Molecular mechanism of cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I.
The trans-activator protein Tax of human T-cell leukemia virus type I (HTLV-I) plays an important role in the development of adult T-cell leukemia through, at least in part, its ability to stimulate cell growth. We previously reported that Tax induced cell cycle progression from G0/G1 phase to S and G2/M phases in human T-cell line Kit 225 cells. To elucidate molecular mechanism of Tax-induced cell cycle progression, we systematically examined the effects of Tax on biochemical events associated with cell cycle progression. Introduction of Tax into resting Kit 225 cells induced activation of the G1/S transition regulation cascade consisting of activation of cyclin dependent kinase 2 (CDK2) and CDK4, phosphorylation of the Rb family proteins and an increase in free E2F. The kinase activation was found to result from Tax-induced expression of genes for cell cycle regulatory molecules including cyclin D2, cyclin E, E2F1, CDK2, CDK4 and CDK6, and Tax-induced reduction of CDK inhibitors p19(INK4d) and p27(Kip1). These modulations by Tax always paralleled the ability of Tax to activate the NF-kappaB transcription pathway. These results indicate the important role of Tax-mediated trans-activation of the genes for cell cycle regulatory molecules in Tax-induced cell cycle progression.
Iwanaga
R
R
Human Gene Sciences Center, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Ohtani
K
K
Hayashi
T
T
Nakamura
M
M
D042846:CDC2-CDC28 Kinases; D002352:Carrier Proteins; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D056742:Cyclin D2; D019927:Cyclin E / Q000096:biosynthesis / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D016356:Gene Products, tax / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D006801:Humans; D007376:Interleukin-2 / Q000172:deficiency; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000473:pathology / Q000821:virology; D009154:Mutation; D016328:NF-kappa B / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology
C080336:CCND2 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D056742:Cyclin D2; D019927:Cyclin E; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D004791:Enzyme Inhibitors; D016356:Gene Products, tax; D007376:Interleukin-2; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; 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