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Research ArticleSpecial Issue IUPHAR Compendium of the Pharmacology and Classification of the Nuclear Receptor Superfamily 2006

International Union of Pharmacology. LXIII. Retinoid X Receptors

Pierre Germain, Pierre Chambon, Gregor Eichele, Ronald M. Evans, Mitchell A. Lazar, Mark Leid, Angel R. De Lera, Reuben Lotan, David J. Mangelsdorf and Hinrich Gronemeyer
Pharmacological Reviews December 2006, 58 (4) 760-772; DOI: https://doi.org/10.1124/pr.58.4.7

Article Figures & Data

Tables

  • 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

    • ↵1. Almasan A, Mangelsdorf DJ, Ong, ES, Wahl GM, and Evans RM (1994) Chromosomal localization of the human retinoid X receptors. Genomics 20: 397-403

    • ↵2. Jones KA, Fitzgibbon J, Woodward KJ, Goudie D, Ferguson-Smith MA, Povey S, Wolfe J, and Solomon E (1993) Localization of the retinoid X receptor α gene (RXRA) to chromosome 9q34. Ann Hum Genet 57: 195-201

    • ↵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

    • ↵4. Gearing KL, Gottlicher M, Teboul M, Widmark E, and Gustafsson JA (1993) Interaction of the peroxisome-proliferator-activated receptor and retinoid X receptor. Proc Natl Acad Sci USA 90: 1440-1444

    • ↵5. 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

    • ↵6. Leid M, Kastner P, and Chambon P (1992) Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci 17: 427-433

    • ↵7. Leid M, Kastner P, Lyons R, Nakshatri H, Saunders M, Zacharewski T, Chen JY, Staub A, Garnier JM, Mader S, et al. (1992) Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell 68: 377-395

    • ↵8. Mangelsdorf DJ, Borgmeyer U, Heyman RA, Zhou JY, Ong ES, Oro AE, Kakizuka A, and Evans RM (1992) Characterization of three RXR genes that mediate the action of 9 cis retinoic acid. Genes Dev 6: 329-344

    • ↵9. Bugge TH, Pohl J, Lonnoy O, and Stunnenberg HG (1992) RXRα, a promiscuous partner of retinoic acid and thyroid hormone receptors. EMBO (Eur Mol Biol Organ) J 11: 1409-1418

    • ↵10. Glass CK (1994) Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers. Endocr Rev 15: 391-407

    • ↵11. 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

    • ↵12. Germain P, Iyer J, Zechel C, and Gronemeyer H (2002) Coregulator recruitment and the mechanism of retinoic acid receptor synergy. Nature (Lond) 415: 187-192

    • ↵13. 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

    • ↵14. 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

    • ↵15. 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

    • ↵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

    • ↵18. 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

    • ↵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

    • ↵22. Blumberg B, Kang H, Bolado J Jr, Chen H, Craig AG, MorenoTA, 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

    • ↵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

    • ↵37. 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

    • ↵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

    • ↵39. Thacher SM, Vasudevan J, and Chandraratna RA (2000) Therapeutic applications for ligands of retinoid receptors. Curr Pharm Des 6: 25-58

    • ↵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

    • ↵49. Chakravarti D, LaMorte VJ, Nelson MC, Nakajima T, Schulman IG, Juguilon H, Montminy M, and Evans RM (1996) Role of CBP/p300 in nuclear receptor signalling. Nature (Lond) 383: 99-103

    • ↵50. 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

    • ↵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

    • ↵52. Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, Lin SC, Heyman RA, Rose DW, Glass CK, et al. (1996) A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85: 403-414

    • ↵53. May M, Mengus G, Lavigne AC, Chambon P, and Davidson I (1996) Human TAF(II28) promotes transcriptional stimulation by activation function 2 of the retinoid X receptors. EMBO (Eur Mol Biol Organ) J 15: 3093-3104

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

    • ↵55. Onate SA, Tsai SY, Tsai MJ, and O'Malley BW (1995) Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270: 1354-1357

    • ↵56. Schulman IG, Chakravarti D, Juguilon H, Romo A, and Evans RM (1995) Interactions between the retinoid X receptor and a conserved region of the TATA-binding protein mediate hormone-dependent transactivation. Proc Natl Acad Sci USA 92: 8288-8292

