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Signal transduction by Smad proteins and their biological activities

Research Project

Project/Area Number 11480215
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Cell biology
Research InstitutionThe University of Tokyo (2000-2001)
Japanese Foundation For Cancer Research (1999)

Principal Investigator

MIYAZONO Kohei  The University of Tokyo, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (90209908)

Co-Investigator(Kenkyū-buntansha) IMAMURA Takeshi  The Cancer Institute of the Japanese Foundation for Cancer Research, Associate member, 癌研究所・生化学部, 主任研究員 (70264421)
KAWABATA Masahiro  The Cancer Institite of the Japanese Foundation for Cancer Reserarch, Associate member, 癌研究所・生化学部, 主任研究員 (60224838)
KATO Mitsuyasu  The Cancer Institute of the Japanese Foudnation for Cancer Research, Associate member, 癌研究所・生化学部, 主任研究員 (20194855)
Project Period (FY) 1999 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 2001: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2000: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 1999: ¥5,800,000 (Direct Cost: ¥5,800,000)
KeywordsTGF-beta / DNA microarray / invasion / receptor / Smad / endotelial cell / transcription / cell differentiation / 骨形成因子 / 骨芽細胞 / シグナル伝達 / 表皮角化細胞 / 血管新生
Research Abstract

1. We have studied the effects of Smads on osteoblast differentiation using adenovirus system. BMPs alone induced synthesis of alkaline phosphatase and differentiation of C2C12 cells, which were further enhanced in the presence of Smad1 or Smad5. Inhibitory Smads repressed the activity of BMPs. When the biological activities of BMP-4 and BMP-6 were studied, BMP-4 was found to bind to ALK-3, and activate Smad1, 5, and 8. In contrast, BMP-6 bound to ALK-2 and activated Smad1 and 5. Interestingly, combination of BMP-4 and BMP-6 induced strong induction of differentiation of C2C 12 cells compared to either BMP alone.
2. Endothelial cells express ALK-1 and ALK-5 for the receptors for TGF-beta, and they activate different sets of Smads. In order to elucidate target genes of ALK-1 and ALK-5, we have infected ALK-1 or ALK-5 adenoviruses into human umbilical vein endothelial cells, and tarried out oligonulceotide microarray analysis. Among 7000 human genes, we found that STAT1, endoglin, Id family transcription factors, Smad6, and Smad7 were induced by ALK-1. In contrast, claudin 5 is repressed by ALK-5, but not by ALK-1, suggesting that formation of tight junction is perturbed by ALK-5. Since ALK-5 induces growth inhibition while ALK-1 induces in vitro differentiation of endothelial cells, we concluded that the genes identified by the present study may be involved in the growth and differentiation of these cells.

Report

(4 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (31 results)

All Other

All Publications (31 results)

