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Glucocorticoids Induce Human Glycoprotein Hormone -Subunit Gene Expression in the Gonadotrope

Departments of Reproductive Medicine and Neuroscience, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093

Address all correspondence and requests for reprints to: Pamela L. Mellon, Department of Reproductive Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0674. E-mail: pmellon{at}ucsd.edu.

The human glycoprotein hormone -subunit (GSU) gene is transcriptionally regulated by glucocorticoids in a cell type-specific fashion. In direct contrast to repression of GSU by glucocorticoids in placenta, glucocorticoid receptor (GR) modulation in the pituitary is little understood. We show that glucocorticoids stimulate the GSU promoter in immortalized pituitary gonadotrope-derived LβT2 cells, whereas estrogens, androgens, and progestins have no significant effect. Moreover, GR acts in a dose-dependent manner at physiological concentrations of glucocorticoids. Transient transfection of GR with dexamethasone (Dex) treatment further stimulates the GSU promoter, but this induction is severely diminished using a receptor mutated in the DNA-binding domain. Truncation and cis mutations demonstrate that glucocorticoid response element 2 (GRE2) and cAMP-response element 2 (CRE2) within –168 bp of the human GSU promoter are critical for induction. Moreover, dominant-negative CRE-binding protein markedly inhibits basal but also Dex induction of GSU promoter activity. Additionally, GR specifically binds to GRE2 in the human GSU promoter in vitro and to the 5' region of the endogenous mouse GSU gene in vivo. Furthermore, overexpression of the homeobox factor, Distal-less 3 that regulates this gene in placental cells through a site partially overlapping GRE2, blocks Dex induction of GSU in gonadotrope cells, indicating that placenta-specific expression of Dlx3 may interfere with GR, resulting in repression in placental cells vs. induction in gonadotrope cells. These results demonstrate the stimulatory role played by glucocorticoids in GSU gene expression in the pituitary gonadotrope, in contrast to repression in placental cells, and highlight the tissue-specific nature of steroid hormone action.