Abstract
Chronic infection with cagA-positive Helicobacter pylori is the strongest risk factor for the development of gastric adenocarcinoma. The cagA gene product CagA is injected into gastric epithelial cells and disturbs cellular functions by physically interacting with and deregulating a variety of cellular signaling molecules. RUNX3 is a tumor suppressor in many tissues, and it is frequently inactivated in gastric cancer. In this study, we show that H. pylori infection inactivates the gastric tumor suppressor RUNX3 in a CagA-dependent manner. CagA directly associates with RUNX3 through a specific recognition of the PY motif of RUNX3 by a WW domain of CagA. Deletion of the WW domains of CagA or mutation of the PY motif in RUNX3 abolishes the ability of CagA to induce the ubiquitination and degradation of RUNX3, thereby extinguishing its ability to inhibit the transcriptional activation of RUNX3. Our studies identify RUNX3 as a novel cellular target of H. pylori CagA and also reveal a mechanism by which CagA functions as an oncoprotein by blocking the activity of gastric tumor suppressor RUNX3.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs / genetics
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Animals
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Antigens, Bacterial / genetics
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Antigens, Bacterial / metabolism*
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism*
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Binding Sites / genetics
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COS Cells
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Cell Line
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Cell Line, Tumor
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Chlorocebus aethiops
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Core Binding Factor Alpha 3 Subunit / genetics
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Core Binding Factor Alpha 3 Subunit / metabolism*
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Gastric Mucosa / metabolism
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Gastric Mucosa / pathology
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Gastric Mucosa / virology
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Helicobacter Infections / metabolism
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Helicobacter Infections / virology
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Helicobacter pylori / genetics
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Helicobacter pylori / metabolism
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Helicobacter pylori / physiology
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Host-Pathogen Interactions
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Humans
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Immunoblotting
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Immunohistochemistry
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Immunoprecipitation
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Mice
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Mutation
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Proteasome Endopeptidase Complex / metabolism*
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Protein Binding
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Stomach Neoplasms / metabolism
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Stomach Neoplasms / pathology
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Stomach Neoplasms / virology
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Transfection
Substances
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Antigens, Bacterial
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Bacterial Proteins
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Core Binding Factor Alpha 3 Subunit
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Runx3 protein, human
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cagA protein, Helicobacter pylori
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Proteasome Endopeptidase Complex