Dong Y, Poellinger L, Gustafsson J A, Okret S
Department of Medical Nutrition, Karolinska Institute, Huddinge University Hospital, Sweden.
Mol Endocrinol. 1988 Dec;2(12):1256-64. doi: 10.1210/mend-2-12-1256.
The mechanism of ligand-induced (homologous) down-regulation of the glucocorticoid receptor (GR) has been studied. Dexamethasone caused a down-regulation of the levels of GR mRNA and protein both in hepatoma tissue culture cells and rat liver in vivo. The decrease in the level of rat liver GR mRNA was due to a reduced transcription rate of the GR gene, as assessed by nuclear run-on transcription experiments. The half-life of GR mRNA in hepatoma tissue culture cells was determined to be approximately 4.5 h and was unaffected by dexamethasone. In addition to the transcriptional regulation of GR gene expression, a dexamethasone-dependent posttranslational modification in the rate of GR protein turnover was observed. In the absence of dexamethasone, GR protein half life was approximately 25 h whereas it decreased to approximately 11 h in the presence of hormone. Down-regulation of GR protein occurred with a 6- to 24-h delay as compared to the decline in GR mRNA. This is most likely due to the differences in half-lives of GR mRNA and protein, respectively. Our results suggest that auto-regulation of GR by its cognate ligand is complex and occurs at both transcriptional and posttranslational levels.
糖皮质激素受体（GR）的配体诱导（同源）下调机制已得到研究。地塞米松可使肝癌组织培养细胞和大鼠肝脏中的GR mRNA及蛋白质水平下调。通过细胞核连续转录实验评估，大鼠肝脏GR mRNA水平的降低是由于GR基因转录速率下降所致。肝癌组织培养细胞中GR mRNA的半衰期约为4.5小时，且不受地塞米松影响。除了GR基因表达的转录调控外，还观察到了地塞米松依赖的GR蛋白质周转速率的翻译后修饰。在没有地塞米松的情况下，GR蛋白半衰期约为25小时，而在有激素存在时则降至约11小时。与GR mRNA的下降相比，GR蛋白的下调出现延迟6至24小时。这很可能分别是由于GR mRNA和蛋白质半衰期的差异所致。我们的结果表明，GR与其同源配体的自调节是复杂的，且发生在转录和翻译后水平。
