| Project/Area Number |
14599004
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
細胞死(アポトーシス)
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| Research Institution | Kyoto University |
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Principal Investigator |
LEE Kyung kwon Kyoto University, Graduate School of Biostudies, Instructor, 生命科学研究科, 助手 (50303912)
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| Co-Investigator(Kenkyū-buntansha) |
YONEHARA Shin Kyoto University, Graduate School of Biostudies, Professor, 生命科学研究科, 教授 (00124503)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2003: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Apoptosis / Fas / Caspase / Cell death / FLIP |
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| Research Abstract |
Many tumor cells are resistant to Fas-mediated apoptosis. These cells were reported to have high expression of FLIP, which inhibits to form a DISC complex. FLIP inhibit autocatalytic activation of caspase8 by competition for recruitment to DISC. However, recent studies revealed that FLIP also has a pro-apoptotic function, depending on the expression level in cells.
We asked whether the state of FLIP expression was responsible for the sensitivity to apoptosis in Fas-resistant tumor cells. We found that many Fas-resistant tumor cells recovered sensitivity to apoptosis by co-stimulation with cycloheximide and Fas-sensitive cells showed more susceptibility to apoptosis. Importantly, FLIP expression was not significantly changed before and after cycloheximide treatment in Fas-resistant and Fas-sensitive cell lines.
Then we investigated whether the cleavage of FLIP affect on sensitivity to apoptosis. We established stable cell lines expressing wild-type or DN mutant FLIP in which the residue at cleavage site was changed to Asparagine. HeLa cells expressing DN FLIP were resistant to Fas-mediated apoptosis although cells expressing wild-type FLIP sensitive to apoptosis. This anti-apoptotic activity of FLIP mutant was still observed in cells expressing much less amount of DN FLIP compared with wild-type FLIP. This result suggests that FLIP may function as pro-apoptotic protein even in cellular protein level and cleavage of FLIP is involved in the regulation of Caspse8.
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