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Interactions of Estrogen- and Thyroid Hormone Receptors on a Progesterone Receptor Estrogen Response Element (ERE) Sequence: a Comparison with the Vitellogenin A2 Consensus ERE

Neurobiology and Behavior (R.E.M.S., X.S.W-P., D.W.P.), Rockefeller University, New York, New York 10021,
Division of Genetics, Brigham and Women’s Hospital and Harvard Medical School (P.M.Y., W.W.C.), Boston, Massachusetts 02115

The identification of hormone response elements in the promoter regions of hormonally regulated genes has revealed a striking similarity between the half-site of the estrogen-response element (ERE) and a consensus sequence constituting the thyroid hormone-response element. Because of the potential for thyroid hormone (T₃) to affect estrogen (E)- and progesterone-dependent female reproductive behavior via EREs, we have begun to investigate the activity of an ERE identified in the progesterone 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 mobility shift assays demonstrated that TR binds to the PR ERE as well as to the consensus ERE sequence in vitro. Further, these two EREs were differentially regulated by T₃ in the presence of TR. T₃ in the presence of TR increased transcription from a PR ERE construct 5-fold and had no inhibitory effect on E induction. Similarly, T₃ also activated a ß-galactosidase reporter construct containing PR promoter sequences spanning -1400 to +700. In addition, the TR isoforms ß1 and ß2 also stimulated transcription from the PR ERE construct by 5- to 6-fold. A TR mutant lacking the ability to bind AGGTCA sequences in vitro failed to activate transcription from the PR ERE construct, demonstrating dependence on DNA binding. In contrast to its actions on the PR ERE construct, TR did not activate transcription from the vit A2 consensus ERE but rather attenuated E-mediated transcriptional activation. Attenuation from the vit A2 consensus ERE is not necessarily dependent on DNA binding as the TR DNA binding mutant was still able to inhibit E-dependent transactivation. In contrast to TR, the isoforms TRß1 and TRß2 failed to inhibit E-induced activation from the vit A2 consensus ERE. These results demonstrate that the PR ERE construct differs from the vit A2 consensus ERE in its ability to respond to TRs and that divergent pathways exist for activation and inhibition by TR. Since ERs, PRs, and TRs are all present in hypothalamic neurons, these findings may be significant for endocrine integration, which is important for reproductive behavior.

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