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Specific function of phosphoinositide 3-kinase beta in the control of DNA replication
Ana M. Povedab,
Philippe Paserob, and
Ana C. Carreraa,2
aDepartment of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid E-28049, Spain; bInstitute of Human Genetics, Centre National de la Recherche Scientifique Unité Propre de Recherche 1142, 141 Rue de la Cardonille, F-34396 Montpellier, France; and cAustralian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia
Edited by Inder M. Verma, The Salk Institute for Biological Studies, La Jolla, CA, and approved March 20, 2009
Received for publication November 25, 2008.
Class IA phosphoinositide 3-kinase (PI3K) are enzymes comprisedof a p85 regulatory and a p110 catalytic subunit that induceformation of 3-polyphosphoinositides, which activate numerousdownstream targets. PI3K controls cell division. Of the 2 ubiquitousPI3K isoforms, has selective action in cell growth and cellcycle entry, but no specific function in cell division has beendescribed for β. We report here a unique function for PI3Kβin the control of DNA replication. PI3Kβ regulated DNAreplication through kinase-dependent and kinase-independentmechanisms. PI3Kβ was found in the nucleus, where it associatedPKB. Modulation of PI3Kβ activity altered the DNA replicationrate by controlling proliferating cell nuclear antigen (PCNA)binding to chromatin and to DNA polymerase . PI3Kβ exertedthis action by regulating the nuclear activation of PKB in Sphase, and in turn phosphorylation of PCNA negative regulatorp21Cip. Also, p110β associated with PCNA and controlledPCNA loading onto chromatin in a kinase-independent manner.These results show a selective function of PI3Kβ in thecontrol of DNA replication.
Author contributions: A.C.C. designed research; M.M., A.K.,A.M.P., S.Z., and C.H. performed research; S.J. contributednew reagents/analytic tools; M.M., A.K., P.P., and A.C.C. analyzeddata; and A.C.C. wrote the paper.