COMPETITION FOR A UNIQUE RESPONSE ELEMENT MEDIATES RETINOIC ACID INHIBITION OF VITAMIN-D-3-STIMULATED TRANSCRIPTION

We have identified a novel steroid hormone response element in the avi an beta(3) integrin promoter. This sequence, comprising three hexameri c direct repeat half-sites separated by nine and three nucleotides bin ds vitamin D receptor (VDR)-retinoid X receptor (RXR) and retinoic aci d receptor (RAR)-RXR heterodimers. VDR-RXR binds direct repeats separa ted by three basepairs, and RAR-RXR recognizes half-sites separated by nine bases, whereas the central half-site interacts with both heterod imers. Retinoic acid and 1,25-dihydroxyvitamin D-3 activate both a gen omic fragment including the transcriptional start site and an oligonuc leotide containing the three repeats, linked to a heterologous promote r. Co-addition of the steroids produces neither synergy nor an additiv e effect; rather the result equals that for retinoic acid alone. Scatc hard analysis demonstrates that RAR-RXR has greater affinity than VDR- RXR for the composite element. Based on these findings we propose a mo del in which there is specific, polarity-defined binding of VDR-RXR an d RAR-RXR to three half-sites, which form two overlapping steroid resp onse elements, with the central half-site common to both, Our results identify a novel mechanism by which one steroid hormone can modulate t he activity of a second, by competing for a shared half-site in a comp osite response element.