Glucocorticoid down-regulation of rat glucocorticoid receptor does not involve differential promoter regulation

Abstract

The level of expression of the glucocorticoid receptor (GR) is the principal determinant of glucocorticoid sensitivity in most cells. GR levels are permanently 'set' in a tissue-specific manner in response to the perinatal environment, an effect we have previously shown to relate to differential expression of tissue-enriched alternative promoters/exons 1 of the GR gene. In adult animals, GR levels are dynamically regulated around the 'set point' by glucocorticoids themselves, with glucocorticoids downregulating GR mRNA in most cells and tissues. Here we have examined whether autoregulation of GR mRNA by glucocorticoids involves differential promoter regulation. We show that, in contrast to tissue-specific programming of GR mRNA levels, autoregulation of GR mRNA in vivo does not involve differential regulation of variant exon 1-containing GR mRNAs in that the major variants are down-regulated to a similar extent by glucocorticoid treatment. Consistent with this, transfections of reporter constructs showed that the majority of GR promoters, which are contained within a 4·4 kb region upstream of exon 2, are similarly regulated by glucocorticoids, with two regions of the promoter redundantly required for glucocorticoid regulation. Thus transcriptional autoregulation can occur in adult tissues around the set point established by promoter selection in early life.

Structure of the glucocorticoid receptor (NR3C1) gene 5′ untranslated region: identification, and tissue distribution of multiple new human exon 1

“…Detailed investigation of the alternative first exon usage in the rat provided no evidence that these exons play a role in this autoregulation (Freeman et al 2004). In these studies expression of exon 1 variants was observed to be concomitantly and uniformly regulated by dexamethasone.…”

Neuroplasticity of the Hypothalamic–Pituitary–Adrenal Axis Early in Life Requires Recurrent Recruitment of Stress-Regulating Brain Regions

“…In addition, reduced PVN-CRH levels attenuate ACTH and corticosterone release after subsequent stress Avishai-Eliner et al, 2001), as found in handled rats already at P23 (Avishai-Eliner et al, 2001). Lower corticosterone levels promote expression of hippocampal GR (Reul and de Kloet, 1985;Kalinyak et al, 1987;Freeman et al, 2004) and an efficient shut-off of hormonal stress responses, yielding the phenotype of attenuated HPA axis function typical of adult rats handled early in life (Plotsky and Meaney, 1993;Fenoglio et al, 2005).…”

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

“…In vivo, adrenalectomy lowers liver and hippocampal 11␤-HSD1 expression in the short-term, but enzyme activity subsequently recovers (317), much like GR itself (202,292). Conversely, elevated glucocorticoids in intact animals increase 11␤-HSD1 in some tissues (adipose tissue, perinatal lung) but not in others (liver) (52, 465,650).…”