Abstract
Cerebellar granule neurons depend on insulin-like growth factor-I (IGF-I) for their survival. However, the mechanism underlying the neuroprotective effects of IGF-I is presently unclear. Here we show that IGF-I protects granule neurons by suppressing key elements of the intrinsic (mitochondrial) death pathway. IGF-I blocked activation of the executioner caspase-3 and the intrinsic initiator caspase-9 in primary cerebellar granule neurons deprived of serum and depolarizing potassium. IGF-I inhibited cytochrome c release from mitochondria and prevented its redistribution to neuronal processes. The effects of IGF-I on cytochrome c release were not mediated by blockade of the mitochondrial permeability transition pore, because IGF-I failed to inhibit mitochondrial swelling or depolarization. In contrast, IGF-I blocked induction of the BH3-only Bcl-2 family member, Bim (Bcl-2 interacting mediator of cell death), a mediator of Bax-dependent cytochrome c release. The suppression of Bim expression by IGF-I did not involve inhibition of the c-Jun transcription factor. Instead, IGF-I prevented activation of the forkhead family member, FKHRL1, another transcriptional regulator of Bim. Finally, adenoviral-mediated expression of dominant-negative AKT activated FKHRL1 and induced expression of Bim. These data suggest that IGF-I signaling via AKT promotes survival of cerebellar granule neurons by blocking the FKHRL1-dependent transcription of Bim, a principal effector of the intrinsic death-signaling cascade.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Animals
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Apoptosis / drug effects
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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 / antagonists & inhibitors*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Caspase 3
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Caspase 9
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Caspases / metabolism
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Cells, Cultured
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Cerebellum / cytology
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Cytochrome c Group / metabolism
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DNA-Binding Proteins / metabolism
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Forkhead Box Protein O1
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology
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Genes, Dominant
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Humans
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Insulin-Like Growth Factor I / pharmacology*
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Insulin-Like Growth Factor I / physiology
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JNK Mitogen-Activated Protein Kinases
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Membrane Proteins*
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Mitochondria / drug effects
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Mitochondria / metabolism
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Nerve Tissue Proteins
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism*
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / pharmacology
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Proto-Oncogene Proteins c-akt
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Rats
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Rats, Sprague-Dawley
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Transcription Factors / metabolism
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Transfection
Substances
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, rat
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Carrier Proteins
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Cytochrome c Group
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DNA-Binding Proteins
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Enzyme Inhibitors
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FOXO1 protein, human
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FOXO3 protein, human
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FOXO3 protein, rat
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Forkhead Box Protein O1
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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Membrane Proteins
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Nerve Tissue Proteins
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Proto-Oncogene Proteins
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Transcription Factors
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Foxo1 protein, rat
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Insulin-Like Growth Factor I
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AKT1 protein, human
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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CASP3 protein, human
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CASP9 protein, human
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Casp3 protein, rat
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Casp9 protein, rat
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Caspase 3
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Caspase 9
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Caspases