TABLE 22

NOR1

Receptor nomenclature NR4A3
Receptor code 4.10.1:OR:4:A3
Other names TEC, MINOR, CHN, NGFI-Bγ
Molecular information Hs: 626aa, Q92570, chr, 9q311,2
Rn: 628aa, P51179, chr. 5q223
Mm: 627aa, Q9QZB6, chr. 4 B2
DNA binding
   Structure Monomer, homodimer, heterodimer
   HRE core sequence AAAGGTCA (half-site, NBRE, NuRE)
Partners NGFI-B (physical): DNA binding4; NURR1 (physical): DNA binding4
Agonists Receptor lacks ligand-binding pocket57
Antagonists Receptor lacks ligand-binding pocket57
Coactivators SIX3, PPARBP, EP300, NCOA2, PCAF810
Corepressors
Biologically important isoforms NOR1α {Hs, Mm}: contains an additional segment in the coding region introducing a stop codon into the sequence, thereby creating a shorter and distinct C terminus compared with NOR111,12; NOR1β {Hs, Mm, Rn}: differs in the 5′-UTR and coding region and contains a longer N terminus than NOR111
Tissue distribution Nervous system, pituitary, adrenal, heart, muscle, thymus, kidney {Hs, Mm, Rn} [Northern blot, in situ hybridization, Western blot, immunohistology]13,13,14
Functional assays
Main target genes Activated: POMC {Hs, Mm, Rn}15,16
Mutant phenotype Knockout mice have been shown to exhibit inner ear defects and partial bidirectional circling behavior {Mm} [knockout]17; knockout mice embryos have also been shown to fail to complete gastrulation and display distinct morphological abnormalities {Mm} [knockout]18
Human disease EMC: three versions of EMCs are the result of reciprocal translocations between this gene and other genes; the translocation breakpoints are associated with NR4A3 (chr. 0.9) and either Ewing sarcoma breakpoint region 1 (chr. 0.22), RNA polymerase II, TATA box-binding protein-associated factor (chr. 0.17), or transcription factor 12 (chr. 0.15)1,1921
  • aa, amino acids; chr., chromosome; HRE, hormone response element; PPARBP, PPAR binding protein; EMC, extraskeletal myxoid chondrosarcoma; NBRE, NGFI-B response element

  • 1. Labelle Y, Zucman J, Stenman G, Kindblom LG, Knight J, Turc-Carel C, Dockhorn-Dworniczak B, Mandahl N, Desmaze C, Peter M, et al. (1995) Oncogenic conversion of a novel orphan nuclear receptor by chromosome translocation. Hum Mol Genet 4: 2219-2226

  • 2. Hedvat CV and Irving SG (1995) The isolation and characterization of MINOR, a novel mitogen-inducible nuclear orphan receptor. Mol Endocrinol 9: 1692-1700

  • 3. Ohkura N, Hijikuro M, Yamamoto A, and Miki K (1994) Molecular cloning of a novel thyroid/steroid receptor superfamily gene from cultured rat neuronal cells. Biochem Biophys Res Commun 205: 1959-1965

  • 4. Maira M, Martens C, Philips A, and Drouin J (1999) Heterodimerization between members of the Nur subfamily of orphan nuclear receptors as a novel mechanism for gene activation. Mol Cell Biol 19: 7549-7557

  • 5. Flaig R, Greschik H, Peluso-Iltis C, and Moras D (2005) Structural basis for the cell-specific activities of the NGFI-B and the Nurr1 ligand-binding domain. J Biol Chem 280: 19250-19258

  • 6. Wang Z, Benoit G, Liu J, Prasad S, Aarnisalo P, Liu X, Xu H, Walker NP, and Perlmann T (2003) Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature (Lond) 423: 555-560

  • 7. Baker KD, Shewchuk LM, Kozlova T, Makishima M, Hassell A, Wisely B, Caravella JA, Lambert MH, Reinking JL, Krause H, et al. (2003) The Drosophila orphan nuclear receptor DHR38 mediates an atypical ecdysteroid signaling pathway. Cell 113: 731-742

