INTERACTIONS OF ESTROGEN-HORMONE AND THYROID-HORMONE RECEPTORS ON A PROGESTERONE-RECEPTOR ESTROGEN RESPONSE ELEMENT (ERE) SEQUENCE - A COMPARISON WITH THE VITELLOGENIN A2 CONSENSUS ERE

The identification of hormone response elements in the promoter region s of hormonally regulated genes has revealed a striking similarity bet ween the half-site of the estrogen-response element (ERE) and a consen sus sequence constituting the thyroid hormone-response element. Becaus e of the potential for thyroid hormone (T-3) to affect estrogen (E)- a nd progesterone-dependent female reproductive behavior via EREs, we ha ve begun to investigate the activity of an ERE identified in the proge sterone receptor (PR) proximal promoter and its interactions with the estrogen receptor (ER) and thyroid hormone receptors (TR). In addition , we have compared ER and TR interactions on the PR ERE construct with that of the vitellogenin A2 (vit A2) consensus ERE. Electrophoretic m obility shift assays demonstrated that TR binds to the PR ERE as well as to the consensus ERE sequence in vitro. Further, these two EREs wer e differentially regulated by T-3 in the presence of TR. T-3 in the pr esence of TR alpha increased transcription from a PR ERE construct sim ilar to 5-fold and had no inhibitory effect an E induction. Similarly, T-3 also activated a beta-galactosidase reporter construct containing PR promoter sequences spanning -1400 to +700. In addition, the TR iso forms beta 1 and beta 2 also stimulated transcription from the PR ERE construct by 5- to 6-fold. A TR alpha mutant lacking the ability to bi nd AGGTCA sequences in vitro failed to activate transcription from the PR ERE construct, demonstrating dependence on DNA binding. In contras t to its actions on the PR ERE construct, TR alpha did not activate tr anscription from the vit A2 consensus ERE but rather attenuated E-medi ated transcriptional activation. Attenuation from the vit A2 consensus ERE is not necessarily dependent on DNA binding as the TR alpha DNA b inding mutant was still able to inhibit E-dependent transactivation. I n contrast to TR alpha, the isoforms TR beta 1 and TR beta 2 failed to inhibit E-induced activation from the vit A2 consensus ERE. These res ults demonstrate that the PR ERE construct differs from the vit A2 con sensus ERE in its ability to respond to TRs and that divergent pathway s exist for activation and inhibition by TR. Since ERs, PRs, and TRs a re ail present in hypothalamic neurons, these findings may be signific ant for endocrine integration, which is important for reproductive beh avior.