    • ↵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

  • TABLE 2

    RXRβ

    Receptor Nomenclature NR2B2
    Receptor code 4.10.1:RX:2:B2
    Other names H-2RIIBP, RCoR-1,
    Molecular information Hs: 533aa, P28702, chr. 6p21.31,2
    Rn: 458aa, P497433
    Mm: 520aa, P28704, chr. 172,4–7
    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 binding2,8–10; VDR (physical, functional): DNA binding8–10; RARα, RARβ, and RARγ (physical, functional): DNA binding2,8–14; PPARα, PPARβ, and PPARγ (physical, functional): DNA binding10,15,16; LXRα and LXRβ (physical, functional): DNA binding10,17–21; FXR (physical, functional): DNA binding10,22; PXR (physical, functional): DNA binding10,23–26; CAR (physical, functional): DNA binding10,27,28; NGFI-B (physical, functional): DNA binding10,29,30; NURR1 (physical, functional): DNA binding10,30
    Agonists LG100268 (3–6.8 nM), LGD1069 (21 nM),* 9-cis-retinoic acid (6.2–117 nM),* [IC50]7,31–39; AGN194204 (3.6 nM) [Kd]40
    Antagonists LG100754 (10 nM) [IC50]36,41,42
    Coactivators NCOA1, NCOA2, NCOA310,43–47
    Biologically important isoforms RXRβ 1 {Hs, Mm}: differs from RXRβ 2 in the A/B domain48,49; RXRβ 2 {Hs, Mm}49,50
    Tissue distribution Ubiquitous {Hs, Mm, Rn} [Northern blot, in situ hybridization, Western blot]3,4,7,51
    Functional assays Differentiation of 3T3-L1 cells to adipocytes measured by the accumulation of triglyceride produced within the cytoplasm of the adipocyte {Mm}34,52,53; induction of apoptosis (associated with RARα activation) in leukemia cell lines {Hs}38,54
    Mutant phenotype Male sterility due to defective spermatogenesis, abnormal lipid metabolism in Sertoli cells and behavioral defects {Mm} [knockout]18,55–57

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

    • ↵* Radioligand

    • ↵1. Almasan A, Mangelsdorf DJ, Ong ES, Wahl GM, and Evans RM (1994) Chromosomal localization of the human retinoid X receptors. Genomics 20: 397-403

    • ↵2. Leid M, Kastner P, Lyons R, Nakshatri H, Saunders M, Zacharewski T, Chen JY, Staub A, Garnier JM, Mader S, et al. (1992) Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell 68: 377-395

    • ↵3. Yu VC, Delsert C, Andersen B, Holloway JM, Devary OV, Naar AM, Kim SY, Boutin JM, Glass CK, and Rosenfeld MG (1991) RXRβ : a coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements. Cell 67: 1251-1266

    • ↵4. Hamada K, Gleason SL, Levi BZ, Hirschfeld S, Appella E, and Ozato K (1989) H-2RIIBP, a member of the nuclear hormone receptor superfamily that binds to both the regulatory element of major histocompatibility class I genes and the estrogen response element. Proc Natl Acad Sci USA 86: 8289-8293

    • ↵5. 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 RXR γ. Genomics 14: 611-617

    • ↵6. Leid M, Kastner P, and Chambon P (1992) Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci 17: 427-433

    • ↵7. Mangelsdorf DJ, Borgmeyer U, Heyman RA, Zhou JY, Ong ES, Oro AE, Kakizuka A, and Evans RM (1992) Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev 6: 329-344

    • ↵8. Bugge TH, Pohl J, Lonnoy O, and Stunnenberg HG (1992) RXRα, a promiscuous partner of retinoic acid and thyroid hormone receptors. EMBO (Eur Mol Biol Organ) J 11: 1409-1418

    • ↵9. Glass CK (1994) Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers. Endocr Rev 15: 391-407

    • ↵10. Laudet V and Gronemeyer H (2002) The Nuclear Receptor Facts Book, Academic Press, San Diego

    • ↵11. 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

    • ↵12. Germain P, Iyer J, Zechel C, and Gronemeyer H (2002) Coregulator recruitment and the mechanism of retinoic acid receptor synergy. Nature (Lond) 415: 187-192

    • ↵13. 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

    • ↵14. 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

    • ↵15 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

    • ↵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

    • ↵18. Mascrez B, Ghyselinck NB, Watanabe M, Annicotte JS, Chambon P, Auwerx J, and Mark M (2004) Ligand-dependent contribution of RXRβ to cholesterol homeostasis in Sertoli cells. EMBO Rep 5: 285-290

