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(In Japanese)脊髄性筋萎縮症発症メカニズムの解析

Research report code R000000278
Posted date Sep 30, 2002
  • (In Japanese)辻本 賀英
  • (In Japanese)大阪大学大学院医学系研究科
Research organization
  • (In Japanese)大阪大学大学院医学系研究科
Report name (In Japanese)脊髄性筋萎縮症発症メカニズムの解析
Technology summary (In Japanese)遺伝性の運動神経変性疾患の一つ「脊髄性筋萎縮症」を対象に,疾患原因遺伝子産物Smnが,神経細胞死を防ぐBcl-2たんぱくに結合し,その活性を促進する機能を持つことを解明してきた成果を基礎に,Bcl-2の持つ細胞死抑制機能の生化学的なメカニズムとSmnによるその機能増強の分子メカニズムを解明すべく研究を展開してきた。ここでは,Bcl-2はミトコンドリアで機能し,神経細胞死を誘導するファクターであるシトクロムcの細胞質への遊離を抑制することで細胞死を抑制することと,シトクロムcの遊離はミトコンドリア膜上に存在するチャネルVDACを介して起こり,Bcl-2はこのチャネルを閉孔することでシトクロムcの遊離を抑制することを明らかにした。また,Bcl-2の機能分子ターゲットの同定によりアポトーシス抑制を目指した薬剤開発への道の基礎を開いた。

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Research field
  • Biological function
  • Genetic variation
  • Function of cell components
  • Central nervous system
  • Basic neurology
  • Nervous system diseases
Published papers related (In Japanese)(1)Imazu, T., Shimizu, S., Tagami, S., Matsushima, M., Nakamura, Y., Miki, T., Okuyama, A. and Tsujimoto. Y. Bcl-2/E1B 19 kDa-interacting protein 3-ike protein (Bnip3L) interacts with Bcl-2/Bcl-xL and induces apoptosis by altering mitochondrial membrane permeability. Oncogene, 18: 4523-4529, 1999
(2)Shimizu, S., Narita, M. and Tsujimoto, Y. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399: 483-487, 1999
(3)Hamada, Y., Kadokawa, Y., Okabe, M., Ikawa, M., Coleman, J. R. and Tsujimoto, Y. Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality. Dev. 126:3 415-3424, 1999
(4)Hagiwara, Y., Saitoh, Y., Arita, N., Eguchi, Y., Tsujimoto, Y., Yoshimine, T. and Hayakawa, T. Long-term functional assessment of encapsulated cells transfected with Tet-on system. Cell Transpl., 8: 431-434, 1999
(5)Lee, J.-H., Takahashi, T., Yasuhara, N., Inazawa, J., Kamada, S. and Tsujimoto, Y.: Bis, a Bcl-2-binding protein that synergizes with Bcl-2 in preventing cell death. Oncogene, 18: 6183-6190, 1999
(6)Ohtsubo, T., Kamada. S., Mikami, T., Murakami, H. and Tsujimoto, Y.: Identification of NRF2, a member of the NF-E2 family of transcription factors, as a substrate for caspase-3(-like) proteases. Cell Death Diff. 6: 865-872, 1999
(7)Sahara, S., Aoto, M., Eguchi, Y., Imamoto, N., Yoneda, Y. and Tsujimoto, Y.: Acinus is a caspase-3-activated protein required for apoptotic chromatin condensation. Nature 401: 168-173, 1999
(8)Nomura, M., Shimizu, S., Ito, T., Narita, M., Matsuda, H. and Tsujimoto, Y.: Apoptotic cytosol facilitates Bax translocation to mitochondria that involves cytosolic factor regulated by Bcl-2. Cancer Res. 59:5542-5548, 1999
(9)Igata, E., Inoue, T., Ohtani-Fujita, N., Sowa, Y., Tsujimoto, Y. and Sakai, T.: Molecular cloning and functional analysis of the murine bax gene promoter. Gene 238: 407-415, 1999
(10)Tsujimoto, Y. and Shimizu, S.: Bcl-2 family: Life-or-death switch, FEBS lett. 466: 6-10, 2000
(11)Shimizu, Y. and Tsujimoto, Y.: Pro-apoptotic BH3-only Bcl-2 family members induce cytochrome c release, but not mitochondrial membrane potential loss, and do not directly modulate VDAC activity. Proc. Natl. Acad. Sci. USA. 97:577-582, 2000
Research project
  • Core Research for Evolutional Science and Technology;Protecting the Brain
Information research report
  • (In Japanese)辻本 賀英. 脳を守る 脊髄性筋萎縮症発症メカニズムの解析. 戦略的基礎研究推進事業 平成11年度 研究年報.科学技術振興事業団, 2000. p.921 - 923.