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Molecular and Cellular Biology, September 2003, p. 6027-6036, Vol. 23, No. 17
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.17.6027-6036.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Lithium Blocks the c-Jun Stress Response and Protects Neurons via Its Action on Glycogen Synthase Kinase 3

Vesa Hongisto,1,2 Nina Smeds,1,2 Stephan Brecht,3 Thomas Herdegen,3 Michael J. Courtney,4 and Eleanor T. Coffey1*

Institute of Pharmacology, University of Kiel, Kiel, Germany,3 Centre for Biotechnology, Åbo Akademi and Turku University,1 Department of Biochemistry and Pharmacy, Åbo Akademi University, Turku,2 and A. I. Virtanen Institute, University of Kuopio, Kuopio, Finland4

Received 2 May 2003/ Accepted 23 May 2003

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.

* Corresponding author. Mailing address: Turku Centre for Biotechnology, Åbo Akademi and Turku University, BioCity, Turku FIN-20521, Finland. Phone: 358-2-3338605. Fax: 358-2-3338000. E-mail: ecoffey{at}btk.utu.fi.

Molecular and Cellular Biology, September 2003, p. 6027-6036, Vol. 23, No. 17
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.17.6027-6036.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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