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.
Original language | English |
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Pages (from-to) | 6027-36 |
Number of pages | 10 |
Journal | Molecular and Cellular Biology |
Volume | 23 |
Issue number | 17 |
DOIs | |
Publication status | Published - Sept 2003 |
MoE publication type | A1 Journal article-refereed |
Keywords
- Adaptor Proteins, Signal Transducing
- Animals
- Apoptosis Regulatory Proteins
- Bcl-2-Like Protein 11
- Carrier Proteins/drug effects
- Cell Death/drug effects
- Cells, Cultured
- Cerebellum/cytology
- Dose-Response Relationship, Drug
- Enzyme Activation/drug effects
- Genes, Reporter
- Glycogen Synthase Kinase 3/drug effects
- Indoles/pharmacology
- JNK Mitogen-Activated Protein Kinases
- Lithium/pharmacology
- Membrane Proteins
- Mice
- Mice, Mutant Strains
- Mitogen-Activated Protein Kinases/drug effects
- Neoplasm Proteins
- Neurons/drug effects
- Neuroprotective Agents/pharmacology
- Oximes/pharmacology
- Phosphoric Monoester Hydrolases/drug effects
- Promoter Regions, Genetic
- Proto-Oncogene Proteins/genetics
- Rats
- Stress, Physiological
- Transcription Factor AP-1/genetics
- Up-Regulation