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Analysis of pharmacological properties and identification of nuclear export signal of novel heat shock cognate protein 54

Research Project

Project/Area Number 13670099
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionTokyo Women's Medical University

Principal Investigator

TSUKAHARA Fujiko  Tokyo Women's Medical University, School of Medicine, Instructor, 医学部, 助手 (40119996)

Co-Investigator(Kenkyū-buntansha) YOSHIOKA Toshimasa  Tokyo Women's Medical University, School of Medicine, Professor, 医学部, 教授 (60146438)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2001: ¥2,000,000 (Direct Cost: ¥2,000,000)
Keywordsheat shock cognate protein 54 / heat shock cognate protein 70 / nuclear export signal / CRM1 / leptomycinB / heat shock protein / molecular chaperone / subcellular localization / heat shock cognate protein 54 / 核内移行 / 核外移行 / CRMI
Research Abstract

1.Heat shock cognate protein 70 (Hsc70) serves nuclear transport of several proteins as a molecular chaperone. We have recently identified a novel variant of human Hsc70, heat shock cognate protein 54 (Hsc54). In the present study, we examined nucleocytoplasmic localization of Hsc70 and Hsc54 using green fluorescent protein (GFP) fusions. GFP-Hsc70 is localized in both the cytoplasm and the nucleus, while GFP-Hsc54 remained exclusively in the cytoplasm. Mutation studies indicated that 20 amino acid residues of nuclear localization-related signal (NLRS) which are missing in Hsc54 but are retained in Hsc70 are required for proper nuclear localization of Hsc70. We further found that Hsc54 contains a functional nuclear export signal (NES : ^<394>LDVTPLSL^<401>). Hsc54 may be actively exported from the nucleus to the cytoplasm through a CRM1-dependent mechanism. In contrast, NLRS may functionally mask NES leading to prolonged retention of Hsc70 in the nucleus. An additional mechanism for unmasking the NES may regulate nucleocytoplasmic trafficking of Hsc70.
2.Role of heat shock protein 90 (Hsp90) on nuclear retention of glucocorticoid receptor (GR) after ligand withdrawal was studied. Hsp90 inhibitors accelerated nuclear export of GR and nuclear-targeted Hsp90 prolonged nuclear retention of GR, suggesting that nuclear Hsp90 regulates the nuclear retention of GR.
3.Interactions between glucocorticoid and Hsp90 inhibitors on their anti-inflammatory molecular mechanism were studied. Hsp90 inhibitor itself inhibited activation of NF-κB and AP-1, however, attenuates dexamethasone(Dex)-induced inhibition of IL-1β induction, which results from attenuation of Dex-mediated GR activation and inhibition of NF-κB and AP-1. Hsp90 inhibitors may reduce the anti-inflammatory action of Dex.

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (34 results)

All Other

All Publications (34 results)

