X-box binding protein 1 regulates brain natriuretic peptide through a novel AP1/CRE-like element in cardiomyocytes
X-box binding protein 1 regulates brain natriuretic peptide through a novel AP1/CRE-like element in cardiomyocytes
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DOI：
10.1016/j.yjmcc.2010.02.004
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发表时间：
2010-06-01
影响因子：
5
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Sawada, Tamaki;Minamino, Tetsuo;Komuro, Issei
当内质网（ER）功能受损时，未折叠蛋白反应（UPR）被触发以协助蛋白质折叠。最近的研究表明内质网应激也可以诱导细胞特异性基因。在这项研究中，我们检测了X-box结合蛋白1 （XBP1）是否调节心肌细胞中脑利钠肽（BNP）的表达。XBP1是一种主要的upr相关转录因子。在人类心脏衰竭的样本中，观察到XBP1的广泛剪接以及剪接XBP1 （sXBP1）的靶点葡萄糖调节蛋白78 kDa （GRP78）的表达增加，这表明UPR在人类心力衰竭中是诱导的。有趣的是，实时荧光定量PCR显示心脏GRP78和BNP的表达呈正相关，这让我们验证了sXBP1调节心肌细胞中BNP和GRP78的假设。药理学内质网应激源引起培养心肌细胞中sXBP1和BNP表达的剂量依赖性增加。靶向XBP1的短干扰RNA抑制药理学内质网应激源或去甲肾上腺素对BNP表达的诱导，这种诱导被腺病毒介导的sXBP1过表达所挽救。过表达sXBP1或去甲肾上腺素的启动子实验表明，BNP启动子区域近端AP1/ crea样元件对sXBP1对BNP的转录调控至关重要。通过染色质免疫沉淀试验证实sXBP1与该元件的直接结合。这些发现表明，衰竭心脏中观察到的内质网应激通过AP1/ crea样元件的一个新的启动子区域调节心脏BNP的表达。(C) 2010 Elsevier Ltd.版权所有。
The unfolded protein response (UPR) is triggered to assist protein folding when endoplasmic reticulum (ER) function is impaired. Recent studies demonstrated that ER stress can also induce cell-specific genes. In this study, we examined whether X-box binding protein 1 (XBP1), a major UPR-linked transcriptional factor, regulates the expression of brain natriuretic peptide (BNP) in cardiomyocytes. In samples from failing human hearts, extensive splicing of XBP1 was observed along with increased expression of glucose-regulated protein of 78 kDa (GRP78), a target of spliced XBP1 (sXBP1), suggesting that the UPR was induced in heart failure in humans. Interestingly, quantitative real-time PCR revealed a positive correlation between cardiac expression of GRP78 and BNP, leading us to test the hypothesis that sXBP1 regulates BNP as well as GRP78 in cardiomyocytes. A pharmacological ER stressor caused a dose-dependent increase in the expression of sXBP1 and BNP by cultured cardiomyocytes. Short interfering RNA targeting XBP1 suppressed the induction of BNP expression by a pharmacological ER stressor or norepinephrine, which was rescued by the adenovirus-mediated overexpression of sXBP1. The promoter assay with overexpression of sXBP1 or norepinephrine showed that the proximal AP1/CRE-like element in the promoter region of BNP was critical for transcriptional regulation of BNP by sXBP1. Direct binding of sXBP1 to this element was confirmed by the chromatin immunoprecipitation assay. These findings suggest that ER stress observed in failing hearts regulates cardiac BNP expression through a novel promoter region of the AP1/CRE-like element. (C) 2010 Elsevier Ltd. All rights reserved.