Steroid receptor coactivator-1 is necessary for regulation of corticotropin-releasing hormone by chronic stress and glucocorticoids

Proc Natl Acad Sci U S A. 2009 May 12;106(19):8038-42. doi: 10.1073/pnas.0812062106. Epub 2009 Apr 29.


Adaptation to stress in vertebrates occurs via activation of hormonal and neuronal signaling cascades in which corticotropin-releasing hormone (CRH) plays a central role. Expression of brain CRH is subject to strong, brain-region specific regulation by glucocorticoid hormones and neurogenic intracellular signals. We hypothesized that Steroid Receptor Coactivator 1 (SRC-1), a transcriptional coregulator of the glucocorticoid receptor, is involved in the sensitivity of CRH regulation by stress-related factors. In the brains of SRC-1 knockout mice we found basal CRH mRNA levels to be lower in the central nucleus of the amygdala. Hypothalamic CRH up-regulation after chronic (but not acute) stress, as well as region-dependent up- and down-regulation induced by synthetic glucocorticoids, were significantly attenuated compared with wild type. The impaired induction of the crh gene by neurogenic signals was corroborated in AtT-20 cells, where siRNA and overexpression experiments showed that SRC-1 is necessary for full induction of a CRH promoter reporter gene by forskolin, suggestive of involvement of transcription factor CREB. In conclusion, SRC-1 is involved in positive and negative regulation of the crh gene, and an important factor for the adaptive capacity of stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / metabolism
  • Animals
  • Colforsin / pharmacology
  • Corticotropin-Releasing Hormone / metabolism*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Gene Expression Regulation*
  • Genotype
  • Glucocorticoids / metabolism*
  • Histone Acetyltransferases / physiology*
  • Hypothalamus / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Coactivator 1
  • Promoter Regions, Genetic
  • Stress, Psychological*
  • Transcription Factors / physiology*


  • Cyclic AMP Response Element-Binding Protein
  • Glucocorticoids
  • Transcription Factors
  • Colforsin
  • Corticotropin-Releasing Hormone
  • Histone Acetyltransferases
  • Ncoa1 protein, mouse
  • Nuclear Receptor Coactivator 1