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

Publication Type:

Journal Article

Source:

PNAS, Volume 106, Number 19, p.8038-8042 (2009)

ISBN:

1091-6490 (Electronic)00

DOI Name (links to online publication)

10.1073/pnas.0812062106

Keywords:

Amygdala/metabolism; Animals; Corticotropin-Releasing Hormone/*metabolism; Cyclic AMP Response Element-Binding Protein/metabolism; Forskolin/pharmacology; *Gene Expression Regulation; Genotype; Glucocorticoids/*metabolism; Histone Acetyltransferases/*phys

Abstract:

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.

18/01/2013