Retinoids pp 215-235 | Cite as

RXR-Specific Agonists and Modulators: A New Retinoid Pharmacology

  • I. G. Schulman
  • D. Crombie
  • R. P. Bissonnette
  • R. Cesario
  • K. Roegner
  • G. Shao
  • R. A. Heyman
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 139)


Receptors for retinoic acid (RARs and RXRs), thyroid hormone (TRs), vitamin D (VDR), prostanoids (PPARs) and numerous orphan receptors for which ligands have not been identified play vital roles in vertebrate cell growth, development, differentiation, metabolism and homcostasis. These receptors, like most members of the nuclear hormone receptor superfamily, function as hormone-dependent transcription factors that regulate the expression of large gene networks. The important biological activities of nuclear hormone receptors combined with the ability to directly regulate their activity with small molecules has long made this superfamily of transcription factors a target for drug discovery. This review focuses on the retinoid X receptors (RXRs), first characterized as receptors for the vitamin A derivative 9-cis retinoic acid (for recent reviews see Mangelsdorf and Evans 1995; Mangelsdorf et al. 1995; Perlmann and Evans 1997). Recent work demonstrating that ligands for RXR may provide effective treatments for several types of cancers as well as for type II diabetes has lead to great interest in this class of nuclear hormone receptors that until recently were thought of as a “silent partner.”


Retinoic Acid Nuclear Hormone Receptor CREB Binding Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Anzano MA, Byers SW, Smith JM, Peer CW, Mullen LT, Brown CC, Roberts AB, Sporn MB (1994) Prevention of breast cancer with 9-cis-retinoic acid as a single agent and in combination with tamoxifen. Cancer Res 54:4614–1617PubMedGoogle Scholar
  2. Apfel CM, Kamber M, Klaus M, Mohr P, Keidel S, LeMotte PK (1995) Enhancement of HL-60 differentiation by a new class of retinoids with selective activity on retinoid X receptor. J Biol Chem 270:30765–30772PubMedCrossRefGoogle Scholar
  3. Baniahmad A, Leng X, Burris TP, Tsai SY, Tsai, M-J, O’Malley BW (1995) The τ4 activation domain of the Thyroid Hormone Receptor is required for the release of a putative corepressor(s) necessary for transcriptional silencing. Mol Cell Biol 15:76–86PubMedGoogle Scholar
  4. Boehm MF, Zhang L, Badea BA, White SA, Mais DE, Berger E, Suto CM, Goldman ME, Heyman RA (1994) Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids. J Med Chem 37:2930–2941PubMedCrossRefGoogle Scholar
  5. Boehm MF, Zhang L, Zhi L, McClurg MR, Berger E, Wagoner M, Mais DE, Suto CM, Davies PJ A, Heyman RA, Nadzan AM (1995) Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells. J Med Chem 38:3146–3155PubMedCrossRefGoogle Scholar
  6. Bourguet W, Ruff M, Chambon P, Gronemeyer H, Moras D (1995) Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-alpha. Nature 375:377–382PubMedCrossRefGoogle Scholar
  7. Brzozowski AM, Pike AC W, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L, Greene GL, Gustafsson J-A, Carlquist M (1997) Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389:753–758PubMedCrossRefGoogle Scholar
  8. Canan Koch SS, Dardashti LJ, Hebert JJ, Croston GE, Flatten KS, Heyman RA, Nadzan AM (1996) Identification of the first retinoid X receptor homodimer antagonist. J Med Chem 39:3229–3234CrossRefGoogle Scholar
