The Pal3 promoter sequence is critical for the regulation of human renin gene transcription by peroxisome proliferator-activated receptor-gamma.
The Pal3 promoter sequence is critical for the regulation of human renin gene transcription by peroxisome proliferator-activated receptor-gamma.
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DOI：
10.1210/en.2008-0127
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发表时间：
2008-09
期刊：
影响因子：
4.8
通讯作者：
V. Todorov;Michael Desch;T. Schubert;A. Kurtz
中科院分区：
文献类型：
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作者：
V. Todorov;Michael Desch;T. Schubert;A. Kurtz
我们最近报道，在肾素生成细胞系 Calu-6 中，人肾素基因转录受到核受体过氧化物酶体增殖物激活受体 (PPAR)-gamma 的刺激。 PPARgamma 的作用被映射到肾素启动子中的两个序列：与经典 PPAR 响应元件 (PPRE) 相关的直接重复激素响应元件 (HRE) 和带有 3 bp 间隔区的非共有回文元件 (Pal3)。我们现在发现 PPARgamma 与肾素 HRE 结合。人肾素 HRE 和共有 PPRE 都不足以达到 PPARγ 激动剂罗格列酮对肾素启动子活性的最大刺激。相比之下，人肾素 Pal3 元件介导完全 PPARgamma 依赖性转录激活和 PPARgamma 驱动的基础肾素基因转录。发现人肾素 Pal3 序列选择性结合来自 Calu-6 核提取物的 PPARgamma 和类视黄醇 X 受体-α。这与可以结合其他核蛋白的共有 PPRE 形成对比。矛盾的是，PPARγ敲低并没有减弱罗格列酮对内源性肾素基因表达的刺激。同样，PPARγ 的缺陷并不会减弱最小人肾素启动子的激活，该启动子含有内源性 Pal3 基序。然而，当人肾素 Pal3 位点被共有 PPRE 序列取代时，PPARgamma 敲低消除了罗格列酮对肾素启动子活性的影响。因此，人肾素 Pal3 位点通过介导最大转录激活，尤其是在 PPARgamma 的低细胞水平下，对 PPARgamma 依赖性基因表达调节至关重要。
We recently reported that human renin gene transcription is stimulated by the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-gamma in the renin-producing cell line Calu-6. The effect of PPARgamma was mapped to two sequences in the renin promoter: a direct repeat hormone response element (HRE), which is related to the classical PPAR response element (PPRE) and a nonconsensus palindromic element with a 3-bp spacer (Pal3). We now find that PPARgamma binds to the renin HRE. Neither the human renin HRE nor the consensus PPRE was sufficient to attain the maximal stimulation of renin promoter activity by the PPARgamma agonist rosiglitazone. In contrast, the human renin Pal3 element mediates both the full PPARgamma-dependent activation of transcription and the PPARgamma-driven basal renin gene transcription. The human renin Pal3 sequence was found to selectively bind PPARgamma and the retinoid X receptor-alpha from Calu-6 nuclear extracts. This is in contrast to the consensus PPRE, which can bind other nuclear proteins. PPARgamma knockdown paradoxically did not attenuate the stimulation of the endogenous renin gene expression by rosiglitazone. Similarly, a deficiency of PPARgamma did not attenuate the activation of the minimal human renin promoter, which contains the endogenous Pal3 motif. However, when the human renin Pal3 site was replaced by the consensus PPRE sequence, PPARgamma knockdown abrogated the effect of rosiglitazone on renin promoter activity. Thus, the human renin Pal3 site appears to be critical for the PPARgamma-dependent regulation of gene expression by mediating maximal transcription activation, particularly at the low cellular level of PPARgamma.