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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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Submitted August 4, 2005
Accepted January 9, 2006
Requirement of the human T-cell leukemia virus (HTLV-1) tax- stimulated hiap-1 gene for the survival of transformed lymphocytes
Katja Waldele, Katrin Silbermann, Grit Schneider, Tobias Ruckes, Bryan Cullen, and Ralph Grassmann*
Institute for Clincal and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA
* Corresponding author; email: Ralph.Grassmann{at}viro.med.uni-erlangen.de.
Human T-cell leukemia virus type 1 (HTLV-1), the cause of adult T-cell leukemia, induces clonal expansion of infected T-cells in non-leukemic 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 upregulation 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 NF- B activation. To address the relevance of virally increased HIAP-1 levels for the survival of HTLV-1-transformed cells, its expression was RNAi-suppressed using a lentiviral transduction system. This resulted in a dramatic reduction of cell growth, a strong induction of apoptosis rates and increased caspase 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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