2003 Fiscal Year Final Research Report Summary
Analysis of pharmacological properties and identification of nuclear export signal of novel heat shock cognate protein 54
| Project/Area Number |
13670099
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | Tokyo Women's Medical University |
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Principal Investigator |
TSUKAHARA Fujiko Tokyo Women's Medical University, School of Medicine, Instructor, 医学部, 助手 (40119996)
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| Co-Investigator(Kenkyū-buntansha) |
YOSHIOKA Toshimasa Tokyo Women's Medical University, School of Medicine, Professor, 医学部, 教授 (60146438)
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| Project Period (FY) |
2001 – 2003
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| Keywords | heat shock cognate protein 54 / heat shock cognate protein 70 / nuclear export signal / CRM1 / leptomycinB / heat shock protein / molecular chaperone / subcellular localization |
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| 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.
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Research Products
(22 results)
