Negative Regulation of AKT Activation by BRCA1

被引：111

作者：

Xiang, Tao ^{[1
]}

Ohashi, Amiko ^{[1
]}

Huang, Yuping ^{[1
]}

Pandita, Tej K. ^{[1
]}

Ludwig, Thomas ^{[2
]}

Powell, Simon N. ^{[1
]}

Yang, Qin ^{[1
]}

机构：

[1] Washington Univ, Sch Med, Dept Radiat Oncol, St Louis, MO 63108 USA

[2] Columbia Univ, Inst Canc Genet, Dept Pathol & Cell Biol, Herbert Irving Comprehens Canc Ctr, New York, NY USA

来源：

CANCER RESEARCH | 2008年 / 68卷 / 24期

关键词：

D O I：

10.1158/0008-5472.CAN-08-3009

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The breast cancer susceptibility gene 1 (BRCA1) plays a key role in mammary tumorigenesis. However, the reasons why silencing the Brca1 gene leads to tumorigenesis are not clearly understood. We report here that BRCA1 deficiency activates the AKT oncogenic pathway, one of the most common alterations associated with human malignancy. Mutation of Brca1 gene increases the phosphorylation and the kinase activity of AKT. The BRCA1-BRCT domains bind to phosphorylated AKT (pAKT) and lead to its ubiquitination toward protein degradation. BRCA1 mutant cells lacking the BRCT repeats accumulate nuclear pAKT and consequently inactivate the transcription functions of FOXO3a, a main nuclear target of pAKT. Our results show that BRCA1 is a negative regulator of the AKT pathway and imply the significance of the BRCA1/AKT pathway in tumorigenesis. [Cancer Res 2008;68(24):10040-4]

引用

页码：10040 / 10044

页数：5

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