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 cell ular proliferation and differentiation. The effects of RA on target gene ex pression are mediated by a family of ligand dependent nuclear transcription factors known as retinoic acid receptors (RAR), RARs have functional domai ns for retinoic acid binding, dimerization, and transactivation, RA respons e 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. Mutationa l analysis of this site indicates that it is necessary for RA- and RAR-depe ndent activation of the ets-1 promoter. RAR alpha 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 lev els. These data suggest that induction of ets-1 expression by RA is mediate d by a novel retinoic acid response element in the promoter region of this gene.