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Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3.
Mol Cell Biol. 2003 Sep; 23(17):6027-36.MC

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.

Links

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Authors+Show Affiliations

Hongisto V
Centre for Biotechnology and Department of Biochemistry and Pharmacy, Abo Akademi University, Turku, Finland.
Smeds N
No affiliation info available
Brecht S
No affiliation info available
Herdegen T
No affiliation info available
Courtney MJ
No affiliation info available
Coffey ET
No affiliation info available

MeSH

Adaptor Proteins, Signal TransducingAnimalsApoptosis Regulatory ProteinsBcl-2-Like Protein 11Carrier ProteinsCell DeathCells, CulturedCerebellumDose-Response Relationship, DrugEnzyme ActivationGenes, ReporterGlycogen Synthase Kinase 3IndolesJNK Mitogen-Activated Protein KinasesLithiumMembrane ProteinsMiceMice, Mutant StrainsMitogen-Activated Protein KinasesNeoplasm ProteinsNeuronsNeuroprotective AgentsOximesPhosphoric Monoester HydrolasesPromoter Regions, GeneticProto-Oncogene ProteinsRatsStress, PhysiologicalTranscription Factor AP-1Up-Regulation

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12917327

Citation

Hongisto, Vesa, et al. "Lithium Blocks the c-Jun Stress Response and Protects Neurons Via Its Action On Glycogen Synthase Kinase 3." Molecular and Cellular Biology, vol. 23, no. 17, 2003, pp. 6027-36.
Hongisto V, Smeds N, Brecht S, et al. Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3. Mol Cell Biol. 2003;23(17):6027-36.
Hongisto, V., Smeds, N., Brecht, S., Herdegen, T., Courtney, M. J., & Coffey, E. T. (2003). Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3. Molecular and Cellular Biology, 23(17), 6027-36.
Hongisto V, et al. Lithium Blocks the c-Jun Stress Response and Protects Neurons Via Its Action On Glycogen Synthase Kinase 3. Mol Cell Biol. 2003;23(17):6027-36. PubMed PMID: 12917327.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3. AU - Hongisto,Vesa, AU - Smeds,Nina, AU - Brecht,Stephan, AU - Herdegen,Thomas, AU - Courtney,Michael J, AU - Coffey,Eleanor T, PY - 2003/8/15/pubmed PY - 2003/9/25/medline PY - 2003/8/15/entrez SP - 6027 EP - 36 JF - Molecular and cellular biology JO - Mol Cell Biol VL - 23 IS - 17 N2 - 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. SN - 0270-7306 UR - https://www.unboundmedicine.com/medline/citation/12917327/Lithium_blocks_the_c_Jun_stress_response_and_protects_neurons_via_its_action_on_glycogen_synthase_kinase_3_ DB - PRIME DP - Unbound Medicine ER -
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