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Submitted on November 22, 2002
Accepted on August 7, 2003
-subunit gene (GSU) in gonadotropes
1 Department of Endocrinology, Barts & the Royal London School of Medicine & Dentistry, West Smithfield, LONDON EC1A 7BE, UK.; Department of Physiology, University of California San Francisco, Box 0444, San Francisco, CA 94143-0444, USA.
* To whom correspondence should be addressed. 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. Over-expression of wild-type SF-1, but not a 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 over-expression of MAPK phosphatase (MKP-1). 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 2-hybrid assay. PACAP quickly activated MAPK (within 5 min) and also resulted in elevated levels of phospho-CREB, and phospho-SF-1 as judged by a specific anti-phospho S203 antibody; this effect was blocked by the MAPK kinase (MEK) 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 Ser 203 via MAPK. These data suggest strongly that induction of GSU gene expression by peptide hormone signaling is coupled directly to the post-translational status of SF-1.
GSU •
gonadotrope •
PACAP •
phosphorylation •
SF-1
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