Requirement of the human T-cell leukemia virus (HTLV-1) tax-stimulated HIAP-1 gene for the survival of transformed lymphocytes.
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-kappaB (NF-kappaB) 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-kappaB activation.
Wäldele
Katja
K
Institut für Klinische und Molekulare Virologie, Universität Erlangen-Nürnberg, Schlossgarten 4, D-91054 Erlangen, Germany.
Silbermann
Katrin
K
Schneider
Grit
G
Ruckes
Tobias
T
Cullen
Bryan R
BR
Grassmann
Ralph
R
D017209:Apoptosis; D002461:Cell Line, Transformed; D002470:Cell Survival; D016356:Gene Products, tax / Q000502:physiology*; D015368:Human T-lymphotropic virus 1 / Q000737:chemistry / Q000502:physiology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000473:pathology / Q000821:virology*; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015854:Up-Regulation / Q000235:genetics
D016356:Gene Products, tax; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B