title: Reduction of p53 by knockdown of theUGT1locus in colon epithelial cells causes an increase in tumorigenesis.
abstract: OBJECTIVE
  The UDP-glucuronosyltransferases (UGTs) are part of the cells machinery that protects the tissues from a toxicant insult by environmental and host cell metabolites. We have investigated the mechanism behind tumor growth and UGT repression.
  
  
  METHODS
  We initially silenced theUgt1locus in human colon cell lines and investigated markers and responses linked to p53 activation. To examine the role of theUgt1locus in p53-directed apoptosis and tumorigenesis, experiments were conducted to induce acute colon inflammation and chemical induced colon cancer in mice where we have selectively deleted theUgt1locus in the intestinal epithelial cells (Ugt1ΔIECmice).
  
  
  RESULTS
  Knockdown of the UGT1A proteins by RNAi in human colon cancer cells and knockout of theUgt1locus in intestinal crypt stem cells reduces phosphorylated p53 activation and compromises the ability of p53 to control apoptosis. Targeted deletion of intestinalUgt1expression inUgt1ΔIECmice represses colon inflammation-induced p53 production and pro-apoptotic protein activation. When we induced colon cancer, the size and number of the tumors were significantly greater in theUgt1ΔIECmice when compared to 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.
authors.affiliation: Laboratory of Environmental Toxicology, Department of Chemistry & Biochemistry and Pharmacology, UCSD, La Jolla, CA, 92023; Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China, 210009.
authors.forename: Miao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Laboratory of Environmental Toxicology, Department of Chemistry & Biochemistry and Pharmacology, UCSD, La Jolla, CA, 92023.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Laboratory of Environmental Toxicology, Department of Chemistry & Biochemistry and Pharmacology, UCSD, La Jolla, CA, 92023.
authors.forename: Mei-Fei
authors.initials: MF
authors.lastname: Yueh
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China, 210009.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China, 210009.
authors.forename: Haiping
authors.initials: H
authors.lastname: Hao
authors.affiliation: Laboratory of Environmental Toxicology, Department of Chemistry & Biochemistry and Pharmacology, UCSD, La Jolla, CA, 92023.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Tukey
keywords: ER stress; UGT1A; apoptosis; colon cancer