Glucocorticoids induce human glycoprotein hormone α-subunit gene expression in the gonadotrope

Abstract

The human glycoprotein hormone α-subunit (αGSU) gene is transcriptionally regulated by glucocorticoids in a cell typespecific fashion. In direct contrast to repression of αGSU by glucocorticoids in placenta, glucocorticoid receptor (GR) modulation in the pituitary is little understood. We show that glucocorticoids stimulate the αGSU 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 αGSU 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 αGSU promoter are critical for induction. Moreover, dominant-negative CRE-binding protein markedly inhibits basal but also Dex induction of αGSU promoter activity. Additionally, GR specifically binds to GRE2 in the human αGSU promoter in vitro and to the 5′ region of the endogenous mouse αGSU 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 αGSU 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 αGSU gene expression in the pituitary gonadotrope, in contrast to repression in placental cells, and highlight the tissue-specific nature of steroid hormone action. Copyright © 2008 by The Endocrine Society.