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Paradoxical effects of a stress signal on pro- and anti-apoptotic machinery in HTLV-1 tax expressing cells

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Abstract

Adult T-cell leukemia (ATL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) are associated with Human T-cell lymphotropic virus type 1 (HTLV-1) infection. The viral transactivator, Tax is able to mediate the cell cycle progression by targeting key regulators of the cell cycle such as p21/waf1, p16/ink4a, p53, cyclins D1–3/cdk complexes, and the mitotic spindle checkpoint MAD apparatus, thereby deregulating cellular DNA damage and checkpoint control.

Genome expression profiling of infected cells exemplified by the development of DNA microarrays represents a major advance in genome-wide functional analysis. Utilizing cDNA microarray analysis, we have observed an apparent opposing and paradoxical regulatory network of host cell gene expression upon the introduction of DNA damage stress signal. We find the apparent induction of cell cycle inhibitors, and pro- as well as anti-apoptotic gene expression is directly linked to whether cells are at either G1, S, or G2/M phases of the cell cycle. Specifically, a G1/S block is induced by p21/waf1 and p16/ink4a, while pro-apoptotic expression at S, and G2/M is associated with caspase activation, and anti-apoptotic gene expression is associated with up regulation of Bcl-2 family member, namely bfl-1 gene. Therefore, the microarray results indicating expression of both pro- and anti-apoptotic genes could easily be explained by the particular stage of the cell cycle. Mechanism and the functional outcome of induction for both pathways are discussed.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, George Washington University, Washington, DC, USA

    Cynthia de la Fuente, Lai Wang, Dai Wang, Longwen Deng & Kaili Wu

  2. Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, MSB, Newark, NJ, 07103, USA

    Hong Li

  3. Department of Pediatrics, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, MSB, Newark, NJ, 07103, USA

    Dana Stein & Thomas Denny

  4. Department of Pathology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, MSB, Newark, NJ, 07103, USA

    Frederick Coffman

  5. Department of Biochemistry and Molecular Biology, George Washington University, 2300 Eye Street, NW, Ross Hall, Room 552, Washington, DC, 20037, USA

    Kylene Kehn, Shanese Baylor, Anil Maddukuri, Ann Pumfery & Fatah Kashanchi

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  1. Cynthia de la Fuente
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de la Fuente, C., Wang, L., Wang, D. et al. Paradoxical effects of a stress signal on pro- and anti-apoptotic machinery in HTLV-1 tax expressing cells. Mol Cell Biochem 245, 99–113 (2003). https://doi.org/10.1023/A:1022866027585

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