Repression of chick multidrug resistance-associated protein 1 ( chMRP1) gene expression by estrogen

Abstract

Although a number of genes have been identified whose transcriptional activities are stimulated by estrogen, relatively few have been discovered that are repressed. In an effort to determine whether estrogen can directly repress gene expression, attempts were made to identify genes that are direct targets of the estrogen receptor and whose activities are repressed by it. Because the development and differentiation of the chick oviduct are exquisitely dependent upon estrogen, this seemed an appropriate model system for testing this hypothesis. RNA was isolated from estrogen-treated and estrogen-withdrawn chick oviducts and was subjected to differential display analysis. Surprisingly, one of the products repressed by estrogen encoded the chick homolog of the multidrug resistance-associated protein 1 ( MRP1) gene. Further cloning resulted in a chick MRP1 ( chMRP1) cDNA clone that is 72% identical with human MRP1. Translation of the chMRP1 sequence indicates a 77% amino acid identity with both the human and mouse MRP1 proteins. Treatment of estrogen-withdrawn chicks with 17β-estradiol decreased chMRP1 mRNA levels to 50% within 30 min and to 70% by 1 h, which is comparable to the level observed with chronic repression by estrogen. ChMRP1 mRNA is present in many other tissues, including the heart, lung, brain, kidney, skeletal muscle, and intestine, but is undetectable in the liver. This study indicates that in estrogen-responsive tissues such as chick oviduct, the regulation of chMRP1 gene expression is controlled by estrogen.