口恵子、山本雅之
  • Publisher: 羊土社
• [Remarks] 東北大学大学院医学系研究科医化学分野
  • URL: http://www.dmbc.med.tohoku.ac.jp/official/index.html
• [Remarks]
  • URL: http://www.dmbc.med.tohoku.ac.jp/official/index.html
• [Remarks]
  • URL: http://www.dmbc.med.tohoku.ac.jp/official/index.html