Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation
Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation
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DOI：
10.1038/sj.emboj.7600145
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发表时间：
2004-04-07
期刊：
影响因子：
11.4
通讯作者：
Wahl, GM
中科院分区：
文献类型：
--
作者：
Stommel, JM;Wahl, GM
P53的激活可以阻止遗传不稳定细胞的增殖。相反，其转录靶标E3泛素连接酶MDM2对P53的拮抗作用对非应激的循环细胞的生存至关重要。我们证明了MDM2诱导了胞核和胞浆中P53的降解。随着P53和MDM2在应激细胞的细胞核中积累，我们研究了使P53激活的机制，尽管在DNA损伤反应中产生了高MDM2水平。我们发现，DNA损伤通过损伤激活的激酶和MDM2的自动泛素化来破坏MDM2的稳定。当MDM2不稳定时，p53在转录水平上是稳定的，但随着损伤反应的减弱和MDM2的稳定，P53变得不稳定和不活跃。重要的是，阻断DNA损伤细胞中的MDM2失稳阻止了P53靶基因的激活。我们的数据显示，受控的MDM2降解是P53调控的重要新步骤。
p53 activation prevents the proliferation of genetically unstable cells. Conversely, p53 antagonism by its transcriptional target, the E3 ubiquitin ligase MDM2, is critical for the viability of unstressed, cycling cells. We demonstrate that MDM2 induces the degradation of p53 in both the nucleus and the cytoplasm. As p53 and MDM2 accumulate in the nuclei of stressed cells, we investigated mechanisms enabling p53 activation despite the high MDM2 levels generated during a DNA-damage response. We show that DNA damage destabilized MDM2 by a mechanism involving damage-activated kinases and MDM2 auto-ubiquitination. p53 was stable and transcriptionally active when MDM2 was unstable, but became unstable and inactive as the damage response waned and MDM2 stabilized. Importantly, blocking MDM2 destabilization in DNA-damaged cells prevented p53 target gene activation. Our data reveal that controlled MDM2 degradation is an important new step in p53 regulation.