Atm and Bax Cooperate in Ionizing Radiation-Induced Apoptosis in the Central Nervous System

• Published in: Proceedings of the National Academy of Sciences - PNAS 2000-01, Vol.97 (2), p.889-894
• Main Authors: Chong, Miriam J., Murray, Michael R., Gosink, Eric C., Helen R. C. Russell, Srinivasan, Anu, Kapsetaki, Manuela, Korsmeyer, Stanley J., McKinnon, Peter J.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - genetics; Apoptosis - radiation effects; Ataxia telangiectasia; Ataxia Telangiectasia Mutated Proteins; Atm gene; ATM protein; Bax gene; bcl-2-Associated X Protein; Biological Sciences; Blotting, Western; Caspase 3; Caspases - metabolism; Cell Cycle Proteins; Cell death; Central nervous system; Central Nervous System - cytology; Central Nervous System - metabolism; Central Nervous System - radiation effects; Cerebellum; Cerebellum - metabolism; Cerebellum - radiation effects; Dentate Gyrus - metabolism; Dentate Gyrus - radiation effects; DNA; DNA damage; DNA-Binding Proteins; Enzyme Activation - radiation effects; Genotype; Mice; Mice, Knockout; Nervous system; Neurological disorders; Neurons; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases - physiology; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-bcl-2; Radiation; Radiation, Ionizing; Retina; Retina - metabolism; Retina - radiation effects; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Protein p53 - physiology; Tumor Suppressor Proteins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.97.2.889

Ataxia-telangiectasia is a hereditary multisystemic disease resulting from mutations of ataxia telangiectasia, mutated (ATM) and is characterized by neurodegeneration, cancer, immune defects, and hypersensitivity to ionizing radiation. The molecular details of ATM function in the nervous system are unclear, although the neurological lesion in ataxia-telangiectasia becomes apparent early in life, suggesting a developmental origin. The central nervous system (CNS) of Atm-null mice shows a pronounced defect in apoptosis induced by genotoxic stress, suggesting ATM functions to eliminate neurons with excessive genomic damage. Here, we report that the death effector Bax is required for a large proportion of Atm-dependent apoptosis in the developing CNS after ionizing radiation (IR). Although many of the same regions of the CNS in both Bax-/- and Atm-/- mice were radioresistant, mice nullizygous for both Bax and Atm showed additional reduction in IR-induced apoptosis in the CNS. Therefore, although the major IR-induced apoptotic pathway in the CNS requires Atm and Bax, a p53-dependent collateral pathway exists that has both Atm- and Bax-independent branches. Further, Atm- and Bax-dependent apoptosis in the CNS also required caspase-3 activation. These data implicate Bax and caspase-3 as death effectors in neurodegenerative pathways.