Regulation of glucocorticoid receptor protein and mRNA levels.
The level of steroid receptors in target cells affects the responsiveness of the cell to the hormone. In mouse AtT-20 cells, it has been shown that chronic glucocorticoid treatment causes a down-regulation of glucocorticoid receptor (GR) levels (F. Svec and M. Rudis, J. Biol. Chem., 256:5984-5987, 1981). The current study shows that chronic hormone treatment reduces the amount of GR mRNA to about 50% of that in untreated cells. A combined treatment of the cells with an inhibitor of RNA transcription and the glucocorticoid hormone causes a more rapid decrease in steady-state GR mRNA levels than either agent alone. This suggests that glucocorticoids regulate the expression of the GR gene posttranscriptionally, perhaps via destabilization of the GR mRNA. An additional transcriptional regulation by the steroid hormone is not ruled out by this observation. It was also found that heat shocking a variety of cell types at 42 degrees C not only causes an induction of heat shock proteins but also results in a dramatic decrease in the level of glucocorticoid-binding activity. GR labeled with a covalent ligand (dexamethasone 21-mesylate) was also reduced by heat shock, implying that heat shock caused an increased degradation in the GR protein itself. Finally, in vitro studies show that the GR is degraded in an ATP- and tRNA-dependent fashion in rabbit reticulocyte lysate. It therefore seems likely that the GR is degraded by the ubiquitin-dependent proteolytic pathway. Because ubiquitin is itself a heat shock protein, this may be the reason that the GR is rapidly degraded in heat-shocked cells. These studies point to possible mechanisms whereby the responsiveness of the cell to steroid hormones is altered by the regulation of the steroid receptor protein and mRNA levels.
Vedeckis
W V
WV
Department of Biochemistry and Molecular Biology, Louisiana State University Medical Center, New Orleans 70112.
Ali
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M
Allen
H R
HR
D000818:Animals; D005786:Gene Expression Regulation; D006706:Homeostasis; D006358:Hot Temperature; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis*; D011965:Receptors, Glucocorticoid / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D014222:Triamcinolone Acetonide / Q000494:pharmacology
D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014222:Triamcinolone Acetonide