A senescence-like growth arrest is induced in mouse primary embryo fibroblasts by inhibitors of phosphoinositide 3-kinase (PI3K Kip1 can induce permanent cell cycle arrest and a senescence-like phenotype in wildtype mouse embryo fibroblasts. We also obtained results suggesting that the kinase inhibitors LY294002 and Wortmannin arrest cell growth and induce a senescence-like phenotype, at least partially, through inhibition of PI3K and protein kinase B/Akt, activation of the forkhead protein AFX, and up-regulation of p27 Kip1 -expression. In summary, these observations taken together suggest that p27Kip1 is an important mediator of the permanent cell cycle arrest induced by PI3K inhibitors. Our data suggest that repression of CDK2 activity by p27Kip1 is required for the PI3K-induced senescence, yet mouse embryo fibroblasts derived from p27

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