Phosphoinositide 3-kinase activation regulates cell division time by coordinated control of cell mass and cell cycle progression rate

Abstract

Cells must increase their mass in coordination with cell cycle progression to ensure that their size and macromolecular composition remain constant for any given proliferation rate. To this end, growth factors activate early signaling cascades that simultaneously promote cell mass increase and induce cell cycle entry. Nonetheless, the mechanism that controls the concerted regulation of cell growth and cell cycle entry in mammals remains unknown. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B pathway regulates cell cycle entry by inactivating forkhead transcription factors and promoting cyclin D synthesis. PI3K/protein kinase B-derived signals also affect activation of p70 S6 kinase and the mammalian target of rapamycin, enzymes involved in cell growth control. We previously showed that enhancement of PI3K activation accelerates cell cycle entry, whereas reduction of PI3K activation retarded this process. Here we examined whether expression of different PI3K mutants affects cell growth during cell division. We show that diminishing or enhancing the magnitude of PI3K activation in a transient manner reduces or increases, respectively, the protein synthesis rate. Alteration of cell growth and cell cycle entry by PI3K forms appears to be concerted, because it results in lengthening or shortening of cell division time without altering cell size. In support of a central role for PI3K in growth control, expression of a deregulated, constitutive active PI3K mutant affects p70 S6 kinase and mammalian target of rapamycin activities and increases cell size. Together, the results show that transient PI3K activation regulates cell growth and cell cycle in a coordinated manner, which in turn controls cell division time.