Evidence of a novel event during neuronal death: development of competence-to-die in response to cytoplasmic cytochrome c.
Sympathetic neurons undergoing programmed cell death after nerve growth factor (NGF) deprivation are shown to exhibit a protein synthesis-dependent, BAX-dependent loss of cytochrome c from the mitochondria. However, cytoplasmic microinjection of cytochrome c was insufficient to induce cell death in NGF-maintained sympathetic neurons. In contrast, microinjection of cytochrome c rapidly induced a caspase-dependent death in NGF-deprived, Bax-deficient or NGF-deprived, cycloheximide-treated neurons. Cells needed to be deprived of NGF for 15-20 hr before they acquired competence to die with injection of cytochrome c. These data suggest that NGF deprivation induced the translocation of cytochrome c and another event, which we term as competence-to-die, that was independent of macromolecular synthesis and BAX function. Both these processes were required for neurons to undergo apoptosis.
Deshmukh
M
M
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Johnson
E M
EM
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D020169:Caspases / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism / Q000494:pharmacology*; D003593:Cytoplasm / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008845:Microinjections; D008928:Mitochondria / Q000378:metabolism; D009414:Nerve Growth Factors / Q000172:deficiency / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D017783:Superior Cervical Ganglion / Q000166:cytology; D051028:bcl-2-Associated X Protein
D000590:Amino Acid Chloromethyl Ketones; C494827:Bax protein, mouse; D003574:Cytochrome c Group; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C103192:butyloxycarbonyl-O-methyl-aspartyl-fluoromethyl ketone; D003513:Cycloheximide; D020169:Caspases