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Negative Regulation of AKT Activation by BRCA1.
- Source :
-
Cancer research [Cancer Res] 2008 Dec 15; Vol. 68 (24), pp. 10040-4. - Publication Year :
- 2008
-
Abstract
- 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.
- Subjects :
- Animals
BRCA1 Protein deficiency
BRCA1 Protein genetics
Breast Neoplasms enzymology
Breast Neoplasms genetics
Breast Neoplasms metabolism
Cell Line, Tumor
Cell Nucleus metabolism
Enzyme Activation
Forkhead Box Protein O3
Forkhead Transcription Factors metabolism
Genes, BRCA1
Humans
Mice
Proto-Oncogene Proteins c-akt genetics
RNA Interference
Signal Transduction
Transfection
Ubiquitination
BRCA1 Protein metabolism
Proto-Oncogene Proteins c-akt metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 68
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 19074868
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-08-3009