Differential crosstalk between estrogen receptor (ER)alpha and ERbeta and the 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. Previous studies from this laboratory have demonstrated crosstalk between the estrogen (ER) and thyroid hormone receptors (TR) on two estrogen responsive physiological promoters, the preproenkephalin and oxytocin receptor gene promoter. Since ERalpha and ERbeta are isoforms possessing overlapping and distinct transactivation properties, we hypothesized that the interaction of ERalpha 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 differences in interaction between ERalpha and beta isoforms and the different TR isoforms in fibroblast cells. Both the ER isoforms transactivate from the consensus ERE, though ERalpha transactivates to a greater extent than ERbeta. Although neither of the TRbeta isoforms have an effect on ERalpha transactivation from the consensus ERE, the liganded TRalpha1 inhibits the ERalpha transactivation from the consensus ERE. In contrast, the liganded TRalpha1 facilitates ERbeta-mediated transactivation. The crosstalk between the TRbeta isoforms with the ERalpha isoform, on the consensus ERE, is different from that with the ERbeta isoform. The use of a TRalpha1 mutant, which is unable to bind DNA, abolishes the ability of the TRalpha1 isoform to interact with either of the ER isoforms. These differences in nuclear receptor crosstalk reveal an important functional difference between isoforms, which provides a novel mechanism for neuroendocrine integration.