DeltaFosB indirectly regulates Cck promoter activity

Abstract

Some of the important biochemical, structural, and behavioral changes induced by chronic exposure to drugs of abuse appear to be mediated by the highly stable transcription factor DeltaFosB. Previous work has shown that DeltaFosB overexpression in mice for 2weeks leads to an increase in the expression of numerous genes in striatum, most of which are later downregulated following 8weeks of FosB expression. Interestingly, a large number of these genes were also upregulated in mice overexpressing the transcription factor CREB. It was unclear from this study, however, whether short-term DeltaFosB regulates these genes via CREB. Here, we find that 2weeks of DeltaFosB overexpression increases CREB expression in striatum, an effect that dissipates by 8weeks. The early induction is associated with increased CREB binding to certain target gene promoters in this brain region. Surprisingly, one gene that was a suspected CREB target based on previous reports, cholecystokinin (Cck), was not controlled by CREB in striatum. To further investigate the regulation of Cck following DeltaFosB overexpression, we confirmed that short-term DeltaFosB overexpression increases both Cck promoter activity and gene expression. It also increases binding activity at a putative CREB binding site (CRE) in the Cck promoter. However, while the CRE site is necessary for normal basal expression of Cck, it is not required for DeltaFosB induction of Cck. Taken together, these results suggest that while short-term DeltaFosB induction increases CREB expression and activity at certain gene promoters, this is not the only mechanism by which genes are upregulated under these conditions.