| Project/Area Number |
09557141
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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 | 展開研究 |
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| Research Field |
Morphological basic dentistry
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| Research Institution | Tokyo Medical and Dental University (1998)
Japanese Foundation For Cancer Research (1997) |
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Principal Investigator |
ICHIJO Hidenori Tokyo Medical and Dental University Faculty of Dentistry, Professor, 歯学部, 教授 (00242206)
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| Co-Investigator(Kenkyū-buntansha) |
SAITOH Masao Tokyo Medical and Dental University Faculty of Dentistry, Research Fellow of the, 歯学部・日本学術振興会, 特別研究員
TAKEDA Kohsuke Cancer Institute, Tokyo, Research Assosiate, 生化学部, 嘱託研究員
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥11,000,000 (Direct Cost: ¥11,000,000)
Fiscal Year 1998: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 1997: ¥5,500,000 (Direct Cost: ¥5,500,000)
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| Keywords | ASKI / Apoptosis / MAP-kinase / Traf / Daxx / ASK1 / 口腔組織 / 発生 |
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| Research Abstract |
The aim of this study is to understand the mechanisms of programmed cell death and morphogenesis in the process of cranio-facial development by analyzing the signal transduction mechanisms through ASK1 (Apoptosis signal-regulating kinase 1). We obtained several lines of evidence that ASK1 activity is regulated by different adaptor molecules.
1) Identification of thioredoxin (Trx) as an ASK1 inhibitor : Through a genetic screen for ASK 1-binding proteins, Trx, a redox protein implicated in anti-apoptotic function, was identified as an interacting partner of ASK 1. Trx associated with the N-terminal part of ASK1 and thereby inhibited ASK1 activity. The implication of Trx as a negative regulator of ASK1 suggests possible mechanisms for the redox regulation of apoptosis signal transduction pathway.
2) Identification of TRAF2 as an activator of ASK1 in TNF signaling : TNF-induced activation of the JNK requires TRAF2. ASK1 is activated by TNF and stimulates JNK activation. Based on these previous results, we investigated the possible connection between TRAF2 and ASK1. ASK1 interacts with and is-activated by TRAF2 overexpression. In untransfected mammalian cells ASK1 rapidly associates with TRAF2 in a TNF-dependent manner. Thus, ASK 1 turned out to be a mediator of TRAF2-induced JNK activation.
3) Identification of Daxx as an activator of ASK1 in Fas signaling : Similar to TRAF2, Fas-specific adaptor molecule called Daxx was found to interact with and activate ASK1. Daxx-ASK1 axis may provide another signaling pathway to Fas-induced apoptosis.
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