Identification of Senescence-Associated Genes and Their Networks Under Oxidative Stress by the Analysis of Bach1
Identification of Senescence-Associated Genes and Their Networks Under Oxidative Stress by the Analysis of Bach1
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DOI：
10.1089/ars.2010.3574
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发表时间：
2011-06-01
影响因子：
6.6
通讯作者：
Igarashi, Kazuhiko
中科院分区：
文献类型：
--
作者：
Ota, Kazushige;Dohi, Yoshihiro;Igarashi, Kazuhiko
细胞衰老是响应于DNA损伤而诱导的，DNA损伤是由遗传毒性应激（包括氧化应激）引起的，并且充当针对恶性转化的屏障。肿瘤抑制蛋白p53诱导细胞衰老关键基因的表达。然而，p53靶基因和其他调节剂，实现氧化应激下的衰老的身份仍有待阐明。基于转录因子Bach 1通过阻碍p53的转录活性来抑制这种反应的事实，寻找氧化应激诱导的细胞衰老的效应基因。pRb在Bach 1缺陷的MEFs中比在野生型细胞中更快地低磷酸化，这表明pRb激活参与了它们的衰老。当使用RNAi同时降低p53靶基因的子集（包括p21、Pai 1、Noxa和Perp）的表达时，Bach 1缺陷型MEFs绕过衰老状态。p21和pRb的联合敲低导致了剧烈的再增殖。这些结果表明，氧化应激诱导的细胞衰老是由多个p53靶基因，其中逮捕增殖冗余，部分通过激活pRb注册。我们的阐明与之前描述单个p53靶基因对衰老的垄断调节的报道形成鲜明对比。抗氧化剂。氧化还原信号。14，2441-2451。
Cellular senescence is induced in response to DNA damage, caused by genotoxic stresses, including oxidative stress, and serves as a barrier against malignant transformation. Tumor-suppressor protein p53 induces genes critical for implementing cellular senescence. However, the identities of p53 target genes and other regulators that achieve senescence under oxidative stress remain to be elucidated. Effector genes for oxidative stress-induced cellular senescence were sought, based on the fact that transcription factor Bach1 inhibits this response by impeding the transcriptional activity of p53. pRb became hypophosphorylated more rapidly in Bach1-deficient MEFs than in wild-type cells, suggesting that pRb activation was involved in their senescence. Bach1-deficient MEFs bypassed the senescence state when the expression of a subset of p53 target genes, including p21, Pai1, Noxa, and Perp, was simultaneously reduced by using RNAi. Combined knockdown of p21 and pRb resulted in vigorous re-proliferation. These results suggest that oxidative stress-induced cellular senescence is registered by multiple p53 target genes, which arrest proliferation redundantly, in part by activating pRb. Our elucidations contrast with previous reports describing monopolistic regulations of senescence by single p53 target genes. Antioxid. Redox Signal. 14, 2441-2451.