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Steroidogenic Factor-1 and The Gonadotrope-Specific Element Enhance Basal and Pituitary Adenylate Cyclase-Activating Polypeptide-Stimulated Transcription of the Human Glycoprotein Hormone -Subunit Gene in Gonadotropes

Department of Endocrinology, Barts and Royal London School of Medicine and Dentistry (R.C.F., M.V.P., S.J.B.A., P.K., J.M.B.), West Smithfield, London, United Kingdom EC1A 7BE; and Department of Physiology, University of California, San Francisco, California 94143-0444

Address all correspondence and requests for reprints to: Dr. R. C. Fowkes, Department of Physiology, S-1479, 513 Parnassus Avenue, University of California, San Francisco, California 94143-0444. E-mail: rfow0187{at}itsa.ucsf.edu.

In the anterior pituitary, expression of the common glycoprotein hormone -subunit (GSU) is mediated in part by multiple response elements residing in the distal promoter (-435 bp). One such site is the gonadotrope-specific element (GSE), which is bound by the orphan nuclear receptor steroidogenic factor-1 (SF-1) and confers pituitary adenylate cyclase-activating polypeptide (PACAP)-stimulated GSU expression. Here we investigated the functional importance of the GSE and SF-1 phosphorylation in both basal and stimulated GSU transcription. Mutation of the GSE reduced basal and PACAP-stimulated GSU promoter activity in the T3-1 gonadotrope cell line. Overexpression of wild-type SF-1, but not an S203A mutant form of SF-1, enhanced basal and PACAP-stimulated GSU promoter activity. The effect of PACAP on GSU promoter activity was inhibited after overexpression of MAPK phosphatase. Helix assembly of the SF-1 ligand-binding domain was stimulated by PACAP in vitro via a MAPK-dependent pathway, as determined using a mammalian two-hybrid assay. PACAP quickly activated MAPK (within 5 min) and also resulted in elevated levels of phospho-cAMP response element-binding protein and phospho-SF-1, as judged by a specific antiphospho-S203 antibody; this effect was blocked by the MAPK kinase inhibitor, UO126. Collectively, these data demonstrate that SF-1 binds to the GSE and activates both basal and PACAP-stimulated GSU transcription, which is further increased by phosphorylation at Ser²⁰³ via MAPK. These data suggest strongly that the induction of GSU gene expression by peptide hormone signaling is coupled directly to the posttranslational status of SF-1.

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Nuclear Receptors:   SF-1

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