オートファジーの破綻によるヒト病態発症機序の解明

• Project/Area Number: 21679002
• Research Category: Grant-in-Aid for Young Scientists (S)
• Allocation Type: Single-year Grants
• Research Field: Pathological medical chemistry
• Research Institution: Tokyo 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: ¥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。

Research Products

• [Journal Article] Autophagy-deficient mice develop multiple liver tumors (2011)
  • Author(s): Takamura, et al.
  • Journal Title: Genes Dev. Volume: 25 Pages: 795-800
  • Peer Reviewed
• [Journal Article] Persistent activation of Nrf2 in hepatocellular carcinoma cells (2011)
  • Author(s): Inami, et al.
  • Journal Title: J.Cell Biol. Volume: 193 Pages: 275-284
  • 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 selection (2010)
  • Author(s): Riley, et al.
  • Journal Title: J.Cell Biol. Volume: 191 Pages: 537-552
  • Peer Reviewed
• [Journal Article] Selective degradation of p62 by autophagy (2010)
  • Author(s): Ichimura, Komatsu
  • Journal Title: Semin.Immunopathol. Volume: 32 Pages: 431-136
  • Peer Reviewed
• [Journal Article] Selective autophagy regulates various cellular functions (2010)
  • Author(s): Komatsu, Ichimura
  • Journal Title: Genes Cells Volume: 15 Pages: 923-933
  • Peer Reviewed
• [Journal Article] The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through Keap1-inactivation (2010)
  • 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
  • Peer Reviewed
• [Journal Article] PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy (2010)
  • 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
  • Peer Reviewed
• [Journal Article] Physiological significance of selective degradation of p62 by autophagy (2010)
  • Author(s): Komatsu, M., Ichimura, Y.
  • Journal Title: FEBS Letters 584 : 1374-1378(2010) 584 Pages: 1374-1378
  • Peer Reviewed
• [Journal Article] Novel type of E3 ligase for Ufm1-conjugating system (2010)
  • 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
  • Peer Reviewed
• [Journal Article] Loss of autophagy in erythroid cells leads to defective removal of mitochondria and severe anemia in vivo (2010)
  • 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
  • Peer Reviewed
• [Journal Article] Adipose-specific deletion of autophagy-related gene 7(atg7)in mice reveals a role in adipogenesis (2009)
  • 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
  • Peer Reviewed
• [Journal Article] Discovery of Atg5/Atg7-independent alternative macroautophagy (2009)
  • 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
  • Peer Reviewed
• [Journal Article] A novel hybrid yeast-human network analysis reveals an essential role for FNBP1L in antibacterial autophagy (2009)
  • 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
  • Peer Reviewed
• [Journal Article] A novel hybrid yeast-human network analysis reveals an essential role for FNBP1L in antibacterial autophagy (2009)
  • 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
  • Peer Reviewed
• [Journal Article] Autophagy regulates lipid metabolism (2009)
  • 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
  • Peer Reviewed
• [Journal Article] Autophagy is essential for mitochondrial clearance in mature T lymphocytes (2009)
  • Author(s): Pua, H.H., Guo, J., Komatsu, M., He, Y.W.
  • Journal Title: J Immunol 182 : 4046-4055(2009) 182 Pages: 14046-14055
  • Peer Reviewed
• [Journal Article] Selective autophagy regulates various cellular functions
  • Author(s): Komatsu, M.
  • Journal Title: Genes Cells (In press)
  • Peer Reviewed
• [Journal Article] Selective degradation of p62 by autophagy
  • Author(s): Ichimura, Y., Komatsu, M.
  • Journal Title: Seminars in Immunopathy (In press)
  • Peer Reviewed
• [Presentation] Selective autophagy regulates various cellular functions (2010)
  • Author(s): Komatsu M
  • Organizer: Pacifichem2010(Symposium)
  • Place of Presentation: Honolulu USA(招待講演)
  • Year and Date: 2010-12-19
• [Presentation] Pathophysiological role of selective autophagy (2010)
  • 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
• [Presentation] The tumorigenesis in autophagy-deficient livers (2010)
  • 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
• [Presentation] Pathophysiological roles of autophagy in mouse liver (2010)
  • 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
• [Presentation] The regulation of stress-response system by autophagy-specific substrate p 62, and its pathophysiological role in hepatocellular carcinoma (2010)
  • 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
• [Presentation] Regulation of Nrf2 by an autophagy-specific substrate, p62 (2010)
  • 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
• [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
• [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
• [Presentation] Important roles of autophagy-specific substrate p62 in environmental stress response (2009)
  • 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
• [Presentation] Pathophysiological role of selective autophagy in hepatocellular carcinoma (2009)
  • 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
• [Presentation] Important roles of autophagy-specific substrate p62 in environmental stress response (2009)
  • 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
• [Remarks]
  • URL: http://www.igakuken.or.jp/
• [Remarks]
  • URL: http://www.rinshoken.or.jp/activities/t100221.html
• [Remarks]
  • URL: http://www.jst.go.jp/pr/announce/20100222/index.html
• [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