Akt enhances Mdm2-mediated ubiquitination and degradation of p53
Akt enhances Mdm2-mediated ubiquitination and degradation of p53
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DOI：
10.1074/jbc.m109745200
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发表时间：
2002-06-14
影响因子：
4.8
通讯作者：
Gotoh, Y
中科院分区：
文献类型：
--
作者：
Ogawara, Y;Kishishita, S;Gotoh, Y
p53在DNA损伤诱导的细胞凋亡中起关键作用。最近的研究报道，磷脂酰肌醇3-OH-激酶-A-kt途径抑制p53介导的转录和凋亡，但其潜在的机制尚未确定。Mdm 2是一种p53的泛素连接酶，在调节p53的稳定性方面起着核心作用，并作为Akt的良好底物。在这项研究中，我们发现Akt的表达降低了p53的蛋白水平，至少部分是通过增强p53的降解。Akt表达和血清处理均诱导Mdm 2在Ser（186）处的磷酸化。Akt介导的Mdm 2 Ser（186）磷酸化对Mdm 2的亚细胞定位几乎没有影响。然而，Akt表达和血清处理均增加了p53的Mdm 2泛素化。磷脂酰肌醇3-OH激酶抑制剂LY 294002可阻断血清诱导的p53泛素化增加。此外，当Ser（186）被Ala取代时，Mdm 2变得抵抗Akt增强的p53泛素化和降解。总的来说，这些结果表明Akt通过Ser（186）的磷酸化增强Mdm 2的泛素化促进功能，这导致p53蛋白的减少。这项研究可能揭示Akt促进生存，增殖和肿瘤发生的机制。
p53 plays a key role in DNA damage-induced apoptosis. Recent studies have reported that the phosphatidylinositol 3-OH-kinase-A-kt pathway inhibits p53-mediated transcription and apoptosis, although the underlying mechanisms have yet to be determined. Mdm2, a ubiquitin ligase for p53, plays a central role in regulation of the stability of p53 and serves as a good substrate for Akt. In this study, we find that expression of Akt reduces the protein levels of p53, at least in part by enhancing the degradation of p53. Both Akt expression and serum treatment induced phosphorylation of Mdm2 at Ser(186). Akt-mediated phosphorylation of Mdm2 at Ser(186) had little effect on the subcellular localization of Mdm2. However, both Akt expression and serum treatment increased Mdm2 ubiquitination of p53. The serum-induced increase in p53 ubiquitination was blocked by LY294002, a phosphatidylinositol 3-OH-kinase inhibitor. Moreover, when Ser(186) was replaced by Ala, Mdm2 became resistant to Akt enhancement of p53 ubiquitination and degradation. Collectively, these results suggest that Akt enhances the ubiquitination-promoting function of Mdm2 by phosphorylation of Ser(186), which results in reduction of p53 protein. This study may shed light on the mechanisms by which Akt promotes survival, proliferation, and tumorigenesis.