| Project/Area Number |
16370086
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cell biology
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| Research Institution | Kyoto University |
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Principal Investigator |
YONEHARA Shin Kyoto University, Graduate School of Biostudies, Professor, 生命科学研究科, 教授 (00124503)
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| Co-Investigator(Kenkyū-buntansha) |
LEE Kyoung-Kwong Kyoto University, Graduate School of Biostudies, Assistant Professor, 生命科学研究科, 助手 (50303912)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥13,300,000 (Direct Cost: ¥13,300,000)
Fiscal Year 2005: ¥6,200,000 (Direct Cost: ¥6,200,000)
Fiscal Year 2004: ¥7,100,000 (Direct Cost: ¥7,100,000)
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| Keywords | signal transduction / biological molecule / gene / cell, organ |
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| Research Abstract |
Human T-cell leukemia virus type I (HTLV-I) is an etiologic agent of adult T-cell leukemia and induces autoimmune disease. Protection of peripheral T-cells from Fas-mediated apoptosis by virus-encoded oncoprotein Tax was previously suggested to be relevant to the onset of HTLV-I-induced diseases. 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 systems also inhibited Fas-mediated apoptosis by up-regulating c-FLIP expression in HTLV-I-negative T-cells. Expression of the dominant negative mutant of either NF-κB or I κB α canceled not only c-FLIP expression but also inhibitory activity against Fas-mediated apoptosis by Tax. Thus, 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.
Fas-mediated apoptosis is potently inhibited by viral FLIP through reduced activation of procaspase-8. Here, we show that equine herpesvirus 2-encoded viral FLIP E8 enhances Wnt/β-catenin signaling in a variety of cell lines. E8 enhanced Wnt signaling downstream of stabilized β-catenin, while a long form of celluar FLIP(c-FLIP_L) enhanced stabilization of β-catenin in only 293T cells. Consequently, coexpression of E8 and c-FLIP_L synergistically increased Wnt signaling in 293T cells. Moreover, E8-mediated stimulation of Wnt signaling induced dramatic growth retardation in untransformed cell lines but not in transformed cell lines. Thus, viral FLIP E8 not only inhibits death receptor-mediated apoptosis but also enhances Wnt signaling pathways that are closely related to those of both ontogenesis and oncogenesis.
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