TY - JOUR
T1 - ΔFosB indirectly regulates Cck promoter activity
AU - Enwright, John F.
AU - Wald, Megan
AU - Paddock, Madison
AU - Hoffman, Elizabeth
AU - Arey, Rachel
AU - Edwards, Scott
AU - Spencer, Sade
AU - Nestler, Eric J.
AU - McClung, Colleen A.
N1 - Funding Information:
We would like to thank Will Renthal and Arvind Kumar for helpful discussions. We would also like to thank NIDA for funding these experiments.
PY - 2010/5/6
Y1 - 2010/5/6
N2 - 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 {increment}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.
AB - 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 {increment}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.
KW - Addiction
KW - Nucleus accumbens
KW - Transcription
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U2 - 10.1016/j.brainres.2010.02.081
DO - 10.1016/j.brainres.2010.02.081
M3 - Article
C2 - 20226774
AN - SCOPUS:77950857921
SN - 0006-8993
VL - 1329
SP - 10
EP - 20
JO - Brain Research
JF - Brain Research
ER -