Abstract
Neurotrophic factors prevent apoptosis of PC12 cells in serum-free medium. The present study determines whether neurotrophic factors can prevent ceramide-induced apoptosis in PC12 cells and investigates the role that c-Jun N-terminal kinase (JNK) activation may play in this system. Ceramide-induced apoptosis was inhibited by nerve growth factor, basic fibroblast growth factor, pituitary adenylyl cyclase-activating peptide, 4-(8-chlorophenylthio)cyclic AMP, and the caspase inhibitor benzyloxycarbonyl-Val-Ala-DL-Asp fluoromethyl ketone (zVAD-FMK). It was surprising that inhibition of extracellular signal-regulated kinase and/or phosphatidylinositol 3-kinase did not markedly block the protective effects exerted by neurotrophic factors against ceramide-induced apoptosis, suggesting that neurotrophic factors can promote survival independently of these signaling pathways. Treatment of PC12 cells with ceramide resulted in a time-dependent increase in JNK activity. However, neither neurotrophic factors nor zVAD-FMK attenuated ceramide-stimulated JNK activation. Further experiments indicated that ceramide-induced apoptosis in PC12 cells requires new protein synthesis, and that nerve growth factor and zVAD-FMK can prevent apoptosis after JNK activity has been detected. These results indicate that ceramide-induced JNK activation is an early event and may be required for the expression of essential components of the apoptotic machinery. It is anticipated that neurotrophic factors inhibit ceramide-induced apoptosis by affecting signaling events downstream of JNK activation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Androstadienes / pharmacology
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Animals
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Apoptosis / drug effects*
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Apoptosis / physiology
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Cell Survival / drug effects
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Chromones / pharmacology
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Cyclic AMP / analogs & derivatives
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Cyclic AMP / pharmacology
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Cysteine Endopeptidases / metabolism
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Cysteine Proteinase Inhibitors / pharmacology
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology*
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Epidermal Growth Factor / pharmacology
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Fibroblast Growth Factor 2 / pharmacology
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Flavonoids / pharmacology
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Hypoglycemic Agents / pharmacology
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Insulin / pharmacology
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Morpholines / pharmacology
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Nerve Growth Factors / pharmacology*
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Neurons / cytology
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Neurons / drug effects
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Neurons / enzymology
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Neuropeptides / pharmacology
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Neuroprotective Agents / pharmacology
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PC12 Cells
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Pituitary Adenylate Cyclase-Activating Polypeptide
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Protein Synthesis Inhibitors / pharmacology
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Proto-Oncogene Proteins c-jun / metabolism*
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Rats
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Sphingosine / analogs & derivatives*
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Sphingosine / pharmacology
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Thionucleotides / pharmacology
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Wortmannin
Substances
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Adcyap1 protein, rat
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Amino Acid Chloromethyl Ketones
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Androstadienes
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Chromones
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Cysteine Proteinase Inhibitors
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Enzyme Inhibitors
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Flavonoids
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Hypoglycemic Agents
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Insulin
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Morpholines
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N-acetylsphingosine
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Nerve Growth Factors
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Neuropeptides
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Neuroprotective Agents
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Pituitary Adenylate Cyclase-Activating Polypeptide
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Protein Synthesis Inhibitors
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Proto-Oncogene Proteins c-jun
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Thionucleotides
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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Fibroblast Growth Factor 2
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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8-((4-chlorophenyl)thio)cyclic-3',5'-AMP
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Epidermal Growth Factor
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Cyclic AMP
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Cysteine Endopeptidases
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Sphingosine
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Wortmannin