Peroxisome proliferator-activated receptor γ(PPARγ) suppresses colonic epithelial cell turnover and colon carcinogenesis through inhibition of the β-catenin/T cell factor (TCF) pathway

DOI Web Site 被引用文献1件 参考文献65件
  • Fujisawa Toshio
    Division of Gastroenterology, Yokohama City University School of Medicine, Japan
  • Nakajima Atsushi
    Division of Gastroenterology, Yokohama City University School of Medicine, Japan Gastroenterology Division, Brigham and Women’s Hospital, Harvard Medical School, USA
  • Fujisawa Nobutaka
    Division of Gastroenterology, Yokohama City University School of Medicine, Japan
  • Takahashi Hirokazu
    Division of Gastroenterology, Yokohama City University School of Medicine, Japan
  • Ikeda Ikuko
    Division of Gastroenterology, Yokohama City University School of Medicine, Japan
  • Tomimoto Ayako
    Division of Gastroenterology, Yokohama City University School of Medicine, Japan
  • Yonemitsu Kyoko
    Division of Gastroenterology, Yokohama City University School of Medicine, Japan
  • Nakajima Noriko
    Department of Pathology, National Institute of Infectious Diseases, Japan
  • Kudo Chiho
    Department of Pharmacology, Graduate School of Dentistry, Osaka University, Japan
  • Wada Koichiro
    Department of Pharmacology, Graduate School of Dentistry, Osaka University, Japan
  • Kubota Naoto
    Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Japan
  • Terauchi Yasuo
    Division of Endocrinology and Metabolism, Yokohama City University School of Medicine, Japan
  • Kadowaki Takashi
    Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Japan
  • Nakagama Hitoshi
    Biochemistry Division, National Cancer Center Research Institute, Japan
  • Blumberg Richard S.
    Gastroenterology Division, Brigham and Women’s Hospital, Harvard Medical School, USA

書誌事項

タイトル別名
  • Peroxisome Proliferator-Activated Receptor .GAMMA. (PPAR.GAMMA.) Suppresses Colonic Epithelial Cell Turnover and Colon Carcinogenesis Through Inhibition of the .BETA.-Catenin / T Cell Factor (TCF) Pathway
  • Peroxisome proliferator activated receptor g PPARg suppresses colonic epithelial cell turnover and colon carcinogenesis through inhibition of the v catenin T cell factor TCF pathway

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Peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor superfamily member, plays a major role in lipid metabolism and insulin sensitivity. We investigated the role of PPARγ in colonic epithelial cell turnover and carcinogenesis in colon because PPARγ is strongly expressed in colonic epithelium. Administration of PPARγ agonists suppressed epithelial cell turnover in mice. Expression level of β-catenin protein, a key molecule in carcinogenesis, was increased in mouse colon treated with PPARγ ligands. A direct interaction between β-catenin and PPARγ in cultured cell lines and colonic epithelium in mice was observed. Ligand-activated PPARγ ligand directly interacts with β-catenin, retaining it in the cytosol and reducing β-catenin / T cell factor (TCF) transcriptional activity that is functionally important on aberrant crypt foci (ACF) formation. PPARγ hetero-deficiency promoted the induction of ACF, but had no effect on the incidence of colonic polyps. These results indicate that PPARγ regulates colonic epithelial cell turnover via direct interactions with β-catenin, resulting in inhibition of β-catenin–mediated transcriptional pathways that are involved in promoting cell proliferation. Our findings suggest that PPARγ plays a role as a physiological regulator of colonic epithelial cell turnover and consequently predisposition to the development of colon cancer in early stage.<br>

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