DREAM is a Ca2+-regulated transcriptional repressor

Fluxes in amounts of intracellular calcium ions are important determinants of gene expression(1-3). So far, Ca2+-regulated kinases and phosphatases ha ve been implicated in changing the phosphorylation status of key transcript ion factors and thereby modulating their function(4,5). In addition, direct effecters of Ca2+ induced gene expression have been suggested to exist in the nucleus(2), although no such effecters have been identified yet. Expres sion of the human prodynorphin gene, which is involved in memory acquisitio n and pain(6,7), is regulated through its downstream regulatory element (DR E) sequence, which acts as a location-dependent gene silencer(8). Here we i solate a new transcriptional repressor, DRE-antagonist modulator (DREAM), w hich specifically binds to the DRE. DREAM contains four Ca2+-binding domain s 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 p romoter, 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.