Activation of p53 by oxidative stress involves platelet-derived growth factor-β receptor-mediated ataxia telangiectasia mutated (ATM) kinase activation
Activation of p53 by oxidative stress involves platelet-derived growth factor-β receptor-mediated ataxia telangiectasia mutated (ATM) kinase activation
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DOI：
10.1074/jbc.m304423200
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发表时间：
2003-10-10
影响因子：
4.8
通讯作者：
Keaney, JF
中科院分区：
文献类型：
--
作者：
Chen, K;Albano, A;Keaney, JF
p53肿瘤抑制蛋白的磷酸化是细胞应激过程中p53上调和激活的关键事件。在这项研究中，我们通过血小板衍生生长因子β (pdgfβ)受体和失调性毛细血管扩张突变（ATM）激酶表征了氧化应激与p53之间的信号通路。在H2O2的作用下，我们观察到p53在丝氨酸15处的磷酸化，而不是在丝氨酸9、20和392处。Ser-15的磷酸化与p53的诱导和功能激活增强相关，表现为p53靶蛋白p21（CIP/WAF）的转录。我们发现H2O2诱导pdgfβ受体磷酸化并增加ATM激酶活性，这是p53激活不可或缺的两个事件，AG1433 （pdgfβ受体抑制剂）或咖啡因（ATM激酶抑制剂）抑制Ser-15磷酸化。类似地，H2O2对p53的激活被激酶无活性形式的pdgfβ受体或ATM抑制。抑制ATM激酶对h2o2诱导的pdgfβ受体酪氨酸磷酸化没有影响，而RNA干扰抑制pdgfβ受体会破坏h2o2诱导的ATM激活，这表明ATM在该信号级联中位于pdgfβ受体的下游。在功能上，抑制pdgfβ受体消除了H2O2处理对细胞增殖的抑制和对细胞凋亡的促进。因此，这些数据将pdgfβ受体的反激活与h2o2诱导的p53磷酸化联系起来，并表明生长因子受体在调节p53功能中的功能作用。
Phosphorylation of the p53 tumor suppressor protein is a critical event in the up-regulation and activation of p53 during cellular stress. In this study, we characterized the signaling pathway linking oxidative stress to p53 through the platelet-derived growth factor beta (PDGFbeta) receptor and the ataxia telangiectasia mutated (ATM) kinase. In response to H2O2, we observed phosphorylation of p53 specifically at serine 15, but not serine 9, 20, or 392. Phosphorylation of Ser-15 was correlated with enhanced induction and functional activation of p53 manifest as transcription of the p53 target p21(CIP/WAF). We found that H2O2 induced phosphorylation of the PDGFbeta receptor and increased ATM kinase activity, two events integral to p53 activation as either AG1433 (a PDGFbeta receptor inhibitor) or caffeine (an ATM kinase inhibitor) inhibited Ser-15 phosphorylation. Similarly, p53 activation by H2O2 was inhibited by kinase-inactive forms of the PDGFbeta receptor or ATM. Inhibition of ATM kinase had no effect on H2O2-induced PDGFbeta receptor tyrosine phosphorylation, whereas PDGFbeta receptor suppression with RNA interference impaired H2O2-induced ATM activation, indicating that ATM lies downstream to the PDGFbeta receptor in this signaling cascade. Functionally, inhibition of the PDGFbeta receptor abrogated the inhibition of cell proliferation, and promotion of apoptosis due to H2O2 treatment. Thus, these data link PDGFbeta receptor transactivation to H2O2-induced p53 phosphorylation and suggest a functional role for growth factor receptors in modulation of p53 function.