| Project/Area Number |
17390084
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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 |
General medical chemistry
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| Research Institution | NAGOYACITY UNIVERSITY |
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Principal Investigator |
NAKANISHI Makoto Nagoya City University, Graduate School of Medical Sciences, Professor, 大学院医学研究科, 教授 (40217774)
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| Co-Investigator(Kenkyū-buntansha) |
MURAKMI Hiroshi Nagoya City University, Graduate School ot Medical Sciences, Associate Professor, 大学院医学研究科, 助教授 (80262020)
NIIDA Hiroyuki Nagoya City University, Graduate School of Medical Sciences, Assistant Professor, 大学院医学研究科, 助手 (20336671)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥14,600,000 (Direct Cost: ¥14,600,000)
Fiscal Year 2006: ¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 2005: ¥9,000,000 (Direct Cost: ¥9,000,000)
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| Keywords | cell cycle / checkpoint / Apoptosis |
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| Research Abstract |
Mitotic catastrophe has been first identified as a lethal phenotype with gross abnormalities of chromosome segregation during mitosis in some fission yeast mutant strains. Similar lethal phenotype was also observed in mammalian cells as a result from premature mitosis or failure to undergo complete mitosis. However, there is no broadly accepted definition of the term "mitotic catastrophe", presumably due to lack of the major processes dictating mitotic catastrophe in molecular and genetic terms. Mitotic catastrophe occurs as a result of uncoupling of the onset of mitosis from the completion of DNA replication, but how the ensuing lethality is regulated or what signals are involved is largely unknown. We demonstrate here the essential role of the ATM/ATR-Chk2-p53 pathway in the mitotic catastrophe observed in Chkl-deficient cells. Chk1 deficiency resulted in a premature onset of mitosis due to abnormal activation of cyclin B-Cdc2, and led to the activation of caspases 3 and 9 through cytoplasmic release of histone H1 and cytochrome c. Chkl-deficient cells were effectively rescued from lethality by the addition of caspase inhibitor. The Chkl deficiency resulted in foci formation of phosphorylated histone H2AX and the activation of Chk2, followed by an increase in the amount of p53 protein. Inhibition of ATM and ATR with caffeine also protected the lethality-prone Chkl-deficient cells. Chk2-deficient and p53-deficient cells were resistant to lethality from Chkl depletion. Our results therefore suggest that ATM/ATR-Chk2-p53 is required for mitotic catastrophe that eliminates cells escaping Chkl-dependent mitotic regulation. Loss of this function might be important in mammalian tumorigenesis.
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