Ataxia telangiectasia-mutated protein can regulate p53 and neuronal death independent of Chk2 in response to DNA damage.
DNA damage is a key initiator of neuronal death. We have previously shown that the tumor suppressor p53, in conjunction with cyclin-dependent kinases (CDKs), regulates the mitochondrial pathway of death in neurons exposed to genotoxic agents. However, the mechanisms by which p53 is regulated is unclear. Presently, we show that p53 is phosphorylated on Ser-15 following DNA damage and this occurs independently of the CDK pathway. Instead, we show that p53 phosphorylation, stability, as well as neuronal death is regulated, in part, by the ataxia telangiectasia-mutated (ATM) protein. Previous reports have suggested that ATM regulation of p53 occurs through Chk2. However, in our present paradigms, we show that ATM functions separately from Chk2 to regulate p53 stability and neuronal death. Chk2 deficiency does not affect p53 stability or neuronal death induced by Topoisomerase I or II inhibition. Taken together, our results provide a model by which DNA damage can activate an ATM-dependent, Chk2-independent pathway of p53-mediated neuronal death.
Keramaris
Elizabeth
E
Neuroscience Research Program of Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Hirao
Atsushi
A
Slack
Ruth S
RS
Mak
Tak W
TW
Park
David S
DS
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D016923:Cell Death; D002478:Cells, Cultured; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004268:DNA-Binding Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000473:pathology*; D011494:Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology*; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases