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Research of the polyp formation in the intestine using Knock-out mouse

Research Project

Project/Area Number 10307002
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionThe University of Tokyo

Principal Investigator

TAKATO M. Makoto  Dept. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Position. Professor, 大学院・薬学系研究科, 教授 (70281714)

Co-Investigator(Kenkyū-buntansha) SASAKI Nobuya  Dept. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Position. Assistant Professor, 大学院・薬学系研究科, 助手 (20302614)
MATSUI Minoru  Dept. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Position. Assistant Professor, 大学院・薬学系研究科, 助手 (50282611)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥36,800,000 (Direct Cost: ¥36,800,000)
Fiscal Year 1999: ¥16,600,000 (Direct Cost: ¥16,600,000)
Fiscal Year 1998: ¥20,200,000 (Direct Cost: ¥20,200,000)
KeywordsAPC / TGF-B / Smad 4 / beta-catenin / Cdx-2 / Cdx-2 / β-cutenin / Apc遺伝子 / COX2 / Dpc4遺伝子 / 悪性化進展
Research Abstract

(1) Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice.
We constructed knockout mice in whichSmad4 was inactivated by homologous recombination. Although simple Smad4 homozygotes were embryonically lethal, the heterozygotes were fertile and appeared normal up to the age of I year. Upon further investigation, however, they have developed inflammatory polyps in the glandular stomach and duodenum. Histologically, the polyps are similar to human juvenile polyps showing moderate stromal bell proliferation and infiltrations by eosinophils and plasma cells. In addition, foci of adenocarcinoma with, signet ring cells ate also found. These results are consistent with a recent report that germ-line SMAD4 mutations are found in a subset of familial juvenile polyposis.
(2) Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene.
Ectopic expression of certain Wnt genes in mouse mammary tissue is tumorigenic, and mutations that stabilize beta-catenin are found in var … More ious human canters including colorectal cancer. To determine the role of stabilized beta-catenin in intestinal tumorigenesis in mice, we constructed by embryonic stem (ES) cell-mediated homologous recombination, a mutant beta-catenin allele which caused adenomatous intestinal polyps resembling those in Apc knockout mice. These results present experimental genetic evidence that activation of the Wnt signaling pathway can cause intestinal and colonic tumors.
(3) Colonic hamartoma development by anomalous duplication in Cdx2 knockout mice.
To determine the biological role of caudal-like homeobox gene Cdx2, we constructed Cdx2 knockout mice by homologous recombination. Although the homozygous mutants died in utero around implantation, the heterozygotes were viable and fertile. The heterozygotes developed cecal and colonic villi by anteriorization and formed hamartomatous polyps in the proximal colon. Several experiments indicate that the Cdx2 haploin-sufficiency caused cecal and colonic villi, whereas the biallelic inactivation of Cdx2 triggered anomalous duplications of the embryonic gut epithelium, which were contained as hamartomas after birth. Less

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Tamai, Y: "Colonic hamartoma development by anomalous duplication in Cdx2 knockout mice"Cancer Res. 59. 2965-2970 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Taketo,M.M.: "Ape gene knockout mice as a model for familial adenomatours polyposis."Prog. Exp. Tumor Res.. 35. 109-119 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Harada, N: "intestinal polyposis in mic e with a dominant stable mutation of the b- catenin gene"EMBOJ.. 18. 5931-5942 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takaku, K.: "Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice"Cancer Res.. 59. 6113-6117 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tamai, Y: "Colonic hamartoma development by anomalous duplication in Cdx2 knockout mice."Cancer Res.. 59. 2965-2970 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Taketo, M. M: "Apc gene knockout mice as a model for familial adenomatous polyposis."Prog. Exp. Tumor Res.. 35. 109-119 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Harada, N: "Intestinal polyposis in mice with a dominant stable mutation of the β-caten5n gene."EMBO J.. 18. 5931-5942 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takaku, K: "Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice."Cancer Res.. 59. 6113-6117 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tamai, Y: "Colonic hamartoma development by anomalous duplication in Cdx2 knockout mice"Cancer Res.. 59. 2965-2970 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Taketo, M. M.: "Apc gene knockout mice as a model for familial adenomatous polyposis"Prog. Exp. Tumor Res.. 35. 109-119 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Harada, N: "International polyposis in mice with a dominant stable mutation of the β-catenin gene"EMBO J.. 18. 5931-5942 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takaku, K.: "Gastric and duodenal polyps in Smad4(Dpc4) knockout mice"Cancer Res.. 59. 6113-6117 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takaku, K et al.: "Intestinal tumoviganesis in compaund mutant nice of both Dpc4 and Apc genes" Cell. 92. 645-656 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fujita, T et al: "Size-and invasion-depcrdent increase in cyclcoyygenase 2 fevels in human colovectal cancinovras." Cancer Research. 58 (21). 4823-4826 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Shida, N.et al: "Estrogen-indneed tumorigenesis in the pitutavy giand of TGFβ(+/-)Knockant nice" Biochem.Biophys.Acta. 1407. 79-83 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sheng.H et al: "Nuclear translocation of β-catenin in nevaditany and cavcin agen-induced intestival adenomas" Cavcinogenesis. 19. 543-549 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sugawara,A et al: "Characterization of mouse retinoid Xreceptor (RXR) -β gene prounotor." Endocrinology. 139. 3030-3033 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Taketo, M.M.: "Cyclooxygenast2 in receptors in tunovigenesis (pant 1&2)" J.Nath.Cancer.Inst. 90. 1529-1536, 1609-1620 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Taketo, M.M.: "Inflammation Inst." COX2 and colon cancer, 5 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Taketo, M.M.: "crinical Significance and Potautial of Seledive COX2 inhibitore" Suppression of intestinal polyposis by inhibition of cyclooxygenatc & in a mouse model for familial adenomations polypovis, 12 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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