Evidence that the death receptor DR4 is a DNA damage-inducible, p53-regulated gene
Evidence that the death receptor DR4 is a DNA damage-inducible, p53-regulated gene
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DOI：
10.1002/jcp.1101
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发表时间：
2001-07-01
影响因子：
5.6
通讯作者：
Sun, SY
中科院分区：
文献类型：
--
作者：
Guan, BX;Yue, P;Sun, SY
DR4(TRAIL-R1)是肿瘤坏死因子受体超家族的一员，是一种细胞表面受体，与其配体肿瘤坏死因子相关的凋亡诱导配体(TRAIL)结合后可触发细胞凋亡机制。尽管另外三种TRAIL受体DR5、DcR1和DcR2是由DNA损伤诱导的，并受野生型p53肿瘤抑制因子的调控，但这些因素是否也影响DR4的表达尚不清楚。在这项研究中，我们发现无论是电离辐射还是化疗药物诱导的DNA损伤都会增强DR4的表达。这种诱导主要是在含有野生型P53的细胞中观察到的，并且类似于DR5和Fas的调节模式，这两个家族成员已知受到P53的调节。将HPV16E6基因导入野生型p57细胞，可降低P53蛋白水平，抑制DNA损伤剂对DR4的诱导作用。反之，外源性野生型p53通过腺病毒感染导致内源性DR4在突变型p53细胞中上调。此外，转录抑制剂放线菌素D可抑制DNA损伤剂诱导的DR4表达。因此，DR4似乎是一个DNA损伤诱导、P53调控的基因。(C)2001年Wiley-Liss，Inc.
DR4 (TRAIL-R1), a member of the tumor necrosis factor receptor superfamily, is a cell surface receptor that triggers the apoptotic machinery upon binding to its: ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Although three other TRAIL receptors DR5, DcR1, and DcR2 are induced by DNA damage and are regulated by the wild-type p53 tumor suppressor, it was not known whether these factors also affect DR4 expression. In this study, we found that DR4 expression is also enhanced by DNA damage whether induced by ionizing radiation or by chemotherapeutic agents. The induction was observed predominantly in cells containing wild-type p53 and was similar to the, regulation patterns of DR5 and Fas, two other members of the family which are known to be regulated by p53. Transfection of HPV 16 E6 gene into cells with wild-type p57, which decreased the level of p53 protein, resulted in suppression of DR4 induction by DNA-damaging agents. Conversely, introduction of exogenous wild-type p53 through adenovirus infection has led to upregulation of endogenous DR4 in cells with mutant p53. Moreover, the transcription inhibitor actinomycin D abolished DNA-damaging agent-induced DR4 expression. Thus, DR4 appears to be a DNA damage-inducible, p53-regulated gene. (C) 2001 Wiley-Liss, Inc.