Abstract
Lithium has been used as an effective mood-stabilizing drug for the treatment of manic episodes and depression for 50 years. More recently, lithium has been found to protect neurons from death induced by a wide array of neurotoxic insults. However, the molecular basis for the prophylactic effects of lithium have remained obscure. A target of lithium, glycogen synthase kinase 3 (GSK-3), is implicated in neuronal death after trophic deprivation. The mechanism whereby GSK-3 exerts its neurotoxic effects is also unknown. Here we show that lithium blocks the canonical c-Jun apoptotic pathway in cerebellar granule neurons deprived of trophic support. This effect is mimicked by the structurally independent inhibitors of GSK-3, FRAT1, and indirubin. Like lithium, these prevent the stress induced c-Jun protein increase and subsequent apoptosis. These events are downstream of c-Jun transactivation, since GSK-3 inhibitors block neuronal death induced by constitutively active c-Jun (Ser/Thr-->Asp) and FRAT1 expression inhibits AP1 reporter activity. Consistent with this, AP1-dependent expression of proapoptotic Bim requires GSK-3-like activity. These data suggest that a GSK-3-like kinase acts in tandem with c-Jun N-terminal kinase to coordinate the full execution of the c-Jun stress response and neuronal death in response to trophic deprivation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Carrier Proteins / drug effects
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Carrier Proteins / metabolism
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Cell Death / drug effects
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Cell Death / physiology
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Cells, Cultured
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Cerebellum / cytology
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Dose-Response Relationship, Drug
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Enzyme Activation / drug effects
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Genes, Reporter
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Glycogen Synthase Kinase 3 / drug effects*
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Glycogen Synthase Kinase 3 / metabolism
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Indoles / pharmacology
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JNK Mitogen-Activated Protein Kinases
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Lithium / pharmacology*
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Membrane Proteins*
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Mice
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Mice, Mutant Strains
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Mitogen-Activated Protein Kinases / drug effects*
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Mitogen-Activated Protein Kinases / metabolism
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Neoplasm Proteins*
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Neurons / drug effects*
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Neurons / metabolism
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Neuroprotective Agents / pharmacology*
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Oximes / pharmacology
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Phosphoric Monoester Hydrolases / drug effects
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Phosphoric Monoester Hydrolases / metabolism
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Promoter Regions, Genetic
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Rats
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Stress, Physiological
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Transcription Factor AP-1 / genetics
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Transcription Factor AP-1 / metabolism
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Up-Regulation
Substances
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5-iodoindirubin-3'-monoxime
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Adaptor Proteins, Signal Transducing
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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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Frat1 protein, mouse
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Indoles
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Membrane Proteins
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Neoplasm Proteins
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Neuroprotective Agents
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Oximes
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Proto-Oncogene Proteins
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Transcription Factor AP-1
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Lithium
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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Glycogen Synthase Kinase 3
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Phosphoric Monoester Hydrolases
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myo-inositol-1 (or 4)-monophosphatase