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Elucidation of cytoprotective mechanisms by structural analysis of stress sensor Keap1

Research Project

Project/Area Number 18K19417
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 48:Biomedical structure and function and related fields
Research InstitutionTohoku University

Principal Investigator

Yamamoto Masayuki  東北大学, 医学系研究科, 教授 (50166823)

Project Period (FY) 2018-06-29 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2018: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Keywordsストレス応答 / Keap1 / Nrf2
Outline of Final Research Achievements

Stress sensor Keap1 is a key factor that controls ubiquitination reaction of transcription factor Nrf2 and plays a central role in the stress defense mechanism. Keap1 regulates Nrf2 ubiquitination in response to various stress stimuli. Regarding the molecular basis of the stress response, it has been suggested that the structural change of the Keap1 protein is the key, but the details are unknown. In this study, we aimed to clarify how the activity of the ubiquitin ligase complex containing Keap1 is inactivated by stress stimulation, and challenged to elucidate the molecular mechanism of Nrf2 activation in our body.

Academic Significance and Societal Importance of the Research Achievements

Keap1のストレス感知機構を構造生物学的に理解することは、現在大きく展開中のNrf2誘導剤の創薬開発に有益な情報を提供する。Nrf2誘導剤はストレス防御・疾患予防などへの応用が期待されているが、これまで開発されてきたNrf2誘導剤には特異性の問題点が指摘されている。Keap1に特異的に反応しNrf2を活性化できる化合物を開発することができれば、より副作用の少ない安全なNrf2誘導剤の開発につながるものと期待される。この点で、本研究の成果は有益な創薬ツールを提供する。

Report

(3 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • Research Products

    (45 results)

All 2020 2019 2018 Other

All Journal Article (26 results) (of which Int'l Joint Research: 16 results,  Peer Reviewed: 26 results,  Open Access: 10 results) Presentation (16 results) (of which Int'l Joint Research: 7 results,  Invited: 16 results) Book (1 results) Remarks (2 results)

  • [Journal Article] Inhibitors of the protein-protein interaction between phosphorylated p62 and Keap1 attenuate chemoresistance in a human hepatocellular carcinoma cell line2020

    • Author(s)
      Daisuke Yasuda, Tomoyuki Ohe, Kyoko Takahashi, Riyo Imamura, Hirotatsu Kojima, Takayoshi Okabe, Yoshinobu Ichimura, Masaaki Komatsu, Masayuki Yamamoto, Tetsuo Nagano, Tadahiko Mashino
    • Journal Title

      Free Radical Research

      Volume: Mar 30 Issue: 11-12 Pages: 1-13

    • DOI

      10.1080/10715762.2020.1732955

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma2020

    • Author(s)
      1.Nabeshima T, Hamada S, Taguchi K, Tanaka Y, Matsumoto R, Yamamoto M, Masamune A
    • Journal Title

      Am J Physiol Gastrointest Liver Physiol

      Volume: 318 Issue: 3 Pages: G419-G427

    • DOI

      10.1152/ajpgi.00296.2019

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Nrf2 suppresses oxidative stress and inflammation in APP knock-in Alzheimer's disease model mice2020

    • Author(s)
      3)(*Equal contribution) Uruno A*, Matsumaru D*, Ryoke R, Saito R, Kadoguchi S, Saigusa D, Saito T, Saido TC, Kawashima R, Yamamoto M.
    • Journal Title

      Mol Cell Biol.

      Volume: 40 Issue: 6

    • DOI

      10.1128/mcb.00467-19

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Impacts of NRF2 activation in non–small-cell lung cancer cell lines on extracellular metabolites2020

    • Author(s)
      Saigusa Daisuke、Motoike Ikuko N.、Saito Sakae、Zorzi Michael、Aoki Yuichi、Kitamura Hiroshi、Suzuki Mikiko、Katsuoka Fumiki、Ishii Hirofumi、Kinoshita Kengo、Motohashi Hozumi、Yamamoto Masayuki
    • Journal Title

      Cancer Science

      Volume: 111 Issue: 2 Pages: 667

    • DOI

      10.1111/cas.14278

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular Mechanism of Cellular Oxidative Stress Sensing by Keap12019

    • Author(s)
      Suzuki Takafumi、Muramatsu Aki、Saito Ryota、Iso Tatsuro、Shibata Takahiro、Kuwata Keiko、Kawaguchi Shin-ichi、Iwawaki Takao、Adachi Saki、Suda Hiromi、Morita Masanobu、Uchida Koji、Baird Liam、Yamamoto Masayuki
    • Journal Title

