Blockade of cyclic AMP-responsive element DNA binding in the brain of CREB delta/alpha mutant mice.
The cAMP-responsive element binding protein (CREB) gene transcription factor has been implicated in the synaptic plasticity and memory. Here, we investigated the mechanisms of CREB and/or cyclic AMP-responsive element modulatory protein (CREM) binding to CRE sites in brain tissues. CRE-DNA binding was determined in nuclear extracts obtained from the several brain structures of wild-type and CREB delta/alpha mutant mice. It was found that antibodies to CREB, phosphorylated CREB, and CREM supershifted the CRE-DNA binding complex in cortical nuclear extracts from wild-type mice, which suggests that the CRE-DNA binding complex contains both CREB and CREM proteins. In contrast, CRE-DNA binding is abolished in the cortex, hippocampus, cerebellum, and amygdala of CREB delta/alpha mutant mice. Because the CREB delta and alpha isoforms have been deleted in CREB mutant mice, consequently, other forms of CREB, such as CREB-beta and CREM, are up-regulated. These results suggest that the binding of CREM to CRE sites requires the presence of CREB delta/alpha, and that CREB-beta may be inefficient in binding to CRE-sites. Thus, these results indicate that CREB delta/alpha mutant mice are a useful animal model for studying the functional role of CREB-dependent gene expression.
Pandey
S C
SC
Department of Psychiatry, Psychiatric Institute, University of Illinois at Chicago and VA Chicago Health Care System, 60612, USA.
Mittal
N
N
Silva
A J
AJ
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D051786:Cyclic AMP Response Element Modulator; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009154:Mutation / Q000502:physiology; D020033:Protein Isoforms / Q000172:deficiency* / Q000235:genetics; D012097:Repressor Proteins; D014158:Transcription, Genetic / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D012097:Repressor Proteins; D051786:Cyclic AMP Response Element Modulator; D004247:DNA