Specific function of phosphoinositide 3-kinase beta in the control of DNA replication.
Class I(A) phosphoinositide 3-kinase (PI3K) are enzymes comprised of a p85 regulatory and a p110 catalytic subunit that induce formation of 3-polyphosphoinositides, which activate numerous downstream targets. PI3K controls cell division. Of the 2 ubiquitous PI3K isoforms, alpha has selective action in cell growth and cell cycle entry, but no specific function in cell division has been described for beta. We report here a unique function for PI3Kbeta in the control of DNA replication. PI3Kbeta regulated DNA replication through kinase-dependent and kinase-independent mechanisms. PI3Kbeta was found in the nucleus, where it associated PKB. Modulation of PI3Kbeta activity altered the DNA replication rate by controlling proliferating cell nuclear antigen (PCNA) binding to chromatin and to DNA polymerase delta. PI3Kbeta exerted this action by regulating the nuclear activation of PKB in S phase, and in turn phosphorylation of PCNA negative regulator p21(Cip). Also, p110beta associated with PCNA and controlled PCNA loading onto chromatin in a kinase-independent manner. These results show a selective function of PI3Kbeta in the control of DNA replication.
Marqués
Miriam
M
Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid E-28049, Spain.
Kumar
Amit
A
Poveda
Ana M
AM
Zuluaga
Susana
S
Hernández
Carmen
C
Jackson
Shaun
S
Pasero
Philippe
P
Carrera
Ana C
AC
D000818:Animals; D002453:Cell Cycle; D002467:Cell Nucleus / Q000201:enzymology; D002843:Chromatin / Q000378:metabolism; D058534:Class I Phosphatidylinositol 3-Kinases; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004261:DNA Replication / Q000235:genetics; D051379:Mice; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
C493957:Cdkn1a protein, mouse; D002843:Chromatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018809:Proliferating Cell Nuclear Antigen; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt