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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...

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Autores principales: Okazaki, Il-mi, Hiai, Hiroshi, Kakazu, Naoki, Yamada, Shuichi, Muramatsu, Masamichi, Kinoshita, Kazuo, Honjo, Tasuku
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2003
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.
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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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