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Submitted on November 17, 2003
Accepted on August 23, 2004
and ER
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht, the Netherlands; Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University Mainz, Duesbergweg 6, 55099 Mainz, Germany; Mental Health Research Institute,205 Zina Pitcher Place, Ann Arbor, MI 48109-0720, USA
* To whom correspondence should be addressed. E-mail: anja{at}niob.knaw.nl.
Corticotropin-Releasing Hormone-Binding Protein (CRH-BP) regulates activation of the hypothalamic-pituitary-adrenal (HPA) axis by binding and inhibiting corticotropin-releasing hormone. We investigated for the first time transcriptional regulation of the human CRH-BP promoter using transient transfections. Estrogen receptors (ER) contributed to ligand-independent constitutive activation of the promoter, while in the presence of estradiol ER
dose-dependently induced and ER
repressed promoter activity. 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 ER in an EMSA, and disruption of ERE half sites by site-directed mutagenesis abolished ligand-independent induction by ER and ER, and promoter enhancement by estradiol-activated ER. Repression by estradiol/ER was unaffected by disruption of ERE half sites, AP1, CRE, GATA or NF
B sites, and reversed to promoter induction by estrogen antagonists tamoxifen and ICI, 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, while in the presence of ER estrogen enhances CRH-BP transcription, causing down-regulation of the HPA axis, and NFB-activating cytokines activate the HPA axis by inhibiting ER.
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