Regulation of the ATF3 gene by a single promoter in response to amino acid availability and endoplasmic reticulum stress in human primary hepatocytes and hepatoma cells.
Regulation of the ATF3 gene by a single promoter in response to amino acid availability and endoplasmic reticulum stress in human primary hepatocytes and hepatoma cells.
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DOI：
10.1016/j.bbagrm.2018.01.002
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Kilberg MS
中科院分区：
文献类型：
--
作者：
Hayner JN;Shan J;Kilberg MS
激活转录因子3（ATF3）是一种高度调节的蛋白质，其与包括炎症和转化在内的广泛病理条件有关。ATF3基因的转录由几种应激诱导的信号传导途径诱导，包括氨基酸限制（氨基酸反应，AAR）和ER应激（未折叠蛋白反应，UPR）。通过这些途径诱导ATF 3转录是由ATF 4和cJUN募集至ATF 3基因内的增强子元件介导的。虽然一个典型的启动子（启动子A）已被许多实验室研究，第二个启动子的活性（启动子A1），43 kb的上游第一，已被报道，以响应应力诱导的信号，并在某些转化细胞中的ATF 3表达的关键。本研究的结果表明，在正常人肝细胞和HepG2人肝癌细胞中，基础以及AAR和UPR诱导的转录几乎完全来自启动子A。两个启动子之间的这种选择性与ATF 4的结合增加、RNA聚合酶II的募集以及基因启动子A区域中预期的组蛋白修饰相关。ATF3转录活性的时程研究表明，ATF3诱导的时间动力学在AAR和UPR之间不同，前者比后者更短暂。总的来说，结果证明正常和转化的人肝脏中的ATF3表达起源于响应多种应激信号的典型启动子A。
Activating transcription factor 3 (ATF3) is a highly regulated protein that is implicated in a wide range of pathological conditions including inflammation and transformation. Transcription from the ATF3 gene is induced by several stress-induced signaling pathways, including amino acid limitation (amino acid response, AAR) and ER stress (unfolded protein response, UPR). Induction of ATF3 transcription by these pathways is mediated by ATF4 and cJUN recruitment to enhancer elements within the ATF3 gene. Although a canonical promoter (promoter A) has been studied by numerous laboratories, a second promoter activity (promoter A1), 43 kb upstream of the first, has been reported to respond to stress-induced signaling and to be critical for ATF3 expression in certain transformed cells. The results of the present study show that in normal human hepatocytes and HepG2 human hepatoma cells both basal as well as AAR- and UPR-induced transcription occurs almost exclusively from promoter A. This selectivity between the two promoters correlated with increased binding of ATF4, recruitment of RNA polymerase II, and the expected histone modifications in the promoter A region of the gene. Time course studies of ATF3 transcription activity revealed that the temporal kinetics for ATF3 induction differ between the AAR and UPR, with the former being more transient than the latter. Collectively, the results document that ATF3 expression in normal and transformed human liver originates from the canonical promoter A that responds to multiple stress signals.
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