      Cell Reports

      Volume: 28 Issue: 3 Pages: 746-758

    • DOI

      10.1016/j.celrep.2019.06.047

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function2019

    • Author(s)
      Nagasu Hajime、Sogawa Yuji、Kidokoro Kengo、Itano Seiji、Yamamoto Toshiya、Satoh Minoru、Sasaki Tamaki、Suzuki Takafumi、Yamamoto Masayuki、Wigley W. Christian、Proksch Joel W.、Meyer Colin J.、Kashihara Naoki
    • Journal Title

      The FASEB Journal

      Volume: 33 Issue: 11 Pages: 12253-12263

    • DOI

      10.1096/fj.201900217r

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Role of Nrf2 in inflammatory response in lung of mice exposed to zinc oxide nanoparticles2019

    • Author(s)
      Sehsah Radwa、Wu Wenting、Ichihara Sahoko、Hashimoto Naozumi、Hasegawa Yoshinori、Zong Cai、Itoh Ken、Yamamoto Masayuki、Elsayed Ahmed Ali、El-Bestar Soheir、Kamel Emily、Ichihara Gaku
    • Journal Title

      Particle and Fibre Toxicology

      Volume: 16 Issue: 1 Pages: 47-47

    • DOI

      10.1186/s12989-019-0328-y

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Dietary supplementation with sulforaphane attenuates liver damage and heme overload in a sickle cell disease murine model2019

    • Author(s)
      Panda Harit、Keleku-Lukwete Nadine、Kuga Ayumi、Fuke Nobuo、Suganuma Hiroyuki、Suzuki Mikiko、Yamamoto Masayuki
    • Journal Title

      Experimental Hematology

      Volume: 77 Pages: 51-60.e1

    • DOI

      10.1016/j.exphem.2019.08.001

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Direct and Specific Functional Evaluation of the Nrf2 and MafG Heterodimer by Introducing a Tethered Dimer into Small Maf-Deficient Cells2019

    • Author(s)
      Katsuoka Fumiki、Otsuki Akihito、Takahashi Mizue、Ito Shin、Yamamoto Masayuki
    • Journal Title

      Molecular and Cellular Biology

      Volume: 39 Issue: 20

    • DOI

      10.1128/mcb.00273-19

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nrf2 deficiency aggravates the increase in osteoclastogenesis and bone loss induced by inorganic arsenic2019

    • Author(s)
      Liu Zhiyuan、Hou Yongyong、Li Lu、Yang Yang、Jia Jingkun、Hong Zhixuan、Li Tingfeng、Xu Yuanyuan、Fu Jingqi、Sun Yongxin、Yamamoto Masayuki、Wang Huihui、Pi Jingbo
    • Journal Title

      Toxicology and Applied Pharmacology

      Volume: 367 Pages: 62-70

    • DOI

      10.1016/j.taap.2019.02.003

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Nrf2 Suppresses Allergic Lung Inflammation by Attenuating the Type 2 Innate Lymphoid Cell Response2019

    • Author(s)
      Nagashima Ryuichi、Kosai Hitomi、Masuo Masahiro、Izumiyama Keiko、Noshikawaji Taketo、Morimoto Motoko、Kumaki Satoru、Miyazaki Yasunari、Motohashi Hozumi、Yamamoto Masayuki、Tanaka Nobuyuki
    • Journal Title

      The Journal of Immunology

      Volume: 202 Issue: 5 Pages: 1331-1339

    • DOI

      10.4049/jimmunol.1801180

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Nrf2 represses the onset of type 1 diabetes in non-obese diabetic mice.2019

    • Author(s)
      Yagishita Y, Uruno A, Chartoumpekis DV, Kensler TW, Yamamoto M.
    • Journal Title

      J Endocrinol

      Volume: 未定 Issue: 3 Pages: 403-416

    • DOI

      10.1530/joe-18-0355

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Sulforaphane enriched transcriptome of lung mitochondrial energy metabolism and provided pulmonary injury protection via Nrf2 in mice2019

    • Author(s)
      Cho Hye-Youn、Miller-DeGraff Laura、Blankenship-Paris Terry、Wang Xuting、Bell Douglas A.、Lih Fred、Deterding Leesa、Panduri Vijayalakshmi、Morgan Daniel L.、Yamamoto Masayuki、Reddy Anita J.、Talalay Paul、Kleeberger Steven R.
    • Journal Title

      Toxicology and Applied Pharmacology

      Volume: 364 Pages: 29-44

    • DOI

      10.1016/j.taap.2018.12.004

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Structural instability of IκB kinase β promotes autophagic degradation through enhancement of Keap1 binding2018

