Abstract
Sympathetic neuronal death induced by nerve growth factor (NGF) deprivation requires the macromolecular synthesis-dependent translocation of BAX from the cytosol to mitochondria and its subsequent integration into the mitochondrial outer membrane, followed by BAX-mediated cytochrome c (cyt c) release. The gene products triggering this process remain unknown. Here, we report that BIM, a member of the BH3-only proapoptotic subfamily of the BCL-2 protein family, is one such molecule. NGF withdrawal induced expression of BIM(EL), an integral mitochondrial membrane protein that functions upstream of (or in parallel with) the BAX/BCL-2 and caspase checkpoints. Bim deletion conferred protection against developmental and induced neuronal apoptosis in both central and peripheral populations, but only transiently, suggesting that BIM--and perhaps other BH3-only proteins--serve partially redundant functions upstream of BAX-mediated cyt c release.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alternative Splicing
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Animals
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Animals, Newborn
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Carrier Proteins / biosynthesis*
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Carrier Proteins / genetics
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Carrier Proteins / physiology
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Caspases / metabolism
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Cells, Cultured
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Cycloheximide / pharmacology
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Cytochrome c Group / metabolism
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Cytosol / metabolism
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Dactinomycin / pharmacology
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Intracellular Membranes / metabolism
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JNK Mitogen-Activated Protein Kinases*
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MAP Kinase Kinase 4
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Membrane Proteins*
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Mice
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Mitochondria / metabolism
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Mitochondria / ultrastructure
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / physiology
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Mutagenesis
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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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Phosphatidylinositol 3-Kinases / physiology
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-bcl-2 / physiology*
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RNA, Messenger / analysis
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Rats
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Reverse Transcriptase Polymerase Chain Reaction
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bcl-2-Associated X Protein
Substances
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Apoptosis Regulatory Proteins
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Bax protein, mouse
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Bax protein, rat
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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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Enzyme Inhibitors
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Membrane Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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bcl-2-Associated X Protein
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Dactinomycin
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Nerve Growth Factor
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Cycloheximide
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases
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Caspases