TABLE 3

RXRγ

Receptor Nomenclature NR2B1
Receptor code 4.10.1:RX:2:B3
Molecular information Hs: 463aa, P48443, chr. 1q22-q231,2
Mm: 463aa, P28705, chr. 12–5
DNA binding
   Structure Homodimer, heterodimer, RXR partner
   HRE core sequence AGGTCA (DR-1, DR-2, DR-3, DR-4, DR-5)
Partners TR2 and TR4 (physical, functional): DNA binding5–8; VDR (physical, functional): DNA binding6–8; RARα, RARβ, and RARγ (physical, functional): DNA binding5–12; PPARα, PPARβ, and PPARγ (physical, functional): DNA binding8,13,1 4; LXRα and LXRβ (physical, functional): DNA binding8,15–18; FXR (physical, functional): DNA binding8,19; PXR (physical, functional): DNA binding8,20–23; CAR (physical, functional): DNA binding8,24,2 5; NGFI-B (physical, functional): DNA binding8,26,2 7; NURR1 (physical, functional): DNA binding8,27
Agonists LG100268 (3–9.7 nM), LGD1069 (29 nM),* 9-cis-retinoic acid (9.7–85 nM)* [IC50]28–36; AGN194204 (3.8 nM) [Kd]37
Antagonists LG100754 (12.2 nM) [IC50]33,38,39
Coactivators NCOA1, NCOA2, NCOA38,40–44
Biologically important isoforms RXRγ1 {Mm}: differs from RXRγ 2 in the A/B domain45,46; RXRγ2 {Mm}45,46.
Tissue distribution RXRγ1 is expressed in the brain and muscle, whereas RXRγ 2 is highly expressed in both cardiac and skeletal muscles {Mm, Rn} [Northern blot, in situ hybridization, Western blot]45,47–49
Mutant phenotype Knockout mice have metabolic and behavioral defects {Mm} [knockout]50–54

  • aa, amino acid; chr, chromosome; HRE, hormone response element; NGFI-B, nerve growth factor-induced clone B

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  • ↵3. Hoopes CW, Taketo M, Ozato K, Liu Q, Howard TA, Linney E, and Seldin MF (1992) Mapping of the mouse Rxr loci encoding nuclear retinoid X receptors RXRα, RXRβ, and RXRγ. Genomics 14: 611-617

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  • ↵9. Berrodin TJ, Marks MS, Ozato K, Linney E, and Lazar MA (1992) Heterodimerization among thyroid hormone receptor, retinoic acid receptor, retinoid X receptor, chicken ovalbumin upstream promoter transcription factor, and an endogenous liver protein. Mol Endocrinol 6: 1468-1478

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  • ↵11. Kliewer SA, Umesono K, Mangelsdorf DJ, and Evans RM (1992) Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling. Nature (Lond) 355: 446-449

  • ↵12. Zhang XK, Lehmann J, Hoffmann B, Dawson MI, Cameron J, Graupner G, Hermann T, Tran P, and Pfahl M (1992) Homodimer formation of retinoid X receptor induced by 9-cis retinoic acid. Nature (Lond) 358: 587-591

  • ↵13. Kliewer SA, Umesono K, Noonan DJ, Heyman RA, and Evans RM (1992) Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature (Lond) 358: 771-774

  • ↵14. Tontonoz P, Graves RA, Budavari AI, Erdjument-Bromage H, Lui M, Hu E, Tempst P, and Spiegelman BM (1994) Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPARγ and RXRα. Nucleic Acids Res 22: 5628-5634

  • ↵15. Feltkamp D, Wiebel FF, Alberti S, and Gustafsson JA (1999) Identification of a novel DNA binding site for nuclear orphan receptor OR1. J Biol Chem 274: 10421-10429

  • ↵16. Teboul M, Enmark E, Li Q, Wikstrom AC, Pelto-Huikko M, and Gustafsson JA (1995) OR-1, a member of the nuclear receptor superfamily that interacts with the 9-cis-retinoic acid receptor. Proc Natl Acad Sci USA 92: 2096-2100