    • Author(s)
      Kanamoto Mayu、Tsuchiya Yoshihiro、Nakao Yuki、Suzuki Takafumi、Motohashi Hozumi、Yamamoto Masayuki、Kamata Hideaki
    • Journal Title

      PLOS ONE

      Volume: 13 Issue: 11 Pages: e0203978-e0203978

    • DOI

      10.1371/journal.pone.0203978

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sulforaphane ameliorates steroid insensitivity through an Nrf2-dependent pathway in cigarette smoke-exposed asthmatic mice2018

    • Author(s)
      Sakurai Hirofumi、Morishima Yuko、Ishii Yukio、Yoshida Kazufumi、Nakajima Masayuki、Tsunoda Yoshiya、Hayashi Shih-Yuan、Kiwamoto Takumi、Matsuno Yosuke、Kawaguchi Mio、Yamamoto Masayuki、Hizawa Nobuyuki
    • Journal Title

      Free Radical Biology and Medicine

      Volume: 129 Pages: 473-485

    • DOI

      10.1016/j.freeradbiomed.2018.10.400

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Roles of the KEAP1-NRF2 system in mammalian skin exposed to UV radiation2018

    • Author(s)
      Ikehata Hironobu、Yamamoto Masayuki
    • Journal Title

      Toxicology and Applied Pharmacology

      Volume: 360 Pages: 69-77

    • DOI

      10.1016/j.taap.2018.09.038

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] NRF2 mitigates acute alcohol-induced hepatic and pancreatic injury in mice2018

    • Author(s)
      Sun Jing、Fu Jingqi、Zhong Yang、Li Lu、Chen Chengjie、Wang Xiaolei、Wang Linlin、Hou Yongyong、Wang Huihui、Zhao Rui、Zhang Xixuan、Yamamoto Masayuki、Xu Yuanyuan、Pi Jingbo
    • Journal Title

      Food and Chemical Toxicology

      Volume: 121 Pages: 495-503

    • DOI

      10.1016/j.fct.2018.09.042

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Nrf2 Activation Ameliorates Hepatotoxicity Induced by a Heme Synthesis Inhibitor2018

    • Author(s)
      Taguchi Keiko、Masui Saho、Itoh Tohru、Miyajima Atsushi、Yamamoto Masayuki
    • Journal Title

      Toxicological Sciences

      Volume: 167 Issue: 1 Pages: 227-238

    • DOI

      10.1093/toxsci/kfy233

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Deficiency in the transcription factor NRF2 worsens inflammatory parameters in a mouse model with combined tauopathy and amyloidopathy2018

    • Author(s)
      Rojo Ana I.、Pajares Marta、Garcia-Yague Angel J.、Buendia Izaskun、Van Leuven Fred、Yamamoto Masayuki、Lopez Manuela G.、Cuadrado Antonio
    • Journal Title

      Redox Biology

      Volume: 18 Pages: 173-180

    • DOI

      10.1016/j.redox.2018.07.006

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape2018

    • Author(s)
      Dayalan Naidu Sharadha、Muramatsu Aki、Saito Ryota、Asami Soichiro、Honda Tadashi、Hosoya Tomonori、Itoh Ken、Yamamoto Masayuki、Suzuki Takafumi、Dinkova-Kostova Albena T.
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 8037-8037

    • DOI

      10.1038/s41598-018-26269-9

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genetic inactivation of Nrf2 prevents clonal expansion of initiated cells in a nutritional model of rat hepatocarcinogenesis2018

    • Author(s)
      Orru Claudia、Szydlowska Marta、Taguchi Keiko、Zavattari Patrizia、Perra Andrea、Yamamoto Masayuki、Columbano Amedeo
    • Journal Title

      Journal of Hepatology

      Volume: 69 Issue: 3 Pages: 635-643

    • DOI

      10.1016/j.jhep.2018.05.010

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] NFE2-Related Transcription Factor 2 Coordinates Antioxidant Defense with Thyroglobulin Production and Iodination in the Thyroid Gland2018

    • Author(s)
      Ziros PG.、Habeos IG.、Chartoumpekis DV.、Ntalampyra E、Somm E、Renaud CO.、Bongiovanni M、Trougakos IP.、Yamamoto M、Kensler TW.、Santisteban P、Carrasco N、Ris-Stalpers C、Amendola E、Liao XH、Rossich L、Thomasz L、Juvenal GJ.、Refetoff S、Sykiotis GP
    • Journal Title

      Thyroid

      Volume: 28 Issue: 6 Pages: 780-798

    • DOI

      10.1089/thy.2018.0018

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis2018

    • Author(s)
      Yamamoto Masayuki、Kensler Thomas W.、Motohashi Hozumi
    • Journal Title

