HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation
HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation
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DOI：
10.1038/ncb1101-973
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发表时间：
2001-11-01
影响因子：
21.3
通讯作者：
Hung, MC
中科院分区：
文献类型：
--
作者：
Zhou, BHP;Liao, Y;Hung, MC
HER-2/neu扩增或过表达可使癌细胞抵抗凋亡并促进其生长。P53在调节细胞生长和凋亡中起着至关重要的作用，在许多类型的肿瘤中经常发生突变或缺失。此外，许多具有p53野生型基因的突变体不具有正常的p53功能，这表明一些致癌信号抑制了p53的功能。在这项研究中，我们发现HER-2/ new介导的对dna损伤剂的抗性需要激活Akt，而Akt会增强mdm2介导的泛素化和p53的降解。Akt物理上与MDM2结合，并使其Ser166和Ser186磷酸化。MDM2的磷酸化增强了其核定位及其与p300的相互作用，抑制了其与P19（ARF）的相互作用，从而增加了p53的降解。我们的研究表明，阻断HER-2/neu介导的Akt通路会增加dna损伤药物对野生型p53肿瘤细胞的细胞毒作用。
HER-2/neu amplification or overexpression can make cancer cells resistant to apoptosis and promotes their growth. p53 is crucial in regulating cell growth and apoptosis, and is often mutated or deleted in many types of tumour. Moreover, many turnours with a wild-type gene for p53 do not have normal p53 function, suggesting that some oncogenic signals suppress the function of p53. In this study, we show that HER-2/neu-mediated resistance to DNA-damaging agents requires the activation of Akt, which enhances MDM2-mediated ubiquitination and degradation of p53. Akt physically associates with MDM2 and phosphorylates it at Ser166 and Ser186. Phosphorylation of MDM2 enhances its nuclear localization and its interaction with p300, and inhibits its interaction with P19(ARF), thus increasing p53 degradation. Our study indicates that blocking the Akt pathway mediated by HER-2/neu would increase the cytotoxic effect of DNA-damaging drugs in tumour cells with wild-type p53.