title: Estrogen response element-dependent regulation of transcriptional activation of estrogen receptors alpha and beta by coactivators and corepressors.
abstract: One mechanism by which ligand-activated estrogen receptors alpha and beta (ERalpha and ERbeta) stimulate gene transcription is through direct ER interaction with specific DNA sequences, estrogen response elements (EREs). ERE-bound ER recruits coactivators that stimulate gene transcription. Binding of ER to natural and synthetic EREs with different nucleotide sequences alters ER binding affinity, conformation, and transcriptional activity, indicating that the ERE sequence is an allosteric effector of ER action. Here we tested the hypothesis that alterations in ER conformation induced by binding to different ERE sequences modulates ER interaction with coactivators and corepressors. CHO-K1 cells transfected with ERalpha or ERbeta show ERE sequence-dependent differences in the functional interaction of ERalpha and ERbeta with coactivators steroid receptor coactivator 1 (SRC-1), SRC-2 (glucocorticoid receptor interacting protein 1 (GRIP1)), SRC-3 amplified in breast cancer 1 (AIB1) and ACTR, cyclic AMP binding protein (CBP), and steroid receptor RNA activator (SRA), corepressors nuclear receptor co-repressor (NCoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT), and secondary coactivators coactivator associated arginine methyltransferase 1 (CARM1) and protein arginine methyltransferase 1 (PRMT1). We note both ligand-independent as well estradiol- and 4-hydroxytamoxifen-dependent differences in ER-coregulator activity. In vitro ER-ERE binding assays using receptor interaction domains of these coregulators failed to recapitulate the cell-based results, substantiating the importance of the full-length proteins in regulating ER activity. These data demonstrated that the ERE sequence impacts estradiol-and 4-hydroxytamoxifen-occupied ERalpha and ERbeta interaction with coregulators as measured by transcriptional activity in mammalian cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA. carolyn.klinge@louisville.edu
authors.forename: C M
authors.initials: CM
authors.lastname: Klinge
authors.forename: S C
authors.initials: SC
authors.lastname: Jernigan
authors.forename: K A
authors.initials: KA
authors.lastname: Mattingly
authors.forename: K E
authors.initials: KE
authors.lastname: Risinger
authors.forename: J
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D050882:CREB-Binding Protein; D006224:Cricetinae; D003412:Cricetulus; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051548:Histone Acetyltransferases; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D056921:Nuclear Receptor Coactivator 3; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects / Q000235:genetics; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D029867:Xenopus Proteins / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C498001:NCOA2 protein, human; C114568:NCOA3 protein, Xenopus; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D051958:Nuclear Receptor Coactivator 2; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D012097:Repressor Proteins; D020845:Selective Estrogen Receptor Modulators; D015534:Trans-Activators; D014157:Transcription Factors; D029867:Xenopus Proteins; C405423:steroid receptor RNA activator; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3