Differential interaction of estrogen receptor and thyroid hormone receptorisoforms on the rat oxytocin receptor promoter leads to differences in transcriptional regulation

Both the estrogen receptor (ER) and thyroid hormone receptor (TR) are membe rs of the nuclear receptor superfamily. Two isoforms of the ER, alpha and b eta, exist. The TR alpha and beta isoforms are products of two distinct gen es that are further differentially spliced to give TR alpha1 and alpha2, TR beta1 and beta2. The TRs have been shown to interfere with ER-mediated tra nscription from both the consensus estrogen response element (ERE) and the rat preproenkephalin (PPE) promoter, possibly by competing with ER binding to the ERE or by squelching coactivators essential for ER-mediated transcri ption. The rat oxytocin receptor (OTR) gene is thought to be involved in se veral facets of reproductive and affiliative behaviors. 17 beta -Estradiol- bound ERs upregulate the OTR gene in the ventromedial hypothalamus, a regio n critical for the induction of lordosis behavior in several species. We in vestigated the effects of the ligand-binding TR isoforms on the ER-mediated transcription from a physiological promoter of a behaviorally relevant gen e such as the OTR. Only ER alpha could induce the OTR gene in two cell line s tested, the CV-1 and the SK-N-BE2C neuroblastoma cell lines. ERP was inca pable of inducing the gene in either cell line. ERa is therefore not equiva lent to ERP on this physiological promoter. Indeed, in the neural cell fine , ERP can inhibit ER alpha -mediated induction from the OTR promoter. While the TR alpha1 isoform inhibited ER alpha -mediated induction in the neural cell line, the TR beta1 isoform stimulated induction, thus demonstrating i soform specificity in the interaction. The use of a DNA-binding mutant, the TR P box mutant, showed that inhibition of ER alpha -mediated induction of the rat OTR gene promoter by the TR alpha1 isoform does not require DNA-bi nding ability. SRC-1 overexpression relieved TR alpha1-mediated inhibition in both cell lines, suggesting that squelching for coactivators is an impor tant molecular mechanism in TR alpha -mediated inhibition. Such interaction s between TR and ER isoforms on the rat OTR promoter provide a mechanism to achieve neuroendocrine integration. Copyright (C) 2001 S. Karger AG, Basel .