Development of small compounds that induce alternative autophagy

• Project/Area Number: 16K15230
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: SHIMIZU Shigeomi 東京医科歯科大学, 難治疾患研究所, 教授 (70271020)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ケミカルバイオロジー / オートファジー / 実験病理学 / Atg5非依存的

Outline of Final Research Achievements

Autophagy is a cellular function that degrades subcellular constituents to contribute cellular homeostasis. The defect of alternative autophagy (Atg5-independent autophagy) may cause various diseases, such as anemia, neurodegenerative diseases, dermatitis, and colitis. In this study, we aimed to identify small chemical compounds/natural compounds that activate alternative autophagy and improve various diseases. As a result, we identified three anti-cancer compounds, two anti-polyglutamine disease compounds, and two anti-tauopathy compounds. We also identified two anti-fatty liver natural compounds.

Research Products

• [Journal Article] Association between autophagy and neurodegenerative diseases (2018)
  • Author(s): Fujikake N, Shin M, Shimizu S
  • Journal Title: Frontiers Neuroscience Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Dram1 regulates DNA damage-induced alternative autophagy (2018)
  • Author(s): Nagata M, Arakawa S, Yamaguchi H, Torii S, Endo H, Tsujioka M, Honda S, Nishida Y, Konishi A, Shimizu S
  • Journal Title: Cell Stress Volume: 2 Issue: 3 Pages: 55-65
  • DOI: 10.15698/cst2018.03.127
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial damage elicits a TCDD-inducible poly(ADP-ribose) polymerase-mediated antiviral response. (2017)
  • Author(s): Kozaki T, Komano J, Kanbayashi D, Takahama M, Misawa T, Satoh T, Takeuchi O, Kawai T, Shimizu S, Matsuura Y, Akira S, Saitoh T
  • Journal Title: Proc Natl Acad Sci U S A Volume: 114 Issue: 10 Pages: 2681-2686
  • DOI: 10.1073/pnas.1621508114
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Autophagy suppresses cell migration by degrading GEF-H1, a RhoA GEF (2016)
  • Author(s): T. Yoshida, M. Tsujioka, S. Honda, S. Shimizu
  • Journal Title: Oncotarget Volume: 7 Issue: 23 Pages: 34420-9
  • DOI: 10.18632/oncotarget.8883
  • Peer Reviewed / Open Access
• [Journal Article] In Situ Characterization of Bak Clusters Responsible for Cell Death Using Single Molecule Localization Microscopy (2016)
  • Author(s): Y. Nasu, A. Benke, S. Arakawa, G. Yoshida, G. Kawamura, S. Manley, S. Shimizu, T. Ozawa
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 27505-27505
  • DOI: 10.1038/srep27505
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Golgi membrane-associated degradation pathway in yeast and mammals (2016)
  • Author(s): H. Yamaguchi, S. Arakawa, T. Kanaseki, T. Miyatsuka, Y. Fujitani, H. Watada, Y. Tsujimoto, S. Shimizu
  • Journal Title: EMBO J. Volume: 35 Issue: 18 Pages: 1991-2007
  • DOI: 10.15252/embj.201593191
  • Peer Reviewed
• [Journal Article] TRF2 Protein Interacts with Core Histones to Stabilize Chromosome Ends. (2016)
  • Author(s): Konishi A, Izumi T, Shimizu S
  • Journal Title: J Biol Chem. Volume: 291(39) Issue: 39 Pages: 20798-810
  • DOI: 10.1074/jbc.m116.719021
  • Peer Reviewed / Open Access
• [Journal Article] Identification of PPM1D as an essential Ulk1 phosphatase for genotoxic stress‐induced autophagy (2016)
  • Author(s): S. Torii, T. Yoshida, S. Arakawa, S. Honda, A. Nakanishi, S. Shimizu
  • Journal Title: EMBO reports Volume: 11 Issue: 11 Pages: 1552-1564
  • DOI: 10.15252/embr.201642565
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Autophagy controls centrosome number by degrading Cep63. (2016)
  • Author(s): Watanabe Y, Honda S, Konishi A, Satoko Arakawa S, Murohashi M, Yamaguchi H, Torii S, Tanabe M, Tanaka S, Warabi E, Shimizu S.
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 13508-13508
  • DOI: 10.1038/ncomms13508
  • NAID: 120007129257
  • Peer Reviewed / Open Access
• [Presentation] オートファジーが関わる細胞死 (2017)
  • Author(s): 清水重臣
  • Organizer: 日本Cell Death学会
• [Presentation] 新規オートファジーの分子機構とその破綻による疾患 (2017)
  • Author(s): 清水重臣
  • Organizer: 第22回 日本病態プロテアーゼ学会
  • Invited
• [Presentation] Development of molecularly targeted anticancer agents based on the regulation of autophagic cell death (2017)
  • Author(s): 清水重臣
  • Organizer: 第76回日本癌学会
• [Presentation] Identification of natural product against fatty liver disease based on the induction of alternative autophagy (2016)
  • Author(s): Shimizu S
  • Organizer: ICNIM2016
  • Place of Presentation: Hotel Royton, Sapporo
  • Int'l Joint Research
• [Presentation] Alternative Autophagy is Essential for Neuronal Cell Maintenance (2016)
  • Author(s): Shimizu S
  • Organizer: Brain Protein Aging and Dementia Control International Workshop
  • Place of Presentation: Kakuyu Kaikan in Nagoya University, Nagoya
  • Int'l Joint Research
• [Presentation] Mitophagy and alternative autophagy (2016)
  • Author(s): Shimizu S
  • Organizer: The 13th Conference of Asian Society for Mitochondrial Research and Medicine
  • Place of Presentation: TKP Garden City Shinagawa, Shinagawa
  • Int'l Joint Research / Invited
• [Presentation] Macroautophagy mediates elimination of mitochondria from embryonic reticulocytes (2016)
  • Author(s): 清水重臣
  • Organizer: 第78回日本血液学会
  • Place of Presentation: パシフィコ横浜, 横浜
  • Invited
• [Remarks] 病態細胞生物ホームページ
  • URL: http://www.tmd.ac.jp/mri/pcb/index.html
• [Remarks] 病態細胞生物学分野ホームページ
  • URL: http://www.tmd.ac.jp/mri/pcb/index.html