DREAM-αCREM interaction via leucine-charged domains derepresses downstream regulatory element-dependent transcription

Protein kinase A-dependent derepression of the human prodynorphin gene is regulated by the differential occupancy of the Dyn downstream regulatory element (DRE) site. Here, we show that a direct protein-protein interaction between DREAM and the CREM repressor isoform, αCREM, prevents binding of DREAM to the DRE and suggests a mechanism for cyclic AMP-dependent derepression of the prodynorphin gene in human neuroblastoma cells. Phosphorylation in the kinase-inducible domain of αCREM is not required for the interaction, but phospho-αCREM shows higher affinity for DREAM. The interaction with αCREM is independent of the Ca²⁺-binding properties of DREAM and is governed by leucine-charged residue-rich domains located in both αCREM and DREAM. Thus, our results propose a new mechanism for DREAM-mediated derepression that can operate independently of changes in nuclear Ca²⁺.