Abstract
A mechanism by which the Ras-mitogen-activated protein kinase (MAPK) signaling pathway mediates growth factor-dependent cell survival was characterized. The MAPK-activated kinases, the Rsks, catalyzed the phosphorylation of the pro-apoptotic protein BAD at serine 112 both in vitro and in vivo. The Rsk-induced phosphorylation of BAD at serine 112 suppressed BAD-mediated apoptosis in neurons. Rsks also are known to phosphorylate the transcription factor CREB (cAMP response element-binding protein) at serine 133. Activated CREB promoted cell survival, and inhibition of CREB phosphorylation at serine 133 triggered apoptosis. These findings suggest that the MAPK signaling pathway promotes cell survival by a dual mechanism comprising the posttranslational modification and inactivation of a component of the cell death machinery and the increased transcription of pro-survival genes.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis*
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Brain-Derived Neurotrophic Factor / pharmacology
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Survival*
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Cells, Cultured
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Cerebellum / cytology
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Cyclic AMP Response Element-Binding Protein / metabolism
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Insulin-Like Growth Factor I / pharmacology
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MAP Kinase Kinase 1
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MAP Kinase Signaling System*
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Mutation
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Neurons / cytology*
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Neurons / metabolism
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Phosphorylation
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Phosphoserine / metabolism
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Protein Serine-Threonine Kinases*
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Rats
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Rats, Long-Evans
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Recombinant Fusion Proteins / metabolism
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Ribosomal Protein S6 Kinases / genetics
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Ribosomal Protein S6 Kinases / metabolism*
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Transcription, Genetic*
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Transfection
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bcl-Associated Death Protein
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ras Proteins / metabolism
Substances
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Bad protein, rat
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Brain-Derived Neurotrophic Factor
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Carrier Proteins
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Cyclic AMP Response Element-Binding Protein
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Enzyme Inhibitors
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Flavonoids
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Recombinant Fusion Proteins
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bcl-Associated Death Protein
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Phosphoserine
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Insulin-Like Growth Factor I
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Protein Serine-Threonine Kinases
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Ribosomal Protein S6 Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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Mitogen-Activated Protein Kinase Kinases
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ras Proteins
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one