  9. Chakravarti D, LaMorte VJ, Nelson MC, Nakajima T, Schulman IG, Juguilon H, Mont-miny M, Evans RM (1996) Role of CBP/P300 in nuclear receptor signaling. Nature 383:99–103PubMedCrossRefGoogle Scholar
  10. Chen H Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM (1997) Nuclear receptor coactivator ACTR is a novel histone acetyl-transferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90:569–580PubMedCrossRefGoogle Scholar
  11. Chen JD, Evans RM (1995) A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377:454–457PubMedCrossRefGoogle Scholar
  12. Chen JY, Clifford J, Zusi C, Starrett J, Tortolini D, Ostrowski J, Reczek PR, Chambon P, Gronemeyer H (1996) Two distinct actions of retinoid-receptor ligands. Nature 382:819–822PubMedCrossRefGoogle Scholar
  13. Costa A, Formelli F, Chiesa F, Decensi A, De Palo G, Veronesi U (1994) Prospects of chemoprevention of human cancers with the synthetic retinoid fenretinide. Cancer Res 54:2032S–2037SPubMedGoogle Scholar
  14. Forman BM, Tontonoz P, Chen J, Brun RP, Speigelman BM, Evans RM (1995a) 15-deoxy-A12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ. Cell 83:803–812PubMedCrossRefGoogle Scholar
  15. Forman BM, Umesono K, Chen J, Evans RM (1995b) Unique response pathways are established by allosteric interactions among nuclear hormone receptors. Cell 81:541–550PubMedCrossRefGoogle Scholar
  16. Fujiwara T, Yoshioka S, Toshioka T, Ushiyama I, Horikoshi H (1988) Characterization of a new oral antidiabetic agent CS-045. Diabetes 37:1549–1558PubMedCrossRefGoogle Scholar
  17. Glass CK, Rose DW, Rosenfeld MG (1997) Nuclear receptor coactivators. Curr Opin Cell Biol 9:222–232PubMedCrossRefGoogle Scholar
  18. Gottardis MM, Bischoff ED, Shirley MA, Wagoner MA, Lamph WW, Heyman RA (1996) Chemoprevention of mammary carcinoma by LGD1069 (targretin): an RXR selective ligand. Cancer Res 15:5566–5570Google Scholar
  19. Heyman RA, Mangelsdorf DJ, Dyck JA, Stein RB, Eichele G, Evans RM, Thaller C (1992) 9-Cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 68:397–406PubMedCrossRefGoogle Scholar
  20. Hong H, Kulwant K, Garabedian M, Stallcup MR (1997) GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors. Mol Cell Biol 15:2735–2744Google Scholar
  21. Hong WK, Sporn MB (1997) Recent advances in chemoprevention of cancer. Science 278:1073–1077PubMedCrossRefGoogle Scholar
  22. Horlein AJ, Naar AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamai Y, Soderstrom M, Glass CK, Rosenfeld MG (1995) Hormone-independent repression by the thyroid hormone receptor is mediated by a nuclear receptor co-repressor N-COR. Nature 377:397–104PubMedCrossRefGoogle Scholar
  23. Horwitz KB, Jackson TA, Bain DL, Richer JK, Takimoto GS, Tung L (1996) Nuclear receptor coactivators and corepressors. J Mol Endocrinol 10:1167–1177CrossRefGoogle Scholar
  24. Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B Lin S-C, Heyman RA, Rose DW, Glass CK, Rosenfeld MG (1996) A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85:403–414PubMedCrossRefGoogle Scholar
  25. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann J (1995) A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 83:813–819PubMedCrossRefGoogle Scholar
  26. Kurokawa R, DiRenzo J, Boehm M, Sugarman J, Gloss B, Rosenfeld MG, Heyman RA, Glass CK (1994) Regulation of retinoid signalling by receptor polarity and allosteric control of ligand binding. Nature 371:528–531PubMedCrossRefGoogle Scholar
