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Submitted on March 16, 2004
Accepted on September 20, 2004
Isoform Suppresses the Transcriptional Activity of hGR
by Interfering with Formation of Active Coactivator Complexes
Pediatric and Reproductive Endocrinology Branch (E.C., G.P.C., T.I., A.V., T.K.), National Institute of Child Health and Human Development, and Diabetes Branch (N.B.), National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, 20892, USA
* To whom correspondence should be addressed. E-mail: charmane{at}mail.nih.gov.
The human glucocorticoid receptor (hGR) 
, a splicing variant of the classic receptor hGR
, functions as a dominant negative inhibitor of hGR. We explored the mechanism(s) underlying this effect of hGR by evaluating the interactions of this isoform with known steroid receptor coactivators. We found that hGR suppressed the transcriptional activity of both activation function (AF)-1 and AF-2 of hGR, indicating that hGR may exert its dominant negative effect by affecting the function of coactivators that are attracted to these transactivation domains. hGR bound to one of the p160 coactivators, the glucocorticoid receptor-interacting protein 1 (GRIP1) via its preserved AF-1 but not via its defective AF-2 in vitro. In a chromatin immunoprecipitation assay, hGR prevented coprecipitation of GRIP1 with hGR tethered to glucocorticoid response elements (GREs) of the endogenous tyrosine aminotransferase promoter, while deletion of the AF-1 of hGR abolished this effect. In further experiments, overexpression of GRIP1 attenuated the suppressive effect of hGR on hGR-mediated transactivation of the mouse mammary tumor virus (MMTV) promoter. Competition for binding to GREs or heterodimerization with hGR via the D loop dimerization interface occurred, but they were not necessary for the suppressive effect of hGR on the transcriptional activity of hGR. Our findings suggest that hGR suppresses the transcriptional activity of hGR by competing with hGR for binding to GRIP1, and possibly other p160 coactivators, through its preserved AF-1. These findings suggest that participation of hGR in the formation of a coactivator complex renders this complex ineffective.
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p160 coactivators
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