We have studied the two estrogen receptor (ER) subtypes, ERα and ERβ, and chimeric constructs with ERα and ERβ to examine the bioactivities of these receptors and their responses to estrogen and antiestrogen ligands. Transcriptional activity of ERβ is highly dependent on cell/promoter context and on the nature of the ligand. ERβ activated significant levels of transcription in response to estrogens in certain cell types, but showed only moderate activity compared with ERα in others. Antiestrogens such as tamoxifen and 2-phenylbenzofuran, which show some agonistic activity with ERα, exhibit no agonistic activity with ERβ. Alteration of the amino- terminal A/B receptor domain can result in a dramatic change in cell type- and ligand-specific transcriptional activity of ERβ. Upon replacing the A/B domain of ERβ with the A/B domain of ERα, this receptor chimera not only exhibits an improved transcriptional response to estrogens, but also is now able to activate transcription upon treatment with these antiestrogens. As antiestrogen agonism was lacking in ERβ and the ERβ/α chimera containing the amino-terminal A/B domain of ERβ fused to domains C through F of ERα, but was restored in an ERα/β chimera containing the A/B domain of ERα, antiestrogen agonism was shown to depend on the A/B domain (activation function-1-containing region) of ERα. Together, these results indicate that the differences in the amino-terminal regions of ERα and ERβ contribute to the cell-and promoter-specific differences in transcriptional activity of these receptors, and their ability to respond to different ligands, thus providing a mechanism for differentially regulated transcription by these two ERs.
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