A 470 bp WAP-promoter fragment confers lactation independent, progesterone regulated mammary-specific gene expression in transgenic mice
The question of how glucocorticoid, progesterone, androgen, and mineralocorticoid receptors can generate distinct patterns of gene expression despite similar, if not identical, DNA sequence recognition properties is a central question in steroid biology. This study addresses the hypothesis that glucocorticoid and progesterone receptors can differentially utilize the promoter context created by a series of receptor recognition sites. This hypothesis predicts that for different receptors an individual (often suboptimal) binding site contributes to the overall response element activity to a different degree. Therefore, mutations to an individual binding site of a multipartite hormone response element may differentially affect the response to different steroids. This study tests this hypothesis by introducing mutations into a receptor recognition site that is part of a hormone responsive promoter derived from the mouse mammary tumor virus. We find that weakening one site of a multipartite element differentially affects glucocorticoid and progestin signaling both in fibroblasts and in mammary carcinoma cells. A similar test was done in a simplified promoter context comprised only of a TATA box and a pair of receptor recognition sites. Mutations introduced into one of these sites impaired glucocorticoid response more than the progestin response. However, high receptor expression can partially overcome the effect of some target site mutations. Thus both receptor expression levels and the inherent ability to utilize the context created by a multipartite response element contribute to quantitative differences in the response to receptors that share DNA sequence recognition properties.