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 Δp85, which more specifically inhibits class IA 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 Δp85 decreased levels of p107 and cyclins D2, D3 and E and reduced retinoblastoma protein (pRb) phosphorylation. Significantly, only LY294002 treatment increased expression of p27Kip1. Interestingly, LY294002 decreased IL-3-induced proliferation of primary bone marrow-derived mast cells (BMMC) derived from both wild-type and p27Kip1-deficient mice and importantly, LY294002 treatment failed to upregulate p27Kip1 in wild-type BMMC. These data support a role for class IA PI3K in regulating optimal cell cycle progression in response to IL-3 and demonstrate that upregulation of p27Kip1 is not essential for attenuation of the cell cycle resulting from PI3K inhibition.