Control of gene expression by glucocorticoid hormones

Abstract

Glucocorticoids control the expression of a small number of transcriptionally active genes by increasing or decreasing mRNA concentration. Either effect can result from a transcriptional or a post-transcriptional mechanism. Induction of mouse mammary tumour virus RNA results from a stimulation of transcription initiation and depends on the presence of defined regions in proviral DNA. These regions bind the glucocorticoid receptor and behave functionally as proto-enhancers. Glucocorticoid-inducible genes can retain their sensitivity to the hormone after transfer to a heterologous cell by transfection techniques. Non-inducible genes can become inducible when linked to the promoter region of an inducible gene. The mechanisms by which the receptor-steroid complex stimulates or inhibits transcription or influences mRNA stability are unknown. Receptor binding to nucleic acids appears to be a necessary but not sufficient condition. It is likely that the receptor also interacts with chromatin proteins. This might lead to a catalytic modification of these proteins, resulting in a modulation of gene expression. Development of glucocorticoid-sensitive, biochemically defined, cell-free transcription systems should provide a tool to delineate the molecular determinants of this essential regulatory mechanism.

Pharmacokinetics and pharmacodynamic modeling of direct suppression effects of methylprednisolone on serum cortisol and blood histamine in human subjects

“…and effect, as has been done previously, 4 the quality of fitting was significantly poorer for blood histamine when fitted to the E max and the threshold models (Table V). For the sigmoid E max model, inconsistancy in parameter estimates such as the IC 50 between doses (Table V), the Hill coefficient value greater than one, which contradicts current steroid-receptor binding data, 1,[15][16][17] and the lack of physiologic meaning for "k co " and the "effect compartment" for this rapid glucocorticoid response, severely limits its usefulness. In addition, for the cortisol data, no effect model has attempted to date to incorporate its physiologic circadian rhythm under baseline and poststeroid elimination conditions.…”

“…1,2,[15][16][17] Free steroid that diffuses from plasma and from within the cell binds reversibly to phospho-protein cytosolic receptor (typically termed glucocorticoid receptor), forming a steroid-receptor complex. Through a process termed activation, presumably dissociation and dephosphorylation of the receptor, this complex is rapidly transformed to an activated steroid-receptor form.…”

Glucocorticoids inhibit prostaglandin synthesis not only at the level of phospholipase A2 but also at the level of cyclo‐oxygenase/PGE isomerase

“…Glucocorticoids exert their multiple metabolic functions by binding to cytoplasmic receptors and subsequent induction of catalytic or regulatory proteins (Rousseau, 1984). Their anti-inflammatory properties have been attributed in part to the liberation and enhanced synthesis of proteins, collectively called lipocortins, which inhibit phospholipase A2, leading to a decreased eicosanoid synthesis (Flower, 1984).…”

Differences in Down-Regulation of Glucocorticoid Receptor mRNA by Cortisol, Prednisolone and Dexamethasone in HeLa Cells.

“…To modulate gene expression, glucocorticoids first bind to cytoplasmic receptors [2,3]. In the absence of glucocorticoids, the glucocorticoid receptor (GR) is bound with heat shock proteins in the form of a heterooligomer.…”