TABLE 20

NGFI-B

Receptor nomenclature NR4A1
Receptor code 4.10.1:OR:4:A1
Other names NAK1, ST-59, TR3, nur77, N10, TIS1, NGFI-Bα
Molecular information Hs: 598aa, P22736, chr. 12q131–3
Rn: 597aa, P22829, chr. 7q364,5
Mm: 601aa, P12813, chr. 15 F36,7
DNA binding
   Structure Monomer, homodimer, heterodimer, RXR partner
   HRE core sequence AAAGGTCA (DR-5, half-site, NBRE, NuRE)
Partners NURR1 (physical, functional): DNA binding8; NOR1 (physical, functional): DNA binding8; GR (physical, functional): DNA binding and antagonism of NuRE-dependent transcription induced by all members of the NR4A subfamily9; BCL-2 (physical, functional): cellular localization—NGFI-B binding induces a BCL-2 conformational change that exposes its BH3 domain, resulting in conversion of BCL-2 from a protector to a killer10; AKT (physical, functional): DNA binding and phosphorylation of Ser350 on the NGFI-B protein within its DNA-binding domain11,12; Notch-1 (physical, functional): interaction with NGFI-B to repress NGFI-B-dependent transcription and rescue T-cell receptor-mediated apoptosis13
Agonists Receptor lacks ligand-binding pocket
Antagonists Receptor lacks ligand-binding pocket
Coactivators NCOA1, NCOA2, NCOA3, EP300, PPARBP14
Corepressors
Biologically important isoforms TRCβ {Hs}: contains a shorter and distinct C terminus compared with NGFI-B
Tissue distribution Nervous system, pituitary, adrenal, thyroid, liver, testis, ovary, thymus, muscle, lung, prostate {Hs, Mm, Rn} [Northern blot, in situ hybridization, Western blot, immunohistology]4,6,7,15–18
Functional assays
Main target genes Activated: POMC {Hs, Mm, Rn},19 steroid 21-hydroxylase {Hs, Mm, Rn},20 steroid 17-hydroxylase {Hs, Mm, Rn},21 INSL3 {Hs, Mm, Rn}
Mutant phenotype Knockout mice exhibit no clear phenotype, suggesting functional redundancy between NR4A subfamily members in vivo; however, an altered neuropeptide expression pattern is observed {Mm} [knockout]22,23
Human disease

  • aa, amino acids; chr., chromosome; HRE, hormone response element; GR, glucocorticoid receptor; PPARBP, PPAR binding protein; NBRE, NGFI-B response element; NuRE, Nur response element; POMC, pro-opiomelanocortin

  • ↵1. Bondy GP (1991) Phorbol ester, forskolin, and serum induction of a human colon nuclear hormone receptor gene related to the NUR 77/NGFI-B genes. Cell Growth Differ 2: 203-208

  • ↵2. Nakai A, Kartha S, Sakurai A, Toback FG, and DeGroot LJ (1990) A human early response gene homologous to murine nur77 and rat NGFI-B, and related to the nuclear receptor superfamily. Mol Endocrinol 4: 1438-1443

  • ↵3. Chang A, Kokontis J, Liao SS, and Chang Y (1989) Isolation and characterization of human TR3 receptor: a member of steroid receptor superfamily. J Steroid Biochem 34: 391-395

  • ↵4. Milbrandt J (1988) Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene. Neuron 1: 183-188

  • ↵5. Altin JG, Kujubu DA, Raffioni S, Eveleth DD, Herschman HR, and Bradshaw RA (1991) Differential induction of primary-response (TIS) genes in PC12 pheochromocytoma cells and the unresponsive variant PC12nnr5. J Biol Chem 266: 5401-5406

  • ↵6. Hazel TG, Nathans D, and Lau LF (1988) A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily. Proc Natl Acad Sci USA 85: 8444-8448

  • ↵7. Ryseck RP, Macdonald-Bravo H, Mattei MG, Ruppert S, and Bravo R (1989) Structure, mapping and expression of a growth factor inducible gene encoding a putative nuclear hormonal binding receptor. EMBO (Eur Mol Biol Organ) J 8: 3327-3335

  • ↵8. 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

  • ↵9. 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

  • ↵10. Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, and Zhang XK (2004) Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell 116: 527-540

  • ↵11. Pekarsky Y, Hallas C, Palamarchuk A, Koval A, Bullrich F, Hirata Y, Bichi R, Letofsky J, and Croce CM (2001) Akt phosphorylates and regulates the orphan nuclear receptor Nur77. Proc Natl Acad Sci USA 98: 3690-3694

  • ↵12. Masuyama N, Oishi K, Mori Y, Ueno T, Takahama Y, and Gotoh Y (2001) Akt inhibits the orphan nuclear receptor Nur77 and T-cell apoptosis. J Biol Chem 276: 32799-32805

  • ↵13. Jehn BM, Bielke W, Pear WS, and Osborne BA (1999) Cutting edge: protective effects of notch-1 on TCR-induced apoptosis. J Immunol 162: 635-638

  • ↵14. Wansa KD, Harris JM, and Muscat GE (2002) The activation function-1 domain of Nur77/NR4A1 mediates trans-activation, cell specificity, and coactivator recruitment. J Biol Chem 277: 33001-33011

  • ↵15. Watson MA and Milbrandt J (1990) Expression of the nerve growth factor-regulated NGFI-A and NGFI-B genes in the developing rat. Development 110: 173-183

  • ↵16. Williams GT and Lau LF (1993) Activation of the inducible orphan receptor gene nur77 by serum growth factors: dissociation of immediate-early and delayed-early responses. Mol Cell Biol 13: 6124-6136

  • ↵17. 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

  • ↵18. Bandoh S, Tsukada T, Maruyama K, Ohkura N, and Yamaguchi K (1997) Differential expression of NGFI-B and RNR-1 genes in various tissues and developing brain of the rat: comparative study by quantitative reverse transcription-polymerase chain reaction. J Neuroendocrinol 9: 3-8

  • ↵19. Philips A, Lesage S, Gingras R, Maira MH, Gauthier Y, Hugo R, and Drouin J (1997) Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Mol Cell Biol 17: 5946-5951

  • ↵20. Wilson TE, Mouw AR, Weaver CA, Milbrandt J, and Parker KL (1993) The orphan nuclear receptor NGFI-B regulates expression of the gene encoding steroid 21-hydroxylase. Mol Cell Biol 13: 861-868

  • ↵21. Zhang P and Mellon SH (1997) Multiple orphan nuclear receptors converge to regulate rat P450c17 gene transcription: novel mechanisms for orphan nuclear receptor action. Mol Endocrinol 11: 891-890

  • ↵22. Lee SL, Wesselschmidt RL, Linette GP, Kanagawa O, Russell JH, and Milbrandt J (1995) Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77). Science (Wash DC) 269: 532-535

  • ↵23. Ethier I, Beaudry G, St-Hilaire M, Milbrandt J, Rouillard C, and Levesque D (2004) The transcription factor NGFI-B (Nur77) and retinoids play a critical role in acute neuroleptic-induced extrapyramidal effect and striatal neuropeptide gene expression. Neuropsychopharmacology 29: 335-346