Estrogen receptor (ER)-mediated transcriptional regulation of the human corticotropin-releasing hormone-binding protein promoter: differential effects of ERalpha and ERbeta

Mol Endocrinol. 2004 Dec;18(12):2908-23. doi: 10.1210/me.2003-0446. Epub 2004 Sep 2.


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 ERalpha induced and ERbeta repressed promoter activity in a dose-dependent manner. TNFalpha inhibited promoter induction by ERalpha in the absence and presence of estradiol. Three ERE half-sites in the CRH-BP promoter bound ERalpha and ERbeta in an EMSA, and disruption of ERE half-sites by site-directed mutagenesis abolished ligand-independent induction by ERalpha and ERbeta and promoter enhancement by estradiol-activated ERalpha. Repression by estradiol/ERbeta was unaffected by disruption of ERE half-sites, activating protein 1, cAMP response element, GATA, or nuclear factor kappaB 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 TNFalpha. We propose a model in which ERs maintain basal CRH-BP expression in pituitary and neurosecretory cells, whereas in the presence of ERalpha estrogen enhances CRH-BP transcription, causing down-regulation of the HPA axis, and nuclear factor kappaB-activating cytokines activate the HPA axis by inhibiting ERalpha.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carrier Proteins / genetics*
  • Conserved Sequence / genetics
  • Estradiol / pharmacology
  • Estradiol / physiology*
  • Estrogen Antagonists / pharmacology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Estrogen Receptor alpha / physiology*
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / metabolism
  • Estrogen Receptor beta / physiology*
  • Humans
  • Mutation / genetics
  • Neurosecretion / genetics
  • Neurosecretion / physiology
  • Pituitary Gland / metabolism
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / genetics*
  • Response Elements / drug effects
  • Response Elements / genetics
  • Tamoxifen / pharmacology
  • Transcription, Genetic
  • Transcriptional Activation*
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Necrosis Factor-alpha / physiology


  • Carrier Proteins
  • Estrogen Antagonists
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Tumor Necrosis Factor-alpha
  • Tamoxifen
  • corticotropin releasing factor-binding protein
  • Estradiol