TABLE 19

ERRγ

Receptor nomenclature NR3B3
Receptor code 4.10.1:OR:3:B3
Other names ERR3, ESRRG
Molecular information Hs: 458aa, P62508, chr. 1q411,2
Rn: 458aa, P62510, chr. 13q26
Mm: 458aa, P62509, chr. 1 H53
DNA binding
   Structure Monomer, homodimer
   HRE core sequence TNA AGGTCA (DR-3, ERE, SFRE)4
Partners Calmodulin (physical, functional): interaction with calmodulin in vitro in a Ca2+-dependent manner5; DAX1 (physical, functional): inhibition of PGC1α -mediated ERRγ transactivation by competing for the AF-2 binding domain6; SHP (physical, functional): inhibition of transcriptional activity7
Agonists 5,7,4′-Trihydroxyisoflavone, 7,4′-dihydroxyisoflavone, 5,7-dihydroxy-4′-methoxyisoflavone, N′-{(1E)-[4-(diethylamino)phenyl]methylene}-4-hydroxybenz ohydrazide)8,9; GSK9089 (substituted phenolic acyl hydrazones) (0.66 μM), GSK4716 (substituted phenolic acyl hydrazones) (2 μM) [IC50]10
Antagonists 4-Hydroxytamoxifen (35 nM) [Kd]11; diethylstilbestrol (5–15 μM) [IC50]11,12
Coactivators PNRC2, PPARGC1A, PPARGC1B, NCOA1, TLE113–15
Corepressors
Biologically important isoforms ERRγ2 {Hs, Mm}: differs from ERRγ1 by an additional 23 N-terminal residues16; ERRγ3 {Hs}: ERRγ3 variant consists of eight exons including three unique 5′-terminal exons and lacks the exon encoding the second zinc finger motif; the expression of ERRγ3 was confined to adipocytes and prostate, whereas that of ERRγ2 was fairly widespread; the ERRγ3 variant was shown by transactivation assay to have no ability to activate ERE-controlled transcription; however, ERRγ3 has an ability to modulate the transcriptional activity of other nuclear hormone receptors17
Tissue distribution Brain, kidney, testis, lung, adrenal gland, pancreas, and bone marrow {Hs, Mm} [Northern blot, RT-PCR, in situ hybridization, Western blot, immunohistology]1,2,3,18
Functional assays
Main target genes Activated: ERRα {Hs},19 DAX-1 {Mm},6 MAOA, and MAOB {Hs, Mm, Rn}20
Mutant phenotype Homozygous mutant mice do not survive to weaning age; heterozygous mice exhibit a significant increase in overall startle amplitude, indicating a possible hypersensitivity to sound-induced motor reflex in these mice {Mm} [disruption caused by insertion of a vector]
Human disease

  • aa, amino acids; chr., chromosome; HRE, hormone response element; PPARGC, coactivator gene; RT-PCR, reverse transcription-polymerase chain reaction; MAO, monoamine oxidase; ERE, estrogen response element; SFRE, SF-1 response element

  • ↵1. Chen F, Zhang Q, McDonald T, Davidoff MJ, Bailey W, Bai C, Liu Q, and Caskey CT (1999) Identification of two hERR2-related novel nuclear receptors utilizing bioinformatics and inverse PCR. Gene 228: 101-109

  • ↵2. Eudy JD, Yao S, Weston MD, Ma-Edmonds M, Talmadge CD, Cheng JJ, Kimberling WJ, and Sumegi J (1998) Isolation of a gene encoding a novel member of the nuclear receptor superfamily from the critical region of Usher syndrome type IIa at 1q41. Genomics 50: 382-384

  • ↵3. Hong H, Yang L, and Stallcup MR (1999) Hormone-independent transcriptional activation and coactivator binding by novel orphan nuclear receptor ERR3. J Biol Chem 274: 22618-22626

  • ↵4. Huppunen J and Aarnisalo P (2004) Dimerization modulates the activity of the orphan nuclear receptor ERRγ. Biochem Biophys Res Commun 314: 964-970

