TABLE 18

ERRβ

Receptor nomenclature NR3B2
Receptor code 4.10.1:OR:3:B2
Other names ERR2, Estrrb
Molecular information Hs: 500aa, O95718, chr. 14q241
Rn: 433aa, P11475, chr. 6q312
Mm: 433aa, Q61539, chr. 12 E1,3
DNA binding
   Structure Monomer, homodimer
   HRE core sequence TNA AGGTCA (DR-3, ERE, SFRE, half-site)
Partners HSP90 (physical, functional): efficient homodimerization and DNA binding2
Agonists 5,7,4′-Trihydroxyisoflavone, 7,4′-dihydroxyisoflavone, 5,7-dihydroxy-4′-methoxyisoflavone, N′-{(1E)-[4-(diethylamino)phenyl]methylene}-4-hydroxybenz ohydrazide)4,5
Antagonists Diethylstilbestrol (5–15 μM) [IC50]6
Coactivators PNRC, NCOA3, NCOA1, NCOA24,7
Corepressors
Biologically important isoforms Short-form hERRβ {Hs}: lacks the F domain found in hERRβ and is the matched homolog of mouse and rat ERR proteins in humans; it is widely expressed, whereas the other two isoforms are restricted to testis and kidney8; hERRβ2-δ 10 {Hs}: lacks the exon 10 present in the canonical transcript and encodes a protein isoform only differing in the F domain of the protein; the canonical transcript and this variant are primate-specific and present a restricted expression in testis and kidney8
Tissue distribution Developmental: trophoblast progenitor cells (these extraembryonic cells are implicated in placental formation); adult: liver, stomach, skeletal muscles, kidney, heart, supraoptic nucleus {Hs, Mm, Rn} [Northern blot, RT-PCR, in situ hybridization, Western blot, immunohistology]1,2,3,8,9
Functional assays
Main target genes
Mutant phenotype Homozygous knockout mice have severely impaired placental formation and die at 10.5 days postcoitum; the mutants display abnormal chorion development associated with an overabundance of trophoblast giant cells and a severe deficiency of diploid trophoblast {Mm} [knockout]9
Human disease
  • aa, amino acids; chr., chromosome; HRE, hormone response element; h, human; RT-PCR, reverse transcription-polymerase chain reaction; 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. Pettersson K, Svensson K, Mattsson R, Carlsson B, Ohlsson R, and Berkenstam A (1996) Expression of a novel member of estrogen response element-binding nuclear receptors is restricted to the early stages of chorion formation during mouse embryogenesis. Mech Dev 54: 211-223

  • 3. Giguere V, Yang N, Segui P, and Evans RM (1988) Identification of a new class of steroid hormone receptors. Nature (Lond) 331: 91-94

  • 4. 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

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

  • 6. 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

  • 7. Xie W, Hong H, Yang NN, Lin RJ, Simon CM, Stallcup MR, and Evans RM (1999) Constitutive activation of transcription and binding of coactivator by estrogen-related receptors 1 and 2. Mol Endocrinol 13: 2151-2162

  • 8. Zhou W, Liu Z, Wu J, Liu JH, Hyder SM, Antoniou E, and Lubahn DB (2006) Identification and characterization of two novel splicing isoforms of human estrogen-related receptor β. J Clin Endocrinol Metab 91: 569-579

  • 9. Luo J, Sladek R, Bader JA, Matthyssen A, Rossant J, and Giguere V (1997) Placental abnormalities in mouse embryos lacking the orphan nuclear receptor ERR-β. Nature (Lond) 388: 778-782