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オートファジーの破綻によるヒト病態発症機序の解明

Research Project

Project/Area Number 21679002
Research Category

Grant-in-Aid for Young Scientists (S)

Allocation TypeSingle-year Grants
Research Field Pathological medical chemistry
Research InstitutionTokyo Metropolitan Organization for Medical Research

Principal Investigator

小松 雅明  Tokyo Metropolitan Organization for Medical Research, 研究員 (90356254)

Project Period (FY) 2009 – 2010
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥66,300,000 (Direct Cost: ¥51,000,000、Indirect Cost: ¥15,300,000)
Fiscal Year 2011: ¥20,800,000 (Direct Cost: ¥16,000,000、Indirect Cost: ¥4,800,000)
Fiscal Year 2010: ¥20,800,000 (Direct Cost: ¥16,000,000、Indirect Cost: ¥4,800,000)
Fiscal Year 2009: ¥24,700,000 (Direct Cost: ¥19,000,000、Indirect Cost: ¥5,700,000)
Keywordsオートファジー / p62 / Keap1 / Nrf2 / 癌 / 凝集体 / ユビキチン / Nbr1 / Alfy
Research Abstract

研究目的
我々は、オートファジーがユビキチン-プロテアソーム系と共にタンパク質やオルガネラの品質管理機構に貢献し、その破綻が肝障害、肝細胞がんや神経変性疾患を引き起こすこと、更に、一般に非選択的分解機構と考えられてきたオートファジーに上記病態発症に関与する選択基質があることを見出した。本研究の特色は、現在、国内外で未曾有の発展を遂げているオートファジー研究の中でも、これまでの我々の研究実績を基軸に「選択的オートファジーの破綻による病態発症」に焦点を当て、健康社会実現を目指した先駆的研究を展開することにある。
研究成果
今回、ヒト肝細胞がん患者の約25%においてオートファジー選択的基質p62が過剰に蓄積しp62とKeap1陽性の凝集体が形成されること、さらにその腫瘍部位において転写因子Nrf2が活性化されていることを発見した。さらに、p62を蓄積し、且つNrf2を活性化しているヒト肝細胞がんにおいて、p62遺伝子を欠損させると足場非依存的ながん細胞の増殖が抑制されること、その増殖障害はp62の野生型の過剰発現で回復する一方、Keap1と相互作用できないp62,変異体の過剰発現では回復されないことを確認した。従って、p62の蓄積、凝集を介したNrf2の活性化は、肝細胞がんの生存戦略に利用されていることを意味する。このことは、オートファジーを欠損したマウス肝臓においてp62の過剰蓄積を伴った腫瘍が形成されること、さらにその腫瘍形成がp62の同時欠損により大幅に抑制される知見とも一致した。

Report

(2 results)
  • 2010 Annual Research Report
  • 2009 Annual Research Report
  • Research Products

    (33 results)

All 2011 2010 2009 Other

All Journal Article (18 results) (of which Peer Reviewed: 18 results) Presentation (11 results) Remarks (3 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Autophagy-deficient mice develop multiple liver tumors2011

    • Author(s)
      Takamura, et al.
    • Journal Title

      Genes Dev.

      Volume: 25 Pages: 795-800

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Persistent activation of Nrf2 in hepatocellular carcinoma cells2011

    • Author(s)
      Inami, et al.
    • Journal Title

      J.Cell Biol.

      Volume: 193 Pages: 275-284

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ubiquitin accumulation in autophagy-deficient, mice is dependent on the Nrf2-mediated stress response pathway : a potential role for protein aggregates in autophagic substrate selection2010

    • Author(s)
      Riley, et al.
    • Journal Title

      J.Cell Biol.

      Volume: 191 Pages: 537-552

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Selective degradation of p62 by autophagy2010

    • Author(s)
      Ichimura, Komatsu
    • Journal Title

      Semin.Immunopathol.

