Negative Regulation of AKT Activation by BRCA1.
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.
Xiang
Tao
T
Department of Radiation Oncology, Washington University School of Medicine, St Louis, Missouri 63108, USA.
Ohashi
Amiko
A
Huang
Yuping
Y
Pandita
Tej K
TK
Ludwig
Thomas
T
Powell
Simon N
SN
Yang
Qin
Q
D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D019398:Genes, BRCA1; D006801:Humans; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D054875:Ubiquitination
D019313:BRCA1 Protein; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt