title: Capacity of type I and II ligands to confer to estrogen receptor alpha an appropriate conformation for the recruitment of coactivators containing a LxxLL motif-Relationship with the regulation of receptor level and ERE-dependent transcription in MCF-7 cells.
abstract: Estrogen receptor alpha (ERalpha) belongs to the superfamily of nuclear receptors and as such acts as a ligand-modulated transcription factor. Ligands elicit in ERalpha conformational changes leading to the recruitment of coactivators required for the transactivation of target genes via cognate response elements. In many cells, activated ERalpha also undergoes downregulation by proteolysis mediated by the ubiquitin/proteasome system. Although these various molecular processes have been well characterized, little is known as to which extent they are interrelated. In the present study, we used a panel of type I (estradiol derivatives and "linear", non-steroidal ligands) and type II ("angular" ligands) estrogens, in order to identify possible relationships between ligand binding affinity, recruitment of LxxLL-containing coactivators, ERalpha downregulation in MCF-7 cells and related transactivation activity of ligand-bound ERalpha. For type I estrogens, there was a clear-cut relationship between ligand binding affinity, hydrophobicity around C-11 of estradiol and ability of ERalpha to associate with LxxLL motifs, both in cell-free condition and in vivo (MCF-7 cells). Moreover, LxxLL motif recruitment by ERalpha seemed to be a prerequisite for the downregulation of the receptor. By contrast, type II ligands, as well as estradiol derivatives bearing a bulky side chain at 11beta, had much less tendency to promote ERalpha-LxxLL interaction or even behaved as antagonists in this respect, in agreement with the well known partial estrogenicity/antiestrogenicity of some of these compounds. Interestingly, some type II ligands which antagonized LxxLL motif recruitment were nonetheless able to enhance ERalpha-mediated gene transactivation.
authors.affiliation: Laboratoire J.-C. Heuson de Cancérologie Mammaire, Université Libre de Bruxelles (U.L.B.), Institut Jules Bordet, 1 rue Héger-Bordet, B-1000 Brussels, Belgium.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Bourgoin-Voillard
authors.forename: Dominique
authors.initials: D
authors.lastname: Gallo
authors.forename: Ioanna
authors.initials: I
authors.lastname: Laïos
authors.forename: Anny
authors.initials: A
authors.lastname: Cleeren
authors.forename: Latifa El
authors.initials: LE
authors.lastname: Bali
authors.forename: Yves
authors.initials: Y
authors.lastname: Jacquot
authors.forename: Denis
authors.initials: D
authors.lastname: Nonclercq
authors.forename: Guy
authors.initials: G
authors.lastname: Laurent
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tabet
authors.forename: Guy
authors.initials: G
authors.lastname: Leclercq
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008024:Ligands; D056918:Nuclear Receptor Coactivators / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D020218:Response Elements / Q000187:drug effects / Q000235:genetics; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D047628:Estrogen Receptor alpha; D008024:Ligands; D056918:Nuclear Receptor Coactivators; D010455:Peptides; D020845:Selective Estrogen Receptor Modulators; D004958:Estradiol