The Human Estrogen Receptor-α Is a Ubiquitinated Protein Whose Stability Is Affected Differentially by Agonists, Antagonists, and Selective Estrogen Receptor Modulators

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