| Dual regulation by apurinic/apyrimidinic endonuclease-1 inhibits gastric epithelial cell apoptosis during Helicobacter pylori infection. | |
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MedLine Citation:
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PMID: 20332233 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Human apurinic/apyrimidinic endonuclease-1 (APE-1), a key enzyme involved in repair of oxidative DNA base damage, is an important transcriptional coregulator. We previously reported that Helicobacter pylori infection induces apoptosis and increases APE-1 expression in human gastric epithelial cells (GEC). Although both the DNA repair activity and the acetylation-mediated transcriptional regulation of APE-1 are required to prevent cell death, the mechanisms of APE-1-mediated inhibition of infection-induced apoptosis are unclear. Here, we show that short hairpin RNA-mediated stable suppression of APE-1 results in increased apoptosis in GEC after H. pylori infection. We show that programmed cell death involves both the caspase-9-mediated mitochondrial pathway and the caspase-8-dependent extrinsic pathway by measuring different markers for both the pathways. Overexpression of wild-type APE-1 in APE-1-suppressed GEC reduced apoptosis after infection; however, overexpression of the DNA repair mutant or the nonacetylable mutant of APE-1 alone was unable to reduce apoptosis, suggesting that both DNA repair and acetylation functions of APE-1 modulate programmed cell death. We show for the first time that the DNA repair activity of APE-1 inhibits the mitochondrial pathway, whereas the acetylation function inhibits the extrinsic pathway during H. pylori infection. Thus, our findings establish that the two different functions of APE-1 differentially regulate the intrinsic and the extrinsic pathway of H. pylori-mediated GEC apoptosis. As proapoptotic and antiapoptotic mechanisms determine the development and progression of gastritis, gastric ulceration, and gastric cancer, this dual regulatory role of APE-1 represents one of the important molecular strategies by H. pylori to sustain chronic infection. |
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Authors:
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Ranajoy Chattopadhyay; Asima Bhattacharyya; Sheila E Crowe |
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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 Date: 2010-03-23 |
Journal Detail:
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Title: Cancer research Volume: 70 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-02 Completed Date: 2010-05-03 Revised Date: 2011-08-01 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 2799-808 Citation Subset: IM |
Affiliation:
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Department of Medicine, University of Virginia, Charlottesville, VA 22908-0708, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetylation Adenocarcinoma / enzymology*, genetics, microbiology, pathology Apoptosis / physiology* Cell Line, Tumor DNA Repair DNA-(Apurinic or Apyrimidinic Site) Lyase / genetics, metabolism* Helicobacter Infections / enzymology*, genetics, pathology Helicobacter pylori / physiology* Humans Mitochondria / physiology Stomach Neoplasms / enzymology*, genetics, microbiology, pathology Transfection |
| Grant Support | |
ID/Acronym/Agency:
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R01 DK061769-07/DK/NIDDK NIH HHS; R01 DK061769-07S1/DK/NIDDK NIH HHS; R01 DK61769/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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EC 4.2.99.18/APEX1 protein, human; EC 4.2.99.18/DNA-(Apurinic or Apyrimidinic Site) Lyase |
| Comments/Corrections | |
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