Human T-cell leukemia virus type 1 Tax activates cyclin-dependent kinase inhibitor p21/Waf1/Cip1 expression through a p53-independent mechanism: Inhibition of cdk2

Int J Cancer. 2003 Nov 20;107(4):603-11. doi: 10.1002/ijc.11316.

Abstract

We investigated the possible involvement of HTLV-1 Tax in the transcriptional activation of p21/Waf1/Cip1 (hereafter p21), a potent inhibitor of cyclin-dependent kinases and cell growth. Tax transfection resulted in enhanced expression of p21 protein in T and fibroblastoid cells. Similarly, Tax-expressing cells have higher amounts of endogenous p21 protein and RNA. However, neither Tax-negative, HTLV-1 transformed cells or HTLV-1-negative T cell lines had detectable levels of p21 protein and RNA. Cotransfection of Tax strongly activated the p21 promoter. CREB/ATF defective Tax mutant (M47) activated the p21 promoter significantly less efficiently. Tax activated wild type (wt) p21 promoter in p53-negative Jurkat and p53-positive A301cells, irrespective of endogenous p53 status, and activated a mutant p21 promoter containing a p53 responsive element (p53RE) deletion as strongly as wt promoter. Of importance, cdk2 activity was almost completely abolished in Tax-induced p21-expressing MT-2 cells, suggesting that Tax-induced p21 predominantly affects the activity of cdk2, a late G1 and S phase kinase. Taken together, these findings suggest that HTLV-1 Tax activates p21/Waf1/Cip1, a cell growth inhibitor, in a p53-independent mechanism through CREB/ATF-related transcription factors, and inhibits cdk2. Tax induction of p21 may balance the T-cell proliferation function of Tax and may contribute to the long clinical latency of HTLV-1 infection and the delayed development of adult T-cell leukemia.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activating Transcription Factors
  • Blood Proteins / genetics
  • Blood Proteins / metabolism
  • Blotting, Western
  • CDC2-CDC28 Kinases / antagonists & inhibitors*
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / genetics
  • Cyclins / metabolism*
  • Gene Products, tax / physiology*
  • Humans
  • Luciferases / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / virology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Activating Transcription Factors
  • Blood Proteins
  • CDKN1A protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Gene Products, tax
  • Neoplasm Proteins
  • RNA, Messenger
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Luciferases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2