TABLE 1

RXRα

Receptor Nomenclature NR2B1
Receptor code 4.1:RX:2:B1
Molecular information Hs:462aa, P19793, chr. 9q34.31–3
Rn:467aa, P287004
Mm: 467aa, Q05343, chr. 25–8
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 binding7,9,10 ; VDR (physical, functional): DNA binding9,10; RARα, RARβ, and RARγ (physical, functional): DNA binding7,9–14; PPARα, PPARβ, and PPARγ (physical, functional): DNA binding15,16; LXRα and LXRβ (physical, functional): DNA binding17–20; FXR (physical, functional): DNA binding21; PXR (physical, functional): DNA binding22–25; CAR (physical, functional): DNA binding26,27; NGFI-B (physical, functional): DNA binding28,29; NURR1 (physical, functional): DNA binding29
Agonists CD3254 (3 nM), LG100268 (3.2 nM), LGD1069 (36 nM),* 9-cis-retinoic acid (6.7–73 nM),* methoprenic acid (2 μM) [IC50]8,12,30–39; AGN194204 (0.4 nM) [Kd]40; SR11237, docosahexaenoic acid, phytanic acid41–44
Antagonists LG100754 (3.4 nM) [IC50]36,45,46; PA451, UVI300347,48
Coactivators NCOA1, NCOA2, NCOA3, PGC-1α, PPARBP, TBP, TAFII110, TAFII28, CREBBP, p30036,49–59
Biologically important isoforms RXRα1 {Mm}: differs from RXRα2 in the A/B domain60; RXRα2 {Mm}: specifically expressed in testis60
Tissue distribution Liver, lung, muscle, kidney, epidermis, and intestine; major isotype in the skin {Hs, Mm, Rn} [Northern blot, in situ hybridization, Western blot]3,8,61
Functional assays Differentiation of 3T3-L1 cells to adipocytes measured by the accumulation of triglyceride produced within the cytoplasm of the adipocyte {Mm}33,62,63 ; induction of apoptosis (associated with RARα activation) in leukemia cell lines {Hs}38,64; primitive endodermal differentiation and morphological differentiation in F9 murine embryonal carcinoma cell line {Mm}65,66
Mutant phenotype Knockout mice have hypoplasia of the myocardium, which leads to animal death due to cardiac failure at around embryonic day 14.5; animals also have ocular malformation {Mm} [knockout]51,67–73

  • aa, amino acid; chr, chromosome; HRE, hormone response element; NGFI-B, nerve growth factor-induced clone B; PGC-1α, PPAR coactivator-1α; PPARBP, PPAR-binding protein; TBP, TATA-box binding protein; CREBBP, cAMP response element-binding protein-binding protein

  • ↵* Radioligand

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  • ↵3. Mangelsdorf DJ, Ong ES, Dyck JA, and Evans RM (1990) Nuclear receptor that identifies a novel retinoic acid response pathway. Nature (Lond) 345: 224-229

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  • ↵16. 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

  • ↵17. 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

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  • ↵19. 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: 3977-3986

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

  • ↵21. 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

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  • ↵23. 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

  • ↵24. 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

  • ↵25. 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

  • ↵26. 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

  • ↵27. 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

  • ↵28. 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

  • ↵29. 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

  • ↵30. 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

  • ↵31. 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

  • ↵32. 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

  • ↵33. 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

  • ↵34. Harmon MA, Boehm MF, Heyman RA, and Mangelsdorf DJ (1995) Activation of mammalian retinoid X receptors by the insect growth regulator methoprene. Proc Natl Acad Sci USA 92: 6157-6160

  • ↵35. 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

  • ↵36. 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

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  • ↵38. 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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  • ↵40. 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

  • ↵41. de Urquiza AM, Liu S, Sjoberg M, Zetterstrom RH, Griffiths W, Sjovall J, and Perlmann T (2000) Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science 290: 2140-2144

  • ↵42. Lampen A, Meyer S, and Nau H (2001) Phytanic acid and docosahexaenoic acid increase the metabolism of all-trans-retinoic acid and CYP26 gene expression in intestinal cells. Biochim Biophys Acta 1521: 97-106

