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J. Biol. Chem., Vol. 282, Issue 50, 36755-36765, December 14, 2007

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Activin Regulates Estrogen Receptor Gene Expression in the Mouse Ovary^*

Jingjing L. Kipp, Signe M. Kilen, Teresa K. Woodruff^¶, and Kelly E. Mayo¹

From the Department of Biochemistry, Molecular Biology and Cell Biology, ^¶Department of Obstetrics and Gynecology, and Center for Reproductive Science, Northwestern University, Evanston, Illinois 60208

Activin, a member of the transforming growth factor-β superfamily, is an important modulator of follicle-stimulating hormone synthesis and secretion in the pituitary and plays autocrine/paracrine roles in the regulation of ovarian follicle development. From a microarray study on mouse ovarian granulosa cells, we discovered that the estrogen receptor β (ERβ) is inducible by activin. We previously demonstrated that estrogen suppresses activin gene expression, suggesting a feedback relationship between these two follicle-regulating hormones. The purpose of this study was to investigate fully activin A regulation of ER expression. Real time reverse transcription-PCR assays on cultured granulosa cells showed that both ER and ERβ mRNAs were induced by activin A at 4, 12, and 24 h in a dose-responsive manner. Western blots confirmed an increase in their protein levels. Consistent with increased ER and ERβ expression, activin A stimulated estradiol-induced estrogen response element promoter activity. Activin A stimulation of ER expression was a direct effect at the level of gene transcription, as it was not abolished by cycloheximide but was abolished by actinomycin D, and in transfected granulosa cells activin A stimulated ER promoter activity. To investigate the effect of activin in vivo and, thus, its biological significance, we examined ER expression in inhibin transgenic mice that have decreased activin expression and discovered that these mice had decreased ER and ERβ expression in the ovary. We also found that ER mRNA levels were decreased in Müllerian inhibiting substance promoter (MIS)-Smad2 dominant negative mice that have impaired activin signaling through Smad2, and small interfering RNAs targeting Smad2 or Smad3 suppressed ER promoter activation, suggesting that Smad2 and Smad3 are involved in regulating ER levels. Therefore, this study reveals an important role for activin in inducing the expression of ERs in the mouse ovary and suggests important interplay between activin and estrogen signaling.

Received for publication, June 22, 2007 , and in revised form, October 19, 2007.

^* This work was supported by National Institutes of Health Endocrinology Training Grant T32 DK007169 (to J. L. K.) and by National Institutes of Health Program Project Grant HD91291. 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 To whom correspondence should be addressed: 2205 Tech Dr., Hogan 4-112, Evanston, IL 60208. Tel.: 847-491-8854; Fax: 847-491-8799; E-mail: k-mayo{at}northwestern.edu.

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