Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3.
Mol Cell Biol
; 23(17): 6027-36, 2003 Sep.
Article
em En
| MEDLINE
| ID: mdl-12917327
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.
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Base de dados:
MEDLINE
Assunto principal:
Fármacos Neuroprotetores
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Proteínas Quinases Ativadas por Mitógeno
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Quinase 3 da Glicogênio Sintase
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Lítio
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Proteínas de Membrana
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Proteínas de Neoplasias
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Neurônios
Idioma:
En
Ano de publicação:
2003
Tipo de documento:
Article