PML regulates p53 stability by sequestering Mdm2 to the nucleolus
PML regulates p53 stability by sequestering Mdm2 to the nucleolus
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DOI：
10.1038/ncb1147
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发表时间：
2004-07-01
影响因子：
21.3
通讯作者：
Pandolfi, PP
中科院分区：
文献类型：
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作者：
Bernardi, R;Scaglioni, PP;Pandolfi, PP
早幼粒细胞白血病(PML)肿瘤抑制蛋白通过调节PML核体(Nb)(3)中CBP依赖的乙酰化(1，2)和Chk2依赖的磷酸化等翻译后修饰来增强P53的功能。PML最近被证明与P53泛素连接酶MDM2相互作用(参考文献4-6)；然而，PML调节MDM2的机制尚不清楚。在这里，我们证明了PML通过将MDM2隔离到核仁来增强P53的稳定性。我们发现DNA损伤后，PML和MDM2以Arf不依赖的方式积聚在核仁中。此外，我们还发现PML的核仁定位依赖于ATR的激活和ATR对PML的磷酸化。值得注意的是，在PML(-/-)细胞中，MDM2与核仁的隔离以及P53的稳定和凋亡的诱导都受到了损害。此外，我们证明了PML在物理上与核仁蛋白L11结合，并且L11基因敲除削弱了PML在DNA损伤后定位到核仁的能力。这些发现证明了PML在核仁网络中对肿瘤抑制的意想不到的作用。
The promyelocytic leukaemia (PML) tumour-suppressor protein potentiates p53 function by regulating post-translational modifications, such as CBP-dependent acetylation(1,2) and Chk2-dependent phosphorylation, in the PML-Nuclear Body (NB)(3). PML was recently shown to interact with the p53 ubiquitin-ligase Mdm2 (refs 4-6); however, the mechanism by which PML regulates Mdm2 remains unclear. Here, we show that PML enhances p53 stability by sequestering Mdm2 to the nucleolus. We found that after DNA damage, PML and Mdm2 accumulate in the nucleolus in an Arf-independent manner. In addition, we found that the nucleolar localization of PML is dependent on ATR activation and phosphorylation of PML by ATR. Notably, in Pml(-/-) cells, sequestration of Mdm2 to the nucleolus was impaired, as well as p53 stabilization and the induction of apoptosis. Furthermore, we demonstrate that PML physically associates with the nucleolar protein L11, and that L11 knockdown impairs the ability of PML to localize to nucleoli after DNA damage. These findings demonstrate an unexpected role of PML in the nucleolar network for tumour suppression.