Direct trans-activation of the human cyclin D2 gene by the oncogene product Tax of human T-cell leukemia virus type I.
Cyclins are one of the pivotal determinants regulating cell cycle progression. We previously reported that the trans-activator Tax of human T-cell leukemia virus type I (HTLV-I) induces endogenous cyclin D2 expression along with cell cycle progression in a resting human T-cell line, Kit 225, suggesting a role of cyclin D2 in Tax-mediated cell cycle progression. The cyclin D2 gene has a typical E2F binding element, raising the possibility that induction of cyclin D2 expression is a consequence of cell cycle progression. In this study, we examined the role and molecular mechanism of induction of the endogenous human cyclin D2 gene by Tax. Introduction of p19(INK4d), a cyclin dependent kinase (CDK) inhibitor of the INK4 family specific for D-type CDK, inhibited Tax-mediated activation of E2F, indicating requirement of D-type CDK in Tax-mediated activation of E2F. Previously indicated E2F binding element and two NF-kappaB-like binding elements in the 1.6 kbp cyclin D2 promoter fragment had little, if any, effect on responsiveness to Tax. We found that trans-activation of the cyclin D2 promoter by Tax was mainly mediated by a newly identified NF-kappaB-like element with auxiliary contribution of a CRE-like element residing in sequences downstream of -444 which were by themselves sufficient for trans-activation by Tax. These results indicate that Tax directly trans-activates the cyclin D2 gene, resulting in growth promotion and perhaps leukemogenesis through activation of D-type CDK.
Huang
Y
Y
Human Gene Sciences Center, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Ohtani
K
K
Iwanaga
R
R
Matsumura
Y
Y
Nakamura
M
M
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D056742:Cyclin D2; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics*; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004587:Electrophoresis, Agar Gel; D017353:Gene Deletion; D016356:Gene Products, tax / Q000494:pharmacology*; D015368:Human T-lymphotropic virus 1 / Q000737:chemistry*; D006801:Humans; D019169:Jurkat Cells / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects
C080336:CCND2 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D056742:Cyclin D2; D016213:Cyclins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016356:Gene Products, tax; D016328:NF-kappa B; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D008156:Luciferases; D015500:Chloramphenicol O-Acetyltransferase; D018844:Cyclin-Dependent Kinases