Abstract
Helicobacter pylori is an etiological agent in the development of mucosa-associated lymphoid tissue lymphoma and gastric adenocarcinoma. Patients infected with H. pylori carry a 3-6-fold increased risk of developing cancer compared with uninfected individuals. H. pylori strains expressing the cytotoxin-associated antigen A (CagA) are more frequently associated with the development of neoplasia than cagA-negative strains. However, the molecular mechanism by which H. pylori causes neoplastic transformation remains unclear. Here we report that exposure of gastric epithelial cells to H. pylori induces activation of the transcription factor activator protein 1. Activation of the proto-oncogenes c-fos and c-jun is strongly induced. We show that H. pylori activates the ERK/MAP kinase cascade, resulting in Elk-1 phosphorylation and increased c-fos transcription. H. pylori strains that do not express CagA or that are mutated in cag genes encoded by the CagI pathogenicity island do not induce activator protein 1, MAP kinase activity, or c-fos or c-jun activation. Proto-oncogene activation may represent a crucial step in the pathomechanism of H. pylori induced neoplasia.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, Bacterial*
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Bacterial Proteins / genetics
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Bacterial Proteins / pharmacology
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Cell Transformation, Neoplastic / genetics
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DNA-Binding Proteins / analysis
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Gastric Mucosa / metabolism
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Gene Expression Regulation, Bacterial
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Gene Expression Regulation, Neoplastic
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Helicobacter pylori / genetics
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Helicobacter pylori / metabolism*
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Helicobacter pylori / pathogenicity
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Humans
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism*
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Phosphorylation
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Proto-Oncogene Mas
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-fos / genetics*
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Proto-Oncogene Proteins c-fos / metabolism
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Proto-Oncogene Proteins c-jun / genetics*
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Proto-Oncogene Proteins c-jun / metabolism
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RNA, Messenger / metabolism
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Signal Transduction
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Transcription Factor AP-1 / metabolism*
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Transcription Factors*
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Tumor Cells, Cultured
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ets-Domain Protein Elk-1
Substances
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Antigens, Bacterial
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Bacterial Proteins
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DNA-Binding Proteins
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ELK1 protein, human
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Enzyme Inhibitors
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MAS1 protein, human
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Proto-Oncogene Mas
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-fos
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Proto-Oncogene Proteins c-jun
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RNA, Messenger
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Transcription Factor AP-1
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Transcription Factors
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cagA protein, Helicobacter pylori
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ets-Domain Protein Elk-1
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Mitogen-Activated Protein Kinases