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Molecular and Cellular Biology, April 2008, p. 2803-2814, Vol. 28, No. 8
0270-7306/08/$08.00+0     doi:10.1128/MCB.01786-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Phosphoinositide 3-Kinases p110 and p110β 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

Received 28 September 2007/ Returned for modification 9 November 2007/ Accepted 29 January 2008

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 the G₀/G₁ transition) and again in late G₁. The two ubiquitous PI3K isoforms (p110 and p110β) are essential during embryonic development and are thought to control cell division. Nonetheless, it is presently unknown at which point each is activated during the 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 p110β activity peak. In late G₁, p110 activation preceded that of p110β, which showed the maximum activity at this time. p110β activation required Ras activity, whereas p110 was first activated by tyrosine kinases and then further induced by active Ras. Interference with p110 and -β activity diminished the activation of downstream effectors with different kinetics, with a selective action of p110 in blocking early G₁ events. We show that inhibition of either p110 or p110β reduced cell cycle entry. These results reveal that PI3K and -β present distinct activation requirements and kinetics in G₁ phase, with a selective action of PI3K at the G₀/G₁ phase transition. Nevertheless, PI3K and -β both regulate S-phase entry.

Published ahead of print on 19 February 2008.