  27. Kurokawa R, Soderstrom M, Horlein A, Halachmi S, Brown M, Rosenfeld MG, Glass CK (1995) A co-repressor specifies polarity-specific activities of retinoic acid receptors. Nature 377:451–457PubMedCrossRefGoogle Scholar
  28. Lala DS, Mukherjee R, Schulman IG, Canan-Koch SS, Dardashti LJ, Nadzan AM, Croston GE, Evans RM, Heyman RA (1996) Activation of specific RXR het-erodimers by an antagonist of RXR homodimers. Nature 383:450–453PubMedCrossRefGoogle Scholar
  29. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA (1995) An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPARV03B3;. J Biol Chem 270:12953–12956PubMedCrossRefGoogle Scholar
  30. Levin LA, Sturzenbecker LJ, Kazmer S, Bosakowski T, Huselton C, Allenby G, Speck J, Kratzeisen C, Rosenberger M, Lovey A, Grippo JF (1992) 9-Cis retinoic acid sterioisomer binds and activates the nuclear receptor RXRα. Nature 355:359–361PubMedCrossRefGoogle Scholar
  31. Li C, Schwabe JW R, Banayo E, Evans RM (1997) Coexpression of nuclear receptor partners increases their solubility and biological activities. Proc Natl Acad Sci 94:2278–2283PubMedCrossRefGoogle Scholar
  32. Lippman SM, Benner SE, Hong WK (1994) Retinoid chemoprevention studies in upper aerodigestive tract and lung carcinogenesis. Cancer Res 54:2025S–2028SPubMedGoogle Scholar
  33. Lotan R (1996) Retinoids in cancer chemoprevention. FASEB J 10:1031–1039PubMedGoogle Scholar
  34. Mandrup S, Lane MD (1997) Regulating adipogenesis. J Biol Chem 272:5367–5370PubMedCrossRefGoogle Scholar
  35. Mangelsdorf DJ, Borgmeyer U, Heyman RA, Zhou JY Ong ES Oro AE, Kakizuka A, Evans RM (1992) Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev 6:329–344PubMedCrossRefGoogle Scholar
  36. Mangelsdorf DJ, Evans RM (1995) The RXR heterodimers and orphan receptors. Cell 83:841–850PubMedCrossRefGoogle Scholar
  37. Mangelsdorf DJ Ong ES, Dyck JA E RM (1990) Nuclear receptor that identifies a novel retinoic acid response pathway. Nature 345:224–229PubMedCrossRefGoogle Scholar
  38. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Kastner P, Mark M, Chambon P, Evans RM (1995) The nuclear receptor superfamily: the second decade. Cell 83:835–839PubMedCrossRefGoogle Scholar
  39. Mangelsdorf DJ, Umesono K, Kliewer SA, Borgmeyer U Ong ES, Evans RM (1991) A direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR. Cell 66:555–561PubMedCrossRefGoogle Scholar
  40. Minucci S, Leid M, Toyama R, Saint-Jeannet J-P, Peterson VJ, Horn V, Ishmael JE, Bhat-tacharyya N, Dey A, Dawid IB, Ozato K (1997) Retinoid X receptor (RXR) within the RXR-retinoic acid receptor heterodimer binds its ligand and enhances retinoid-dependent gene expression. Mol Cell Biol 17:644–655PubMedGoogle Scholar
  41. Mukherjee R, Davies PJ A, Crombie DL, Bischoff ED, Cesario RM, Jow L, Hamann LG, Boehm MF, Mondon CE, Nadzan AM, Paterniti Jr JR, Heyman RA (1997) Sensitization of diabetic and obese mice to insulin by retinod X receptor agonists. Nature 386:407–410PubMedCrossRefGoogle Scholar
  42. Onate SA, Tsai SY, Tsai, M-J, O’Malley BW (1995) Sequence and characterization of a coactivator for thr steroid hormone receptor superfamily. Science 270:1354–1347PubMedCrossRefGoogle Scholar
