| Up-regulation of activation-induced cytidine deaminase causes genetic aberrations at the CDKN2b-CDKN2a in gastric cancer. | |
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MedLine Citation:
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PMID: 20637757 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND & AIMS: The DNA/RNA editing enzyme activation-induced cytidine deaminase (AID) is mutagenic and has been implicated in human tumorigenesis. Helicobacter pylori infection of gastric epithelial cells leads to aberrant expression of AID and somatic gene mutations. We investigated whether AID induces genetic aberrations at specific chromosomal loci that encode tumor-related proteins in gastric epithelial cells. METHODS: Human gastric epithelial cell lines that express activated AID and gastric cells from AID transgenic mice were examined for DNA copy number changes and nucleotide alterations. Copy number aberrations in stomach cells of H pylori-infected mice and gastric tissues (normal and tumor) from H pylori-positive patients were also analyzed. RESULTS: In human gastric cells, aberrant AID activity induced copy number changes at various chromosomal loci. In AID-expressing cells and gastric mucosa of AID transgenic mice, point mutations and reductions in copy number were observed frequently in the tumor suppressor genes CDKN2A and CDKN2B. Oral infection of wild-type mice with H pylori reduced the copy number of the Cdkn2b-Cdkn2a locus, whereas no such changes were observed in the gastric mucosa of H pylori-infected AID-deficient mice. In human samples, the relative copy numbers of CDKN2A and CDKN2B were reduced in a subset of gastric cancer tissues compared with the surrounding noncancerous region. CONCLUSIONS: H pylori infection leads to aberrant expression of AID and might be a mechanism of the accumulation of submicroscopic deletions and somatic mutations in gastric epithelial cells. AID-mediated genotoxic effects appear to occur frequently at the CDKN2b-CDKN2a locus and contribute to malignant transformation of the gastric mucosa. |
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Authors:
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Yuko Matsumoto; Hiroyuki Marusawa; Kazuo Kinoshita; Yoko Niwa; Yoshiharu Sakai; Tsutomu Chiba |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-14 |
Journal Detail:
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Title: Gastroenterology Volume: 139 ISSN: 1528-0012 ISO Abbreviation: Gastroenterology Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-03 Completed Date: 2011-01-04 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0374630 Medline TA: Gastroenterology Country: United States |
Other Details:
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Languages: eng Pagination: 1984-94 Citation Subset: AIM; IM |
Copyright Information:
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Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Cell Transformation, Neoplastic / metabolism, pathology Chromosome Aberrations Cyclin-Dependent Kinase Inhibitor p15 / genetics*, metabolism Cyclin-Dependent Kinase Inhibitor p16 / genetics*, metabolism Cytidine Deaminase / genetics*, metabolism Epithelial Cells / enzymology*, microbiology, pathology* Gene Dosage Gene Expression Regulation, Enzymologic / physiology Gene Expression Regulation, Neoplastic / physiology Helicobacter Infections / genetics, metabolism, pathology Helicobacter pylori Humans Mice Mice, Inbred C57BL Mice, Transgenic Stomach / pathology Stomach Neoplasms* / genetics, metabolism, pathology Up-Regulation / physiology |
| Chemical | |
Reg. No./Substance:
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0/CDKN2B protein, human; 0/Cdkn2a protein, mouse; 0/Cdkn2b protein, mouse; 0/Cyclin-Dependent Kinase Inhibitor p15; 0/Cyclin-Dependent Kinase Inhibitor p16; EC 3.5.4.5/Cytidine Deaminase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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