title: Death in the balance: alternative participation of the caspase-2 and -9 pathways in neuronal death induced by nerve growth factor deprivation.
abstract: The data presented here demonstrate that sympathetic neurons have the potential to activate two alternative caspase-dependent pathways either of which is capable of mediating death induced by NGF deprivation and that these neurons have the potential to switch from one pathway to the other. The presence of these two alternative pathways to trophic factor deprivation-induced death may have implications for ensuring the correct development of the nervous system. In wild-type neurons, a caspase-2-dependent pathway is required for death, and a caspase-9-dependent pathway appears to be suppressed by endogenous inhibitors of apoptosis proteins (IAPs). In contrast, for caspase-2-null neurons, death is dependent on the caspase-9 pathway. The mechanism underlying the shift is the result of a threefold compensatory elevation of caspase-9 expression and a doubling of levels of direct IAP binding protein with low pI/(DIABLO)/second mitochondria-derived activator of caspase (Smac), an IAP inhibitor, both at the mRNA and protein levels [corrected]. These findings resolve seemingly discrepant findings regarding the roles of various caspases after NGF deprivation and raise a cautionary note regarding the interpretation of findings with caspase-null animals. The choice of the death-mediating caspase pathway in the sympathetic neurons is thus dependent on the regulated relative expression of components of the pathways including those of caspases, IAPs, and IAP inhibitors.
authors: Department of Pathology, Taub Institute for the Study of Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. cmt2@columbia.edu.
authors: C M
authors: CM
authors: Troy
authors: S A
authors: SA
authors: Rabacchi
authors: J B
authors: JB
authors: Hohl
authors: J M
authors: JM
authors: Angelastro
authors: L A
authors: LA
authors: Greene
authors: M L
authors: ML
authors: Shelanski
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053143:Caspase 2; D053148:Caspase 3; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D029543:Nucleocytoplasmic Transport Proteins; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: C506593:Apaf1 protein, mouse; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D001426:Bacterial Proteins; D002352:Carrier Proteins; D061945:Caspase Inhibitors; C499605:Diablo protein, mouse; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins; D024101:Mitochondrial Proteins; D029543:Nucleocytoplasmic Transport Proteins; C402484:Nxt1 protein, mouse; D016376:Oligonucleotides, Antisense; D011506:Proteins; D012333:RNA, Messenger; D020932:Nerve Growth Factor; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053143:Caspase 2; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases