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2006 Fiscal Year Final Research Report Summary

Identification of the crosstalk between Notch signaling and Wnt signaling in the differentiation of the intestinal epithelial cells.

Research Project

Project/Area Number 17209027
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionTokyo Medical and Dental University

Principal Investigator

WATANABE Mamoru  Tokyo Medical and Dental University, Department of Gastroenterology and Hepatology, Professor, 大学院医歯学総合研究科, 教授 (10175127)

Co-Investigator(Kenkyū-buntansha) TSUCHIYA Kiichiro  Tokyo Medical and Dental University, Department of Gastroenterology and Hepatology, Instructor, 大学院医歯学総合研究科, 助手 (40376786)
KIYONO Hiroshi  The University of Tokyo, The Institute of Medical Science, Professor, 医科学研究所, 教授 (10271032)
HANDA Hiroshi  Tokyo Institute of Technology, Professor, 大学院生命理工学研究科, 教授 (80107432)
Project Period (FY) 2005 – 2006
KeywordsDifferentiation / Regenerative medicine / Translational research / Signal transduction / Atoh1 / Hath1 / Wnt / Notch
Research Abstract

In this study, we revealed the crosstalk between Ant and Notch signaling in the regulation of the intestinal differentiation via Hath1 gene that plays a crucial role in intestinal differentiation.
Atoh1/Hath1 is indispensable to the differentiation of the intestinal epithelial cells, however what regulates Hath1 function has unknown. So we assessed the effect of Ant and Notch signal for Hath1 and then, we revealed new signaling pathway for Hath1 in both signals. Notch signal suppresses the Hath1 mRNA transcription besides increasing HES1 gene expression. Moreover Ant signal degrades Hath1 protein via GSK3 besides stabilizing beta-catenin protein, resulting the differentiation of intestinal epithelial cells.
Next we demonstrated whether the failure of these systems misses Hath1 expression and causes colon disease. In colon cancer, aberrant Ant signal caused the degradation of Hath1 protein in inverse of the stabilization of beta-catenin protein. In ulcerative colitis. Notch signal is aberrantly activated, causing Hath1 gene suppression and goblet cell depletion.
All these data indicate that intestinal differentiation is regulated by Hath1 expression controlled in two distinct points on which Notch signal and Ant signal have effects respectively. Moreover, the failure of these systems causes major colon disease such as cancer or inflammation. Therefore, these new mechanisms may be new targets on the therapy for colon diseases.

  • Research Products

    (9 results)

All 2007 2006

All Journal Article (9 results)

  • [Journal Article] IL-7 is essential for the development and the persistence of chronic colitis.2007

    • Author(s)
      Totsuka T, Watanabe M, et al.
    • Journal Title

      J Immunol. 178

      Pages: 4737-4748

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Intestinal Lamina Propria Retaining CD4+CD25+ Regulatory T Cells Is A Suppressive Site of Intestinal Inflammation.2007

    • Author(s)
      Makita S, Watanabe M, et al.
    • Journal Title

      J Immunol. 178

      Pages: 4937-4946

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Bone marrow retaining colitogenic CD4+ T cells may be a pathogenic reservoir for chronic colitis.2007

    • Author(s)
      Nemoto Y, Watanabe M, et al.
    • Journal Title

      Gastroenterology. 132

      Pages: 176-189

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Reciprocal targeting of Hath1 and β-catenin by Wnt-glycogen synthase kinase 3 β in human colon cancer.2007

    • Author(s)
      Tsuchiya K, Watanabe M, et al.
    • Journal Title

      Gastroenterology. 132

      Pages: 208-220

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Intestinal Lamina Propria Retaining CD4+CD25+Regulatory T Cells Is A Suppressive Site of Intestinal Inflammation.2007

    • Author(s)
      Makita S, Watanabe M, et al.
    • Journal Title

      J Immunol. 178

      Pages: 4937-4946

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Reciprocal targeting of Hath1 and β-catenin by Wnt-glycogen synthase kinase 3βin human colon cancer.2007

    • Author(s)
      Tsuchiya K, Watanabe M, et al.
    • Journal Title

      Gastroenterology. 132

      Pages: 208-220

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] FTY720 suppresses CD4^+CD44^<high> CD62L^- effector memory T cell-mediated colitis.2006

    • Author(s)
      Fujii R, Watanabe M, et al.
    • Journal Title

      Am J Physiol. 291

      Pages: G267-G274

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Regeneration of the intestinal epithelia : Regulation of bone marrow-derived epithelial cell differentiation towards secretory lineage cells.2006

    • Author(s)
      Okamoto R, Watanabe M, et al.
    • Journal Title

      Human Cell. 19

      Pages: 71-75

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] FTY720 suppresses CD4^+CD44^<high>CD62L^- effector memory T cell-mediated colitis.2006

    • Author(s)
      Fujii R, Watanabe M, et al.
    • Journal Title

      Am J Physiol. 291

      Pages: G267-G274

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2008-05-27  

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