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Repression of the Inhibin -Subunit Gene by the Transcription Factor CCAAT/Enhancer-Binding Protein-ß

Department of Biochemistry, Molecular Biology and Cell Biology, and Center for Reproductive Science, Northwestern University (A.D.B., K.E.M.), Evanston, Illinois 60208; Reproductive Endocrine Unit, Massachusetts General Hospital, Harvard Medical School (A.M.), Boston, Massachusetts 02114; and Molecular Mechanisms in Development Group, Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute (E.S.), and Eukaryotic Transcriptional Regulation Section, Laboratory of Protein Dynamics and Signaling, National Cancer Institute (P.F.J.), Frederick, Maryland 21702-1201

Address all correspondence and requests for reprints to: Dr. Kelly E. Mayo, Department of Biochemistry, Molecular Biology, and Cell Biology, and Center for Reproductive Science, Northwestern University, Evanston, Illinois 60208. E-mail: k-mayo{at}northwestern.edu.

Inhibin is a dimeric peptide hormone produced in ovarian granulosa cells that suppresses FSH synthesis and secretion in the pituitary. Expression of inhibin - and ß-subunit genes in the rodent ovary is positively regulated by FSH and negatively regulated after the preovulatory LH surge. We have investigated the role of the transcription factor CCAAT/enhancer-binding protein-ß (C/EBPß) in repressing the inhibin -subunit gene. C/EBPß knockout mice fail to appropriately down-regulate inhibin -subunit mRNA levels after treatment with human chorionic gonadotropin, indicating that C/EBPß may function to repress inhibin gene expression. The expression and regulation of C/EBPß were examined in rodent ovary, and these studies show that C/EBPß is expressed in ovary and granulosa cells and is induced in response to human chorionic gonadotropin. Transient cotransfections with an inhibin promoter-luciferase reporter in a mouse granulosa cell line, GRMO2 cells, show that C/EBPß is capable of repressing both basal and forskolin-stimulated inhibin gene promoter activities. An upstream binding site for C/EBPß in the inhibin -subunit promoter was identified by electrophoretic mobility shift assays, which, when mutated, results in elevated inhibin promoter activity. However, C/EBPß also represses shorter promoter constructs lacking this site, and this component of repression is dependent on the more proximal promoter cAMP response element (CRE). Electrophoretic mobility shift assays show that C/EBPß effectively competes with CRE-binding protein for binding to this atypical CRE. Thus, there are two distinct mechanisms by which C/EBPß represses inhibin -subunit gene expression in ovarian granulosa cells.

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