Abstract
Recent in vivo and in vitro studies have implicated the orphan nuclear receptor, steroidogenic factor-1 (SF-1), and the early growth response protein 1 (Egr-1) in the transcriptional regulation of the luteinizing hormone beta-subunit (LHbeta) gene. We have previously demonstrated the ability of SF-1 to bind to and transactivate the rat LHbeta gene promoter acting at a consensus gonadotrope-specific element (GSE) located at position -127. We have now identified a second functional GSE site at position -59. In addition, based on electrophoretic mobility shift assay, in vitro translated Egr-1 is shown to bind to two putative Egr-1 binding sites (positions -112 and -50), which appear to be paired with the identified GSE sites. By transient transfection assay in pituitary-derived GH3 cells, it was seen that Egr-1 increases promoter activity of region -207/+5 of the rat LHbeta gene promoter through action at both Egr-1 sites. Furthermore, LHbeta gene promoter activity is markedly augmented in the presence of both factors together relative to activity in the presence of SF-1 or Egr-1 alone (150-fold versus 14-fold and 12-fold, respectively). These data define two composite SF-1-Egr-1 response-elements in the proximal LHbeta gene promoter and suggest that SF-1 and Egr-1 act synergistically to increase expression of the LHbeta gene in the gonadotrope.
Highlights
Precise regulation of gonadotropin gene expression is required for normal reproductive function
steroidogenic factor-1 (SF-1) Binds to the Putative 3ЈGSE Site—We have previously demonstrated the ability of SF-1 to increase rat LH gene promoter activity through action at a functional gonadotrope-specific element (GSE) site located at position Ϫ127/Ϫ119, designated as the 5ЈGSE site [9]
These results suggested two possibilities: 1) the importance of additional base pairs in this GSE site to the SF-1response, or 2) the presence of additional SF-1 binding sites that contribute to the regulation of LH gene promoter activity
Summary
Precise regulation of gonadotropin gene expression is required for normal reproductive function. It was previously considered to be an orphan member of this family, it has recently been reported that SF1-dependent transcriptional activity is increased in the presence of cholesterol metabolites, 25-OH-cholesterol [7]. It is currently unknown whether this putative ligand is important for SF-1 function in nonsteroidogenic tissues, such as the pituitary gland. Targeted disruption of the Ftz-F1 gene encoding SF-1 results in transgenic mice that lack transcripts for the gonadotrope markers LH, FSH, and gonadotropin-releasing hormone receptor and have greatly diminished levels of ␣-subunit mRNA [3]. Gonadotropin-releasing hormone replacement was able to restore gonadotropin expression in four out of five of these animals, suggesting that cells from the gonadotrope lineage are present but that a specific defect in gonadotropin subunit gene expression exists [8]
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