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Constitutive Expression of AID Leads to Tumorigenesis
Genome stability is regulated by the balance between efficiencies of the repair machinery and genetic alterations such as mutations and chromosomal rearrangements. It has been postulated that deregulation of class switch recombination (CSR) and somatic hypermutation (SHM), which modify the immunoglo...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2003
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193972/ https://www.ncbi.nlm.nih.gov/pubmed/12732658 http://dx.doi.org/10.1084/jem.20030275 |
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author | Okazaki, Il-mi Hiai, Hiroshi Kakazu, Naoki Yamada, Shuichi Muramatsu, Masamichi Kinoshita, Kazuo Honjo, Tasuku |
author_facet | Okazaki, Il-mi Hiai, Hiroshi Kakazu, Naoki Yamada, Shuichi Muramatsu, Masamichi Kinoshita, Kazuo Honjo, Tasuku |
author_sort | Okazaki, Il-mi |
collection | PubMed |
description | Genome stability is regulated by the balance between efficiencies of the repair machinery and genetic alterations such as mutations and chromosomal rearrangements. It has been postulated that deregulation of class switch recombination (CSR) and somatic hypermutation (SHM), which modify the immunoglobulin (Ig) genes in activated B cells, may be responsible for aberrant chromosomal translocations and mutations of non-Ig genes that lead to lymphocyte malignancy. However, the molecular basis for these genetic instabilities is not clearly understood. Activation-induced cytidine deaminase (AID) is shown to be essential and sufficient to induce both CSR and SHM in artificial substrates in fibroblasts as well as B cells. Here we show that constitutive and ubiquitous expression of AID in transgenic mice caused both T cell lymphomas and dysgenetic lesions of epithelium of respiratory bronchioles (micro-adenomas) in all individual mice. Point mutations, but not translocations, were massively introduced in expressed T cell receptor (TCR) and c-myc genes in T lymphoma cells. The results indicate that AID can mutate non-Ig genes including oncogenes, implying that aberrant AID expression could be a cause of human malignancy. |
format | Text |
id | pubmed-2193972 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2003 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-21939722008-04-11 Constitutive Expression of AID Leads to Tumorigenesis Okazaki, Il-mi Hiai, Hiroshi Kakazu, Naoki Yamada, Shuichi Muramatsu, Masamichi Kinoshita, Kazuo Honjo, Tasuku J Exp Med Article Genome stability is regulated by the balance between efficiencies of the repair machinery and genetic alterations such as mutations and chromosomal rearrangements. It has been postulated that deregulation of class switch recombination (CSR) and somatic hypermutation (SHM), which modify the immunoglobulin (Ig) genes in activated B cells, may be responsible for aberrant chromosomal translocations and mutations of non-Ig genes that lead to lymphocyte malignancy. However, the molecular basis for these genetic instabilities is not clearly understood. Activation-induced cytidine deaminase (AID) is shown to be essential and sufficient to induce both CSR and SHM in artificial substrates in fibroblasts as well as B cells. Here we show that constitutive and ubiquitous expression of AID in transgenic mice caused both T cell lymphomas and dysgenetic lesions of epithelium of respiratory bronchioles (micro-adenomas) in all individual mice. Point mutations, but not translocations, were massively introduced in expressed T cell receptor (TCR) and c-myc genes in T lymphoma cells. The results indicate that AID can mutate non-Ig genes including oncogenes, implying that aberrant AID expression could be a cause of human malignancy. The Rockefeller University Press 2003-05-05 /pmc/articles/PMC2193972/ /pubmed/12732658 http://dx.doi.org/10.1084/jem.20030275 Text en Copyright © 2003, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Okazaki, Il-mi Hiai, Hiroshi Kakazu, Naoki Yamada, Shuichi Muramatsu, Masamichi Kinoshita, Kazuo Honjo, Tasuku Constitutive Expression of AID Leads to Tumorigenesis |
title | Constitutive Expression of AID Leads to Tumorigenesis |
title_full | Constitutive Expression of AID Leads to Tumorigenesis |
title_fullStr | Constitutive Expression of AID Leads to Tumorigenesis |
title_full_unstemmed | Constitutive Expression of AID Leads to Tumorigenesis |
title_short | Constitutive Expression of AID Leads to Tumorigenesis |
title_sort | constitutive expression of aid leads to tumorigenesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193972/ https://www.ncbi.nlm.nih.gov/pubmed/12732658 http://dx.doi.org/10.1084/jem.20030275 |
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