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J. Biol. Chem., Vol. 281, Issue 30, 20817-20824, July 28, 2006

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Steroid Receptor Coactivator-3 Is Required for Progesterone Receptor Trans-activation of Target Genes in Response to Gonadotropin-releasing Hormone Treatment of Pituitary Cells^*

Beum-Soo An¹, David M. Selva, Geoffrey L. Hammond², Adolfo Rivero-Muller, Nafis Rahman, and Peter C. K. Leung³

From the Department of Obstetrics and Gynecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V6H 3V5, Canada and the Department of Physiology, Institute of Biomedicine, University of Turku, 20520 Turku, Finland

Regulation of gonadotropin production involves interplay between steroids and neuropeptides, and we have examined the effects of gonadotropin-releasing hormones (GnRH I and GnRH II) on progesterone receptor (PR) activation in T3-1 pituitary cells. Treatment with GnRHs activated a progester-one response element (PRE)-luciferase reporter gene, and this was blocked by protein kinase C and protein kinase A inhibitors but not by RU486. Treatment with GnRHs phosphorylated the PR at Ser²⁹⁴ and increased PR translocation to the nucleus within 1 h. Interactions between the PR and several coactivators were examined, and treatment with GnRHs specifically induced PR-steroid receptor coactivator-3 (SRC-3) interactions within 8 h. In chromatin immunoprecipitation assays, recruitment of PR and SRC-3 by the PREs of the luciferase reporter gene or the gonadotopin -subunit gene promoter was also increased by GnRHs within 8 h, while progesterone-induced recruitment of PR to the PREs occurred in association with much less SRC-3. A small interfering RNA knockdown of type I GnRH receptor levels reduced PR activation by GnRHs, while progesterone-dependent PR activation was unaffected. Moreover, small interfering RNA knockdown of SRC-3 abolished PRE-luciferase trans-activation by the PR in response to GnRHs. Collectively, these data indicate that PR activation by GnRHs in T3-1 cells is type I GnRH receptor-mediated and that trans-activation of PR-responsive genes requires SRC-3 in this context.

Received for publication, January 25, 2006 , and in revised form, May 17, 2006.

^* This work was supported in part by the Canadian Institutes of Health Research. 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.

¹ Recipient of bursary award from the Strategic Training Initiative in Research in the Reproductive Health Sciences.

² Holds a Canada Research Chair in Reproductive Health.

³ A distinguished scholar of the Michael Smith Foundation for Health Research. To whom correspondence should be addressed: Dept. of Obstetrics and Gynecology, University of British Columbia, 2H-30, 4490 Oak St., Vancouver, BC V6H 3V5, Canada. Tel.: 604-875-2718; Fax: 604-875-2717; E-mail: peleung{at}interchange.ubc.ca.

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