      Volume: 32 Pages: 431-136

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Selective autophagy regulates various cellular functions2010

    • Author(s)
      Komatsu, Ichimura
    • Journal Title

      Genes Cells

      Volume: 15 Pages: 923-933

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through Keap1-inactivation2010

    • Author(s)
      Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y., Sou, Y-s., Ueno, I., Sakamoto, A., Tong, K.I., Kim, M., Nishito, Y., Iemura, SI., Natsume, T., Ueno, T., Kominami, E., Motohashi, H., Tanaka K., Yamamoto M.
    • Journal Title

      Nature Cell Biology 12

      Pages: 213-223

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy2010

    • Author(s)
      Matsuda, N., Sato, S., Shiba, K., Okatsu, K., Saisho, K., Gautier, C.A., Sou, Y.-s., Saiki, S., Kawajiri, S., Sato, F., Kimura, M., Komatsu, M., Hattori, N., Tanaka, K.
    • Journal Title

      J Cell Biol 189

      Pages: 211-221

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Physiological significance of selective degradation of p62 by autophagy2010

    • Author(s)
      Komatsu, M., Ichimura, Y.
    • Journal Title

      FEBS Letters 584 : 1374-1378(2010) 584

      Pages: 1374-1378

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel type of E3 ligase for Ufm1-conjugating system2010

    • Author(s)
      Tatsumi, K., Sou, Y-s., Tada, N., Nakamura, E., Iemura, SI., Natsume, T., Kang, S-H., Chung, C-H., Kasahara, M., Kominami, E., Tanaka, K., Komatsu, M.
    • Journal Title

      J Biol Chem 285

      Pages: 5417-5427

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Loss of autophagy in erythroid cells leads to defective removal of mitochondria and severe anemia in vivo2010

    • Author(s)
      Mortensen, M., Ferguson, DJ., Edelmann, M., Kessler, B., Morten, KJ., Komatsu, M., Simon AK.
    • Journal Title

      Proc Natl Acad Sci USA 107

      Pages: 832-837

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Adipose-specific deletion of autophagy-related gene 7(atg7)in mice reveals a role in adipogenesis2009

    • Author(s)
      Zhang, Y., Goldman, S., Baerga, R., Zhao, Y., Komatsu, M., Jin, S.
    • Journal Title

      Proc Natl Acad Sci USA 106

      Pages: 19860-19865

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Discovery of Atg5/Atg7-independent alternative macroautophagy2009

    • Author(s)
      Nishida, Y., Arakawa, S., Fujitani, K., Yamaguchi, H., Mizuta, T., Kanaseki, T., Komatsu, M., Otsu, K., Tsujimoto, Y., Shimizu, S.
    • Journal Title

      Nature 461

      Pages: 654-658

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A novel hybrid yeast-human network analysis reveals an essential role for FNBP1L in antibacterial autophagy2009

    • Author(s)
      Huett, A., Ng, A., Cao, Z., Kuballa, P., Komatsu, M., Daly, M.J., Podolsky, D.K., Xavier, R.
    • Journal Title

      J Immunol 182 : 4917-4930(2009) 182

      Pages: 4917-4930

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A novel hybrid yeast-human network analysis reveals an essential role for FNBP1L in antibacterial autophagy2009

    • Author(s)
      Wu, JJ., Quijano, C., Chen, E., Liu, H., Cao, L., Fergusson, MM., Rovira, II., Gutkind, S., Daniels, MP., Komatsu, M., Finkel, T.
    • Journal Title

      Aging(Albany NY) 9

      Pages: 425-437

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Autophagy regulates lipid metabolism2009

    • Author(s)
      Singh, R., Kaushik, S., Wang, Y, Xiang, Y, Novak, I., Komatsu, M., Tanaka, K., Cuervo, A-M., Czaja, M.J.
    • Journal Title

      Nature 458 : 1131-1135(2009) 458

      Pages: 1131-1135

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Autophagy is essential for mitochondrial clearance in mature T lymphocytes2009

    • Author(s)
      Pua, H.H., Guo, J., Komatsu, M., He, Y.W.
    • Journal Title

      J Immunol 182 : 4046-4055(2009) 182

      Pages: 14046-14055

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Selective autophagy regulates various cellular functions

    • Author(s)
      Komatsu, M.
    • Journal Title

      Genes Cells (In press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Selective degradation of p62 by autophagy

    • Author(s)
      Ichimura, Y., Komatsu, M.
    • Journal Title

      Seminars in Immunopathy (In press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Presentation] Selective autophagy regulates various cellular functions2010

    • Author(s)
      Komatsu M
    • Organizer
      Pacifichem2010(Symposium)
    • Place of Presentation
      Honolulu USA(招待講演)
    • Year and Date
      2010-12-19
    • Related Report
      2010 Annual Research Report
  • [Presentation] Pathophysiological role of selective autophagy2010

