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Analysis of mechanism of tress-responsive and temperature-sensitive nuclear transport

Research Project

Project/Area Number 13460035
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 応用微生物学・応用生物化学
Research InstitutionRIKEN (2002)
The University of Tokyo (2001)

Principal Investigator

YOSHIDA Minoru  RIKEN, Chemical Genetics Laboratory Director of Laboratory, 化学遺伝学研究室, 主任研究員 (80191617)

Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥16,800,000 (Direct Cost: ¥16,800,000)
Fiscal Year 2002: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 2001: ¥10,800,000 (Direct Cost: ¥10,800,000)
KeywordsNuclear export signal / CRM1 / Oxidative stress / p53 / Pap1 / レプトマイシン / 温度感受性変異 / 転写制御 / 分裂酵母
Research Abstract

The target molecule of leptomycin B (LMB), a potent antitumor agent, was genetically and biochemically identified as CRM1 , a protein reported as being required for chromosome structure control. We showed that CRM1 was a receptor for the nuclear export signal (NES) and that LMB inhibited nuclear export of proteins. It therefore became able to easily determine whether a protein of interest can be exported from the nucleus by using LMB. Mouse temperature-sensitive p53^<Val135> (tsp53) accumulates in the nucleus and acts as a wild-type at 32℃, while it is sequestered in the cytoplasm at 37℃. The cytoplasmic tsp53 relocalized into the nucleus upon inhibition of the nudear export by LMB at 37℃, whereas a mutation in a major bipartite NLS caused constitutive cytoplasmic localization, indicating that it shuttled between the cytoplasm and the nucleus by its NES and NLS rather than tethered to cytoplasmic structures. We showed that the association with the Hsc70-containing complex prevents the NLS from the access of the import receptor through the C- terminal region of tsp53 at 37℃, whereas its dissociation at 32℃ allows rapid nuclear import. Using LMB, we identified a novel NES in the fission yeast transcription factor Pap1 , the function of which is abolished by oxidative stress in a manner conserved in eukaryotes. A single mutation in Crm1 (Cys-529 to Ser) caused a marked decrease in exporting Pap1 but not other typical NESs. These results suggest that the cysteine residue in Crm1 is involved in the stress-responsive nuclear export of Pap1.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] Akakura et al.: "A role for Hsc7O in regulating nucleo-cytoplasmic transport of a temperature-sensitive p53 (p53Val135)"J. Biol. Chem.. 276. 14649-14657 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Forgues et al.: "Interaction of the Hepatitis B virus X protein with the Crm1-dependent nuclear export pathway"J. Biol. Chem.. 276. 22797-22803 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishida, N. et al.: "Phosphorylation of p27Kip1 on serine-10 is required for its binding to CRM1 and nuclear export"J. Biol. Chem.. 277. 14355-14358 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Zeng, R. et al.: "Stat5B shuttles between cytoplasm and nucleus in cytokine-dependent and independent manners"J. Immunol.. 168. 4567-4575 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Murakami, N. et al.: "New Rev-transport inhibitor with anti-HIV activity from Valerianae Radix"Bioorg. Med. Chem. Lett.. 12. 2807-2810 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Jang, B.-C.et al.: "Leptomycin B, an inhibitor of nuclear export receptor CRM1, inhibits COX-2 expression"J. Biol. Chem.. 278. 2773-2776 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Akakura et al.: "A role for Hsc70 in regulating nucleo-cytoplasmic transport of a temperature-sensitive p53 (p53^<Val135>)"J. Biol. Chem.. 276. 14649-14657 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Forgues et al.: "Interaction of the Hepatitis B virus X protein with the Crm1-dependent nuclear export pathway"J. Biol. Chem.. 276. 22797-22803 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishida, N. et al.: "Phosphorylation of p27Kip1 on serine-10 is required for its binding to CRM1 and nuclear export"J. Biol. Chem.. 277. 14355-14358 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Zeng, R. et al.: "Stat5B shuttles between cytoplasm and nucleus in cytokine-dependent and independent manners"J. Immunol.. 168. 4567-4575 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Murakami, N. et al.: "New Rev-transport inhibitor with anti-HIV activity from Valerianae Radix"Bioorg. Med. Chem. Lett.. 12. 2807-2810 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Jang, B.-C. et al.: "Leptomycin B, an inhibitor of nuclear export receptor CRM1, inhibits COX-2 expression"J. Biol. Chem.. 278. 2773-2776 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishida, N., et al.: "Phosphorylation of p27Kip1 on serine-10 is required for its binding to CRM1 and nuclear export"J.Biol.Chem. 277. 14355-14358 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Zeng, R., et al.: "Stat5B shuttles between cytoplasm and nucleus in cytokine-dependent and independent manners"J.Immunol.. 168. 4567-4575 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Murakami, N., et al.: "New Rev-transport inhibitor with anti-HIV activity from Valerianae Radix"Bioorg.Med.Chem.Lett.. 12. 2807-2810 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Jang, B.-C., et al.: "Leptomycin B, an inhibitor of nuclear export receptor CRM1, inhibits COX-2 expression"J.Biol.Chem.. 278(in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Akakura, et al.: "A role for Hsc70 in regulating nucleo-cytoplasmic transport of a temperature-sensitive p53 (p53^<Val135>)"J. Biol. Chem.. 276. 14649-14657 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Forgues, et al.: "Interaction of the Hepatitis B virus X protein with the Crm1-dependent nuclear export pathway"J. Biol. Chem.. 276. 22797-22803 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Eleftheriou, et al.: "Nuclear export of human β-catenin can occur independent of CRM1 and APC"J. Biol. Chem.. 276. 25883-25888 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hirano, et al.: "Direct demonstration of rapid degradation of nuclear sterol regulatory element-binding proteins by ubiquitin-proteasome pathway"J. Biol. Chem.. 276. 36431-36437 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tomoda, et al.: "The cytoplasmic shuttling and subsequent degradation of p27^<Kip1> mediated by Jab1/CSN5 and the COP9 signalosome complex"J. Biol. Chem.. 277. 2302-2310 (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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