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Blood, 1 June 2006, Vol. 107, No. 11, pp. 4491-4499.
Prepublished online as a Blood First Edition Paper on February 7, 2006; DOI 10.1182/blood-2005-08-3138.
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NEOPLASIA
Requirement of the human T-cell leukemia virus (HTLV-1) tax-stimulated HIAP-1 gene for the survival of transformed lymphocytes
Katja Wäldele,
Katrin Silbermann,
Grit Schneider,
Tobias Ruckes,
Bryan R. Cullen, and
Ralph Grassmann
From the Institut für Klinische und Molekulare Virologie, Universität Erlangen-Nürnberg, Erlangen, Germany; and the Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC.
Human T cell leukemia virus type 1 (HTLV-1), the cause of adult T cell leukemia (ATL), induces clonal expansion of infected T-cells in nonleukemic individuals and immortalizes T cells in vitro. The resistance against apoptotic stimuli of these cells hints at a viral survival function in addition to a proliferation-stimulating activity. Here we describe the up-regulation of the antiapoptotic HIAP-1/CIAP-2 gene as a consistent phenotype of HTLV-1–transformed and ATL-derived cultures and its stimulation by the viral oncoprotein Tax. Cotransfections revealed a 60-fold increase of HIAP-1 promoter activity mediated by Tax mainly via nuclear factor- B (NF-B) activation. To address the relevance of virally increased HIAP-1 levels for the survival of HTLV-1–transformed cells, its expression was RNA interference (RNAi) suppressed using a lentiviral transduction system. This resulted in a dramatic reduction of cell growth, a strong induction of apoptosis rates, and increased caspases 3/7 activity, which is known to be suppressed by HIAP-1. Thus, the Tax-mediated HIAP-1 overexpression is required to suppress endogenous apoptosis and, therefore, is essential for the survival of HTLV-1–transformed lymphocytes. Moreover, this points to HIAP-1 as an important target of the HTLV-1–mediated NF-B activation.
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