Lithium stimulates gene expression through the AP-1 transcription factor pathway.
Lithium, a monovalent cation, is the mainstay in the treatment of manic-depressive (MDI) illness, but despite extensive research, its mechanism of action remains to be elucidated. Since lithium requires chronic administration for therapeutic efficacy, and because its beneficial effects last well beyond its discontinuation, it has been postulated that lithium may exert major effects at the genomic level. In the present study we found that lithium, at therapeutically relevant concentrations, increases AP-1 DNA binding activity in human SH-SY5Y cells and rat C6 glioma cells. Additionally, in both SY5Y and C6 cells transiently transfected with a reporter gene vector driven by an SV40 promoter, lithium increased the activity of the reporter gene in a time- and concentration-dependent manner. Furthermore, mutations in the AP-1 sites of the reporter gene promoter significantly attenuated lithium's effects. These data indicate that lithium stimulates gene expression through the AP-1 transcription factor pathway, effects which may play a role in its long-term mood-stabilizing effects.
Molecular Pathophysiology Program, Department of Psychiatry and Behavioral Neurosciences, and Pharmacology, WSU School of Medicine, 5V, DRH, 4201 St. Antoine Blvd., Detroit, MI 48201, USA.
P X
PX
Yuan
G
G
Chen
L D
LD
Huang
H K
HK
Manji
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002712:Chlorides / Q000494:pharmacology; D016384:Consensus Sequence; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter; D005910:Glioma; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology*; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009447:Neuroblastoma; D011189:Potassium Chloride / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012413:Rubidium / Q000494:pharmacology; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D013539:Simian virus 40 / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D002712:Chlorides; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D011189:Potassium Chloride; D008156:Luciferases; D018021:Lithium Chloride; D012413:Rubidium; C032710:rubidium chloride