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J. Biol. Chem., Vol. 278, Issue 43, 41779-41788, October 24, 2003

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Identification of Glucocorticoid Receptor Domains Involved in Transrepression of Transforming Growth Factor- Action^*

Gangyong Li, Shengfu Wang, and Thomas D. Gelehrter¶

From the Departments of Human Genetics and Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109

The transforming growth factor- (TGF-) and glucocorticoid signaling pathways interact both positively and negatively in regulating a variety of physiological and pathologic processes. We previously reported that liganded glucocorticoid receptor (GR) repressed TGF- induction of human plasminogen activator inhibitor-1 gene transcription by directly targeting the transcriptional activation function of Smad3. To identify the domain(s) in the glucocorticoid receptor involved in this repression, we have examined the ability of various GR truncation, deletion, and substitution mutants to repress TGF- transactivation in Hep3B human hepatoma cells that lack functional endogenous GR. Partial deletions in the ligand-binding domain (LBD), including the 2 and c regions, greatly reduced or eliminated GR repression, whereas deletion of the N-terminal AF1 (1) domain and substitution mutations in the DNA-binding domain had little or no effect. Liganded androgen receptor repressed TGF- transactivation, whereas mineralocorticoid receptor did not, and studies with rat GR-mineralocorticoid receptor chimeras confirmed that the GR C-terminal domains were required for repression. RU486, a strong antagonist of transactivation by GR, partially reversed repression by wild type GR. Co-immunoprecipitation experiments in Hep3B cells indicated that physical interaction between GR and Smad3 is necessary but not sufficient for repression. Physical interaction required activation of Smad3 by TGF- but not dexamethasone binding to GR. Glutathione S-transferase pull-down assays demonstrated that several regions of the LBD could mediate GR-Smad3 physical interaction. We conclude that the LBD of GR, but not the DNA-binding domain or the N-terminal activation domain, is required for GR-mediated transrepression of TGF- transactivation.

Received for publication, May 21, 2003 , and in revised form, July 14, 2003.

^* This work was supported by an Arthritis Foundation Biomedical Science grant and, in part, by pilot/feasibility study grants from the University of Michigan Multipurpose Arthritis Center Grant P60 AR20557 and the Michigan Diabetes Research and Training Center Grant P60 DK20572 from the National Institutes of Health (to T. D. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Human Genetics, 4909 Buhl Bldg., Box 0618, 1241 East Catherine St., Ann Arbor, MI 48109-0618. Tel.: 734-764-5491; Fax: 734-763-5831; E-mail: tdgum{at}umich.edu.

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