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Abstract:
Human T-cell leukemia virus type I (HTVL-I) is an etiologic agent of adult T-cell leukemia and induces autoimmune disease. Previous analyses of tax transgenic mice suggested that protection of peripheral T-cells from Fas-mediated apoptosis by virus-encoded oncoprotein Tax was relavant to the onset of HTLV-1-induced diseases. Here, we show the high level expression of cellular FLICE/caspase-8-inhibitory protein (c-FLIP) in Tax-expressing HTLV-I-infected T-cells. The silencing of c-FLIP expression by a lentivirus-based RNA interference system rendered Tax-positive HTLV-I-infected T-cells sensitive to Fas-mediated apoptosis. Exogenously expressed Tax by using a conditional Cre-loxP-mediated inducible system also inhibited Fas-mediated apoptosis by up-regulating c-FLIP expression in HTLV/I-negative T-cells. Tax mutant d3 which cannot activate CREB/ATF1, while another M22 mutant which cannot activate NF-κB did not, suppressed Fas-mediated apoptosis by inducing c-FLIP expression. Furthermore, expression of the dominant negative mutant of either NF-κB or IκBα cancelled not only c-FLIP expression but also inhibitory activity against Fas-mediated apoptosis by Tax. Inactivation of NFAT, however, did not decrease the expression of c-FLIP in HTLV-I infected T-cells. Taken together, Tax inhibits Fas-mediated apoptosis by up-regulating c-FLIP expression in HTLV-I-infected cells, and NF-κB activity plays an essential role in the up-regulation of c-FLIP.
