Decoy receptor 2 (DcR2) is a p53 target gene and regulates chemosensitivity
Decoy receptor 2 (DcR2) is a p53 target gene and regulates chemosensitivity
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DOI：
10.1158/0008-5472.can-05-0939
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发表时间：
2005-10-15
期刊：
影响因子：
11.2
通讯作者：
Sun, SY
中科院分区：
文献类型：
--
作者：
Liu, XG;Yue, P;Sun, SY
诱骗受体2(DcR2)是肿瘤坏死因子相关的凋亡诱导配体(TRAIL)受体之一，可抑制TRAIL诱导的细胞凋亡。其表达与其他三种TRAIL受体(即DR4、DR5和DcR1)一样，受P53调控。在这里，我们报告DcR2是一个P53靶基因，调节化疗敏感性。在本研究中，我们在DcR2基因的第一内含子中发现了一个p53结合位点(P53BS)。这个p53BS与其他三个TRAIL受体基因的第一内含子中发现的几乎相同。通过染色质免疫沉淀实验，我们检测到在完整细胞中P53蛋白与DcR2 p53BS结合。将DcR2 p53BS亚克隆到由SV40启动子驱动的荧光素酶报告载体中，当瞬时与野生型(Wt)p53表达载体在p53缺失的细胞系中共转染时，或在具有wt p53的细胞系中用DNA损伤剂刺激时，显示出增强的荧光素酶活性。此外，将DcR2 p53BS与其相应的启动子区域一起亚克隆到不含启动子元件的碱性荧光素酶载体中时，共转染wt p53基因可显著提高其转录活性。然而，当该p53BS从构建体中被删除时，wt p53未能反式激活该报告构建体。总而言之，我们得出结论，p53通过内含子p53BS直接调节DcR2基因的表达。此外，DcR2的过表达增强了对TRAIL介导的细胞凋亡的抵抗力，并减弱了细胞对DNA损伤剂的反应，而沉默DcR2的表达则增强了化疗药物诱导的细胞凋亡。这些结果表明DcR2调节化疗敏感性。
Decoy receptor 2 (DcR2) is one of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors and suppresses TRAIL-induced apoptosis. Its expression, like the other three TRAIL receptors (i.e., DR4, DR5, and DcR1), is regulated by p53. Here, we report that DcR2 is a p53 target gene and regulates chemosensitivity. In this study, we identified a p53-binding site (p53BS) in the first intron of the DcR2 gene. This p53BS is almost identical to the ones found in the first introns of other three TRAIL receptor genes. By a chromatin immunoprecipitation assay, we detected that the p53 protein bound to the DcR2 p53BS in intact cells. Subcloning of the DcR2 p53BS into a luciferase reporter vector driven by a SV40 promoter exhibited enhanced luciferase activity when transiently cotransfected with a wild-type (wt) p53 expression vector in p53-null cell lines or stimulated with DNA-damaging agents in cell lines having wt p53. Moreover, when the DcR2 p53BS, together with its own corresponding promoter regions, was subcloned into a basic luciferase vector without a promoter element, its transcriptional activities were strikingly increased by cotransfection of the wt p53 gene. However, when this p53BS was deleted from the construct, wt p53 failed to transactivate this reporter construct. Collectively, we conclude that p53 directly regulates the DcR2 gene expression via an intronic p53BS. In addition, overexpression of DcR2 conferred resistance to TRAIL-mediated apoptosis and attenuated cell response to DNA-damaging agents, whereas silencing of DcR2 expression enhanced chemotherapeutic agent-induced apoptosis. These results suggest that DcR2 regulates chemosensitivity.