    • Author(s)
      小松雅明
    • Organizer
      第69回BMB2010(シンポジウム)
    • Place of Presentation
      神戸
    • Year and Date
      2010-12-08
    • Related Report
      2010 Annual Research Report
  • [Presentation] The tumorigenesis in autophagy-deficient livers2010

    • Author(s)
      小松雅明
    • Organizer
      第69回日本癌学会学術総会(モーニングレクチャー)
    • Place of Presentation
      大阪
    • Year and Date
      2010-09-24
    • Related Report
      2010 Annual Research Report
  • [Presentation] Pathophysiological roles of autophagy in mouse liver2010

    • Author(s)
      Komatsu M
    • Organizer
      17^<th> IMHCVRV (Plenary Lecture)
    • Place of Presentation
      Yokohama, Japan(招待講演)
    • Year and Date
      2010-09-10
    • Related Report
      2010 Annual Research Report
  • [Presentation] The regulation of stress-response system by autophagy-specific substrate p 62, and its pathophysiological role in hepatocellular carcinoma2010

    • Author(s)
      Komatsu M
    • Organizer
      30th SAPPORO INTERNATIONAL CANCER SYMPOSIUM MEMBRANE TRAFFIC AND CANCER
    • Place of Presentation
      Sapporo, Japan(招待講演)
    • Year and Date
      2010-06-29
    • Related Report
      2010 Annual Research Report
  • [Presentation] Regulation of Nrf2 by an autophagy-specific substrate, p622010

    • Author(s)
      Komatsu M
    • Organizer
      4^<th> Gordon Research Conference, Autophagy in Stress, Development & Diseases
    • Place of Presentation
      Barga, Italy(招待講演)
    • Year and Date
      2010-04-27
    • Related Report
      2010 Annual Research Report
  • [Presentation] 健康と病態における選択的オートファジーの先駆的研究2009

    • Author(s)
      小松雅明
    • Organizer
      第32回日本分子生物学会年会
    • Place of Presentation
      神奈川県・横浜市
    • Year and Date
      2009-12-11
    • Related Report
      2009 Annual Research Report
  • [Presentation] Autophagy -the selectivity and pathophysiology-2009

    • Author(s)
      小松雅明
    • Organizer
      Seminar, University of Cambridge UK
    • Place of Presentation
      Cambridge・UK
    • Year and Date
      2009-10-22
    • Related Report
      2009 Annual Research Report
  • [Presentation] Important roles of autophagy-specific substrate p62 in environmental stress response2009

    • Author(s)
      小松雅明
    • Organizer
      EMBO Conference on : Autophagy, Cell Biology, Physiology and Pathology
    • Place of Presentation
      Monte Verita Ascona・Switzerland
    • Year and Date
      2009-10-19
    • Related Report
      2009 Annual Research Report
  • [Presentation] Pathophysiological role of selective autophagy in hepatocellular carcinoma2009

    • Author(s)
      小松雅明
    • Organizer
      第68回日本癌学会学術総会
    • Place of Presentation
      神奈川県・横浜市
    • Year and Date
      2009-10-03
    • Related Report
      2009 Annual Research Report
  • [Presentation] Important roles of autophagy-specific substrate p62 in environmental stress response2009

    • Author(s)
      小松雅明
    • Organizer
      International Symposium on Autophagy
    • Place of Presentation
      滋賀県・大津市
    • Year and Date
      2009-09-28
    • Related Report
      2009 Annual Research Report
  • [Remarks]

    • URL

      http://www.igakuken.or.jp/

    • Related Report
      2010 Annual Research Report
  • [Remarks]

    • URL

      http://www.rinshoken.or.jp/activities/t100221.html

    • Related Report
      2009 Annual Research Report
  • [Remarks]

    • URL

      http://www.jst.go.jp/pr/announce/20100222/index.html

    • Related Report
      2009 Annual Research Report
  • [Patent(Industrial Property Rights)] 肝疾患治療薬2010

    • Inventor(s)
      小松雅明、田中啓二、丹羽眞一郎, 牧野泰孝、笠間隆志
    • Industrial Property Rights Holder
      財団法人 東京都医学研究機構、(株)リンク・ジェノミクス
    • Industrial Property Number
      2010-001892
    • Filing Date
      2010-01-07
    • Related Report
      2009 Annual Research Report

URL: 

Published: 2009-04-01   Modified: 2016-04-21  

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