Differential crosstalk between estrogen receptor (ER)alpha and ER beta andthe thyroid hormone receptor isoforms results in flexible regulation of the consensus ERE

Crosstalk between nuclear receptors is important for conversion of external and internal stimuli to a physiologically meaningful response by cells. Pr evious studies from this laboratory have demonstrated crosstalk between the estrogen (ER) and thyroid hormone receptors (TR) on two estrogen responsiv e physiological promoters, the preproenkephalin and oxytocin receptor gene promoter. Since ER alpha and ER beta are isoforms possessing overlapping an d distinct transactivation properties; we hypothesized that the interaction of ER alpha and beta with the various TR isoforms would not be equivalent. To explore this hypothesis, the consensus estrogen response element (ERE) derived from the Xenopus vitellogenin gene is used to investigate the diffe rences in interaction between ER alpha and beta isoforms and the different TR isoforms in fibroblast cells. Both the ER isoforms transactivate from th e consensus ERE, though ER alpha transactivates to a greater extent than ER beta. Although neither of the TR beta isoforms have an effect on ER alpha transactivation from the consensus ERE, the liganded TR alpha1 inhibits the ER alpha transactivation from the consensus ERE. In contrast, the liganded TR alpha1 facilitates ER beta -mediated trans activation. The crosstalk be tween the TR beta isoforms with the ER alpha isoform, on the consensus ERE, is different from that with the ER beta isoform. The use of a TR alpha1 mu tant, which is unable to bind DNA, abolishes the ability of the TR alpha1 i soform to interact with either of the ER isoforms. These differences in nuc lear receptor crosstalk reveal an important functional difference between i soforms, which provides a novel mechanism for neuroendocrine integration. ( C) 2001 Elsevier Science B.V. All rights reserved.