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細胞周期と細胞死のシグナル伝達阻害剤の開発とその分子作用機構

Research Project

Project/Area Number 09256205
Research Category

Grant-in-Aid for Scientific Research on Priority Areas (A)

Allocation TypeSingle-year Grants
Research InstitutionThe University of Tokyo

Principal Investigator

吉田 稔  東京大学, 大学院・農学生命科学研究科, 助教授 (80191617)

Co-Investigator(Kenkyū-buntansha) 堀之内 末治  東京大学, 大学院・農学生命科学研究科, 教授 (80143410)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥48,000,000 (Direct Cost: ¥48,000,000)
Fiscal Year 1999: ¥18,000,000 (Direct Cost: ¥18,000,000)
Fiscal Year 1998: ¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 1997: ¥15,000,000 (Direct Cost: ¥15,000,000)
Keywordsヒストンアセチル化 / トリコスタチン / トラポキシン / 核外移行シグナル / レプトマイシン / CRM1 / 細胞周期 / 細胞死 / CDK / MAPキナーゼ / 遺伝子発現 / アポトーシス / シグナル伝達 / サイクリン依存症キナーゼ / 核外移行
Research Abstract

1.昨年度までにヒストン脱アセチル化酵素(HDAC)の阻害剤が高い抗腫瘍活性を示すことが示されたので、本年度は構造の多様なHDAC阻害剤の開発を目指した。酵素と共有結合することにより不可逆阻害を引き起こすトラポキシンと、HDACの活性中心亜鉛イオンと相互作用する可逆阻害剤トリコスタチンAとのハイブリッド化合物(CHAP)を合成し、その強力なHDAC阻害活性を明らかにした。さらにCHAPにおける基質アナログとなるメチレン鎖の長さやその先端の阻害基の種類を変えることにより、阻害剤構造の最適化を行った。これにより環状ペプチド骨格部分の改変による阻害剤の特異性変換のためのリード化合物が得られた。
2.抗腫瘍抗生物質レプトマイシンB(LMB)の標的として同定したヒトCRM1が蛋白質核外移行シグナル(NES)の受容体であることを明らかにしたが、本年度はレプトマイシンによるCRM1機能の阻害作用の詳細を検討した。まず、分裂酵母のLMB高度耐性変異株を取得し、その耐性変異が分裂酵母Crm1の中央保存領域のCys-529がSerへ置換したものであることを明らかにした。LMBとの結合実験からCys-529がLMBとの結合に必須であること、Cys-529とLMBとの結合は、LMBの不飽和ラクトンとSH基との付加反応であり、このようなLMBとの共有結合が起こる蛋白質はin vivoではCRM1のみであることを証明した。

Report

(3 results)
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (19 results)

All Other

All Publications (19 results)

  • [Publications] Kim, Y.B. et al.: "Oxamflatin is a novel compound that inhibits mammalian histone deacetylase"Oncogene. 18. 2461-2470 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kudo, N., et al.: "A novel nuclear export signal sensitive to oxidative stress in the fission yeast transcription factor Papl"J. Biol. Chem.. 274. 15151-15158 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kudo, N., et al.: "Leptomycin B inactivates CRM1/expoetin 1 by covalent modification at a cysteine residue in the central conserved region"Proc. Natil. Acad. Sci. USA. 96. 9112-9117 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kose, S., et al.: "β-subunit of nuclear pore-targeting complex (importin-β) can be exported from the nucleus in Ran-independent manner"J. Biol. Chem.. 274. 3946-3952 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yoshida, M., et al.: "Trichostatin and leptomycin. Inhibition of histone deacetylation and signal dependent nuclear export"Ann. N Y Acad. Sci.. 886. 23-36 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yang, J., et al.: "Maintenance of G2 arrest in the Xenopus oocyte: a role for 14-3-3-mediated inhibition of Cdc25 nuclear import"EMBO J.. 18. 2174-2183 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kudo et al.: "Molecular cloning and cell cycle-dependent expression of mammalian CRM1,a protein involved in nuclear export of proteins." J.Biol.Chem.272. 29742-29751 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fornerod et al.: "CRM1 is an export receptor for leucine-rich nuclear export signals." Cell. 90. 1051-1060 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fukuda et al.: "CRM1 is responsible for intracellular transport mediated by the nuclear export signal." Nature. 390. 308-311 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kudo et al.: "Leptomycin B inhibition of signal-mediated nuclear export by direct binding to CRM1." Exp.Cell Res.242. 540-547 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kim et al.: "phdl+,a histone deacetylase gene of Schizosaccharomyces pombe,is required for the meiotic cell cycle and resistance to trichostatin A." FEBS Lett.436. 193-196 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nakajima et al.: "FR901228,a potent antitumor antibiotic,is a novel histone deacetylase inhibitor." Exp.Cell Res.241. 126-133 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yoshida,M. and Horinouchi S: "G proteins,Cytoskeleton and Cancer." R.G.Landes, 342 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] M.Yoshida et al.: "Biochemical differences between staurosporine-induced apoptosis and premature mitosis" Experimental Cell Research. 232. 225-239 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] N.Kudo et al.: "Molecular cloning and cell cycle-dependent expression of mammalian CRM1,a protein involued in nuclear export of proteins" Journal of Biological Chemistry. 272. 29742-29751 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] M.Fornerod et al.: "CRM1 is an export receptor for leucine-rich nuclear export signals" Cell. 90. 1051-1060 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] M.Fukuda et al.: "CRM1 is responsible for intracellular transport mediated by the nuclear export signal" Nature. 390. 308-311 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] H.J.Kwon et al.: "Suppression of morphological transformation by radicicol is accompanied by ennanced geisolin expression" Oncogene. 15. 2625-2631 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] K.Kasahara et al.: "Identification of preussin as a selective inhibitor for cell grocoth of the fission yeast ts mutants defective in cdcz-regnlatory genes." Journal of Antibiotics. 50. 267-269 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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