Document Detail


Activity of any class IA PI3K isoform can sustain cell proliferation and survival.
MedLine Citation:
PMID:  20534549     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Small molecule inhibitors of PI3K for oncology mainly target the class I PI3Ks, comprising the p110alpha, beta, gamma, and delta isoforms, of which only p110alpha is mutated in cancer. To assess the roles of class I PI3K isoforms in cell proliferation and survival, we generated immortalized mouse leukocyte and fibroblast models in which class I PI3Ks were inactivated by genetic and pharmacological approaches. In IL3-dependent hemopoietic progenitor cells (which express all four class I PI3K isoforms), genetic inactivation of either p110alpha or p110delta did not affect cell proliferation or survival or sensitize to p110beta or p110gamma inactivation. Upon compound inactivation of p110alpha and p110delta, which removed >90% of p85-associated PI3K activity, remarkably, cells continued to proliferate effectively, with p110beta assuming an essential role in signaling and cell survival. Furthermore, under these conditions of diminished class I PI3K activity, input from the ERK pathway became important for cell survival. Similar observations were made in mouse embryonic fibroblasts (which mainly express p110alpha and p110beta) in which p110alpha or p110beta could sustain cell proliferation as a single isoform. Taken together, these data demonstrate that a small fraction of total class I PI3K activity is sufficient to sustain cell survival and proliferation. Persistent inhibition of selected PI3K isoforms can allow the remaining isoform(s) to couple to upstream signaling pathways in which they are not normally engaged. Such functional redundancy of class IA PI3K isoforms upon sustained PI3K inhibition has implications for the development and use of PI3K inhibitors in cancer.
Authors:
Lazaros C Foukas; Inma M Berenjeno; Alexander Gray; Asim Khwaja; Bart Vanhaesebroeck
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-06-07
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-23     Completed Date:  2010-07-22     Revised Date:  2014-03-17    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  11381-6     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis
Cell Proliferation
Class I Phosphatidylinositol 3-Kinases
Enzyme Inhibitors / pharmacology
Extracellular Signal-Regulated MAP Kinases / metabolism
Fibroblasts / enzymology*
Gene Expression Regulation, Enzymologic*
Leukocytes / enzymology*
MAP Kinase Signaling System
Mice
Mutation
Neoplasms / drug therapy*
Phosphatidylinositol 3-Kinases / chemistry,  metabolism*
Protein Isoforms
Grant Support
ID/Acronym/Agency:
10200//Cancer Research UK; C23338/A10200//Cancer Research UK; G0801865//Medical Research Council; G9403619//Medical Research Council; //Department of Health; //Wellcome Trust
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Protein Isoforms; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.1.137/1-phosphatidylinositol 3-kinase p110 subunit, mouse; EC 2.7.1.137/Class I Phosphatidylinositol 3-Kinases; EC 2.7.1.137/Pik3cd protein, mouse; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases
Comments/Corrections

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