title: Requirements for transcriptional regulation by the orphan nuclear receptor ERRgamma.
abstract: Estrogen-related receptor gamma (ERRgamma) is an orphan nuclear receptor lacking identified natural ligands. We have addressed the requirements for ERRgamma-mediated gene regulation. ERRgamma transactivates constitutively reporter genes driven by ERR response elements (ERREs) or estrogen response elements (EREs). The activation depends on an intact DNA-binding domain (DBD) and activation function-2 (AF2). ERRgamma-mediated transactivation is further enhanced by peroxisome proliferator-activated receptor coactivator-1. Interestingly, ligand-binding domain (LBD) mutations predicted to either enlarge or diminish the putative ligand-binding pocket have no effect on the transcriptional activity implying that ERRgamma activity does not depend on any ligands. Antiestrogens 4OH-tamoxifen (4OHT) and 4-hydroxytoremifene (4OHtor) inhibit the ability of ERR to transactivate ERRE and ERE reporters. In contrast, ERRgamma activates transcription at AP-1 sites in the presence of 4OHT and 4OHtor. Thus, the transcriptional activity of ERRgamma seems not to require ligand binding but is modulated by binding of certain small synthetic ligands.
authors.affiliation: Biomedicum Helsinki, Institute of Biomedicine, University of Helsinki, P.O. Box 63, FIN-00014 Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Huppunen
authors.forename: Gerd
authors.initials: G
authors.lastname: Wohlfahrt
authors.forename: Piia
authors.initials: P
authors.lastname: Aarnisalo
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000032:analysis; D017354:Point Mutation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D011960:Receptors, Estrogen / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D017312:Toremifene / Q000737:chemistry / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; C490917:ESRRG protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D013629:Tamoxifen; C016601:afimoxifene; D017312:Toremifene; D008156:Luciferases