Poly(ADP-ribose) polymerase-1 (PARP-1) transcriptionally regulates angiotensin AT2 receptor (AT2R) and AT2R binding protein (ATBP) genes
Poly(ADP-ribose) polymerase-1 (PARP-1) transcriptionally regulates angiotensin AT2 receptor (AT2R) and AT2R binding protein (ATBP) genes
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DOI：
10.1016/j.bcp.2009.02.025
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发表时间：
2009-06-15
影响因子：
5.8
通讯作者：
Funke-Kaiser, Heiko
中科院分区：
文献类型：
--
作者：
Reinemund, Jana;Seidel, Kerstin;Funke-Kaiser, Heiko
肾素-血管紧张素系统（RAS）在心血管和神经（病理）生理学中起着至关重要的作用。血管紧张素AT 2受体（AT 2 R）似乎可以抵消AT 1受体的促炎、促肥大和促纤维化作用。最近，我们发现了一种新的蛋白质，称为“AT 2 R结合蛋白”（ATBP/ATIP），它似乎是AT 2 R介导的生长抑制所必需的。本研究克隆了人AT 2 R和ATIP 1的启动子，在ATIP 1启动子中发现了两个转录起始位点，而在AT 2 R启动子中只发现了一个。启动子分析表明，AT 2 R的外显子1-内含子1区域是AT 2 R启动子活性所必需和充分的。反向克隆实验表明，该调控区是启动子而不是增强子元件，暗示了该区域中的另外的起始位点。一致地，AT 2 R的外显子1-内含子1区域被示出拴系基础转录机器。PARP的过表达、药理学抑制和消融表明，PARP-1在体外和体内脑组织中激活ATIP 1基因，但在启动子和mRNA水平上抑制AT 2 R。另外的实验表明，AT 2 R激活不调节PARP-1的转录水平，但增加AT 2 R启动子的活性，从而创建一个正反馈mechanism.Our的结果表明，PARP-1作为一个新的节点RAS网络的基础上，它能够调节下游目标，如AT 2 R及其衔接蛋白ATBP。(c)2009 Elsevier Inc. All rights reserved.
The renin-angiotensin system (RAS) plays a crucial role in cardiovascular and neuronal (patho-) physiology. The angiotensin AT2 receptor (AT2R) seems to counteract the proinflammatory, prohypertrophic and profibrotic actions of the AT1 receptor. Recently, we identified a novel protein, termed "AT2R binding protein" (ATBP/ATIP) which seems essential for AT2R-mediated growth inhibition. Poly(ADP-ribose) polymerase-1 (PARP-1) can act as a nuclear integrator of angiotensin II-mediated cell signalling, and has been implicated in the pathogenesis of cardiovascular and neuronal disease.In this study, promoters of human AT2R and ATIP1 were cloned and two transcriptional start sites in the ATIP1 promoter were identified whereas only one was detected in the AT2R promoter. Promoter assays indicated that the exon 1-intron 1 region of AT2R is necessary and sufficient for AT2R promoter activity. Inverse cloning experiments indicated that this regulatory region is a promoter but not an enhancer element implicating (a) further start site(s) in this region. Consistently, the exon 1-intron 1 region of AT2R was shown to tether the basal transcriptional machinery. Overexpression, pharmacological inhibition and ablation of PARP demonstrated that PARP-1 activates the ATIP1 gene but represses the AT2R on promoter and mRNA levels in vitro, and in brain tissue in vivo. Additional experiments indicated that AT2R activation does not modulate PARP-1 transcript levels but increases AT2R promoter activity, thereby creating a positive feedback mechanism.Our results demonstrate that PARP-1 acts as novel node within the RAS network based on its ability to regulate downstream targets such as AT2R and its adapter protein ATBP. (c) 2009 Elsevier Inc. All rights reserved.