title: Atm and Bax cooperate in ionizing radiation-induced apoptosis in the central nervous system.
abstract: 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.
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38101, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Chong
authors.forename: M R
authors.initials: MR
authors.lastname: Murray
authors.forename: E C
authors.initials: EC
authors.lastname: Gosink
authors.forename: H R
authors.initials: HR
authors.lastname: Russell
authors.forename: A
authors.initials: A
authors.lastname: Srinivasan
authors.forename: M
authors.initials: M
authors.lastname: Kapsetaki
authors.forename: S J
authors.initials: SJ
authors.lastname: Korsmeyer
authors.forename: P J
authors.initials: PJ
authors.lastname: McKinnon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D002531:Cerebellum / Q000378:metabolism / Q000528:radiation effects; D004268:DNA-Binding Proteins; D018891:Dentate Gyrus / Q000378:metabolism / Q000528:radiation effects; D004789:Enzyme Activation / Q000528:radiation effects; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D011839:Radiation, Ionizing; D012160:Retina / Q000378:metabolism / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein
chemical_list: C494827:Bax protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases