Dual roles of ATM in the cellular response to radiation and in cell growth control
- Creators
- Xu, Yang
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Baltimore, David
Abstract
The gene mutated in ataxia-telangiectasia (AT) patients, denoted ATM, encodes a putative protein or lipid kinase. To elucidate the functions of ATM, we disrupted the mouse ATM gene through homologous recombination in mice. Consistent with cellular defects of AT patients, the ATM-/- cells are hypersensitive to gamma-irradiation and defective in cell-cycle arrest following radiation, correlating with a defective up-regulation of p53. In addition, ATM-/- mouse thymocytes are more resistant to apoptosis induced by gamma-irradiation than normal thymocytes. ATM-/- fibroblasts are inefficient in G1 to S-phase progression following serum stimulation and senesce after only a few passages in culture. They have an increased constitutive level of p21CP1/WAF1. The ATM protein is therefore critical both for cellular responses to ionizing radiation and for normal cell-cycle progression. ATM+/- fibroblasts and thymocytes showed intermediately defective responses to irradiation but no growth defect, suggesting that the increased cancer risk of AT heterozygotes could be attributable to poor checkpoint function.
Additional Information
© 1996 by Cold Spring Harbor Laboratory Press. Received June 6, 1996; revised version accepted July 26, 1996. We thank J. Lawitts and the transgenic facility of Beth Israel Hospital for generating chimeric mice, J. Brugarolos for advice on cell-cycle analysis, and A. Beg for critically reading the manuscript. This project was supported by a National Institutes of Health grant to D.B.Y.X. was supported by the Cancer Research Fund of Damon Runyon-Walter Winchell Foundation. D.B. is an American Cancer Society Research Professor. The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.Additional details
- Eprint ID
- 103069
- DOI
- 10.1101/gad.10.19.2401
- Resolver ID
- CaltechAUTHORS:20200507-110624593
- NIH
- Damon Runyon-Walter Winchell Cancer Fund
- American Cancer Society
- Created
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2020-05-08Created from EPrint's datestamp field
- Updated
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2021-11-16Created from EPrint's last_modified field