Essential postmitochondrial function of p53 uncovered in DNA damage-induced apoptosis in neurons.
In postmitotic sympathetic neurons, unlike most mitotic cells, death by apoptosis requires not only the release of cytochrome c from the mitochondria, but also an additional step to relieve X-linked inhibitor of apoptosis protein (XIAP)'s inhibition of caspases. Here, we examined the mechanism by which XIAP is inactivated following DNA damage and found that it is achieved by a mechanism completely different from that following apoptosis by nerve growth factor (NGF) deprivation. NGF deprivation relieves XIAP by selectively degrading it, whereas DNA damage overcomes XIAP via a p53-mediated induction of Apaf-1. Unlike wild-type neurons, p53-deficient neurons fail to overcome XIAP and remain resistant to cytochrome c after DNA damage. Restoring Apaf-1 induction in p53-deficient neurons is sufficient to overcome XIAP and sensitize cells to cytochrome c. Although a role for p53 in apoptosis upstream of cytochrome c release has been well established, this study uncovers an additional, essential role for p53 in regulating caspase activation downstream of mitochondria following DNA damage in neurons.
Vaughn
A E
AE
Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
Deshmukh
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053478:Apoptosomes / Q000378:metabolism; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D020932:Nerve Growth Factor / Q000172:deficiency; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis
D053478:Apoptosomes; D053477:Apoptotic Protease-Activating Factor 1; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; D005047:Etoposide; D045304:Cytochromes c; D020932:Nerve Growth Factor