Nature Genetics32, 185 - 190 (2002)
Published online: 26 August 2002; | doi:10.1038/ng958
Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer
Kevin Spring1, Farida Ahangari1, Shaun P. Scott1, Paul Waring2, David M. Purdie1, Philip C. Chen1, Kevin Hourigan3, Jonathan Ramsay1, Peter J. McKinnon4, Michael Swift5
& Martin F. Lavin1, 6
1
Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Herston, 4029, Australia.
2
Peter MacCallum Cancer Institute, St. Andrews Place, East Melbourne, Victoria, Australia.
3
Alexandra House, 201 Wickham Terrace, Brisbane, Australia.
4
Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
5
Department of Biological Sciences, Pace University, Pleasantville, New York, USA.
6
Department of Surgery, Clinical Sciences Building, Royal Brisbane Hospital, Herston, 4029, Australia.
Ataxia-telangiectasia is characterized by radiosensitivity, genome instability and predisposition to cancer1,
2. Heterozygous carriers of ATM, the gene defective in ataxia-telangiectasia, have a higher than normal risk of developing breast and other cancers3,
4,
5,
6. We demonstrate here that Atm 'knock-in' (Atm-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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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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