Cytokine-induced phosphoinositide 3-kinase activity promotes Cdk2 activation in factor-dependent hematopoietic cells.
Cytokine growth factors regulate the proliferation of hematopoietic cells through activation of several distinct signaling pathways. We have assessed the contribution of phosphoinositide 3-kinase (PI3K) pathways to erythropoietin (Epo) and interleukin (IL)-3-induced proliferation of factor-dependent hematopoietic cells. Lack of cytokine-induced PI3K activation caused by receptor mutation or treatment with a specific inhibitor (LY294002) did not prevent proliferation but resulted in an increase in the G1 phase content and doubling time of cell cultures. The reduced proliferation of cells lacking cytokine-induced PI3K activity could be partially restored by overexpressing constitutively active Akt. Inhibition of PI3K activity decreased the proportion of cytokine-treated cells entering S phase and was associated with a significant reduction in cytokine-induced phosphorylation and activation of Cdk2. By contrast, Cdk4 activity and p27(Kip1) expression were not significantly altered by inhibition of PI3K. Together, these observations identify a mechanism through which cytokine-activated PI3K contributes to G1 to S phase progression in factor-dependent hematopoietic cells by enhancing the phosphorylation and activation of Cdk2.
Henry
Matthew K
MK
Department of Pharmacology, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA.
Nimbalkar
Dipali
D
Hohl
Raymond J
RJ
Quelle
Frederick W
FW
D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004921:Erythropoietin / Q000378:metabolism / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology*; D007377:Interleukin-3 / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D016207:Cytokines; D004791:Enzyme Inhibitors; D004921:Erythropoietin; D007377:Interleukin-3; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins; C493961:Cdkn1b protein, mouse; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse