HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation

被引：763

作者：

Zhou, BHP ^{[1
]}

Liao, Y ^{[1
]}

Xia, WY ^{[1
]}

Zou, YY ^{[1
]}

Spohn, B ^{[1
]}

Hung, MC ^{[1
]}

机构：

[1] Univ Texas, MD Anderson Canc Ctr, Breast Canc Basic Res Program, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

来源：

NATURE CELL BIOLOGY | 2001年 / 3卷 / 11期

关键词：

D O I：

10.1038/ncb1101-973

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：973 / 982

页数：10

共 37 条

[1] Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor [J].