title: Identification of mutations in distinct regions of p85 alpha in urothelial cancer.
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.
authors.affiliation: Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds, United Kingdom.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Ross
authors.affiliation: Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds, United Kingdom.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Burns
authors.affiliation: Leeds Cancer Research United Kingdom Centre Genomics Facility, Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds, United Kingdom.
authors.forename: Claire F
authors.initials: CF
authors.lastname: Taylor
authors.affiliation: Cancer Research Unit, Saskatchewan Cancer Agency and the University of Saskatchewan, Saskatoon, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Mellor
authors.affiliation: Cancer Research Unit, Saskatchewan Cancer Agency and the University of Saskatchewan, Saskatoon, Canada.
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Anderson
authors.affiliation: Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds, United Kingdom.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Knowles
mesh_terms: D000818:Animals; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058543:Class Ia Phosphatidylinositol 3-Kinase; D020558:GTP Phosphohydrolases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D019459:Urothelium / Q000201:enzymology* / Q000473:pathology; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D058543:Class Ia Phosphatidylinositol 3-Kinase; D020558:GTP Phosphohydrolases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020696:rab5 GTP-Binding Proteins; C588001:PIK3R1 protein, human