Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release.
Sympathetic neurons require nerve growth factor for survival and die by apoptosis in its absence. Key steps in the death pathway include c-Jun activation, mitochondrial cytochrome c release, and caspase activation. Here, we show that neurons rescued from NGF withdrawal-induced apoptosis by expression of dominant-negative c-Jun do not release cytochrome c from their mitochondria. Furthermore, we find that the mRNA for BIM(EL), a proapoptotic BCL-2 family member, increases in level after NGF withdrawal and that this is reduced by dominant-negative c-Jun. Finally, overexpression of BIM(EL) in neurons induces cytochrome c redistribution and apoptosis in the presence of NGF, and neurons injected with Bim antisense oligonucleotides or isolated from Bim(-/-) knockout mice die more slowly after NGF withdrawal.
Whitfield
J
J
Eisai London Research Laboratories, Bernard Katz Building, University College London, Gower Street, WC1E 6BT, London, United Kingdom.
Neame
S J
SJ
Paquet
L
L
Bernard
O
O
Ham
J
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism*; D004789:Enzyme Activation; D015870:Gene Expression; D048728:MAP Kinase Kinase Kinase 1; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008845:Microinjections; D008928:Mitochondria / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000008:administration & dosage / Q000502:physiology; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017783:Superior Cervical Ganglion / Q000166:cytology; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C000606778:Bcl2l11 protein, rat; D002352:Carrier Proteins; D003574:Cytochrome c Group; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun; D020932:Nerve Growth Factor; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse; D020169:Caspases