Interactive Roles of Ets-1, Sp1, and Acetylated Histones in the Retinoic Acid-dependent Activation of Guanylyl Cyclase/Atrial Natriuretic Peptide Receptor-A Gene Transcription
Interactive Roles of Ets-1, Sp1, and Acetylated Histones in the Retinoic Acid-dependent Activation of Guanylyl Cyclase/Atrial Natriuretic Peptide Receptor-A Gene Transcription
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DOI：
10.1074/jbc.m110.132795
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发表时间：
2010-11-26
影响因子：
4.8
通讯作者：
Pandey, Kailash N.
中科院分区：
文献类型：
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作者：
Kumar, Prerna;Garg, Renu;Pandey, Kailash N.
心脏激素心房肽和脑利钠肽激活鸟苷酸环化酶/利钠肽受体-A（GC-A/NPRA），其在降低血压和血容量中起关键作用。目前，负责调节Npr 1基因（编码GC-A/NPRA）转录的机制还不清楚。本研究旨在探讨全反式维甲酸（ATRA）、Ets-1、Sp1和组蛋白乙酰化对Npr 1基因转录调控和功能的相互作用。Npr 1启动子的缺失分析和荧光素酶分析表明，ATRA增强了16倍的Npr 1启动子活性，并极大地刺激了受体蛋白的鸟苷酸环化酶（GC）活性，无论是心房钠尿肽（ANP）依赖的还是非依赖的方式。凝胶位移和染色质免疫沉淀试验证实，全反式维甲酸增强了Ets-1和Sp1的Npr 1启动子的结合。视黄酸受体α（RAR α）被Ets-1和Sp1募集，与Npr 1启动子中的结合位点形成转录激活因子复合物。有趣的是，全反式维甲酸还增加了组蛋白H3和H4的乙酰化，并增强了它们在Npr 1启动子内的Ets-1和Sp1结合位点的募集。总的来说，目前的结果表明，ATRA调节Npr 1基因转录和GC活性的受体，涉及Ets-1，Sp1，和组蛋白乙酰化的相互作用。
Cardiac hormones atrial and brain natriuretic peptides activate guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), which plays a critical role in reduction of blood pressure and blood volume. Currently, the mechanisms responsible for regulating the Npr1 gene (coding for GC-A/NPRA) transcription are not well understood. The present study was conducted to examine the interactive roles of all-trans retinoic acid (ATRA), Ets-1, Sp1, and histone acetylation on the transcriptional regulation and function of the Npr1 gene. Deletion analysis of the Npr1 promoter and luciferase assays showed that ATRA enhanced a 16-fold Npr1 promoter activity and greatly stimulated guanylyl cyclase (GC) activity of the receptor protein in both atrial natriuretic peptide (ANP)-dependent and -independent manner. As confirmed by gel shift and chromatin immunoprecipitation assays, ATRA enhanced the binding of both Ets-1 and Sp1 to the Npr1 promoter. The retinoic acid receptor alpha (RAR alpha) was recruited by Ets-1 and Sp1 to form a transcriptional activator complex with their binding sites in the Npr1 promoter. Interestingly, ATRA also increased the acetylation of histones H3 and H4 and enhanced their recruitment to Ets-1 and Sp1 binding sites within the Npr1 promoter. Collectively, the present results demonstrate that ATRA regulates Npr1 gene transcription and GC activity of the receptor by involving the interactive actions of Ets-1, Sp1, and histone acetylation.