The human estrogen receptor-α is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators

The human estrogen receptor a-isoform (ER alpha) is a nuclear transcription factor that displays a complex pharmacology. In addition to classical agonists and antagonists, the transcriptional activity of ER alpha can be regulated by selective estrogen receptor modulators, a new class of drugs whose relative agonist/antagonist activity is determined by cell context. It has been demonstrated that the binding of different ligands to ER alpha results in the formation of unique ER alpha -ligand conformations. These conformations have been shown to influence ER alpha -cofactor binding and, therefore, have a profound impact on ER alpha pharmacology. In this study, we demonstrate that the nature of the bound ligand also influences the stability of ER alpha, revealing an additional mechanism by which the pharmacological activity of a compound is determined. Of note we found that although all ER alpha -ligand complexes can be ubiquitinated and degraded by the 26 S proteasome in vivo, the mechanisms by which they are targeted for proteolysis appear to be different. Specifically, for agonist-activated ER alpha, an inverse relationship between transcriptional activity and receptor stability was observed. This relationship does not extend to selective estrogen receptor modulators and pure antagonists. Instead, it appears that with these compounds, the determinant of receptor stability is the ligand-induced conformation of ER alpha. We conclude that the different conformational states adopted by ER alpha in the presence of different ligands influence transcriptional activity directly by regulating cofactor binding and indirectly by modulating receptor stability.