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Inhibition of HTLV-1 transcription by cyclin dependent kinase inhibitors

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Abstract

HTLV-1 is the etiologic agent for adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), where viral replication and transformation are largely dependent upon modification of regulatory and host cell cycle proteins. The mechanism of HTLV-1 transformation appears to be distinct from that of many known chronic or acute leukemia viruses and is related to the viral activator Tax. Here we show that cyclin E, can associate tightly with the coactivator p300 and Pol II complex in HTLV-1 infected cells. The cyclin E associated complex is kinase active and phosphorylates the carboxy terminal domain of RNA Pol II. More importantly, p21/Waf1, a well-known cdk inhibitor at the G1/S border, inhibits transcription of HTLV-1 in both transfections and in in vitro transcription assays. Finally, specific cdk chemical inhibitors, functionally similar to cellular cdkIs, such as p21/Waf1 which inhibits cyclin E/cdk2 activity, also inhibit transcription of the HTLV-1 promoter. In particular, Purvalanol A, with an IC50 of 0.035 μm inhibits activated, but not basal transcription, as well as HTLV-1 infected cells. Collectively, the role of cyclin E/cdk2 in HTLV-1 infected cells and its involvement in RNA Pol II phosphorylation is discussed.

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Authors and Affiliations

  1. School of Medicine, George Washington University, 2300 Eye Street, NW, Ross Hall, Room 552, Washington DC, 20037, USA

    Lai Wang, Longwen Den, Kaili Wu, Cynthia de la Fuente, Dai Wang, Kylene Kehn, Anil Maddukuri, Shanese Baylor, Francisco Santiago, Emmanuel Agbottah & Fatah Kashanchi

  2. Unité de Génétique Moléculaire, Ecole Normale Superieure, 46 rue d'Ulm, 75230, Paris Cedex 05, France

    Sylviane Trigon & Michel Morange

  3. Unite d'Epidemiologie et Physiopathologie des Virus Oncogenes, Batiment SIDA-Retrovirus, Institut Pasteur, 28, rue du Dr Roux, 75724, Paris Cedex 15, France

    Renaud Mahieux

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  1. Lai Wang
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Wang, L., Den, L., Wu, K. et al. Inhibition of HTLV-1 transcription by cyclin dependent kinase inhibitors. Mol Cell Biochem 237, 137–153 (2002). https://doi.org/10.1023/A:1016555821581

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