Glucocorticoid regulation of corticotropin-releasing factor(1) receptor expression in pituitary-derived AtT-20 cells
Glucocorticoid regulation of corticotropin-releasing factor(1) receptor expression in pituitary-derived AtT-20 cells
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DOI：
10.1124/mol.51.5.794
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发表时间：
1997-05-01
影响因子：
3.6
通讯作者：
Duman, RS
中科院分区：
文献类型：
--
作者：
Iredale, PA;Duman, RS
促肾上腺皮质激素释放因子（CRF）受体是肾上腺皮质糖皮质激素对垂体负反馈的主要部位之一；然而，所涉及的分子机制尚未阐明。本研究探讨了糖皮质激素调节垂体细胞系at -20中CRF-RI表达的机制。用地塞米松处理这些细胞导致CRF-RI mRNA的浓度和时间依赖性抑制，这种抑制在1小时内显著，在4小时后达到最大。24小时后，CRF-R1 mRNA水平恢复到对照水平。当细胞用皮质酮处理时，观察到类似的变化。地塞米松预处理后，阿皮素原mRNA也降低；然而，时间过程要慢得多，仅在6小时后才检测到显著效果。我们进一步分析了糖皮质激素调控CRF-R1 mRNA的机制。这些研究表明，糖皮质激素的孵育显著降低了CRF-R1基因的转录率，这是由核运行分析确定的。此外，结果表明，糖皮质激素孵育显著降低CRF-RI mRNA稳定性约50%。CRF-R1 mRNA的下调依赖于从头蛋白合成，因为它被环己亚胺预处理阻断。这代表了糖皮质激素负反馈调节CRF-R1表达的新机制。
Corticotropin-releasing factor (CRF) receptors represent one of the primary sites for negative feedback of the pituitary by adrenocortical glucocorticoid hormones; however, the molecular mechanisms involved have yet to be elucidated. The present study examines the mechanisms by which glucocorticoids regulate CRF-RI expression in the pituitary cell line, AtT-20. Treatment of these cells with dexamethasone resulted in a concentration- and time-dependent inhibition of CRF-RI mRNA that was significant by 1 hr and maximal after 4 hr. Levels of CRF-R1 mRNA then returned to control levels after 24 hr. Similar changes were observed when the cells were treated with corticosterone. Pro-opiomelanocortin mRNA was also decreased after dexamethasone pretreatment; however, the time course was much slower with a significant effect only detected after 6 hr. Further analysis of the mechanisms that mediate glucocorticoid regulation of CRF-R1 mRNA was conducted. These studies demonstrated that glucocorticoid incubation significantly decreases the rate of CRF-R1 gene transcription, as determined by nuclear run-on analysis. In addition, the results demonstrate that glucocorticoid incubation significantly decreases CRF-RI mRNA stability by approximately 50%. The down-regulation of CRF-R1 mRNA was dependent on de novo protein synthesis, as it was blocked by pretreatment with cycloheximide. This represents a novel mechanism for glucocorticoid negative feedback regulation of CRF-R1 expression.