Article

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, Darwin 3, Campus de Cantoblanco, Madrid E-28049, Spain.
Molecular and Cellular Biology (impact factor: 5.53). 01/2007; 26(23):9116-25. DOI:10.1128/MCB.00783-06 pp.9116-25
Source: PubMed

ABSTRACT 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 G(1) phase. The first peak is observed immediately following GF addition and the second in late G(1), before S phase entry. This second activity peak is essential for transition from G(1) 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-G(1) PI3K activation. Inhibition of late-G(1) 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-G(1) PI3K was c-Myc destabilization, as conditional activation of c-Myc in advanced G(1) 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 G(1), which mediates initiation of DNA synthesis by inducing c-Myc stabilization.

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Keywords

Cdk2 activity
 
cell cycle entry
 
conditional activation
 
cyclin
 
distinct time points
 
DNA synthesis
 
early-signaling molecules induced
 
GF addition
 
growth factor
 
loading
 
low c-Myc
 
MCM2
 
mediates initiation
 
minichromosome maintenance protein
 
Phosphoinositide 3-kinase
 
PI3K
 
PI3K activation
 
primary consequence
 
second activity peak
 
second PI3K activity peak