Steroid receptor coactivator-1 is necessary for regulation of corticotropin-releasing hormone by chronic stress and glucocorticoids.
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.
Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
Servane
S
Lachize
Ede M
EM
Apostolakis
Siem
S
van der Laan
Ans M I
AM
Tijssen
Jianming
J
Xu
E Ronald
ER
de Kloet
Onno C
OC
Meijer
D000679:Amygdala / Q000378:metabolism; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D005938:Glucocorticoids / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D056920:Nuclear Receptor Coactivator 1; D011401:Promoter Regions, Genetic; D013315:Stress, Psychological; D014157:Transcription Factors / Q000502:physiology*
D017362:Cyclic AMP Response Element-Binding Protein; D005938:Glucocorticoids; D014157:Transcription Factors; D005576:Colforsin; D003346:Corticotropin-Releasing Hormone; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1