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Mol. Cell. Biol. doi:10.1128/MCB.01786-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Phosphoinositide 3-kinase p110alpha and beta regulate cell cycle entry exhibiting distinct activation kinetics in G1 phase

Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, Madrid E-28049, Spain

^* To whom correspondence should be addressed. Email: acarrera{at}cnb.uam.

	Abstract

Phosphoinositide 3-kinase (PI3K) is an early signaling molecule that regulates cell growth and cell cycle entry. PI3K is activated immediately after growth factor receptor stimulation (at G0/G1 transition) and again in late G1. The two ubiquitous PI3K isoforms (p110 and ) are essential during embryonic development and are though to control cell division. Nonetheless, it is presently unknown which one is activated during cell cycle and whether or not they both control S phase entry. We found that p110 was activated first in G0/G1, followed by a minor p110 activity peak. In late G1, p110 activation preceded that of , which showed maximum activity at this time. p110 activation required Ras-activity, whereas p110 was first activated by Tyrosine kinases and then further induced by active-Ras. Interference with p110 and activity diminished activation of downstream effectors with different kinetics, with a selective action of p110 at blocking early G1 events. We show that inhibition of either p110 or p110 reduced cell cycle entry. These results reveal that PI3K and present distinct activation requirements and kinetics in G1 phase, with a selective action of PI3K at G0/G1 phase transition. Nevertheless, both PI3K and regulate S phase entry.