  • ↵17. Wiebel, FF and Gustafsson JA (1997) Heterodimeric interaction between retinoid X receptor α and orphan nuclear receptor OR1 reveals dimerization-induced activation as a novel mechanism of nuclear receptor activation. Mol Cell Biol 17: 3977-3398

  • ↵18. Willy PJ and Mangelsdorf DJ (1997) Unique requirements for retinoid-dependent transcriptional activation by the orphan receptor LXR. Genes Dev 11: 289-298

  • ↵19. Seol W, Choi HS, and Moore DD (1995) Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors. Mol Endocrinol 9: 72-85

  • ↵20. Blumberg B, Kang H, Bolado J Jr, Chen H, Craig AG, Moreno TA, Umesono K, Perlmann T, De Robertis EM, and Evans RM (1998) BXR, an embryonic orphan nuclear receptor activated by a novel class of endogenous benzoate metabolites. Genes Dev 12: 1269-1277

  • ↵21. Blumberg B, Sabbagh W Jr, Juguilon H, Bolado J Jr, van Meter CM, Ong ES, and Evans RM (1998) SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev 12: 3195-3205

  • ↵22. Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, McKee DD, Oliver BB, Willson TM, Zetterstrom RH, et al. (1998) An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92: 73-82

  • ↵23. Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, and Kliewer SA (1998) The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Investig 102: 1016-1023

  • ↵24. Baes M, Gulick T, Choi HS, Martinoli MG, Simha D, and Moore DD (1994) A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements. Mol Cell Biol 14: 1544-1552

  • ↵25. Choi HS, Chung M, Tzameli I, Simha D, Lee YK, Seol W, and Moore DD (1997) Differential transactivation by two isoforms of the orphan nuclear hormone receptor CAR. J Biol Chem 272: 23565-23571

  • ↵26. Forman BM, Umesono K, Chen J, and Evans RM (1995) Unique response pathways are established by allosteric interactions among nuclear hormone receptors. Cell 81: 541-550

  • ↵27. Perlmann T and Jansson L (1995) A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1. Genes Dev 9: 769-782

  • ↵28. Allenby G, Bocquel MT, Saunders M, Kazmer S, Speck J, Rosenberger M, Lovey A, Kastner P, Grippo JF, Chambon P, et al. (1993) Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci USA 90: 30-34

  • ↵29. Boehm MF, McClurg MR, Pathirana C, Mangelsdorf D, White SK, Hebert J, Winn D, Goldman ME, and Heyman RA (1994) Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties. J Med Chem 37: 408-414

  • ↵30. Boehm MF, Zhang L, Badea BA, White SK, Mais DE, Berger E, Suto CM, Goldman ME, and Heyman RA (1994) Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids. J Med Chem 37: 2930-2941

  • ↵31. Canan Koch SS, Dardashti LJ, Cesario RM, Croston GE, Boehm MF, Heyman RA, and Nadzan AM (1999) Synthesis of retinoid X receptor-specific ligands that are potent inducers of adipogenesis in 3T3-L1 cells. J Med Chem 42: 742-750

  • ↵32. Heyman RA, Mangelsdorf DJ, Dyck JA, Stein RB, Eichele G, Evans RM, and Thaller C (1992) 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 68: 397-406

  • ↵33. Lala DS, Mukherjee R, Schulman IG, Koch SS, Dardashti LJ, Nadzan AM, Croston GE, Evans RM, and Heyman RA (1996) Activation of specific RXR heterodimers by an antagonist of RXR homodimers. Nature (Lond) 383: 450-453

  • ↵34. Levin AA, Sturzenbecker LJ, Kazmer S, Bosakowski T, Huselton C, Allenby G, Speck J, Kratzeisen C, Rosenberger M, Lovey A, et al. (1992) 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXRα. Nature (Lond) 355: 359-361

