ΔFosB 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 ΔFosB. Previous work has shown that ΔFosB overexpression in mice for 2 weeks leads to an increase in the expression of numerous genes in striatum, most of which are later downregulated following 8 weeks 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 ΔFosB regulates these genes via CREB. Here, we find that 2 weeks of ΔFosB overexpression increases CREB expression in striatum, an effect that dissipates by 8 weeks. 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 ΔFosB overexpression, we confirmed that short-term ΔFosB 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 ΔFosB induction of Cck. Taken together, these results suggest that while short-term ΔFosB induction increases CREB expression and activity at certain gene promoters, this is not the only mechanism by which genes are upregulated under these conditions.