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Binding of Estrogen Receptor ß to Estrogen Response Element in Situ Is Independent of Estradiol and Impaired by Its Amino Terminus

University of Rochester School of Medicine and Dentistry, Department of Biochemistry and Biophysics (J.H., X.L., R.H., R.A.B., M.M.) and Department of Microbiology and Immunology (C.A.M.), Rochester, New York 14642

Address all correspondence and requests for reprints to: Mesut Muyan, University of Rochester School of Medicine and Dentistry, Department of Biochemistry and Biophysics, Rochester, New York 14642. E-mail: mesut_muyan{at}urmc.rochester.edu.

The functions of 17ß-estradiol (E2) are mediated by estrogen receptor (ER) and ß. ERs display similar DNA- and ligand-binding properties in vitro. However, ERß shows lower transcriptional activity than ER from the estrogen response element (ERE)-dependent signaling. We predicted that distinct amino termini contribute to differences in transcription efficacies of ERs by affecting in situ ER-ERE interactions. We used chromatin immunoprecipitation and a novel in situ ERE competition assay, which is based on the ability of ER to compete for ERE binding with a designer activator that constitutively induces transcription from an ERE-driven reporter construct. Interference of activator-mediated transcription by unliganded or liganded ERs was taken as an indication of ER-ERE interaction. Results revealed that ERs interacted with ERE similarly in the absence of E2. However, E2 enhanced the ERE binding of ER but not that of ERß. The removal of the amino terminus increased the ERß-ERE interaction independent of E2. The ERß amino terminus also prevented E2-mediated enhancement of the chimeric ER-ERE interaction. Thus, the amino terminus of ERß impairs the binding of ERß to ERE. The abrogation of ligand-dependent activation function 2 of the amino-terminally truncated ERß resulted in the manifestation of E2 effect on ERß-ERE interaction. This implies that E2-mediated enhancement of ERß-ERE interaction is masked by the activation function 2, whereas the intact amino terminus is a dominant region that decreases the binding of ERß to ERE. Thus, ERß-ERE interaction is independent of E2 and is impaired by its amino terminus. These findings provide an additional explanation for differences between ER and ERß functions that could differentially affect the physiology and pathophysiology of E2 signaling.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen

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