title: Ligand structure influences autologous downregulation of estrogen receptor-alpha messenger RNA.
abstract: A series of A- and D-ring substituted estrogen analogues have been examined for their effect on estrogen receptor-alpha (ERalpha) mRNA downregulation. Recently it has been proposed that ERalpha autologous downregulation occurs via transcriptional repression exerted by the binding of the ERalpha-ligand complex to the 5' region of the coding region of the ERalpha gene. Placement of the phenolic hydroxyl group on the various carbons of the aromatic A-ring of estratrien-17betaol (carbons 1-3) produced ligands which diminished the steady state level of ERalpha mRNA in relation to their affinity for receptor. 4-Hydoxyestratrien-17betaol, on the other hand, was inactive in the downregulation of ERalpha mRNA. Although this A-ring isomer brought about apparent processing of the nuclear receptor, the ERalpha reappeared in the cytosol within 24 h. Unlike the stimulation of genes regulated via estrogen response elements, maximum autologous negative regulation of the ERalpha gene required the presence of an hydroxyl group on carbon 17 of the D-ring. These results suggest that the conformational alterations elicited in the ERalpha molecule by various ligands create surfaces capable of interacting with other transcription factors in a manner which is different when the receptor functions via a response element mechanism relative to interactions during autologous negative regulation of the ERalpha gene.
authors.affiliation: Department of Biochemistry and Molecular Biology and the Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Davis
authors.forename: J A
authors.initials: JA
authors.lastname: VanderKuur
authors.forename: S C
authors.initials: SC
authors.lastname: Brooks
mesh_terms: D015536:Down-Regulation; D004958:Estradiol / Q000378:metabolism; D045166:Estradiol Congeners / Q000378:metabolism; D020847:Estrogen Receptor Modulators / Q000378:metabolism; D047628:Estrogen Receptor alpha; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D045165:Testosterone Congeners / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D045166:Estradiol Congeners; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D008024:Ligands; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D045165:Testosterone Congeners; D004958:Estradiol