2003 Fiscal Year Final Research Report Summary
Research on Regulation Mechanism of Death Inducing Signaling Complex (DISC) Formation
| Project/Area Number |
14599004
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
細胞死(アポトーシス)
|
|---|
| Research Institution | Kyoto University |
|---|
Principal Investigator |
LEE Kyung kwon Kyoto University, Graduate School of Biostudies, Instructor, 生命科学研究科, 助手 (50303912)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
YONEHARA Shin Kyoto University, Graduate School of Biostudies, Professor, 生命科学研究科, 教授 (00124503)
|
|---|
| Project Period (FY) |
2002 – 2003
|
| Keywords | Apoptosis / Fas / Caspase / Cell death / FLIP |
|---|
| 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.
|
Research Products
(6 results)
