| Project/Area Number |
12470493
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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 |
Biological pharmacy
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| Research Institution | The University of Tokyo |
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Principal Investigator |
NISHINA Hiroshi The University of Tokyo, Graduate School of Pharmaceutical Sciences, Dept. of Physiol. Chem., Associate Professor, 大学院・薬学研究科, 助教授 (60212122)
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| Co-Investigator(Kenkyū-buntansha) |
KONTANI Kenji The University of Tokyo, Graduate Schdor of Pharmaceutical Sciences, Dept. of Physiol. Chem., Research fellow, 大学院・薬学研究科, 助手 (30302615)
HOSHINO Shin-ichi The University of Tokyo, Graduate Schdor of Pharmaceutical Sciences, Dept. of Physiol. Chem., Lecturer, 大学院・薬学研究科, 講師 (40219168)
TAKADA Toshiaki The University of Tokyo, Graduate School of Pharmaceutical Sciences, Dept. of Physiol. Chem., Professor, 大学院・薬学研究科, 教授 (10088859)
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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 |
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2001: ¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 2000: ¥7,400,000 (Direct Cost: ¥7,400,000)
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| Keywords | fetal liver / hepatic bud / MAP kinase / SEK1 / JNK / c-Jun / hematopoietic stem cells / NFκB / MAPキナ-ゼ / AML-1 |
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| Research Abstract |
Mice lacking stress-signaling kinase SEK1 die from embryonic day 10.5 (E10.5) to E12.5. Although a defect in liver formation is accompanied with the embryonic lethality of sek1-/- mice, the mechanism leading to the liver defect has remained unknown. Here we investigated liver development in sek1-/- embryos using a monoclonal antibody specifically recognizing murine hepatoblasts and genetic interaction of sek1 with proto-oncogene c-jun and tumor necrosis factor-α receptor 1 gene, tnfr1, which are also responsible for liver formation and the cell apoptosis. There was a progressive increase in the hepatoblast cell numbers of wild-type embryos from E10.5 to 12.5. The hepatoblast proliferation required no hematopoiesis, since transcription factor AML1-deficient mice had no defect in the cell growth. Instead, impaired hepatoblast proliferation was observed in sek1-/- livers from E10.5, though fetal liver-specific gene expression was normal. The impaired phenotype in sek1-/- livers was more severe than in c-jun-/- embryos, and sek1-/- c-jun-/- embryos more rapidly died before E8.5. Stimulation of stress-activatied protein kinase/c-Jun N-terminal kinase by hepatocyte growth factor was attenuated in sek1-/- livers. The defective liver formation in sek1-/- embryos was not protected by additional tnfr1 mutation that rescues the embryonic lethality of mice lacking NF-κB signaling components. Thus, SEK1 appears to play a crucial role in hepatoblast proliferation and survival in a manner apparently different from c-Jun or NF-κB.
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