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Identification of Mutations in Distinct Regions of p85 Alpha in Urothelial Cancer
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 screen...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867501/ https://www.ncbi.nlm.nih.gov/pubmed/24367658 http://dx.doi.org/10.1371/journal.pone.0084411 |
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author | Ross, Rebecca L. Burns, Julie E. Taylor, Claire F. Mellor, Paul Anderson, Deborah H. Knowles, Margaret A. |
author_facet | Ross, Rebecca L. Burns, Julie E. Taylor, Claire F. Mellor, Paul Anderson, Deborah H. Knowles, Margaret A. |
author_sort | Ross, Rebecca L. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3867501 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-38675012013-12-23 Identification of Mutations in Distinct Regions of p85 Alpha in Urothelial Cancer Ross, Rebecca L. Burns, Julie E. Taylor, Claire F. Mellor, Paul Anderson, Deborah H. Knowles, Margaret A. PLoS One Research Article 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. Public Library of Science 2013-12-18 /pmc/articles/PMC3867501/ /pubmed/24367658 http://dx.doi.org/10.1371/journal.pone.0084411 Text en © 2013 Ross et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Ross, Rebecca L. Burns, Julie E. Taylor, Claire F. Mellor, Paul Anderson, Deborah H. Knowles, Margaret A. Identification of Mutations in Distinct Regions of p85 Alpha in Urothelial Cancer |
title | Identification of Mutations in Distinct Regions of p85 Alpha in Urothelial Cancer |
title_full | Identification of Mutations in Distinct Regions of p85 Alpha in Urothelial Cancer |
title_fullStr | Identification of Mutations in Distinct Regions of p85 Alpha in Urothelial Cancer |
title_full_unstemmed | Identification of Mutations in Distinct Regions of p85 Alpha in Urothelial Cancer |
title_short | Identification of Mutations in Distinct Regions of p85 Alpha in Urothelial Cancer |
title_sort | identification of mutations in distinct regions of p85 alpha in urothelial cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867501/ https://www.ncbi.nlm.nih.gov/pubmed/24367658 http://dx.doi.org/10.1371/journal.pone.0084411 |
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