2002 Fiscal Year Final Research Report Summary
Identification of hepatic stem cells and development of its separation methods : Analysis of the self-replication and survival of the cells
| 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)
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| Project Period (FY) |
2001 – 2002
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| Keywords | fetal liver / hepatic bud / MAP kinase / SEK1 / JNK / c-Jun / hematopoietic stem cells / NFκB |
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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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Research Products
(12 results)
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[Publications] T. Wada, K. Nakagawa, G. Nishitai, J. Seo, H. Kishimoto, T. Watanabe, D. Kitagawa, T. Sasaki, J. M. Penninger, H. Nishina, & T Katada: "Impaired synergistic activation of stress-activated protein kinase SAPK/JNK in ES cells lacking SEK1/MKK4"J. Biol. Chem.. 276. 30892-30897 (2001)
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「研究成果報告書概要(欧文)」より
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[Publications] T. Sasaki, T. Wada, H. Kishimoto, J. Irie-Sasaki, G. Matsumoto, T. Goto, Z. Yao, A. Wakeham, T.W. Mak, A. Suzuki, T. Katada, H. Nishina, & J.M. Penninger: "The stress kinase MKK7 is a negative regulator of antigen receptor and growth factor receptor induced proliferation in hematopoietic cells"J. Exp. Med.. 17. 757-768 (2001)
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「研究成果報告書概要(欧文)」より
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[Publications] Kitagawa D, Tanemura S, Ohata S, Shimizu N, Seo J, Nishitai G, Watanabe T, Nakagawa K, Kishimoto H, Wada T, Tezuka T, Yamamoto T, Nishina H, & Katada T: "Activation of extracellular signal-regulated kinase by ultraviolet is mediated through Src-dependent epidermal growth factor receptor phosphorylation. Its implication in an anti-apoptotic function"J. Biol. Chem.. 277. 366-371 (2002)
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「研究成果報告書概要(欧文)」より
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[Publications] Yamamoto A, Miyazaki T, Kadono Y, Takayanagi H, Miura T, Nishina H, Katada T, Wakabayashi K, Oda H, Nakamura K, & Tanaka S: "Possible involvement of IkappaB kinase 2 and MKK7 in osteoclastogenesis induced by receptor activator of nuclear factor kappaB ligand"J. Bone Miner. Res.. 17. 612-621 (2002)
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「研究成果報告書概要(欧文)」より
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[Publications] T. Watanabe, K. Nakagawa, S. Ohata, D. Kitagawa, G. Nishitai, J. Seo, S. Tanemura, N. Shimizu, H. Kishimoto, T. Wada, J. Aoki, H. Arai, T. Iwatsubo, M. Mochita, T. Watanabe, M. Satake, Y. Ito, T. Matsuyama, T. W. Mak, J. M. Penninger, H. Nishina H, & T. Katada: "SEKl/MKK4-mediated SAPK/JNK signaling participates in embryonic hepatoblast proliferation via a pathway different from NF-kappaB-induced anti- apoptosis"Dev Biol.. 15. 332-347 (2002)
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「研究成果報告書概要(欧文)」より
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[Publications] Takayanagi H, Kim S, Koga T, Nishina H, Isshi M M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J, Wagner E F, Mak T W, Kodama T, & Taniguchi T: "Induction and activation of the transcription factor NFATc1(NFAT2)integrate RANKL signaling"Dev. Cell. 3. 889-901 (2002)
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「研究成果報告書概要(欧文)」より
