DNA elements mediating retinoid and thyroid hormone regulation of alcohol dehydrogenase gene expression.

Abstract

Vertebrate alcohol dehydrogenase (ADH) plays a role in many alcohol/aldehyde interconversions including the oxidation of retinol to retinaldehyde, the rate-limiting step in the synthesis of retinoic acid. Recent molecular genetic studies on human ADH genes has lent support to a physiological role for ADH in retinoic acid synthesis. A region in the promoter for the human ADH3 gene was previously shown to function as a retinoic acid response element (RARE), prompting an hypothesis for a positive feedback mechanism for controlling retinoic acid synthesis. The ADH3 RARE contains three direct AGGTCA repeats which constitute the critical nucleotides of RAREs present in other genes. We compared the ADH3 RARE to RAREs present in other genes and determined that a region containing two AGGTCA motifs separated by 5 bp was sufficient for regulating gene expression in tissue culture cells. Our experiments also indicate that ADH3 gene expression is repressed by thyroid hormone receptor in the presence of thyroid hormone. The region of the ADH3 promoter containing the RARE was found to harbor a negative thyroid hormone response element. Regulation of ADH gene expression by retinoid and thyroid hormones suggests that ADH plays an important role in retinoic acid synthesis.