Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response
Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response
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DOI：
10.1042/0264-6021:3390135
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发表时间：
1999-04-01
影响因子：
4.1
通讯作者：
Holbrook, NJ
中科院分区：
文献类型：
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作者：
Fawcett, TW;Martindale, JL;Holbrook, NJ
Gadd 153，也称为chop，编码CCAAT/增强子结合蛋白（C/EBP）转录因子家族的成员，并被细胞应激信号转录激活。我们最近证明，亚砷酸盐治疗大鼠嗜铬细胞瘤PC 12细胞的结果在Gadd 153 mRNA表达的双相诱导，控制部分通过结合C/EBP β和两个未知的蛋白质复合物的C/EBP-ATF（转录激活因子）复合网站在Gadd 153启动子。在这份报告中，我们确定了这些额外的复合物的成分为两个ATF/CREB（cAMP反应元件结合蛋白）转录因子具有依赖于砷暴露时间的差异结合活性。在PC 12细胞的砷处理过程中，我们观察到随着Gadd 153 mRNA水平的增加，ATF 4与C/EBP-ATF位点的结合在2 h时增强，随着Gadd 153表达的下降，6 h时ATF 3复合物的结合增强。我们进一步证明了ATF 4通过C/EBP-ATF位点激活Gadd 153启动子活性，而ATF 3则通过C/EBP-ATF位点抑制Gadd 153启动子活性。ATF 3还抑制ATF 4介导的反式激活和亚砷酸盐诱导的Gadd 153启动子的激活。我们的研究结果表明，ATF/CREB家族的许多成员都参与了细胞的应激反应，并在PC 12细胞中的应激诱导的双相Gadd 153表达的调节涉及有序的，顺序结合的多个转录因子复合物的C/EBP-ATF复合网站。
Gadd153, also known as chop, encodes a member of the CCAAT/enhancer-binding protein (C/EBP) transcription factor family and is transcriptionally activated by cellular stress signals. We recently demonstrated that arsenite treatment of rat pheochromocytoma PC12 cells results in the biphasic induction of Gadd153 mRNA expression, controlled in part through binding of C/EBP beta and two uncharacterized protein complexes to the C/EBP-ATF (activating transcription factor) composite site in the Gadd153 promoter. In this report, we identified components of these additional complexes as two ATF/CREB (cAMP-responsive-element-binding protein) transcription factors having differential binding activities dependent upon the time of arsenite exposure, During arsenite treatment of PC12 cells, we observed enhanced binding of ATF4 to the C/EBP-ATF site at 2 h as Gadd153 mRNA levels increased, and enhanced binding of ATF3 complexes at 6 h as Gadd153 expression declined. We further demonstrated that ATF4 activates, while ATF3 represses, Gadd153 promoter activity through the C/EBP-ATF site. ATF3 also repressed ATF4-mediated transactivation and arsenite-induced activation of the Gadd153 promoter. Our results suggest that numerous members of the ATF/CREB family are involved in the cellular stress response, and that regulation of stress-induced biphasic Gadd153 expression in PC12 cells involves the ordered, sequential binding of multiple transcription factor complexes to the C/EBP-ATF composite site.