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Heat shock protein 90 is an essential molecular chaperone for nuclear transport of glucocorticoid receptor beta.

Abstract：

PURPOSE:Glucocorticoid sensitivity in glaucoma has been attributed to differences in the expression of the two glucocorticoid receptors, GRalpha and GRbeta. GRalpha undergoes steroid-dependent nuclear translocation by associating with a heat shock protein (Hsp)90 multiprotein heterocomplex. The nuclear transport of the non-ligand-binding GRbeta is still unknown. In this study, the roles of Hsp90 in the nuclear transport of GRbeta were investigated. METHODS:Immunocytochemistry and Western blot analysis were performed to detect the subcellular expression of GRbeta and Hsp90 in normal and glaucomatous trabecular meshwork (TM) cells, as well as in TM cells overexpressing GRbeta. The role of Hsp90 in GRbeta transport and stability were determined with the Hsp90 inhibitor, 17-AAG and the proteasome inhibitor lactacystin. Coimmunoprecipitation was performed to study GRbeta-Hsp90 complexes. RESULTS:In normal and glaucomatous TM cells, the nuclear concentration of Hsp90 correlates with the nuclear expression of GRbeta. Transfection with a GRbeta expression construct produces an overexpression and accumulation of GRbeta in the nucleus with a corresponding increase in nuclear Hsp90 amount. 17-AAG, a specific Hsp90 inhibitor, completely blocks the nuclear accumulation of GRbeta and consequently leads to the degradation of GRbeta in proteasomes. Coimmunoprecipitation experiments verify that GRbeta complexes with Hsp90 and the microtubule motor protein dynein. CONCLUSIONS:These data provide strong evidence that Hsp90 is an essential molecular chaperone for the nuclear transport of GRbeta. This transport appears to occur along micotubular tracks. Because nuclear GRbeta is important in regulating the glucocorticoid responsiveness, changes in GRbeta nuclear transport could influence subsequent responses that are often seen clinically, such as glucocorticoid resistance in some inflammatory and autoimmune diseases or enhanced glucocorticoid sensitivity in glaucoma.

journal_name

Invest Ophthalmol Vis Sci

journal_title

Investigative ophthalmology & visual science

authors

Zhang X,Clark AF,Yorio T

doi

10.1167/iovs.05-0697

keywords:

subject

Has Abstract

pub_date

2006-02-01 00:00:00

pages

700-8

issue

eissn

0146-0404

issn

1552-5783

pii

47/2/700

journal_volume

pub_type

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Heat shock protein 90 is an essential molecular chaperone for nuclear transport of glucocorticoid receptor beta.