Progesterone inhibits transcriptional activation of human chorionic gonadotropin-α gene through protein kinase A pathway in trophoblast cells

The purpose of this study was to analyze the mechanism of transcriptional inhibition of human chorionic gonadotropin-alpha, (hCG alpha) gene by progesterone in trophoblast cells. We stably transfected - 290 bp hCG alpha promoter-CAT constructs (-290h alpha CAT) into Rcho-1 cells and monitored the promoter activities. Differentiation-dependent activation of -290 bp hCG alpha promoter containing a tandem repeat of cAMP response element (CRE) was inhibited by progesterone in a dose-dependent manner. To further analyze the mechanism of the progesterone action, Rcho-1 cells stably transfected with -290h alpha CAT were treated with forskolin in the presence of progesterone. Progesterone inhibited forskolin-induced transcriptional activation of hCGa gene. Moreover, progesterone inhibited forskolin-induced transcriptional activation of CRE-CRE-tk-CAT. These results suggest that progesterone may inhibit cAMP-induced transcriptional activation of hCG alpha gene through CRE. Although progesterone did not alter the amount of CRE-binding protein (CREB), which is a main transcriptional factor bound to CRE(s) on hCG alpha. promoter, progesterone abolished forskolin-induced CREB phosphorylation. In addition, pretreatment with progesterone abolished forskolin-induced activation of nuclear protein kinase A (PKA). In conclusion, progesterone inhibits hCG alpha gene transcription, at least in part, via the CRE region by inhibiting CREB phosphorylation through PKA pathway in trophoblast cells. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.