Valproate robustly enhances AP-1 mediated gene expression.
Valproic acid (VPA) is a potent broad spectrum anticonvulsant with demonstrated efficacy in the treatment of Bipolar Affective Disorder, but the biochemical basis for VPA's antimanic or mood-stabilizing actions have not been fully elucidated. It has been demonstrated that VPA, at therapeutically relevant concentrations, increases AP-1 DNA binding activity in cultured cells in vitro. These findings raise the possibility that VPA may produce its mood-stabilizing effects by regulating the expression of subsets of genes via its effects on the AP-1 family of transcription factors. To determine if VPA does, in fact, enhance AP-1 mediated gene expression, the effects of VPA on the expression of a luciferase reporter gene were studied in transiently transfected rat C6 glioma and human SH-SY5Y neuroblastoma cells using the pGL2-control vector. The luciferase gene in the vector is driven by an SV40 promoter which contains well characterized AP-1 sites. VPA produced a greater than doubling of luciferase activity in a time- and concentration-dependent manner in both cell lines. Furthermore, mutations of the AP-1 sites in the SV40 promoter markedly attenuated the VPA-induced increases in luciferase activity. These effects of VPA on AP-1 mediated gene expression are very similar to the effects observed with lithium, and suggest that the temporal regulation of AP-1 mediated gene expression in critical neuronal circuits may play a role in the long-term therapeutic efficacy of these agents.
Chen
G
G
Laboratory of Molecular Pathophysiology, Department of Psychiatry and Behavioral Neurosciences, WSU School of Medicine, 2301 Scott Hall, 540 E. Canfield Avenue, Detroit, MI 48201, USA. gchen@med.wayne.edu
Yuan
P X
PX
Jiang
Y M
YM
Huang
L D
LD
Manji
H K
HK
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001714:Bipolar Disorder / Q000188:drug therapy; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D005910:Glioma; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D051381:Rats; D017386:Sequence Homology, Amino Acid; D018808:Transcription Factor AP-1 / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology*
D000927:Anticonvulsants; D004268:DNA-Binding Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014635:Valproic Acid; D008156:Luciferases