| Project/Area Number |
12470396
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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 |
ICHIJO Hidenori Tokyo Medical and Dental University Graduate School, Professor, 大学院・医歯学総合研究科, 教授 (00242206)
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| Co-Investigator(Kenkyū-buntansha) |
TAKADA Kohsuke Tokyo Medical and Dental University Graduate School, Research Associate, 大学院・医歯学総合研究科, 助手 (10313230)
飛梅 圭 日本学術振興会, 特別研究員
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥16,100,000 (Direct Cost: ¥16,100,000)
Fiscal Year 2001: ¥7,500,000 (Direct Cost: ¥7,500,000)
Fiscal Year 2000: ¥8,600,000 (Direct Cost: ¥8,600,000)
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| Keywords | ASK1 / ASK2 / MAP kinase / apoptosis / stress / Nef / c-Myc / TAK1 |
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| Research Abstract |
This study aimed at analyzing the roles for stress-activated MAP kinases in the muco-epithelial tissues with special focus on the roles of Apoptosis Signal-regulating Kinase 1(ASK1) and ASK2. Physiological and Patho-physiological functions of ASK1 were analyzed by generation of ASK1 knock-out mouse, and following findings were obtained.
1) By deleting ASK1 in mice, TNF- and H_2O_2-induced sustained activations of JNK and p38 were found to be lost in ASK1-/- embryonic fibroblasts, and ASK1-/- cells were resistant to TNF- and H_2O_2-induced apoptosis. Thus, ASK1 is selectively required for TNF- and oxidative stress-induced sustained activations of JNK/p38 and apoptosis.
2) Homo-oligomerization-dependent auto-phosphorylation was found to be an important step for activation of ASK1.
3) ASK1 induces not only apoptosis but also differentiation of keratinocytes depending on its extent of activation.
4) At least two phosphatases PP5 and CDC25A were found to inhibit ASK1 activity through different mechanisms.
5) Endoplasmic reticulum (ER) stress was found to induce apoptosis through ASK1-MAP kinase cascades.
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