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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‐κB
Author(s) -
Okamoto Kazuo,
Fujisawa Junichi,
Reth Michael,
Yonehara Shin
Publication year - 2006
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2006.00927.x
Subject(s) - flip , apoptosis , biology , caspase 8 , nfat , microbiology and biotechnology , cancer research , programmed cell death , caspase 3 , transcription factor , biochemistry , gene
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‐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 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‐κB activity plays an essential role in the up‐regulation of c‐FLIP.