Document Detail


FK506-binding protein 51 regulates nuclear transport of the glucocorticoid receptor beta and glucocorticoid responsiveness.
MedLine Citation:
PMID:  18326728     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: A spliced variant of the human glucocorticoid receptor GRbeta has been implicated in glucocorticoid responsiveness in glaucoma. Over-expression of the FK506-binding immunophilin FKBP51 also causes a generalized state of glucocorticoid resistance. In the present study, the roles of FKBP51 in the nuclear transport of GRbeta and glucocorticoid responsiveness were investigated.
METHODS: Human trabecular meshwork cells (GTM3 and TM5) and HeLa cells were treated with dexamethasone (DEX) and FK506 and transfected with GRbeta and FKBP51 expression vectors. Coimmunoprecipitation and Western blot analyses were performed to study interactions of FKBP51 and FKBP52 with GRalpha, GRbeta, Hsp90, or dynein. The cells were transfected with a GRE-luciferase reporter to evaluate the effects of DEX and FK506 and the overexpression of GRbeta and FKBP51 on glucocorticoid-mediated gene expression.
RESULTS: FKBP51 was involved in constitutive nuclear transport of both GRalpha and -beta in the absence of ligands. FKBP52 appeared to be solely responsible for the nuclear transport of ligand-activated GRalpha. DEX stimulated the translocation of GRalpha but not GRbeta. Overexpression of either GRbeta or FKBP51 stimulated GRbeta translocation and reduced DEX-induced luciferase in HeLa cells. FK506 did not alter DEX-induced translocation of GRalpha. However, FK506 increased the association of FKBP51 with GRbeta and stimulated DEX-induced translocation of GRbeta in normal TM cells, but not in glaucoma TM cells. Increased nuclear GRbeta significantly inhibited glucocorticoid responsiveness in TM cells.
CONCLUSIONS: Nuclear transport of GRbeta represents a novel mechanism through which FKBP51 alters GC sensitivity. GRbeta and FKBP51 may be responsible for increased responsiveness in steroid-induced ocular hypertensive individuals as well as in patients with glaucoma.
Authors:
Xinyu Zhang; Abbot F Clark; Thomas Yorio
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Investigative ophthalmology & visual science     Volume:  49     ISSN:  0146-0404     ISO Abbreviation:  Invest. Ophthalmol. Vis. Sci.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-10     Completed Date:  2008-04-15     Revised Date:  2014-09-15    
Medline Journal Info:
Nlm Unique ID:  7703701     Medline TA:  Invest Ophthalmol Vis Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1037-47     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Active Transport, Cell Nucleus
Blotting, Western
Cell Nucleus / metabolism*
Dexamethasone / pharmacology*
Dyneins / metabolism
Fluorescent Antibody Technique, Indirect
Genetic Vectors
Glucocorticoids / pharmacology*
HSP90 Heat-Shock Proteins / metabolism
HeLa Cells
Humans
Immunoprecipitation
Plasmids
Receptors, Glucocorticoid / metabolism*
Tacrolimus / pharmacology
Tacrolimus Binding Proteins / physiology*
Trabecular Meshwork / drug effects*,  metabolism
Transfection
Grant Support
ID/Acronym/Agency:
EY016242/EY/NEI NIH HHS; EY11979/EY/NEI NIH HHS; R01 EY016242/EY/NEI NIH HHS; R01 EY016242-01A1/EY/NEI NIH HHS; R01 EY016242-02/EY/NEI NIH HHS; R01 EY016242-03/EY/NEI NIH HHS
Chemical
Reg. No./Substance:
0/Glucocorticoids; 0/HSP90 Heat-Shock Proteins; 0/Receptors, Glucocorticoid; 0/glucocorticoid receptor alpha; 0/glucocorticoid receptor beta; 7S5I7G3JQL/Dexamethasone; EC 3.6.4.2/Dyneins; EC 5.2.1.-/Tacrolimus Binding Proteins; EC 5.2.1.-/tacrolimus binding protein 4; EC 5.2.1.8/tacrolimus binding protein 5; WM0HAQ4WNM/Tacrolimus
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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