Transcriptional inhibition of the human insulin receptor gene by aldosterone
Transcriptional inhibition of the human insulin receptor gene by aldosterone
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DOI：
10.1016/s0960-0760(03)00072-4
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发表时间：
2003-04-01
影响因子：
4.1
通讯作者：
Dávila, N
中科院分区：
文献类型：
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作者：
Calle, C;Campión, J;Dávila, N
在早期的研究中，我们报道了醛固酮处理的U-937人前单核细胞中人胰岛素受体（hIR）mRNA水平、胰岛素结合和胰岛素反应性降低。这种抑制作用的机制可能是由于醛固酮不影响hIR mRNA的稳定性，从而降低了IR基因的转录。所有的影响都是通过下调盐皮质激素受体（MR，NR 3C 2）在RNA和蛋白质水平上的表达介导的，这表明MR可以作为一个转录因子，结合到hIR基因启动子中的激素反应元件。事实上，MR已显示结合靶基因中的糖皮质激素反应元件（GRES）。考虑到五个GRES已在hIR启动子中表征，我们决定测试这些元件是否可以介导我们在U-937细胞中检测到的醛固酮引起的hIR表达抑制。在本报告中，我们证明，醛固酮抑制活性的hIR野生型启动子的23%，并导致23和31%的活性的逐步删除该启动子组成的片段高达-1473和-876 bp，分别减少。这表明hIR启动子的-876至-271 bp区域可能足以用于醛固酮的这种转录抑制。我们还提供了直接MR相互作用的证据，与该启动子区域的一些GRES，特别是与cGRE 1和cGRE 3，大概作为MR-MR同源二聚体，并与pGRE作为MR-GR异源二聚体。这种异二聚体可能发挥最相关的作用，并参与盐皮质激素，糖皮质激素和胰岛素信号之间的串扰在U-937细胞。(C)2003爱思唯尔科技有限公司版权所有。
In earlier studies, we reported reduced human insulin receptor (hIR) mRNA levels, insulin binding and insulin responsiveness in U-937 human promonocytic cells treated with aldosterone. The mechanism for this inhibition could be diminished IR gene transcription, since aldosterone did not affect hIR mRNA stability. All the effects were mediated by a downregulation of the mineralocorticoid receptor (MR, NR3C2) expressed at both the RNA and protein levels, suggesting that MR could act as a transcription factor that binds to hormone response elements in the hIR gene promoter. Indeed, MR has been shown to bind glucocorticoid response elements (GREs) in target genes. Given that five GREs have been characterized in the hIR promoter, we decided to test whether these elements could mediate the aldosterone-elicited inhibition of hIR expression detected by us in U-937 cells. In the present report, we demonstrate that aldosterone inhibits the activity of the hIR wild-type promoter by 23%, and causes 23 and 31% reductions in the activity of progressive deletions of this promoter comprised of fragments up to -1473 and -876 bp, respectively. This indicates that the -876 to -271 bp region of the hIR promoter may be sufficient for this transcriptional inhibition by aldosterone. We also provide evidence for direct MR interaction with some of the GREs of this promoter region, specifically with the cGRE1 and cGRE3, presumably as MR-MR homodimers, and with pGRE as a MR-GR heterodimer. This heterodimer may play the most relevant role and participate in the cross-talk between mineralocorticoids, glucocorticoids and insulin signalling in U-937 cells. (C) 2003 Elsevier Science Ltd. All rights reserved.