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This version published online on August 28, 2003
Molecular Endocrinology, doi:10.1210/me.2003-0217
A more recent version of this article appeared on December 1, 2003
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Submitted on June 6, 2003
Accepted on August 22, 2003

An AP-1-like Motif Mediates 17{beta} -Estradiol Repression of GnRH Receptor Promoter via an Estrogen Receptor {alpha} -Dependent Mechanism in Ovarian and Breast Cancer Cells

Chi Keung Cheng1, Billy K. C. Chow1, and Peter C. K. Leung1*

1 Department of Obstetrics and Gynecology, University of British Columbia (C. K. C., P. C. K. L.), Vancouver, Canada V6H 3V5; Department of Zoology, University of Hong Kong (B. K. C. C.), Hong Kong, China

* To whom correspondence should be addressed. E-mail: peleung{at}interchange.ubc.ca.

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 17{beta} -estradiol (E2) repressed human GnRHR promoter via an AP-1-like motif and estrogen receptor (ER){alpha}, of which the DNA-binding domain (DBD) and the ligand-binding domain (LBD) 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 (PMA) responsiveness of the GnRHR promoter. EMSAs indicated that multiple transcription factors including c-Jun and c-Fos bound to the AP-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 PMA, which stimulated c-Jun phosphorylation on serine 63, a process that is prerequisite for recruitment of the transcriptional coactivator CREB-binding protein (CBP). Concomitantly, we found that overexpression of CBP could dose-dependently reverse the suppression. Taken together, our data indicate that E2-activated ER{alpha} represses human GnRHR gene transcription via an indirect mechanism involving CBP and possibly other transcriptional regulators.
Key words: GnRH receptor • promoter • estrogen receptor • AP-1 • CREB-binding protein • cancer

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ
Coregulators:   CBP
Ligands:   17β-Estradiol



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