title: Differential effects of transforming growth factor on cell cycle regulatory molecules in human myeloid leukemia cells.
abstract: In this report we have studied the mechanism by which Transforming Growth Factor beta (TGF beta) inhibits growth of human myeloid leukemia cell lines. TGF beta 1 arrested cells in G1 phase and significantly downregulated the expression of cyclin D2, cyclin D3, cdk4, cyclin A, and cdk2. The downregulation of the molecules resulted in approximately 50-90% decrease of the molecule-dependent kinase activity, varying with each molecule. Although treatment of cells with TGF beta 1 up-regulated accumulation of p27(kip1) in both nucleus and cytoplasm, the association of the p27(kip1) with cdk2, cyclin A, cyclin D2, cyclin D3, and cdk4 was markedly down-regulated, suggesting that p27(kip1) is not responsible for the downregulation of the kinase activity. In contrast, TGF beta 1 upregulated cyclin E-associated p27(kip1) with no effect on the expression of cyclin E. p27(kip1)-immunodepletion upregulated cyclin E-dependent kinase activity by more than 10-fold in TGF beta 1-treated cells but not in proliferating cells; whereas immunodepletion of p27(kip1) from cdk2-immunoprecipitates markedly downregulated cdk2 kinase activity in the lysates extracted from both proliferating and TGF beta-treated cells. Consistent with this observation, TGF beta 1 and p27(kip1) antisense cDNA had a synergistic or additive inhibitory effect on cdk2 but not cyclin E-dependent kinase activity. Our data suggest that (1) TGF beta 1-mediated growth inhibition is accomplished through multiple pathways and (2) p27(kip1) has opposing effects on cdk2 and cyclin E activity in response to TGF beta 1.
authors.affiliation: Interdisciplinary Oncology Program, University of South Florida, and H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA. hu@moffitt.usf.esu
authors.forename: X
authors.initials: X
authors.lastname: Hu
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: Q
authors.initials: Q
authors.lastname: Zhong
authors.forename: A B
authors.initials: AB
authors.lastname: Fisher
authors.forename: M
authors.initials: M
authors.lastname: Bryington
authors.forename: K S
authors.initials: KS
authors.lastname: Zuckerman
mesh_terms: D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins / Q000378:metabolism* / Q000502:physiology; D002455:Cell Division; D056741:Cyclin D; D019927:Cyclin E / Q000037:antagonists & inhibitors / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D015536:Down-Regulation; D016193:G1 Phase; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D056741:Cyclin D; D019927:Cyclin E; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases