Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27(Kip1)

A senescence-like growth arrest is induced in mouse primary embryo fibrobla sts by inhibitors of phosphoinositide 3-kinase (PI3K), We observed that sen escence like growth arrest is correlated with an increase in p27(Kip1) but that down-regulation of other cyclin-dependent kinase (CDK) inhibitors, inc luding p15(INK4b) p16(INK4a), p19 (INK4d), and p21(Cip1) as well as other n egative cell cycle regulators such as p53 and p19(ARF), implies that this s enescence-related growth arrest is independent of the activity of p53, p19( ARF), p16(INK4a),and p21(Cip1) which are associated with replicative senesc ence. The p27(Kip1) binds to the cyclin/CDK2 complexes and causes a decreas e in CDK2 kinase activity. We demonstrated that ectopic expression of p27(K ip1) 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 i nduce a senescence-like phenotype, at least partially, through inhibition o f PI3K and protein kinase B/Akt, activation of the forkhead protein AFX, an d up-regulation of p27(Kip1)-expression. In summary, these observations tak en together suggest that p27(Kip1) is an important mediator of the permanen t cell cycle arrest induced by PI3K inhibitors Our data suggest that repres sion of CDK2 activity by p27(Kip1) is required for the PI3K-induced senesce nce, yet mouse embryo fibroblasts derived from p27(Kip1-/-) mice entered ce ll cycle arrest after treatment with LY294002, We show that this is due to a compensatory mechanism by which p130 functionally substitutes for the los s of p27(Kip1). This is the first description that p130 may have a role in inhibiting CDK activity during senescence.