title: Ligand-specific regulation of proteasome-mediated proteolysis of estrogen receptor-alpha.
abstract: Proteasome-mediated proteolysis modulates the cellular concentration of estrogen receptor-alpha (ERalpha) and is induced by treatment of cells with 17beta-estradiol. Herein, we show that multiple receptor agonists, including 17alpha-estradiol and estriol as well as the antagonist ICI-182780, stimulate proteasome-dependent proteolysis of ERalpha in a process that requires ligand binding to the receptor. Proteolysis of receptor depends on ligand concentration, and there exists a direct correlation between ligand-binding affinity and the half-maximal dose of ligand required to stimulate receptor degradation. Furthermore, introduction of a point mutation into the receptor ligand-binding pocket yields a stable receptor resistant to proteolysis. Interestingly, although all ligands stimulate receptor degradation, the extent to which overall ER levels are affected varies with each ligand and is not related to ligand-binding affinity or activation of transcription. These results demonstrate ligand-specific regulation of ERalpha proteolysis, and they introduce the concept that cellular receptor concentration is governed not only at the level of induction of proteolysis but also by the efficiency with which the receptor is degraded.
authors.affiliation: Department of Physiology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors.forename: Mara T
authors.initials: MT
authors.lastname: Preisler-Mashek
authors.forename: Natalia
authors.initials: N
authors.lastname: Solodin
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Stark
authors.forename: Michael K
authors.initials: MK
authors.lastname: Tyriver
authors.forename: Elaine T
authors.initials: ET
authors.lastname: Alarid
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D015153:Blotting, Western; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004964:Estriol / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000378:metabolism / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology*; D000077267:Fulvestrant; D006801:Humans; D008024:Ligands; D009097:Multienzyme Complexes / Q000502:physiology*; D016296:Mutagenesis; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011388:Prolactin / Q000032:analysis; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D011916:Rats, Inbred F344; D011960:Receptors, Estrogen / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008024:Ligands; D009097:Multienzyme Complexes; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol; D011388:Prolactin; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D004964:Estriol