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 - PubMed (original) (raw)

. 2003 Nov 20;107(4):603-11.

doi: 10.1002/ijc.11316.

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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

Iqbal H Chowdhury et al. Int J Cancer. 2003.

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.

Copyright 2003 Wiley-Liss, Inc.

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