NOR-1/NR4A3 regulates the cellular inhibitor of apoptosis 2 (cIAP2) in vascular cells: role in the survival response to hypoxic stress.
NOR-1/NR4A3 regulates the cellular inhibitor of apoptosis 2 (cIAP2) in vascular cells: role in the survival response to hypoxic stress.
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NOR-1/NR4A3调节血管细胞中细胞凋亡2（CIAP2）的细胞抑制剂：在对低氧应激的生存反应中的作用。
DOI：
10.1038/srep34056
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发表时间：
2016-09-22
影响因子：
4.6
通讯作者：
Martínez-González J
中科院分区：
文献类型：
--
作者：
Alonso J;Galán M;Martí-Pàmies I;Romero JM;Camacho M;Rodríguez C;Martínez-González J
在腹主动脉瘤 (AAA) 等病理条件下，血管细胞的存活会受到损害。我们之前已经证明核受体NOR-1参与血管细胞对缺氧的生存反应。在这里，我们将抗凋亡蛋白 cIAP2 确定为 NOR-1 的下游效应子。 NOR-1 和 cIAP2 在人类 AAA 样本中上调，共定位于血管平滑肌细胞 (VSMC)。虽然 NOR-1 沉默降低了血管细胞中 cIAP2 的表达，但该受体的慢病毒过度表达却增加了 cIAP2 mRNA 和蛋白水平。通过荧光素酶报告基因检测、电泳迁移率变动分析和染色质免疫沉淀分析了过表达 NOR-1 的细胞中人 cIAP2 启动子的转录调控，确定了 NOR-1 反应性所必需的 NGFI-B 位点 (NBRE-358/-351)。缺氧和缺氧模拟物上调 NOR-1 和 cIAP2，显示出类似的时间依赖性模式。缺失和定点突变研究表明 NOR-1 介导缺氧诱导的 cIAP2 表达。虽然 NOR-1 过表达上调 cIAP2 并限制缺氧应激诱导的 VSMC 凋亡，但 cIAP2 沉默部分阻止了 NOR-1 的这种促生存作用。这些结果表明cIAP2是NOR-1的靶标，并表明这种抗凋亡蛋白参与血管细胞中NOR-1介导的对缺氧应激的生存反应。
Vascular cell survival is compromised under pathological conditions such as abdominal aortic aneurysm (AAA). We have previously shown that the nuclear receptor NOR-1 is involved in the survival response of vascular cells to hypoxia. Here, we identify the anti-apoptotic protein cIAP2 as a downstream effector of NOR-1. NOR-1 and cIAP2 were up-regulated in human AAA samples, colocalizing in vascular smooth muscle cells (VSMC). While NOR-1 silencing reduced cIAP2 expression in vascular cells, lentiviral over-expression of this receptor increased cIAP2 mRNA and protein levels. The transcriptional regulation of the human cIAP2 promoter was analyzed in cells over-expressing NOR-1 by luciferase reporter assays, electrophoretic mobility shift analysis and chromatin immunoprecipitation, identifying a NGFI-B site (NBRE-358/-351) essential for NOR-1 responsiveness. NOR-1 and cIAP2 were up-regulated by hypoxia and by a hypoxia mimetic showing a similar time-dependent pattern. Deletion and site-directed mutagenesis studies show that NOR-1 mediates the hypoxia-induced cIAP2 expression. While NOR-1 over-expression up-regulated cIAP2 and limited VSMC apoptosis induced by hypoxic stress, cIAP2 silencing partially prevented this NOR-1 pro-survival effect. These results indicate that cIAP2 is a target of NOR-1, and suggest that this anti-apoptotic protein is involved in the survival response to hypoxic stress mediated by NOR-1 in vascular cells.
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