Physilogical role of CAD-mediated DNA fragmentation
| Project/Area Number |
12670134
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Osaka University |
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Principal Investigator |
FUKUYAMA Hidehiro Medical School, Osaka University, Assistant Professor, 医学系研究科, 助手 (70303956)
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| Co-Investigator(Kenkyū-buntansha) |
NAGATA Shigekazu Medical School, Osaka University, Professor, 医学系研究科, 教授 (70114428)
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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 |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2001: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2000: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Keywords | Apoptosis / DNA fragmentation / CAD / DNase / Knockout mouse / Red blood cells / Enucleation |
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| Research Abstract |
Apoptosis is a cell death during exclusion of unwanted cells with morphological change of membrane blebing, nuclear condensation and fragmentation, and chromosomal DNA fragmentation. We identified CAD as a DNase for DNA fragmentation and ICAD as an inhibitor of CAD. We established both CAD and ICAD knockout mice to reveal the physiological roles of apoptotic DNA fragmentation by gene targeting. Various apoptotic stimulation induced apoptosis in thymocytes but not DNA fragmentation in vitro. This indicated CAD/ICAD systems are required and sufficient for cellautonomous apoptotic DNA fragmentation. We still found DNA fragmentation in vivo in CAD dysfunction mice. This implied the existence of another non-cell autonomous DNA fragmentation as back-up systems. CAD or ICAD knockout mice indeed showed no apparent abnormal phenotype over a year. Further we established knockout mice of DNase II as the most possible candidate for non-cell autonomous DNA fragmentation. This mice showed severe anemia during embryogenesis and died at late embryonic stage. DNase II plays an important role to digest nucleic DNA expelled from erythroblasts during definitive erythropoiesis. Double knockout mice of CAD knockout mice and autoimmune-prone Fas knockout mice accelerated autoimmune phenotypes.
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Research Products
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