An activator protein 1-like motif mediates 17beta-estradiol repression of gonadotropin-releasing hormone receptor promoter via an estrogen receptor alpha-dependent mechanism in ovarian and breast cancer cells.
Although it is recognized that estrogen is one of the most important regulators of GnRH receptor (GnRHR) gene expression, the mechanism underlying the regulation at the transcriptional level is unknown. In the present study, we demonstrated that 17beta-estradiol (E2) repressed human GnRHR promoter via an activator protein 1-like motif and estrogen receptor-alpha, of which the DNA-binding domain and the ligand-binding domain were indispensable for the repression. Interestingly, the same cis-acting motif was also found to be important for both the basal activity and phorbol 12-myristate 13-acetate responsiveness of the GnRHR promoter. EMSAs indicated that multiple transcription factors including c-Jun and c-Fos bound to the activator protein 1-like site and that their DNA binding activity was not significantly affected by E2 treatment. In addition, we demonstrated that the E2 repression could be antagonized by phorbol 12-myristate 13-acetate, which stimulated c-Jun phosphorylation on serine 63, a process that is a prerequisite for recruitment of the transcriptional coactivator cAMP response element binding protein (CREB)-binding protein (CBP). Concomitantly, we found that overexpression of CBP could reverse the suppression in a dose-dependent manner. Taken together, our data indicate that E2-activated estrogen receptor-alpha represses human GnRHR gene transcription via an indirect mechanism involving CBP and possibly other transcriptional regulators.
Cheng
Chi Keung
CK
Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada V6H 3V5.
Chow
Billy K C
BK
Leung
Peter C K
PC
D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D005576:Colforsin / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000737:chemistry / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010051:Ovarian Neoplasms; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics*; D011960:Receptors, Estrogen / Q000502:physiology*; D011966:Receptors, LHRH / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
D004273:DNA, Neoplasm; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D011966:Receptors, LHRH; D018808:Transcription Factor AP-1; D005576:Colforsin; D004958:Estradiol; D013755:Tetradecanoylphorbol Acetate