Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviridae / genetics
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Animals
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Apoptosis
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Carrier Proteins / genetics*
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Carrier Proteins / physiology
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Caspases / metabolism
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Cell Survival*
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Cells, Cultured
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Cytochrome c Group / metabolism*
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Enzyme Activation
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Gene Expression
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MAP Kinase Kinase Kinase 1*
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Membrane Proteins*
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Mice
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Mice, Knockout
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Microinjections
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Mitochondria / metabolism*
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Nerve Growth Factor / administration & dosage
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Nerve Growth Factor / physiology
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Neurons / physiology*
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Neurons / ultrastructure
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Oligonucleotides, Antisense / pharmacology
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Protein Serine-Threonine Kinases / genetics
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-jun / physiology*
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Proto-Oncogene Proteins*
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Rats
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Rats, Sprague-Dawley
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Superior Cervical Ganglion / cytology
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Transfection
Substances
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Bcl2l11 protein, rat
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Carrier Proteins
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Cytochrome c Group
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Membrane Proteins
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Oligonucleotides, Antisense
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Proto-Oncogene Proteins c-jun
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Nerve Growth Factor
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Protein Serine-Threonine Kinases
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MAP Kinase Kinase Kinase 1
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Map3k1 protein, mouse
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Caspases