  • 8. Laflamme C, Filion C, Bridge JA, Ladanyi M, Goldring MB, and Labelle Y (2003) The homeotic protein Six3 is a coactivator of the nuclear receptor NOR-1 and a corepressor of the fusion protein EWS/NOR-1 in human extraskeletal myxoid chondrosarcomas. Cancer Res 63: 449-454

  • 9. Ohkura N, Ohkubo T, Maruyama K, Tsukada T, and Yamaguchi K (2001) The orphan nuclear receptor NOR-1 interacts with the homeobox containing protein Six3. Dev Neurosci 23: 17-24

  • 10. Wansa KD, Harris JM, Yan G, Ordentlich P, and Muscat GE (2003) The AF-1 domain of the orphan nuclear receptor NOR-1 mediates trans-activation, coactivator recruitment, and activation by the purine anti-metabolite 6-mercaptopurine. J Biol Chem 278: 24776-24790

  • 11. Ohkura N, Ito M, Tsukada T, Sasaki K, Yamaguchi K, and Miki K (1998) Alternative splicing generates isoforms of human neuron-derived orphan receptor-1 (NOR-1) mRNA. Gene 211: 79-85

  • 12. Maltais A and Labelle Y (2000) Structure and expression of the mouse gene encoding the orphan nuclear receptor TEC. DNA Cell Biol 19: 121-130

  • 13. Zetterstrom RH, Williams R, Perlmann T, and Olson L (1996) Cellular expression of the immediate early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigrostriatal dopamine system. Brain Res Mol Brain Res 41: 111-120

  • 14. Maruyama K, Tsukada T, Bandoh S, Sasaki K, Ohkura N, and Yamaguchi K (1997) Expression of the putative transcription factor NOR-1 in the nervous, the endocrine and the immune systems and the developing brain of the rat. Neuroendocrinology 65: 2-8

  • 15. Maira M, Martens C, Batsche E, Gauthier Y, and Drouin J (2003) Dimer-specific potentiation of NGFI-B (Nur77) transcriptional activity by the protein kinase A pathway and AF-1-dependent coactivator recruitment. Mol Cell Biol 23: 763-776

  • 16. Martens C, Bilodeau S, Maira M, Gauthier Y, and Drouin J (2005) Protein-protein interactions and transcriptional antagonism between the subfamily of NGFI-B/Nur77 orphan nuclear receptors and glucocorticoid receptor. Mol Endocrinol 19: 885-897

  • 17. DeYoung RA, Baker JC, Cado D, and Winoto A (2003) The orphan steroid receptor Nur77 family member Nor-1 is essential for early mouse embryogenesis. J Biol Chem 278: 47104-471109

  • 18. Ponnio T, Burton Q, Pereira FA, Wu DK, and Conneely OM (2002) The nuclear receptor Nor-1 is essential for proliferation of the semicircular canals of the mouse inner ear. Mol Cell Biol 22: 935-945

  • 19. Clark J, Benjamin H, Gill S, Sidhar S, Goodwin G, Crew J, Gusterson BA, Shipley J, and Cooper CS (1996) Fusion of the EWS gene to CHN, a member of the steroid/thyroid receptor gene superfamily, in a human myxoid chondrosarcoma. Oncogene 12: 229-235

  • 20. Gill S, McManus AP, Crew AJ, Benjamin H, Sheer D, Gusterson BA, Pinkerton CR, Patel K, Cooper CS, and Shipley JM (1995) Fusion of the EWS gene to a DNA segment from 9q22–31 in a human myxoid chondrosarcoma. Genes Chromosomes Cancer 12: 307-310

  • 21. Labelle Y, Bussieres J, Courjal R, and Goldring MB (1999) The EWS/TEC fusion protein encoded by the t(9;22) chromosomal translocation in human chondrosarcomas is a highly potent transcriptional activator. Oncogene 18: 3303-3308