Characterization of a retinoic acid responsive element in the human ets-1 promoter

The vitamin A metabolite retinoic acid (RA) is a powerful regulator of cellular proliferation and differentiation. The effects of RA on target gene expression are mediated by a family of ligand dependent nuclear transcription factors known as retinoic acid receptors (RAR). RARs have functional domains for retinoic acid binding, dimerization, and transactivation. RA response elements (RARE) found in the promoters of many genes consist of variable direct repeats of the sequence PuGGTCA spaced by five nucleotides (DR5). We have identified a novel DR5 element in the human ets-1 promoter. Mutational analysis of this site indicates that it is necessary for RA- and RAR-dependent activation of the ets-1 promoter. RARalpha can bind specifically to this site as determined by electrophoretic mobility shift analysis. Finally, RA mediates induction of the human ets-1 gene at the mRNA and protein levels. These data suggest that induction of ets-1 expression by RA is mediated by a novel retinoic acid response element in the promoter region of this gene.