Regulation of glucocorticoid receptor protein and mRNA levels.
Regulation of glucocorticoid receptor protein and mRNA levels.
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发表时间：
1989-04
期刊：
影响因子：
11.2
通讯作者：
W. V. Vedeckis;Masarrat Ali;H. R. Allen
中科院分区：
文献类型：
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作者：
W. V. Vedeckis;Masarrat Ali;H. R. Allen
靶细胞中类固醇受体的水平影响细胞对激素的反应性。在小鼠AtT-20细胞中，已经表明慢性糖皮质激素治疗引起糖皮质激素受体（GR）水平的下调（F. Svec和M. Rudis，生物化学杂志，256：5984-5987，1981）。目前的研究表明，慢性激素治疗将GR mRNA的量减少到未治疗细胞的约50%。用RNA转录抑制剂和糖皮质激素联合处理细胞比单独使用任何一种药物会导致稳态GR mRNA水平更快地下降。这表明，糖皮质激素调节GR基因的表达转录后，可能通过不稳定的GR mRNA。这一观察结果不排除类固醇激素的额外转录调节。研究还发现，在42摄氏度下对各种细胞类型进行热休克不仅会导致热休克蛋白的诱导，而且还会导致糖皮质激素结合活性水平的急剧下降。GR标记的共价配体（地塞米松21-甲磺酸盐）也减少了热休克，这意味着热休克引起的GR蛋白本身的降解增加。最后，体外研究表明，GR在兔网织红细胞裂解物中以ATP和tRNA依赖的方式降解。因此，GR可能通过泛素依赖性蛋白水解途径降解。由于泛素本身是一种热休克蛋白，这可能是GR在热休克细胞中迅速降解的原因。这些研究指出了通过调节类固醇受体蛋白和mRNA水平来改变细胞对类固醇激素的反应性的可能机制。
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.