Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer.
Nat Genet
; 32(1): 185-90, 2002 Sep.
Article
em En
| MEDLINE
| ID: mdl-12195425
ABSTRACT
Ataxia-telangiectasia is characterized by radiosensitivity, genome instability and predisposition to cancer. Heterozygous carriers of ATM, the gene defective in ataxia-telangiectasia, have a higher than normal risk of developing breast and other cancers. We demonstrate here that Atm 'knock-in' (Atm-Delta SRI) heterozygous mice harboring an in-frame deletion corresponding to the human 7636del9 mutation show an increased susceptibility to developing tumors. In contrast, no tumors are observed in Atm knockout (Atm(+/-)) heterozygous mice. In parallel, we report the appearance of tumors in 6 humans from 12 families who are heterozygous for the 7636del9 mutation. Expression of ATM cDNA containing the 7636del9 mutation had a dominant-negative effect in control cells, inhibiting radiation-induced ATM kinase activity in vivo and in vitro. This reduces the survival of these cells after radiation exposure and enhances the level of radiation-induced chromosomal aberrations. These results show for the first time that mouse carriers of a mutated Atm that are capable of expressing Atm have a higher risk of cancer. This finding provides further support for cancer predisposition in human ataxia-telangiectasia carriers.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ataxia Telangiectasia
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Proteínas Serina-Treonina Quinases
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Predisposição Genética para Doença
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Mutação de Sentido Incorreto
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Neoplasias
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Nat Genet
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2002
Tipo de documento:
Article
País de afiliação:
Austrália