Direct Trans-Activation of the Human Cyclin D2 Gene by the Oncogene Product Tax of Human T-cell Leukemia Virus Type I

Oncogene. 2001 Mar 1;20(9):1094-102. doi: 10.1038/sj.onc.1204198.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins*
  • Cell Cycle Proteins*
  • Cell Line
  • Chloramphenicol O-Acetyltransferase / metabolism
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclin D2
  • Cyclin-Dependent Kinases / genetics
  • Cyclins / biosynthesis
  • Cyclins / genetics*
  • DNA Primers / chemistry
  • DNA-Binding Proteins*
  • E2F Transcription Factors
  • Electrophoresis, Agar Gel
  • Gene Deletion
  • Gene Products, tax / pharmacology*
  • Human T-lymphotropic virus 1 / chemistry*
  • Humans
  • Jurkat Cells / metabolism
  • Luciferases / metabolism
  • NF-kappa B / metabolism
  • Promoter Regions, Genetic
  • Retinoblastoma-Binding Protein 1
  • Transcription Factor DP1
  • Transcription Factors / metabolism*
  • Transcriptional Activation* / drug effects

Substances

  • CCND2 protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cyclic AMP Response Element-Binding Protein
  • Cyclin D2
  • Cyclins
  • DNA Primers
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • Gene Products, tax
  • NF-kappa B
  • Retinoblastoma-Binding Protein 1
  • Transcription Factor DP1
  • Transcription Factors
  • Luciferases
  • Chloramphenicol O-Acetyltransferase
  • Cyclin-Dependent Kinases