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Identification of mutations in distinct regions of p85 alpha in urothelial cancer.
- Source :
-
PloS one [PLoS One] 2013 Dec 18; Vol. 8 (12), pp. e84411. Date of Electronic Publication: 2013 Dec 18 (Print Publication: 2013). - Publication Year :
- 2013
-
Abstract
- Bladder cancers commonly show genetic aberrations in the phosphatidylinositol 3-kinase signaling pathway. Here we have screened for mutations in PIK3R1, which encodes p85α, one of the regulatory subunits of PI3K. Two hundred and sixty-four bladder tumours and 41 bladder tumour cell lines were screened and 18 mutations were detected. Thirteen mutations were in C-terminal domains and are predicted to interfere with the interaction between p85α and p110α. Five mutations were in the BH domain of PIK3R1. This region has been implicated in p110α-independent roles of p85α, such as binding to and altering the activities of PTEN, Rab4 and Rab5. Expression of these mutant BH-p85α forms in mouse embryonic fibroblasts with p85α knockout indicated that all forms, except the truncation mutants, could bind and stabilize p110α but did not increase AKT phosphorylation, suggesting that BH mutations function independently of p110α. In a panel of 44 bladder tumour cell lines, 80% had reduced PIK3R1 mRNA expression relative to normal urothelial cells. This, along with mutation of PIK3R1, may alter BH domain functioning. Our findings suggest that mutant forms of p85α may play an oncogenic role in bladder cancer, not only via loss of ability to regulate p110α but also via altered function of the BH domain.
- Subjects :
- Animals
Cattle
Cell Line, Tumor
Cell Proliferation
Class Ia Phosphatidylinositol 3-Kinase
GTP Phosphohydrolases metabolism
Gene Expression Regulation, Neoplastic
Humans
Models, Molecular
Phosphatidylinositol 3-Kinases chemistry
Phosphatidylinositol 3-Kinases metabolism
Protein Stability
Protein Structure, Tertiary
Proto-Oncogene Proteins c-akt metabolism
Signal Transduction
Urinary Bladder Neoplasms pathology
Urothelium pathology
rab5 GTP-Binding Proteins metabolism
Mutation
Phosphatidylinositol 3-Kinases genetics
Urinary Bladder Neoplasms genetics
Urothelium enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 24367658
- Full Text :
- https://doi.org/10.1371/journal.pone.0084411