| Project/Area Number |
13558083
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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 | 展開研究 |
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| Research Field |
Functional biochemistry
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| Research Institution | The University of Tokyo |
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Principal Investigator |
NISHINA Hiroshi Graduate School of Pharmaceutical Sciences, Dept. of Physiol. Chem., Professor, 大学院・薬学系研究科, 助教授 (60212122)
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| Co-Investigator(Kenkyū-buntansha) |
ARAKI Yasuhiro The University of Tokyo, Graduate School of Pharmaceutical Sciences, Dept. of Physiol. Chem., Research Associate, 大学院・薬学系研究科, 助手 (60345254)
HOSHINO Shin-ichi The University of Tokyo, Graduate School of Pharmaceutical Sciences, Dept. of Physiol. Chem., Lecturer, 大学院・薬学系研究科, 講師 (40219168)
KATADA Toshiaki The University of Tokyo, Graduate School of Pharmaceutical Sciences, Dept. of Physiol. Chem., Professor, 大学院・薬学系研究科, 教授 (10088859)
紺谷 圏二 東京大学, 大学院・薬学系研究科, 助手 (30302615)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2002: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2001: ¥7,200,000 (Direct Cost: ¥7,200,000)
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| Keywords | fetal liver / hepatic bud / MAP kinase / SEK1 / JNK / c-Jun / hematopoietic stem cells / NFκB / 骨髄細胞 / 幹細胞 / モノクローナル抗体 / アルブミン |
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| Research Abstract |
Mice lacking stress-signaling kinase SEK1 die from embryonic day 10.5 (El0.5) 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, tnfrl, 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 sekl-/- 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-kB 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-kB.
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