  • ↵35. Nagy L, Thomazy VA, Shipley GL, Fesus L, Lamph W, Heyman RA, Chandraratna RA, and Davies PJ (1995) Activation of retinoid X receptors induces apoptosis in HL-60 cell lines. Mol Cell Biol 15: 3540-3551

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  • ↵37. Vuligonda V, Thacher SM, and Chandraratna RA (2001) Enantioselective syntheses of potent retinoid X receptor ligands: differential biological activities of individual antipodes. J Med Chem 44: 2298-2303

  • ↵38. Cesario RM, Klausing K, Razzaghi H, Crombie D, Rungta D, Heyman RA, and Lala DS (2001) The rexinoid LG100754 is a novel RXR:PPARγ agonist and decreases glucose levels in vivo. Mol Endocrinol 15: 1360-1369

  • ↵39. Forman BM (2002) The antidiabetic agent LG100754 sensitizes cells to low concentrations of peroxisome proliferator-activated receptor γ ligands. J Biol Chem 277: 12503-12506

  • ↵40. Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, and Evans RM (1997) Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90: 569-580

  • ↵41. McKenna NJ, Lanz RB, and O'Malley BW (1999) Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 20: 321-344

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  • ↵43. Voegel JJ, Heine MJ, Tini M, Vivat V, Chambon P, and Gronemeyer H (1998) The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and -independent pathways. EMBO (Eur Mol Biol Organ) J 17: 507-519

  • ↵44. Voegel JJ, Heine MJ, Zechel C, Chambon P, and Gronemeyer H (1996) TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO (Eur Mol Biol Organ) J 15: 3667-3675

  • ↵45. Liu Q and Linney E (1993) The mouse retinoid-X receptor-γ gene: genomic organization and evidence for functional isoforms. Mol Endocrinol 7: 651-658

  • ↵46. Nagata T, Kanno Y, Ozato K, and Taketo M (1994) The mouse Rxrb gene encoding RXRβ : genomic organization and two mRNA isoforms generated by alternative splicing of transcripts initiated from CpG island promoters. Gene 142: 183-189

  • ↵47. Chiang MY, Misner D, Kempermann G, Schikorski T, Giguere V, Sucov HM, Gage FH, Stevens CF, and Evans RM (1998) An essential role for retinoid receptors RARβ and RXRγ in long-term potentiation and depression. Neuron 21: 1353-1361

  • ↵48. Dolle P, Fraulob V, Kastner P, and Chambon P (1994) Developmental expression of murine retinoid X receptor (RXR) genes. Mech Dev 45: 91-104

  • ↵49. Haugen BR, Brown NS, Wood WM, Gordon DF, and Ridgway EC (1997) The thyrotrope-restricted isoform of the retinoid-X receptor-γ 1 mediates 9-cis-retinoic acid suppression of thyrotropin-β promoter activity. Mol Endocrinol 11: 481-489

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  • ↵51. Krezel W, Dupe V, Mark M, Dierich A, Kastner P, and Chambon P (1996) RXR γ null mice are apparently normal and compound RXRα +/–/RXRβ –/–/RXRγ –/– mutant mice are viable. Proc Natl Acad Sci USA 93: 9010-9014

  • ↵52. Krezel W, Ghyselinck N, Samad TA, Dupe V, Kastner P, Borrelli E, and Chambon P. (1998) Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science 279: 863-867

  • ↵53. Mark M and Chambon P (2003) Functions of RARs and RXRs in vivo: genetic dissection of the retinoid signaling pathway. Pure Appl Chem 75: 1709-1732

  • ↵54. Mark M, Ghyselinck NB, and Chambon P (2006) Function of retinoid nuclear receptors: lessons from genetic and pharmacological dissections of the retinoic acid signalling pathway during mouse embryogenesis. Annu Rev Pharmacol Toxicol 46: 451-480