Dual roles of ATM in the cellular response to radiation and in cell growth control.
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.
Xu
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Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA.
Baltimore
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D000818:Animals; D017209:Apoptosis; D001260:Ataxia Telangiectasia / Q000209:etiology; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000502:physiology* / Q000528:radiation effects; D018797:Cell Cycle Proteins; D002455:Cell Division; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004249:DNA Damage; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000166:cytology; D016193:G1 Phase / Q000502:physiology; D005720:Gamma Rays; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D011836:Radiation Tolerance; D013234:Stem Cells / Q000528:radiation effects; D013950:Thymus Gland / Q000166:cytology / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D025521:Tumor Suppressor Proteins
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D011506:Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases