Regulation of p53 tumor suppressor by helicobacter pylori in gastric epithelial cells

Jinxiong Wei, Toni A. Nagy, Anna Vilgelm, Elena Zaika, Seth R. Ogden, Judith Romerogallo, Maria B. Piazuelo, Pelayo Correa, Mary K. Washington, Wael Elrifai, Richard M. Peek, Alexander Zaika

Research output: Contribution to journalArticle

97 Scopus citations

Abstract

Background & Aims Infection with the gastric mucosal pathogen Helicobacter pylori is the strongest identified risk factor for distal gastric cancer. These bacteria colonize a significant part of the world's population. We investigated the molecular mechanisms of p53 regulation in H pyloriinfected cells. Methods Mongolian gerbils were challenged with H pylori and their gastric tissues were analyzed by immunohistochemistry and immunoblotting with p53 antibodies. Gastric epithelial cells were co-cultured with H pylori and the regulation of p53 was assessed by real-time polymerase chain reaction, immunoblotting, immunofluorescence, and cell survival assays. Short hairpin RNA and dominant-negative mutants were used to inhibit activities of Human Double Minute 2 (HDM2) and AKT1 proteins. Results We found that in addition to previously reported up-regulation of p53, H pylori can also negatively regulate p53 by increasing ubiquitination and proteasomal degradation via activation of the serine/threonine kinase AKT1, which phosphorylates and activates the ubiquitin ligase HDM2. These effects were mediated by the bacterial virulence factor CagA; ectopic expression of CagA in gastric epithelial cells increased phosphorylation of HDM2 along with the ubiquitination and proteasomal degradation of p53. The decrease in p53 levels increased survival of gastric epithelial cells that had sustained DNA damage. Conclusions H pylori is able to inhibit the tumor suppressor p53. H pylori activates AKT1, resulting in phosphorylation and activation of HDM2 and subsequent degradation of p53 in gastric epithelial cells. H pyloriinduced dysregulation of p53 is a potential mechanism by which the microorganism increases the risk of gastric cancer in infected individuals.

Original languageEnglish (US)
Pages (from-to)1333-1343.e4
JournalGastroenterology
Volume139
Issue number4
DOIs
StatePublished - Oct 2010

Keywords

  • Apoptosis
  • P53 Protein Family
  • P73
  • Stomach Cancer

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Fingerprint Dive into the research topics of 'Regulation of p53 tumor suppressor by helicobacter pylori in gastric epithelial cells'. Together they form a unique fingerprint.

  • Cite this

    Wei, J., Nagy, T. A., Vilgelm, A., Zaika, E., Ogden, S. R., Romerogallo, J., Piazuelo, M. B., Correa, P., Washington, M. K., Elrifai, W., Peek, R. M., & Zaika, A. (2010). Regulation of p53 tumor suppressor by helicobacter pylori in gastric epithelial cells. Gastroenterology, 139(4), 1333-1343.e4. https://doi.org/10.1053/j.gastro.2010.06.018