Interaction of Helicobacter pylori with gastric epithelial cells is mediated by the p53 protein family.

Wei J, O'Brien D, Vilgelm A, Piazuelo MB, Correa P, Washington MK, El-Rifai W, Peek RM, Zaika A
Gastroenterology. 2008 134 (5): 1412-23

PMID: 18343378 · PMCID: PMC2430883 · DOI:10.1053/j.gastro.2008.01.072

BACKGROUND & AIMS - Although the p53 tumor suppressor has been extensively studied, many critical questions remain unanswered about the biological functions of p53 homologs, p73 and p63. Accumulating evidence suggests that both p73 and p63 play important roles in regulation of apoptosis, cell differentiation, and therapeutic drug sensitivity.

METHODS - Gastric epithelial cells were cocultured with Helicobacter pylori, and the roles of p63 and p73 proteins were assessed by luciferase reporter, real-time polymerase chain reaction, immunoblotting, and cell survival assays. Short hairpin RNA and dominant-negative mutants were used to inhibit activity of p73 and p63 isoforms. Human and murine gastric tissues were analyzed by immunohistochemistry with p73 and p63 antibodies and modified Steiner's silver method.

RESULTS - Interaction of H pylori with gastric epithelial cells leads to robust up-regulation of p73 protein in vitro and in vivo in human gastritis specimens and H pylori-infected mice. The p73 increase resulted in up-regulation of pro-apoptotic genes, NOXA, PUMA, and FAS receptor in gastric epithelial cells. Down-regulation of p73 activity suppressed cell death and Fas receptor induced by H pylori. Bacterial virulence factors within the cag pathogenicity island, c-Abl tyrosine kinase, and interaction with p63 isoforms control the activity of p73.

CONCLUSION - Our findings implicate p73 in H pylori-induced apoptosis and more generally suggest that the p53 family may play a role in the epithelial cell response to H pylori infection.

MeSH Terms (28)

Animals Antibodies, Bacterial Apoptosis Apoptosis Regulatory Proteins Coculture Techniques Disease Models, Animal DNA-Binding Proteins Epithelial Cells fas Receptor Flow Cytometry Gastric Mucosa Gastritis Genetic Vectors Helicobacter Infections Helicobacter pylori Humans Immunohistochemistry In Situ Nick-End Labeling Mice Mice, Inbred C57BL Mice, Transgenic Nuclear Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 RNA Tumor Protein p73 Tumor Suppressor Protein p53 Tumor Suppressor Proteins

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