Estradiol inhibits transcription of the human glycoprotein hormone α-subunit gene despite the absence of a high affinity binding site for estrogen receptor

Abstract

Chronic administration of estradiol inhibits transcription of the gene encoding the α-subunit of pituitary glycoprotein hormones. Here, we show, using transfection analyses and a filter binding assay, that 1500 basepairs of proximal 5′ flanking sequence of the human α-subunit gene lack a functional estrogen response element when transfected into heterologous cell lines, and fail to bind estrogen receptor purified from calf uterus. Yet, this same region of the α-subunit gene confers estradiol responsiveness (transcriptional suppression) to the bacterial chloramphenicol acetyltransferase gene in transgenic mice. A smaller promoter fragment of the bovine α-subunit gene also confers responsiveness to estradiol in transgenic mice, suggesting that the same element may mediate the steroid responsiveness of both promoters. Furthermore, regulation by estradiol of the chimeric human or bovine a-chloramphenicol acetyltransferase genes is pituitary specific, underscoring the physiological significance of these studies. Based on these results, we conclude that estradiol regulates expression of the α-subunit gene in vivo through a mechanism that does not involve high affinity binding of estrogen receptor to the α-subunit gene. Whether this mechanism is manifest at the level of the pituitary or hypothalamus remains to be determined.