| Helicobacter pylori induces ERK-dependent formation of a phospho-c-Fos c-Jun activator protein-1 complex that causes apoptosis in macrophages. | |
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MedLine Citation:
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PMID: 20410304 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Macrophages are essential components of innate immunity, and apoptosis of these cells impairs mucosal defense to microbes. Helicobacter pylori is a gastric pathogen that infects half of the world population and causes peptic ulcer disease and gastric cancer. The host inflammatory response fails to eradicate the organism. We have reported that H. pylori induces apoptosis of macrophages by generation of polyamines from ornithine decarboxylase (ODC), which is dependent on c-Myc as a transcriptional enhancer. We have now demonstrated that expression of c-Myc requires phosphorylation and nuclear translocation of ERK, which results in phosphorylation of c-Fos and formation of a specific activator protein (AP)-1 complex. Electromobility shift assay and immunoprecipitation revealed a previously unrecognized complex of phospho-c-Fos (pc-Fos) and c-Jun in the nucleus. Fluorescence resonance energy transfer demonstrated the interaction of pc-Fos and c-Jun. The capacity of this AP-1 complex to bind to putative AP-1 sequences was demonstrated by oligonucleotide pulldown and fluorescence polarization. Binding of the pc-Fos.c-Jun complex to the c-Myc promoter was demonstrated by chromatin immunoprecipitation. A dominant-negative c-Fos inhibited H. pylori-induced expression of c-Myc and ODC and apoptosis. H. pylori infection of mice induced a rapid infiltration of macrophages into the stomach. Concomitant apoptosis depleted these cells, and this was associated with formation of a pc-Fos.c-Jun complex. Treatment of mice with an inhibitor of ERK phosphorylation attenuated phosphorylation of c-Fos, expression of ODC, and apoptosis in gastric macrophages. A unique AP-1 complex in gastric macrophages contributes to the immune escape of H. pylori. |
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Authors:
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Mohammad Asim; Rupesh Chaturvedi; Svea Hoge; Nuruddeen D Lewis; Kshipra Singh; Daniel P Barry; Holly S Algood; Thibaut de Sablet; Alain P Gobert; Keith T Wilson |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-04-21 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-06-21 Completed Date: 2010-08-24 Revised Date: 2011-08-01 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 20343-57 Citation Subset: IM |
Affiliation:
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Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anthracenes / pharmacology Apoptosis* Cell Line Cell Nucleus / metabolism Cell Survival / drug effects Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors, metabolism* Flavonoids / pharmacology Fluorescence Resonance Energy Transfer Helicobacter Infections / genetics, metabolism, microbiology Helicobacter pylori / physiology* Host-Pathogen Interactions Imidazoles / pharmacology Immunoblotting Macromolecular Substances / metabolism* Macrophages / cytology, metabolism, microbiology* Mice Mice, Inbred C57BL Ornithine Decarboxylase / genetics, metabolism Phosphorylation / drug effects Protein Binding Proto-Oncogene Proteins c-fos / genetics, metabolism Proto-Oncogene Proteins c-jun / genetics, metabolism Pyridines / pharmacology Reverse Transcriptase Polymerase Chain Reaction Transcription Factor AP-1 / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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F31GM083500/GM/NIGMS NIH HHS; P01CA028842/CA/NCI NIH HHS; P01CA116087/CA/NCI NIH HHS; P30DK058404/DK/NIDDK NIH HHS; R01AT004821/AT/NCCAM NIH HHS; R01DK053620/DK/NIDDK NIH HHS; T32CA009592/CA/NCI NIH HHS; T32DK007673/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Anthracenes; 0/Flavonoids; 0/Imidazoles; 0/Macromolecular Substances; 0/PD 98059; 0/Proto-Oncogene Proteins c-fos; 0/Proto-Oncogene Proteins c-jun; 0/Pyridines; 0/SB 203580; 0/Transcription Factor AP-1; 0/anthra(1,9-cd)pyrazol-6(2H)-one; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 4.1.1.17/Ornithine Decarboxylase |
| Comments/Corrections | |
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