  • ↵5. Hentschke M, Schulze C, Susens U, and Borgmeyer U (2003) Characterization of calmodulin binding to the orphan nuclear receptor Errγ. Biol Chem 384: 473-482

  • ↵6. Park YY, Ahn SW, Kim HJ, Kim JM, Lee IK, Kang H, and Choi HS (2005) An autoregulatory loop controlling orphan nuclear receptor DAX-1 gene expression by orphan nuclear receptor ERRγ. Nucleic Acids Res 33: 6756-6768

  • ↵7. Razzaque MA, Masuda N, Maeda Y, Endo Y, Tsukamoto T, and Osumi T (2004) Estrogen receptor-related receptor γ has an exceptionally broad specificity of DNA sequence recognition. Gene 340: 275-282

  • ↵8. Suetsugi M, Su L, Karlsberg K, Yuan YC, and Chen S (2003) Flavone and isoflavone phytoestrogens are agonists of estrogen-related receptors. Mol Cancer Res 1: 981-991

  • ↵9. Yu DD and Forman YM (2005) Identification of an agonist ligand for estrogen-related receptors ERRβ/γ. Bioorg Med Chem Lett 15: 1311-1313

  • ↵10. Zuercher WJ, Gaillard S, Orband-Miller LA, Chao EY, Shearer BG, Jones DG, Miller AB, Collins JL, McDonnell DP, and Willson TM (2005) Identification and structure-activity relationship of phenolic acyl hydrazones as selective agonists for the estrogen-related orphan nuclear receptors ERRβ and ERRγ. J Med Chem 48: 3107-3109

  • ↵11. Coward P, Lee D, Hull MV, and Lehmann JM (2001) 4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor γ. Proc Natl Acad Sci USA 98: 8880-8884

  • ↵12. Tremblay GB, Kunath T, Bergeron D, Lapointe L, Champigny C, Bader JA, Rossant J, and Giguere V (2001) Diethylstilbestrol regulates trophoblast stem cell differentiation as a ligand of orphan nuclear receptor ERRβ. Genes Dev 15: 833-838

  • ↵13. Hentschke M and Borgmeyer U (2003) Identification of PNRC2 and TLE1 as activation function-1 cofactors of the orphan nuclear receptor ERRγ. Biochem Biophys Res Commun 312: 975-982

  • ↵14. Hentschke M, Susens U, and Borgmeyer U (2002) PGC-1 and PERC, coactivators of the estrogen receptor-related receptor γ. Biochem Biophys Res Commun 299: 872-879

  • ↵15. Greschik H, Wurtz JM, Sanglier S, Bourguet W, van Dorsselaer A, Moras D, and Renaud JP (2002) Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3. Mol Cell 9: 303-313

  • ↵16. Susens U, Hermans-Borgmeyer I, and Borgmeyer U (2000) Alternative splicing and expression of the mouse estrogen receptor-related receptor γ. Biochem Biophys Res Commun 267: 532-535

  • ↵17. Kojo H, Tajima K, Fukagawa M, Isogai T, and Nishimura S (2006) A novel estrogen receptor-related protein γ splice variant lacking a DNA binding domain exon modulates transcriptional activity of a moderate range of nuclear receptors. J Steroid Biochem Mol Biol 98: 181-192

  • ↵18. Heard DJ, Norby PL, Holloway J, and Vissing H (2000) Human ERRγ, a third member of the estrogen receptor-related receptor (ERR) subfamily of orphan nuclear receptors: tissue-specific isoforms are expressed during development and in the adult. Mol Endocrinol 14: 382-392

  • ↵19. Liu D, Zhang Z, and Teng CT (2005) Estrogen-related receptor-γ and peroxisome proliferator-activated receptor-γ coactivator-1α regulate estrogen-related receptor-α gene expression via a conserved multi-hormone response element. J Mol Endocrinol 34: 473-487

  • ↵20. Zhang Z, Chen K, Shih JC, and Teng CT (2006) Estrogen-related receptors stimulated MAO-B promoter activity is down regulated by estrogen receptors. Mol Endocrinol 20: 1547-1561