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.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Chowdhury, IH; Farhadi, A; Wang, X-F; Robb, ML; Birx, DL; Kim, JH

Published Date

  • November 20, 2003

Published In

Volume / Issue

  • 107 / 4

Start / End Page

  • 603 - 611

PubMed ID

  • 14520699

International Standard Serial Number (ISSN)

  • 0020-7136

Digital Object Identifier (DOI)

  • 10.1002/ijc.11316


  • eng

Conference Location

  • United States