
<ArticleTitle>The human <prot>estrogen receptor-alpha</prot> is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators.</ArticleTitle>
<AbstractText>The human <prot>estrogen receptor alpha-isoform</prot> (<prot>ERalpha</prot>) is a nuclear transcription factor that displays a complex pharmacology. In addition to classical agonists and antagonists, the transcriptional activity of <prot>ERalpha</prot> 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 <prot>ERalpha</prot> results in the formation of unique ERalpha-ligand conformations. These conformations have been shown to influence ERalpha-cofactor binding and, therefore, have a profound impact on <prot>ERalpha</prot> pharmacology. In this study, we demonstrate that the nature of the bound ligand also influences the stability of <prot>ERalpha</prot>, revealing an additional mechanism by which the pharmacological activity of a compound is determined. Of note we found that although all ERalpha-ligand complexes can be ubiquitinated and degraded by the <prot>26 S proteasome</prot> in vivo, the mechanisms by which they are targeted for proteolysis appear to be different. Specifically, for agonist-activated <prot>ERalpha</prot>, 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 <prot>ERalpha</prot>. We conclude that the different conformational states adopte <prot><prot>OATP-C </prot>Ralpha</prot> in the presence of different ligands influence transcriptional activity directly by regulating cofactor binding and indirectly by modulating receptor stability.</AbstractText>