    • ↵19. 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

    • ↵20. 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

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

    • ↵22. 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

    • ↵23. 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

    • ↵24. 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

    • ↵25. 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

    • ↵26. 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

    • ↵27 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

    • ↵28. 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

    • ↵29. 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

    • ↵30. 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

    • ↵31. 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

    • ↵32. 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

    • ↵33. 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

    • ↵34. 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

    • ↵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

    • ↵37. 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

    • ↵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

    • ↵39. Thacher SM, Vasudevan J, and Chandraratna RA (2000) Therapeutic applications for ligands of retinoid receptors. Curr Pharm Des 6: 25-58

    • ↵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. 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

    • ↵42. 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

    • ↵43. 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

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

    • ↵45. Onate SA, Tsai SY, Tsai MJ, and O'Malley BW (1995) Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270: 1354-1357

    • ↵46. 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

    • ↵47. 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

    • ↵48. Fleischhauer K, Park JH, DiSanto JP, Marks M, Ozato K, and Yang SY (1992) Isolation of a full-length cDNA clone encoding a N-terminally variant form of the human retinoid X receptor β. Nucleic Acids Res 20: 1801

    • ↵49. 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

    • ↵50. Numasawa T, Koga H, Ueyama K, Maeda S, Sakou T, Harata S, Leppert M, and Inoue I (1999) Human retinoic X receptor β : complete genomic sequence and mutation search for ossification of posterior longitudinal ligament of the spine. J Bone Miner Res 14: 500-508

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

    • ↵52. 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

    • ↵53. 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

    • ↵54. 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

    • ↵55. Kastner P, Mark M, Leid M, Gansmuller A, Chin W, Grondona JM, Decimo D, Krezel W, Dierich A, and Chambon P (1996) Abnormal spermatogenesis in RXRβ mutant mice. Genes Dev 10: 80-92

    • ↵56. 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

    • ↵57. 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

  • 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

    • ↵1. Almasan A, Mangelsdorf DJ, Ong ES, Wahl GM, and Evans RM (1994) Chromosomal localization of the human retinoid X receptors. Genomics 20: 397-403

    • ↵2. Mangelsdorf DJ, Borgmeyer U, Heyman RA, Zhou JY, Ong ES, Oro AE, Kakizuka A, and Evans RM (1992) Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev 6: 329-344

    • ↵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

    • ↵4. Leid M, Kastner P, and Chambon P (1992) Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci 17: 427-433

    • ↵5. Leid M, Kastner P, Lyons R, Nakshatri H, Saunders M, Zacharewski T, Chen JY, Staub A, Garnier JM, Mader S, et al. (1992) Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell 68: 377-395

    • ↵6. Bugge TH, Pohl J, Lonnoy O, and Stunnenberg HG (1992) RXRα, a promiscuous partner of retinoic acid and thyroid hormone receptors. EMBO (Eur Mol Biol Organ) J 11: 1409-1418

    • ↵7. Glass CK (1994) Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers. Endocr Rev 15: 391-407

    • ↵8. Laudet V and Gronemeyer H (2002) The Nuclear Receptor Facts Book, Academic Press, San Diego

    • ↵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

    • ↵10. Germain P, Iyer J, Zechel C, and Gronemeyer H (2002) Coregulator recruitment and the mechanism of retinoic acid receptor synergy. Nature (Lond) 415: 187-192

    • ↵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

    • ↵36. Thacher SM, Vasudevan J, and Chandraratna RA (2000) Therapeutic applications for ligands of retinoid receptors. Curr Pharm Des 6: 25-58

    • ↵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

    • ↵42. Onate SA, Tsai SY, Tsai MJ, and O'Malley BW (1995) Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270: 1354-1357

    • ↵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

    • ↵50. Brown NS, Smart A, Sharma V, Brinkmeier ML, Greenlee L, Camper SA, Jensen DR, Eckel RH, Krezel W, Chambon P, et al. (2000) Thyroid hormone resistance and increased metabolic rate in the RXR-γ -deficient mouse. J Clin Investig 106: 73-79

    • ↵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

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Research ArticleSpecial Issue IUPHAR Compendium of the Pharmacology and Classification of the Nuclear Receptor Superfamily 2006

International Union of Pharmacology. LXIII. Retinoid X Receptors

Pierre Germain, Pierre Chambon, Gregor Eichele, Ronald M. Evans, Mitchell A. Lazar, Mark Leid, Angel R. De Lera, Reuben Lotan, David J. Mangelsdorf and Hinrich Gronemeyer
Pharmacological Reviews December 1, 2006, 58 (4) 760-772; DOI: https://doi.org/10.1124/pr.58.4.7
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