DREAM is a Ca2+-regulated transcriptional repressor

Abstract

Fluxes in amounts of intracellular calcium ions are important determinants of gene expression^1,2,3. So far, Ca²⁺-regulated kinases and phosphatases have been implicated in changing the phosphorylation status of key transcription factors and thereby modulating their function⁴,⁵. In addition, direct effectors of Ca²⁺-induced gene expression have been suggested to exist in the nucleus², although no such effectors have been identified yet. Expression of the human prodynorphin gene, which is involved inmemory acquisition and pain⁶,⁷, is regulated through its downstream regulatory element (DRE) sequence, which acts as a location-dependent gene silencer⁸. Here we isolate a new transcriptional repressor, DRE-antagonist modulator (DREAM), which specifically binds to the DRE. DREAM contains four Ca²⁺-binding domains of the EF-hand type. Upon stimulation by Ca²⁺, DREAM's ability to bind to the DRE and its repressor function are prevented. Mutation of the EF-hands abolishes the response of DREAM to Ca²⁺. In addition to the prodynorphin promoter, DREAM represses transcription from the early response gene c-fos. Thus, DREAM represents the first known Ca²⁺-binding protein to function as a DNA-binding transcriptional regulator.