Phosphoinositide 3-kinases can act independently of p27Kip1 to regulate optimal IL-3-dependent cell cycle progression and proliferation.

We have examined the role of phosphoinositide 3-kinases (PI3K) in interleukin (IL)-3-dependent cell cycle progression and compared the effects of LY294002 with expression of a dominant negative form of p85, termed Deltap85, which more specifically inhibits class I(A) PI3Ks. Inhibition of PI3Ks in BaF/3 led to accumulation of cells in G1 and extension of cell cycle transit times. Biochemically, both LY294002 and Deltap85 decreased levels of p107 and cyclins D2, D3 and E and reduced retinoblastoma protein (pRb) phosphorylation. Significantly, only LY294002 treatment increased expression of p27(Kip1). Interestingly, LY294002 decreased IL-3-induced proliferation of primary bone marrow-derived mast cells (BMMC) derived from both wild-type and p27(Kip1)-deficient mice and importantly, LY294002 treatment failed to upregulate p27(Kip1) in wild-type BMMC. These data support a role for class I(A) PI3K in regulating optimal cell cycle progression in response to IL-3 and demonstrate that upregulation of p27(Kip1) is not essential for attenuation of the cell cycle resulting from PI3K inhibition.