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.
Fox
Bridget C
BC
Department of Pharmacy and Pharmacology, The University of Bath, Claverton Down, Bath BA2 7AY, UK.
Crew
Tracey E
TE
Welham
Melanie J
MJ
D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017353:Gene Deletion; D007377:Interleukin-3 / Q000378:metabolism*; D008407:Mast Cells / Q000166:cytology; D051379:Mice; D008969:Molecular Sequence Data; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D002867:Chromones; D050760:Cyclin-Dependent Kinase Inhibitor p27; D007377:Interleukin-3; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D025521:Tumor Suppressor Proteins; C493961:Cdkn1b protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one