Alcohol dysregulates corticotropin-releasing-hormone (CRH) promoter activity by interfering with the negative glucocorticoid response element (nGRE).
Alcohol dysregulates corticotropin-releasing-hormone (CRH) promoter activity by interfering with the negative glucocorticoid response element (nGRE).
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DOI：
10.1371/journal.pone.0026647
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Pak TR
中科院分区：
文献类型：
--
作者：
Przybycien-Szymanska MM;Mott NN;Pak TR
雄性大鼠的乙醇暴露增加了下丘脑室旁核（PVN）中促肾上腺皮质激素释放激素（CRH）mRNA，PVN是负责协调压力和焦虑反应的大脑区域。在这项研究中，我们确定了参与介导这些影响的分子机制，通过检查直接影响乙醇对CRH启动子活性的神经元细胞系来自PVN（IVB）。此外，我们研究了乙醇和糖皮质激素对CRH启动子的潜在相互作用，伴随处理细胞与乙醇和糖皮质激素受体（GR）拮抗剂RU486，并通过顺序删除糖皮质激素反应元件（GRE）内的GR结合位点的CRH启动子。用含有2.5kb的大鼠野生型（WT）或突变的CRH启动子的萤火虫荧光素酶报告基因构建体瞬时转染细胞。我们的研究结果表明，乙醇处理诱导CRH启动子活性的双相反应。与溶剂处理的对照相比，EtOH暴露0.5 h显著降低启动子活性，而在EtOH暴露2.0 h后启动子活性显著增加。用RU486处理，或删除GR结合位点1和2内的GRE，废除乙醇诱导的启动子活性的增加，但不影响乙醇诱导的CRH启动子活性在较早的时间点下降。总的来说，我们的数据表明，酒精暴露直接调节CRH启动子的活性，通过干扰糖皮质激素介导的GR信号在GRE网站的CRH启动子的正常反馈机制。
EtOH exposure in male rats increases corticotropin-releasing hormone (CRH) mRNA in the paraventricular nucleus of the hypothalamus (PVN), a brain region responsible for coordinating stress and anxiety responses. In this study we identified the molecular mechanisms involved in mediating these effects by examining the direct effects of EtOH on CRH promoter activity in a neuronal cell line derived from the PVN (IVB). In addition, we investigated the potential interactions of EtOH and glucocorticoids on the CRH promoter by concomitantly treating cells with EtOH and the glucocorticoid receptor (GR) antagonist RU486, and by sequentially deleting GR binding sites within glucocorticoid response element (GRE) on the CRH promoter. Cells were transiently transfected with a firefly luciferase reporter construct containing 2.5 kb of the rat wild type (WT) or mutated CRH promoter. Our results showed that EtOH treatment induced a biphasic response in CRH promoter activity. EtOH exposure for 0.5 h significantly decreased promoter activity compared to vehicle treated controls, whereas promoter activity was significantly increased after 2.0 h of EtOH exposure. Treatment with RU486, or deletion of the GR binding sites 1 and 2 within the GRE, abolished the EtOH-induced increase in the promoter activity, however did not affect EtOH-induced decrease in CRH promoter activity at an earlier time point. Overall, our data suggest that alcohol exposure directly regulates CRH promoter activity by interfering with the normal feedback mechanisms of glucocorticoids mediated by GR signaling at the GRE site of the CRH promoter.
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影响因子：
4.1
作者：
SPENCER, RL;MCEWEN, BS
通讯作者：
MCEWEN, BS
DOI：
10.1111/j.1530-0277.1993.tb00853.x
发表时间：
1993-08-01
影响因子：
3.2
作者：
RIVIER, C
通讯作者：
RIVIER, C
影响因子：
2.9
作者：
Ogilvie, KM;Rivier, C
通讯作者：
Rivier, C
影响因子：
3.5
作者：
Li, ZQ;Kang, SS;Rivier, C
通讯作者：
Rivier, C
影响因子：
3.2
作者：
Morsink, MC;Steenbergen, PJ;Datson, NA
通讯作者：
Datson, NA