  • [Publications] Oh, S.P., et al.: "Activin receptor-like kinase 1 modulates transforming growth factor-β1 signaling in the regulation of angiogenesis"Proc. Natl. Acad. Sci. USA. 97・6. 2626-2631 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Zhang, Y.-W., et al.: "A RUNX2/PEBP2aA/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia"Proc. Natl. Acad. Sci. USA. 97・19. 10549-10554 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ebisawa, T., et al.: "Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation"J. Biol. Chem.. 276・16. 12477-12480 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Fukuchi, M., et al.: "Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins"Mol. Biol. Cell. 12・5. 1431-1443 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kusanagi, K., et al.: "α-Helix 2 in the amino-terminal Mad homology 1 domain is responsible for specific DNA-binding of Smad3"J. Biol. Chem.. 276・30. 28155-28163 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hanyu, A., et al.: "The N-domain of Smad7 is essential for specific inhibition of transforming growth factor-β signaling"J. Cell Biol.. 155・6. 1017-1028 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Oh, S.P., et al.: "Activin receptor-like kinase 1 modulates transforming growth factor-β1 signaling in the regulation of angiogenesis"Proc. Natl. Acad. Sc. USA. 97・6. 2626-2631 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Zhang, Y.W., et al.: "A RUNX2/PEBP2aA/CBFA1 mutation displaying impaired transactivation ad Smad interaction in cleidocranial dysplasia"Proc. Natl. Acad. Sci. USA. 97・19. 10549-10554 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ebisawa, T., et al.: "Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation"J. Biol. Chem.. 276・16. 12477-12480 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Fukuchi, M., et al.: "Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins"Mol. Biol. Cell. 12・5. 1431-1443 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kusanagi, K., et la.: "α-Helix 2 in the amino-terminal Mad homology 1 domain is resposible for specific DNA-binding of Smad3"J. Biol. Chem.. 276・30. 28155-28163 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hanyu, A., et al.: "The N-domain of Smad7 is essential for specific inhibition of transforming growth factor-β signaling"J. Cell Biol.. 155・6. 1017-1028 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ebisawa, T., et al.: "Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induced receptor degradation"J. Biol. Chem.. 276・16. 12477-12480 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fukuchi, M., et al.: "Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins"Mol. Biol. Cell. 12・5. 1431-1443 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Furuhashi, M., et al.: "Axin facilitates Smad3 activation in the transforming growth factor-β signaling pathway"Mol. Cell. Biol.. 21・15. 5132-5141 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kusanagi, K., et al.: "α-Helix 2 in the amino-terminal Mad homology 1 domain is responsible for specific DNA-binding of Smad3"J. Biol. Chem. 276・30. 28155-28163 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hanyu, A., et al.: "The N-domain of Smad7 is essential for specific inhibition of transforming growth factor-β signaling"J. Cell Biol.. 155・6. 1017-1028 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Suzawa, M., et al.: "Stimulation of Smad1 transcriptional activity by Ras-extracellular signal-regulated kinase pathway : a possible mechanism for collagen-dependent osteoblastic differentiation"J. Bone Miner. Res.. 17・2. 240-248 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] 宮澤 恵二, 横手 幸太郎, 宮園 浩平: "新 細胞増殖因子のバイオロジー"羊土社. 159 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Miyazono,K.,ten Dijke,P.,and Heldin,C.-H.: "TGF-b signaling by Smad proteins."Adv.Immunol.. 75. 115-157 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Oh,S.P.,Seki,T.,Goss,K.A.,Imamura,T., et al.: "Activin receptor-like kinase 1 modulates transforming growth factor-b1 signaling in the regulation of angiogenesis"Proc.Natl.Acad.Sci.USA. 97(6). 2626-2631 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Zhang,Y.-W.,Yasui,N.,Huang,G.,Fujii,M., et al.: "A RUNX2/PEBP2aA/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia."Proc.Natl.Acad.Sci.USA. 97(19). 10549-10554 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ebisawa,T.,Fukuchi,M.,Murakami,G., et al.: "Smurf 1 interacts with transforming growth factor-b type 1 receptor through Smad7 and induces receptor degradation."J.Biol.Chem.. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Miyazono,K.,Kusanagi,K.,and Inoue,H.: "Divergence and convergence of TGF-b/BMP signaling."J.Cell.Physiol.. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Fukuchi,M.,Imamura,T.,Chiba,T., et al.: "Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins."Mol.Biol.Cell. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nakao A.,Fujii M.,Miyazono K.et al.: "Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice"J.Clin.Invest.. 104(1). 5-11 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ebisawa T.,Tada K.,Miyazono K.et al.: "Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation"J.Cell Sci.. 112(20). 3519-3527 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Fuji M.,Takeda K.,Miyazono K.et al.: "Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblastic and chondroblastic differentiation"Mol.Biol.Cell. 10(11). 3801-3813 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tada K.,Inoue H.,Miyazono K.et al.: "Region between a-helices 3 and 4 of the Mad homology 2 domain of Smad4 : Functional roles in oligomer formation and transcriptional activation"Genes Cells. 4(12). 731-741 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Oh,S.P.,Seki T.,Miyazono K.et al.: "Activin receptor-like kinase 1 (ALK1) modulated TGF-b1 signaling in regulation of angiogenesis"Proc.Natl. Acad. Sci. USA. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Miyzaono K: "Positive and negative regulation of TGF-b signaling"J. Cell Sci.. (in press). (2000)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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