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Genes to Cells (2006) 11, 177-191. doi:10.1111/j.1365-2443.2006.00927.x
© 2006 Blackwell Publishing or its licensors

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Human T-cell leukemia virus type-I oncoprotein Tax inhibits Fas-mediated apoptosis by inducing cellular FLIP through activation of NF-{kappa}B

Kazuo Okamoto1, Jun-ichi Fujisawa2, Michael Reth3 and Shin Yonehara1,*

1 Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan
2 Department of Microbiology, Kansai Medical University, Osaka 570-8506, Japan
3 Department of Molecular Immunology, Biology III, University of Freiburg and Max-Planck Institute for Immunobiology, Stuebeweg 51, 79108 Freiburg, Germany

Human T-cell leukemia virus type I (HTLV-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 relevant to the onset of HTLV-I-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-{kappa}B did not, suppressed Fas-mediated apoptosis by inducing c-FLIP expression. Furthermore, expression of the dominant negative mutant of either NF-{kappa}B or I{kappa}B{alpha} canceled 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-{kappa}B activity plays an essential role in the up-regulation of c-FLIP.


Communicated by: Shigekazu Nagata

* Correspondence: E-mail: yonehara{at}lif.kyoto-u.ac.jp




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