HIPK2 neutralizes MDM2 inhibition rescuing p53 transcriptional activity and apoptotic function
HIPK2 neutralizes MDM2 inhibition rescuing p53 transcriptional activity and apoptotic function
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DOI：
10.1038/sj.onc.1207656
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发表时间：
2004-07-01
期刊：
影响因子：
8
通讯作者：
D'Orazi, G
中科院分区：
文献类型：
--
作者：
Di Stefano, V;Blandino, G;D'Orazi, G
P53癌抑制蛋白受到MDM2的负调控，MDM2通过自动调节环有效地抑制其活性。然而，作为对压力的反应，p53经历了翻译后莫迪。使蛋白质逃脱MDM2控制、积累并变得活跃的阳离子。最近的研究表明，DNA损伤后，HIPK2丝氨酸/苏氨酸激酶结合并磷酸化P53，诱导P53转录活性和凋亡功能。在这里，我们研究了在MDM2存在的情况下，HIPK2在P53激活中的作用。我们发现，HIPK2可以挽救P53的转录活性，克服MDM2的抑制，并且恢复这一P53功能可以诱导细胞凋亡。在体外和体内的遗传毒性应激后，通过阻止p53核输出和MDM2介导的泛素化，实现了p53依赖的细胞凋亡的恢复。这些结果为HIPK2/P53途径促进细胞凋亡和抑制肿瘤发生的机制提供了新的线索。
The p53 oncosuppressor protein is subject to negative regulation by MDM2, which efficiently inhibits its activity through an autoregulatory loop. In response to stress, however, p53 undergoes post-translational modi. cations that allow the protein to escape MDM2 control, accumulate, and become active. Recent studies have shown that, following DNA damage, the HIPK2 serine/ threonine kinase binds and phosphorylates p53, inducing p53 transcriptional activity and apoptotic function. Here, we investigated the role of HIPK2 in the activation of p53 in the presence of MDM2. We found that HIPK2 rescues p53 transcriptional activity overcoming MDM2 inhibition, and that restoration of this p53 function induces apoptosis. Recovery of p53-dependent apoptosis is achieved by preventing p53 nuclear export and ubiquitination mediated by MDM2 in vitro and in vivo following genotoxic stress. These results shed new light on the mechanisms by which the HIPK2/p53 pathway promotes apoptosis and suppression of tumorigenesis.