Protective roles for ATM in cellular response to oxidative stress.
ATM (ataxia telangiectasia mutated), the gene mutated in ataxia telangiectasia, is related to a family of large phosphatidylinositol 3-kinase domain-containing proteins involved in cell cycle control and DNA repair. We found that ATM(-/-) DT40 cells were more susceptible than wild-type cells to apoptosis induced not only by ionizing radiation and bleomycin but also by non-DNA-damaging apoptotic stimuli such as C(2)-ceramide. Furthermore, the apoptosis induced by C(2)-ceramide and H(2)O(2) was blocked by anti-oxidants, indicating that the ATM(-/-) DT40 cells had a heightened susceptibility to apoptosis induced by reactive oxygen intermediates (ROI), presumably due to defective ROI-detoxification activities. In support of this hypothesis, we found that more ROI were generated in ATM(-/-) DT40 cells than in wild-type cells, following treatment with the above apoptotic stimuli. These results indicate that ATM plays important roles in the maintenance of the cell homeostasis in response to oxidative damage.
Takao
N
N
Department of Molecular Pathology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Li
Y
Y
Yamamoto
K
K
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D001260:Ataxia Telangiectasia / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D001761:Bleomycin / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D018797:Cell Cycle Proteins; D002460:Cell Line; D002645:Chickens; D002869:Chromosome Aberrations; D004268:DNA-Binding Proteins; D003907:Dexamethasone / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D009154:Mutation; D016877:Oxidants / Q000096:biosynthesis; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D025521:Tumor Suppressor Proteins; D014965:X-Rays
D000975:Antioxidants; D064007:Ataxia Telangiectasia Mutated Proteins; D001761:Bleomycin; D002374:Catalase; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D003907:Dexamethasone; D005979:Glutathione Peroxidase; D006861:Hydrogen Peroxide; D016877:Oxidants; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D013110:Sphingosine; D025521:Tumor Suppressor Proteins; C064769:N-acetylsphingosine