| Project/Area Number |
13043013
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
TSUBATA Takeshi Tokyo Medical and Dental University, Laboratory of Immunolog, School of Biomedical Science, Professor, 疾患生命科学研究部, 教授 (80197756)
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| Co-Investigator(Kenkyū-buntansha) |
宮島 篤 東京大学, 分子細胞生物学研究所, 教授 (50135232)
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| Project Period (FY) |
2001 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥106,200,000 (Direct Cost: ¥106,200,000)
Fiscal Year 2005: ¥19,400,000 (Direct Cost: ¥19,400,000)
Fiscal Year 2004: ¥19,000,000 (Direct Cost: ¥19,000,000)
Fiscal Year 2003: ¥22,600,000 (Direct Cost: ¥22,600,000)
Fiscal Year 2002: ¥23,700,000 (Direct Cost: ¥23,700,000)
Fiscal Year 2001: ¥21,500,000 (Direct Cost: ¥21,500,000)
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| Keywords | Cell death / c-Myc / Reactive oxygen species / CDK inhibitor / lymphocyte / アポトーシス / 細胞周期回転 / 活性酸素 / p38MAPK / ApoE / Serf2 / CD40 / PDIP1 / siRNA / p27kip1 / 分化 / 肝細胞 / Ras |
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| Research Abstract |
Cellular defects that perturb cell cycle progression induce checkpoint-mediated cell cycle arrest, and the defect in this arrest causes cell death. However, checkpoint-independent cell cycle arrest is known to either induce or block cell death. In this study, we addressed mechanisms for cell cycling-mediated regulation of cell death and its biological significance. By using B lymphoma line that undergoes efficient apoptosis upon cell cycle arrest, we established the experimental system in which gene fragments regulating cell cycle arrest-induced apoptosis are enriched We isolated the c-myc gene as a regulator of cell cycle arrestinduced cell death. We further demonstrated that cell cycle arrest induces apoptosis in cells expressing a high level of c-myc, but induces survival in c-myclo cells. This result suggests that cMyc determines whether cell cycling regulates cell death positively or negatively. Further, we isolated genes involved in RNA metabolism such as SMN as regulators of cell cycling-regulated cell death. B lymphocytes undergo cell death upon antigen stimulation, and the antigen-induced cell death is abrogated by CD40 signaling for generating immune responses. We demonstrated that CD40mediated cell survival requires cell cycling, suggesting that regulation of cell death by cell cycling play a crucial role in the immune system. Further, we demonstrated that ROS is generated upon induction of cell death by cell cycle arrest or antigen stimulation, and plays a crucial role in the cell death.
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