      Physiological Reviews

      Volume: 98 Issue: 3 Pages: 1169-1203

    • DOI

      10.1152/physrev.00023.2017

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Phenethyl Isothiocyanate, a Dual Activator of Transcription Factors NRF2 and HSF12018

    • Author(s)
      Dayalan Naidu Sharadha、Suzuki Takafumi、Yamamoto Masayuki、Fahey Jed W.、Dinkova-Kostova Albena T.
    • Journal Title

      Molecular Nutrition & Food Research

      Volume: 62 Issue: 18 Pages: 1700908-1700908

    • DOI

      10.1002/mnfr.201700908

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Hyperactivation of Nrf2 leads to hypoplasia of bone in vivo.2018

    • Author(s)
      Yoshida E, Suzuki T, Morita M, Taguchi K, Tsuchida K, Motohashi H, Doita M, and Yamamoto M
    • Journal Title

      Genes to Cells

      Volume: - Issue: 5 Pages: 386-392

    • DOI

      10.1111/gtc.12579

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy2018

    • Author(s)
      Shekh-Ahmad Tawfeeq、Eckel Ramona、Dayalan Naidu Sharadha、Higgins Maureen、Yamamoto Masayuki、Dinkova-Kostova Albena T、Kovac Stjepana、Abramov Andrey Y、Walker Matthew C
    • Journal Title

      Brain

      Volume: 141 Issue: 5 Pages: 1390-1403

    • DOI

      10.1093/brain/awy071

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Presentation] KEAP1-NRF2 regulatory pathway for environmental stress response and renal erythropoietin producing cells2019

    • Author(s)
      Yamamoto M
    • Organizer
      Boehringer Ingelheim
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Keap1-Nrf2 Antioxidative stress response system2019

    • Author(s)
      Yamamoto M
    • Organizer
      Paris Redox 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] KEAP1-NRF2 制御系と発がん2019

    • Author(s)
      山本雅之
    • Organizer
      第7回がんと代謝研究会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 酸化ストレス応答の分子メカニズムと病態2019

    • Author(s)
      山本雅之
    • Organizer
      わかもと先進眼科医療研究会特別講演
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] KEAP1センサー機能の分子基盤の解明2019

    • Author(s)
      山本雅之
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 酸化ストレス応答の分子メカニズムと病態2019

    • Author(s)
      山本雅之
    • Organizer
      CVMW2019心血管代謝週間
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] The Keap1-Nrf2 System for Understanding of Diseases and Drug Development2018

    • Author(s)
      Yamamoto M
    • Organizer
      World Congress of Basic and Clinical Pharmacology (WCP2018)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] KEAP1-NRF2システムと病態・創薬2018

    • Author(s)
      山本雅之
    • Organizer
      バルドキソロン全国研究会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] KEAP1-NRF2 システムとがんの治療2018

    • Author(s)
      山本雅之
    • Organizer
      秋田大学病院がんプロ講演
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] KEAP1-NRF2 Regulatory Pathway for Environmental Stress Response2018

    • Author(s)
      Yamamoto M
    • Organizer
      Environmental Health and Toxicology meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Keap1-Nrf2制御系の構造生物学的アプローチと病態2018

    • Author(s)
      山本雅之
    • Organizer
      第42回蛋白質と酸素の構造と機能に関する九州シンポジウム
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Nrf2 and its future2018

    • Author(s)
      Yamamoto M
    • Organizer
      EUROTOX2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] KEAP1-NRF2 System Regulating Cellular Oxidative Stress Response2018

    • Author(s)
      Yamamoto M
    • Organizer
      Nrf2 Seminar, Faculty of Pharmacy Paris Sud
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] がんの生物学と医学におけるKEAP1-NRF2制御系の役割2018

    • Author(s)
      山本雅之
    • Organizer
      第77回日本癌学会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] KEAP1-NRF2 System Regulating Oxidative Stress Response2018

    • Author(s)
      Yamamoto M
    • Organizer
      NHRI-ToMMo conference
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Roles KEAP1-NRF2 System Plays in Neurosciences and Diseases2018

    • Author(s)
      Yamamoto M
    • Organizer
      Stanford University symposium
    • Related Report
      2018 Research-status Report
    • Invited
  • [Book] 人体の細胞生物学 : カラー図解 第3章3.遺伝子発現の調節2018

    • Author(s)
      鈴木隆史、山本雅之
    • Total Pages
      271
    • Publisher
      日本医事新報社
    • ISBN
      9784784932320
    • Related Report
      2018 Research-status Report
  • [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

    • Related Report
      2019 Annual Research Report
  • [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

    • Related Report
      2018 Research-status Report

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Published: 2018-07-25   Modified: 2021-02-19  

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