Transcriptional repressor activating transcription factor 3 protects human umbilical vein endothelial cells from tumor necrosis factor-α-induced apoptosis through down-regulation of p53 transcription
Transcriptional repressor activating transcription factor 3 protects human umbilical vein endothelial cells from tumor necrosis factor-α-induced apoptosis through down-regulation of p53 transcription
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DOI：
10.1074/jbc.m202974200
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发表时间：
2002-10-11
影响因子：
4.8
通讯作者：
Kitajima, S
中科院分区：
文献类型：
--
作者：
Kawauchi, J;Zhang, C;Kitajima, S
激活转录因子3 （ATF3）是一种转录抑制因子，在暴露于广泛应激刺激的细胞中被迅速诱导。为了阐明ATF3在决定细胞命运中的作用，我们通过腺病毒介导的基因转移在人脐静脉内皮细胞（HUVECs）中过表达ATF3。通过流式细胞术分析、台锥蓝排除试验和原aspase 3和聚（adp -核糖）聚合酶的裂解检测，ATF3保护这些细胞免受肿瘤坏死因子(TNF)- α诱导的细胞凋亡。Northern blot和核运行实验显示，atf3过表达细胞中肿瘤抑制基因p53的转录下调。在瞬时表达实验中，ATF3通过特异性结合p53基因启动子中的非典型AP-1元件PF-1位点来抑制p53基因启动子的活性。此外，在p53缺陷细胞中，ATF3的细胞保护作用显著降低。这些结果表明，ATF3的过表达至少在一定程度上通过下调p53基因的转录抑制tnf - α诱导的huvec细胞死亡。在血管炎症和动脉粥样硬化过程中，ATF3可能是内皮细胞的一种细胞存活因子。
Activating transcription factor 3 (ATF3) is a transcriptional repressor that is rapidly induced in cells exposed to a wide range of stress stimuli. To clarify the role of ATF3 in determining cell fate, we overexpressed it in human umbilical vein endothelial cells (HUVECs) by adenovirus-mediated gene transfer. ATF3 protected these cells from tumor necrosis factor (TNF)-alpha-induced apoptosis, as measured by flow cytometric analysis, trypan blue exclusion assay, and cleavage of procaspase 3 and poly(ADP-ribose) polymerase. Northern blot and nuclear run on assay showed that the transcription of tumor suppressor gene p53 was down-regulated in the ATF3-overexpressing cells. In the transient expression assay, ATF3 suppressed the p53 gene promoter activity through its specific binding to an atypical AP-1 element, PF-1 site, in the p53 gene promoter. Furthermore, the cell-protecting effect of ATF3 was remarkably reduced in p53-deficient cells. These results demonstrate that overexpression of ATF3 suppresses TNF-alpha-induced cell death of HUVECs, at least in part, through down-regulating the transcription of p53 gene. ATF3 may function as a cell survival factor of endothelial cells during vascular inflammation and atherogenesis.