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Molecular and Cellular Biology, December 2006, p. 9116-9125, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.00783-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Phosphoinositide 3-Kinase Activation in Late G₁ Is Required for c-Myc Stabilization and S Phase Entry

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

Received 4 May 2006/ Returned for modification 16 June 2006/ Accepted 18 September 2006

Phosphoinositide 3-kinase (PI3K) is one of the early-signaling molecules induced by growth factor (GF) receptor stimulation that are necessary for cell growth and cell cycle entry. PI3K activation occurs at two distinct time points during G₁ phase. The first peak is observed immediately following GF addition and the second in late G₁, before S phase entry. This second activity peak is essential for transition from G₁ to S phase; nonetheless, the mechanism by which this peak is induced and regulates S phase entry is poorly understood. Here, we show that activation of Ras and Tyr kinases is required for late-G₁ PI3K activation. Inhibition of late-G₁ PI3K activity results in low c-Myc and cyclin A expression, impaired Cdk2 activity, and reduced loading of MCM2 (minichromosome maintenance protein) onto chromatin. The primary consequence of inhibiting late-G₁ PI3K was c-Myc destabilization, as conditional activation of c-Myc in advanced G₁ as well as expression of a stable c-Myc mutant rescued all of these defects, restoring S phase entry. These results show that Tyr kinases and Ras cooperate to induce the second PI3K activity peak in G₁, which mediates initiation of DNA synthesis by inducing c-Myc stabilization.

Published ahead of print on 2 October 2006.

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• Marques, M., Kumar, A., Cortes, I., Gonzalez-Garcia, A., Hernandez, C., Moreno-Ortiz, M. C., Carrera, A. C. (2008). Phosphoinositide 3-Kinases p110{alpha} and p110{beta} Regulate Cell Cycle Entry, Exhibiting Distinct Activation Kinetics in G1 Phase. Mol. Cell. Biol. 28: 2803-2814 [Abstract] [Full Text]