Valproate robustly enhances AP-1 mediated gene expression.

Abstract

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.

• Authors: G Chen, P X Yuan, Y M Jiang, L D Huang, H K Manji
• Journal: Brain research. Molecular brain research (Brain Res Mol Brain Res) Vol. 64 Issue 1 Pg. 52-8 (Jan 22 1999) ISSN: 0169-328X [Print] Netherlands
• PMID: 9889318 (Publication Type: Journal Article)
• Copyright: Copyright 1999 Elsevier Science B.V.

Chemical References

• Anticonvulsants
• DNA-Binding Proteins
• Proto-Oncogene Proteins c-fos
• Proto-Oncogene Proteins c-jun
• Transcription Factor AP-1
• Valproic Acid
• Luciferases

Topics

• Animals
• Anticonvulsants (pharmacology)
• Bipolar Disorder (drug therapy)
• DNA-Binding Proteins (genetics)
• Gene Expression Regulation (drug effects)
• Genes, Reporter
• Glioma
• Humans
• Luciferases (genetics)
• Molecular Sequence Data
• Mutation (physiology)
• Neuroblastoma
• Neurons (drug effects, physiology)
• Proto-Oncogene Proteins c-fos (genetics)
• Proto-Oncogene Proteins c-jun (genetics)
• Rats
• Sequence Homology, Amino Acid
• Transcription Factor AP-1 (genetics)
• Transfection
• Tumor Cells, Cultured
• Valproic Acid (pharmacology)