The Estrogen Receptor -Isoform (ER ) of the Human Estrogen Receptor Modulates ER Transcriptional Activity and Is a Key Regulator of the Cellular Response to Estrogens and Antiestrogens
The human estrogen receptor a (ERa) and the recently identified ERb share a high degree of amino acid homology; however, there are significant differences in regions of these receptors that would be expected to influence transcriptional activity. Consequently, we com- pared the mechanism(s) by which these receptors regulate target gene transcription, and evaluated the cellular consequences of coexpres- sion of both ER subtypes. Previously, it has been determined that ERa contains two distinct activation domains, ERa-AF-1 and ERa-AF-2, whose transcriptional activity is influenced by cell and promoter con- text. We determined that ERb, like ERa, contains a functional AF-2, however, the ERb-AF-2 domain functions independently within the receptor. Of additional significance was the finding that ERb does not contain a strong AF-1 within its amino-terminus but, rather, contains a repressor domain that when removed, increases the overall tran- scriptional activity of the receptor. The importance of these findings was revealed when it was determined that ERb functions as a trans- dominant inhibitor of ERa transcriptional activity at subsaturating hormone levels and that ERb decreases overall cellular sensitivity to estradiol. Additionally, the partial agonist activity of tamoxifen man- ifest through ERa in some contexts was completely abolished upon coexpression of ERb. In probing the mechanisms underlying ERb- mediated repression of ERa transcriptional activity we have deter- mined that 1) ERa and ERb can form heterodimers within target cells; and 2) ERb interacts with target gene promoters in a ligand-inde- pendent manner. Cumulatively, these data indicate that one role of ERb is to modulate ERa transcriptional activity, and thus the relative expression level of the two isoforms will be a key determinant of cellular responses to agonists and antagonists. (Endocrinology 140: 5566 -5578, 1999)