2006 Fiscal Year Final Research Report Summary
Clarification of the mechanisms for cell death regulation by DAP3 and CLIPR59, new binding proteins to death receptors
| Project/Area Number |
17590430
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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 |
Immunology
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| Research Institution | Hokkaido University |
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Principal Investigator |
MIYAZAKI Tadaaki Hokkaido University Research Center for Zoonosis Control, Department of Bioresources, Professor, 人獣共通感染症リサーチセンター, 教授 (60272431)
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| Project Period (FY) |
2005 – 2006
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| Keywords | death receptor / apoptosis / DR4,5,6 / DAP3 / LKB1 / LIP1 / CLIPR-59 / TRAIL |
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| Research Abstract |
Despite improvements in chemotherapy and surgery in the treatment of osteosarcoma, satisfactory results are still difficult to achieve. New therapeutic modalities need to be developed for these treatments. TRAIL (TNF-related apoptosis inducing ligand) is known as a selective apoptosis inducer in most tumor cells, but not in normal cells. Therefore, TRAIL is a good candidate target for the treatment of tumors. However, sensitivity of osteosarcoma cells to TRAIL-induced apoptosis is lower than that of other types of tumor cells. We found that LKB1, a serine/threonine kinase, expressed in bone and soft tissue sarcoma cells, associated with DAP3. We also demonstrated that expression of DAP3 induced apoptosis in osteosarcoma cells. Furthermore, expression of LKB1 induced apoptosis and co-expression of LKB1 with DAP3 strongly induced apoptosis in osteosarcoma cells. In addition, expression of LKB1 kinase dead mutant, LKB1 (K78M) inhibited DAP3-induced apoptosis in these cells. These results suggest that LKB1 is critical for TRAIL-induced apoptosis induction, cooperating with DAP3 in osteosarcoma cells. It is predicted that LKB1 and DAP3 could be critical target molecules for the treatment of osteosarcomas.
Death receptor (DR) 6 is the newest member of death receptor family, which induces apoptosis in response to their specific ligand stimulation. We show that CLIPR-59 directly interacts with the cytoplasmic tail of DR6. CLIPR-59 is shown to be crucial for apoptosis induction or JNK activation in DR6-mediated signal. More interestingly, reduction of CLIPR-59 gene expression significantly reduced apoptosis induction and JNK activation mediated by death receptor stimulation. We also identified the interaction of CLIPR-59 with ASK1 and the dominant negative form of ASK1 could prevent CLIPR-59-dependent apoptosis induction. These data suggested that CLIPR-59 plays an important role for apoptosis induction and JNK activation through ASK1 in DR signal.
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