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Negative Regulation of AKT Activation by BRCA1

¹ Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri and ² Institute for Cancer Genetics, Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York

Requests for reprints: Qin Yang, Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park, St. Louis, MO 63108. Phone: 314-747-5445; Fax: 314-362-9790; E-mail: qyang{at}wustl.edu.

Key Words: BRCA1 • PKB/AKT • Phosphorylation • Ubiquitination

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]