Requirements for transcriptional regulation by the orphan nuclear receptor ERRgamma.
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.
Huppunen
Johanna
J
Biomedicum Helsinki, Institute of Biomedicine, University of Helsinki, P.O. Box 63, FIN-00014 Helsinki, Finland.
Wohlfahrt
Gerd
G
Aarnisalo
Piia
P
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
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