reduction of p53 by knockdown of the ugt1 locus in colon epithelial cells causes an increase in tumorigenesissummary

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ID: 131273
2016
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Abstract
Background & Aims: The UDP-glucuronosyltransferases (UGTs) are a part of the cell machinery that protects the tissues from a toxicant insult by environmental and host cell metabolites. We investigated the mechanism behind tumor growth and UGT repression. Methods: We initially silenced the Ugt1 locus in human colon cell lines and investigated markers and responses linked to p53 activation. To examine the role of the Ugt1 locus in p53-directed apoptosis and tumorigenesis, experiments were conducted to induce acute colon inflammation and chemically induced colon cancer in mice where we have selectively deleted the Ugt1 locus in the intestinal epithelial cells (Ugt1ΔIEC mice). Results: Knockdown of the UGT1A proteins by RNAi in human colon cancer cells and knockout of the Ugt1 locus in intestinal crypt stem cells reduces phosphorylated p53 activation and compromises the ability of p53 to control apoptosis. Targeted deletion of intestinal Ugt1 expression in Ugt1ΔIEC mice represses colon inflammation-induced p53 production and proapoptotic protein activation. When we induced colon cancer, the size and number of the tumors were significantly greater in the Ugt1ΔIEC mice when compared with wild-type mice. Furthermore, analysis of endoplasmic reticulum (ER) stress-related markers indicated that lack of UGT1A expression causes higher ER stress in intestinal epithelial cells and tissue, which may account for the lower expression of p53. Conclusions: Our results demonstrate that UGT1A expression is required to maintain and sustain p53 activation in stress-induced colon epithelial cells and has a significant impact on p53-mediated apoptosis and tumor suppression, thus protecting the colon tissue from neoplastic transformation. Keywords: Apoptosis, Colon Cancer, ER Stress, UGT1A
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liu2016cellularreduction Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Miao Liu;Shujuan Chen;Mei-Fei Yueh;Guangji Wang;Haiping Hao;Robert H. Tukey
Journal pamukkale university journal of engineering sciences
Year 2016
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