  • ↵43. Lehmann JM, Jong L, Fanjul A, Cameron JF, Lu XP, Haefner P, Dawson MI, and Pfahl M (1992) Retinoids selective for retinoid X receptor response pathways. Science 258: 1944-1946

  • ↵44. Lemotte PK, Keidel S, and Apfel CM (1996) Phytanic acid is a retinoid X receptor ligand. Eur J Biochem 236: 328-333

  • ↵45. 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

  • ↵46. 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

  • ↵47. Pogenberg V, Guichou JF, Vivat-Hannah V, Kammerer S, Perez E, Germain P, de Lera AR, Gronemeyer H, Royer CA, and Bourguet W (2005) Characterization of the interaction between retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers and transcriptional coactivators through structural and fluorescence anisotropy studies. J Biol Chem 280: 1625-1633

  • ↵48. Takahashi B, Ohta K, Kawachi E, Fukasawa H, Hashimoto Y, and Kagechika H (2002) Novel retinoid X receptor antagonists: specific inhibition of retinoid synergism in RXR-RAR heterodimer actions. J Med Chem 45: 3327-3330

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  • ↵51. Delerive P, Wu Y, Burris TP, Chin WW, and Suen CS (2002) PGC-1 functions as a transcriptional coactivator for the retinoid X receptors. J Biol Chem 277: 3913-3917

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  • ↵57. 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

  • ↵58. 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

  • ↵59. Yuan CX, Ito M, Fondell JD, Fu ZY, and Roeder RG (1998) The TRAP220 component of a thyroid hormone receptor- associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion. Proc Natl Acad Sci USA 95: 7939-7944

  • ↵60. Brocard J, Kastner P, and Chambon P (1996) Two novel RXRα isoforms from mouse testis. Biochem Biophys Res Commun 229: 211-218

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

  • ↵62. Chawla A and Lazar MA (1993) Induction of Rev-ErbAα, an orphan receptor encoded on the opposite strand of the α -thyroid hormone receptor gene, during adipocyte differentiation. J Biol Chem 268: 16265-16269

  • ↵63. Chawla A and Lazar MA (1994) Peroxisome proliferator and retinoid signaling pathways co-regulate preadipocyte phenotype and survival. Proc Natl Acad Sci USA 91: 1786-1790

  • ↵64. Monczak Y, Trudel M, Lamph WW, and Miller WH Jr (1997) Induction of apoptosis without differentiation by retinoic acid in PLB-985 cells requires the activation of both RAR and RXR. Blood 90: 3345-3355

  • ↵65. Chiba H, Clifford J, Metzger D, and Chambon P (1997) Distinct retinoid X receptor-retinoic acid receptor heterodimers are differentially involved in the control of expression of retinoid target genes in F9 embryonal carcinoma cells. Mol Cell Biol 17: 3013-3020

  • ↵66. Clifford J, Chiba H, Sobieszczuk D, Metzger D, and Chambon P (1996) RXRα -null F9 embryonal carcinoma cells are resistant to the differentiation, anti-proliferative and apoptotic effects of retinoids. EMBO (Eur Mol Biol Organ) J 15: 4142-4155

  • ↵67. Kastner P, Grondona JM, Mark M, Gansmuller A, LeMeur M, Decimo D, Vonesch JL, Dolle P, and Chambon P (1994) Genetic analysis of RXRα developmental function: convergence of RXR and RAR signaling pathways in heart and eye morphogenesis. Cell 78: 987-1003

  • ↵68. Kastner P, Mark M, and Chambon P (1995) Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 83: 859-869

  • ↵69. Kastner P, Messaddeq N, Mark M, Wendling O, Grondona JM, Ward S, Ghyselinck N, and Chambon P (1997) Vitamin A deficiency and mutations of RXRα, RXRβ and RARα lead to early differentiation of embryonic ventricular cardiomyocytes. Development 124: 4749-4758

  • ↵70. 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

  • ↵71. 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

  • ↵72. Sucov HM, Dyson E, Gumeringer CL, Price J, Chien KR, and Evans RM (1994) RXRα mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis. Genes Dev 8: 1007-1018

  • ↵73. Sucov HM, Izpisua-Belmonte JC, Ganan Y, and Evans RM (1995) Mouse embryos lacking RXRα are resistant to retinoic-acid-induced limb defects. Development 121: 3997-4003