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Estrogen Receptor (ER)-Mediated Transcriptional Regulation of the Human Corticotropin-Releasing Hormone-Binding Protein Promoter: Differential Effects of ER and ERß

Hubrecht Laboratory (A.v.d.S., A.J.S., M.O.R., A.W.M.Z., P.T.v.d.S.) Netherlands Institute for Developmental Biology, 3584 CT Utrecht, The Netherlands; Institute of Physiological Chemistry and Pathobiochemistry (S.G., C.B.), Johannes Gutenberg University Mainz, 55099 Mainz, Germany; and Mental Health Research Institute (A.F.S.), Ann Arbor, Michigan 48109-0720

Address all correspondence and requests for reprints to: Anja van de Stolpe, M.D., Ph.D., Hubrecht Laboratory, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands. E-mail: anja{at}niob.knaw.nl.

CRH-binding protein (CRH-BP) regulates activation of the hypothalamic-pituitary-adrenal (HPA) axis by binding and inhibiting CRH. We investigated for the first time transcriptional regulation of the human CRH-BP promoter using transient transfections. Estrogen receptors (ERs) contributed to ligand-independent constitutive activation of the promoter, whereas in the presence of estradiol ER induced and ERß repressed promoter activity in a dose-dependent manner. TNF inhibited promoter induction by ER in the absence and presence of estradiol. Three ERE half-sites in the CRH-BP promoter bound ER and ERß in an EMSA, and disruption of ERE half-sites by site-directed mutagenesis abolished ligand-independent induction by ER and ERß and promoter enhancement by estradiol-activated ER. Repression by estradiol/ERß was unaffected by disruption of ERE half-sites, activating protein 1, cAMP response element, GATA, or nuclear factor B sites, and reversed to promoter induction by estrogen antagonists, tamoxifen and ICI 182,780, suggesting corepressor involvement. In hypothalamic GT1–7 cells, Western blotting demonstrated rapid induction of endogenous CRH-BP expression by estradiol-bound ER, which was inhibited by TNF. We propose a model in which ERs maintain basal CRH-BP expression in pituitary and neurosecretory cells, whereas in the presence of ER estrogen enhances CRH-BP transcription, causing down-regulation of the HPA axis, and nuclear factor B-activating cytokines activate the HPA axis by inhibiting ER.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol

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