| Project/Area Number |
13470400
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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 |
病態科学系歯学(含放射線系歯学)
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
TAKEDA Kohsuke Tokyo Medical and Dental University Graduate School, Research Associate, 大学院・医歯学総合研究科, 助手 (10313230)
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| Co-Investigator(Kenkyū-buntansha) |
ICHIJO Hidenori The University of Tokyo Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学系研究科, 教授 (00242206)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥13,700,000 (Direct Cost: ¥13,700,000)
Fiscal Year 2002: ¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 2001: ¥7,100,000 (Direct Cost: ¥7,100,000)
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| Keywords | Nitric oxide(NO) / Signal transduction / MAP kinase / Apoptosis / stress |
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| Research Abstract |
In this research project, we have shown the following two results.
1. We have shown that nitric oxide (NO) strongly activated apoptosis signal-regulating kinase 1(ASK1), which is known to regulate the JNK and p38 MAP kinase pathways, and that NO-induced early activation of p38 was impaired in mouse embryonic fibroblasts obtained from ASK 1-deficient mice. These results strongly suggest that ASK1 is a pivotal regulator of NO-induced activation of the MAP kinase pathways.
2. Recently, we have found that calcium influx activates ASK1. It has been reported that the calcium influx triggers the NO production and that, conversely, NO regulates the calcium homeostasis, suggesting the intimate relationship between NO and calcium signaling. To know how calcium signal affects NO-medicated activation of the ASK1-MAP kinase pathways in calcium signaling, we investigated the activation mechanism of ASK1 by calcium signal. We have shown that a kinase cascade composed of calcium/calmodulin-dependent protein kinase type II (CaMKII)-ASK1-MKK3/MKK6-p38 constituted a novel calcium-signaling pathway. Calcium influx activated CaMKII, and activated CaMKII recruited and activated ASK1 by phosphorylation. Moreover, calcium influx evoked by membrane depolarization in primary neurons and synaptosomes induced strong activation of p38, which was impaired in those derived from ASK 1-deficient mice. Thus, ASK1 appears to be a critical intermediate of calcium signaling between CaMKII and p38.
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