  • [Publications] Fujiko Tsukahara, Yoshiro Maru: "Identification of novel nuclear export and nuclear localization-related signals in human heat shock cognate protein 70"Journal of Biological Chemistry. 279. 8867-8872 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Katsuya Tago et al.: "Regulation of nuclear retention of glucocorticoid receptor by nuclear Hsp90"Molecular Cellular Endocrinology. 213(2). 131-138 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Katsuya Tago et al.: "Hsp90 inhibitors attenuate effect of dexamethasone on activated NF-κB and AP-1"Life Science. 74(16). 1981-1992 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Fujiko Tsukahara, Yoshiro Maru: "Mechanism of stability and degradation of the chronionyelogenous leukemia oncoproteia BCR-ABL"Journal of Pharmacological Science. 94 Suppl.I. 105 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Michiko Mori et al.: "Suppression by 17β-estradiol of monocyte celt adhesion to vascular endothelial cells is mediated by estrogen receptor."Life Science. (in press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Fujiko Tsukahara et al.: "Molecular mechanism for nuclear export of human heat shock protein 54(Hsc54)."Journal of Pharmacological Science. 94 Suppl.I. 225 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Fujiko Tsukahara et al.: "Regulation of nucleocytoplasmic shuttling and turnover of dioxin receptor(AhR) by nuclear heat shock protein 90"The Pharmacologist. 44(2). A177 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Fujiko Tsukahara et al.: "Nuclear heat shock protein 90 (hsp90) negatively regulates nuclear export of dioxin receptor (AhR)"Jpn.J.Pharmacol.. 88・Suppl I. 275 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Katsuya Tago et al.: "Interaction between glucocorticoid and heat shock protein 90 inhibitor on activated NF-κB and AP-1"Jpn.J.Pharmacol.. 88・Suppl I. 275 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Michiko Mori et al.: "Suppressive effect of 17β-estradiol on monocytoid cell adhesion to vascular endothelial cells is mediated by estrogen receptor-α or-β"Jpn.J.Pharmacol.. 88・Suppl I. 221 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 多胡克哉: "グルココルチコイド受容体(GR)の核-細胞質間移行における熱ショック蛋白質(HSP)の役割"日本内分泌学雑誌. 77巻1号. 184 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tsukahara F, Maru Y: "Identification of novel nuclear export and nuclear localization-related signals in human heat shock cognate protein 70."J.Biol.Chem.. 10. 8867-8872 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tsukahara F, Maru Y: "Mechanism of stability and degradation of the chronic myelogenous leukemia oncoprotein, BCR-ABL."J.Pharmacol.Sci.. 94, Suppl. 105 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tago K, Tsukahara F, Naruse M, Yoshioka T, Takano K: "Regulation of nuclear retention of glucocorticoid receptor by nuclear Hsp90."Mol.Cell.Endocrinol.. 213, 2. 131-138 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tago K, Tsukahara F, Naruse M, Yoshioka T, Takano K: "Hsp90 inhibitors attenuate effect of dexamethasone on activated NF-κB and AP-1."Life Sci.. 74, 16. 1981-1992 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mori M, Tsukahara F, Yoshioka T, Irie K, Ohta K: "Suppression by 17β-estradiol of monocyte cell adhesion to vascular endothelial cells is mediated by estrogen receptor."Life Sci.. (In press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tsukahara F, Yoshioka T, Maru Y: "Molecular mechanism for nuclear export of human heat shock protein 54 (Hsc54)."J.Pharmacol.Sci.. 94, Suppl.I. 225 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tsukahara F, Yoshioka T, Tago K, Mori M, Muraki T: "Regulation of nucleocytoplasmic shuttling and turnover of dioxin receptor (AhR) by nuclear heat shock protein 90."Pharmacologist. 44, 2. A177 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tsukahara F, Yoshioka T, Tago K, Mori M, Muraki T.: "Nuclear heat shock protein 90 (hsp90) negatively regulates nuclear export of dioxin receptor (AhR)."Jpn.J.Pharmacol.. 88, Suppl I. 275 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tago K, Tsukahara F, Yoshioka T, Muraki T, Takano K: "Interaction between glucocorticoid and heat shock protein 90 inhibitor on activated NF-κB and AP-1"Jpn.J.Pharmacol.. 88, Suppl I. 275 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mori M, Tsukahara F, Yoshioka T, Muraki T, Ohta H: "Suppressive effect of 17β-estradiol on monocytoid cell adhesion to vascular endothelial cells is mediated by estrogen receptor-α or -β."Jpn.J.Pharmacol.. 88, Suppl I. 221 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tago K, Yoshioka T, Tsukahara F, Muraki T, Takano K.: "Role of heat shock proteins on nucleocytoplasmic shuttling of glucocorticoid receptor."Folia Endocrinologica Japonica. 77, 1. 184 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Fujiko Tsukahara, Yoshiro Maru: "Identification of novel nuclear export and nuclear localization-related signals in human heat shock cognate protein 70"Journal of Biological Chemistry. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Katsuya Tago et al.: "Regulation of nuclear retention of glucocorticoid receptor by nuclear Hsp90"Molecular Cellular Endocrinology. 213(2). 131-138 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Katsuya Tago et al.: "Hsp90 inhibitors attenuate effect of dexamethasone on activated NF-κB and AP-1"Life Science. 74(16). 1981-1992 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Fujiko Tsukahara, Yoshiro Maru: "Mechanism of stability and degradation of the chronic myelogenous leukemia oncoprotein, BCR-ABL"Journal of Pharmacological Science. 94 Suppl.I. 105 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Fujiko Tsukahara: "Molecular mechanism for nuclear export of human heat shock cognate protein 54 (Hsc54)"Jpn. J. Pharmacol. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fujiko Tsukahara: "Regulation of nucleocytoplasmic shuttling and turnover of dioxin receptor (AhR) by nuclear heat shock protein 90"The Pharmacologist. 44 2. A177 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 多胡克哉: "NF-kB, AP-1およびp38MAPKの活性化に対するグルココルチコイドと熱ショックタンパク質90阻害薬の相互作用"東京女子医科大学総合研究所紀要. 22. 109 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 多胡克哉: "グルココルチコイド受容体(GR)の核-細胞質間移行における熱ショック蛋白質(HSP)の役割"日本内分泌学雑誌. 77巻1号. 184 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fujiko Tsukahara: "Nuclear heat shock protein 90 (hsp90) negatively regulates nuclear export of dioxin receptor (AhR)"Jpn.J.Pharmacol.. 88・Suppl I. 275 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Katsuya Tago: "Interaction between glucocorticoid and heat shock protein 90 inhibitor on activated NF-κB and AP-1"Jpn.J.Pharmacol.. 88・Suppl I. 275 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Michiko Mori: "Suppressive effect of 17β-estradiol on monocytoid cell adhesion to vascular endothelial cells is mediated by estrogen receptor-α or-β"Jpn.J.Pharmacol.. 88・Suppl I. 221 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fujiko Tsukahara: "Regulation of nucleocytoplasmic shuttling and turnover of dioxin receptor (AhR) by nuclear heat shock protein 90"The Pharmacologist. 44(In press). (2002)

    • Related Report
      2001 Annual Research Report

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

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