The human estrogen receptor-alpha 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 agon ists and antagonists, the transcriptional activity of ER alpha can be regul ated 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 conformat ions have been shown to influence ER alpha -cofactor binding and, therefore , have a profound impact on ER alpha pharmacology. In this study, we demons trate that the nature of the bound ligand also influences the stability of ER alpha, revealing an additional mechanism by which the pharmacological ac tivity of a compound is determined. Of note we found that although all ER a lpha -ligand complexes can be ubiquitinated and degraded by the 26 S protea some in vivo, the mechanisms by which they are targeted for proteolysis app ear to be different. Specifically, for agonist-activated ER alpha, an inver se 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 compo unds, the determinant of receptor stability is the ligand-induced conformat ion of ER alpha. We conclude that the different conformational states adopt ed by ER alpha in the presence of different ligands influence transcription al activity directly by regulating cofactor binding and indirectly by modul ating receptor stability.