  43. Oro AE, McKeown M, Evans RM (1990) Relationship between the product of the Drosophila ultraspiracle locus and the vertebrate retinoid X receptor. Nature 347:298–301PubMedCrossRefGoogle Scholar
  44. Perlmann T, Evans RM (1997) Nuclear receptors in Sicily: All in the famiglia. Cell 90:391–397PubMedCrossRefGoogle Scholar
  45. Renaud J-P, Rochel N, Ruff M, Vivat V, Chambon P, Gronemeyer H, Moras D (1995) Crystal structure of the RAR-V03B3;ligand-binding domain bound to all-trans retinoic acid. Nature 378:681–689PubMedCrossRefGoogle Scholar
  46. Schulman IG, Chakravarti D, Juguilon H, Romo A, 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 92:8288–8292PubMedCrossRefGoogle Scholar
  47. Schulman IG, Juguilon H, Evans RM (1996) Activation and repression by nuclear hormone receptors: hormone modulates an equilibrium between active and repressive states. Mol Cell Biol 16:3807–3818PubMedGoogle Scholar
  48. Schulman IG, Li C, Schwabe JW R, Evans RM (1997) The phantom ligand effect: allosteric control of transcription by the retinoid X receptor. Genes Dev 11:299–308PubMedCrossRefGoogle Scholar
  49. Schwabe JW R (1996) Transcriptional control: How nuclear receptors get turned on. Curr Biol 6:372–374PubMedCrossRefGoogle Scholar
  50. Suter SL, Nolan JJ, Wallace P, Gumbiner B, Olefsky JM (1992) Metabolic effects of new oral hypoglycemie agent CS-045 in NIDDM subjects. Diabetes Care 15 193–203PubMedCrossRefGoogle Scholar
  51. Tontonoz P, Hu E, Speigelman BM (1994) Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 79:1147–1156PubMedCrossRefGoogle Scholar
  52. Torchia J, Rose DW, Inostroza J, Kamei Y, Westin S, Glass CK, Rosenfeld MG (1997) The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387:677–684PubMedCrossRefGoogle Scholar
  53. Umesono K, Murakami KK, Thompson CC, Evans RM (1991) Direct repeats as selective response elements for the thyroid hormone, retinoic acid and vitamin D3 receptors. Cell 65:1255–1266PubMedCrossRefGoogle Scholar
  54. Vivat V, Zechel C, Wurtz J-M, Bourguet W, Kagechika H, Umemiya H, Shudo K DM, Gronemeyer H, Chambon H (1997) A mutation mimicking ligand-induced con-formational changes yields a constitutive RXR that senses allosteric effects in het-erodimers. EMBO J 16:5697–5079PubMedCrossRefGoogle Scholar
  55. Voegel JJ, Heine MJ S, Zechel C, Chambon P, Gronemeyer H (1996) TIF2, a 160 kDa transcriptional mediator for ligand-dependent activation function AF-2 of nuclear receptors. EMBO J 15:3667–3675PubMedGoogle Scholar
  56. Wagner RL, Apriletti JW, McGrath ME, West BL, Baxter JD, Fletterick RJ (1995) A structural role for hormone in the thyroid hormone receptor. Nature 378:690–697PubMedCrossRefGoogle Scholar
  57. Willson TM, Cobb JE, Cowan DJ, Wiethe RW, Correa ID, Prakash SR, Beck KD, Moore LB, Kliewer SA, Lehmann JM (1996) The structure-activity relationship between peroxisome-proliferator-activated receptor gamma and the antihyperglycemic activity of thiazolidinediones. J Med Chem 39:665–668PubMedCrossRefGoogle Scholar
  58. Yao T-P, Segraves WA Oro AE, Mckeown M, Evans RM (1992) Drosophila ultraspir-acle modulates ecdysone receptor function via heterodimer formation. Cell 71:63–72PubMedCrossRefGoogle Scholar
  59. Zamir I, Zhang J, Lazar MA (1997) Stoichiometric and steric principles governing repression by nuclear hormone receptors. Genes Dev 11:835–846PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1999

Authors and Affiliations

  • I. G. Schulman
  • D. Crombie
  • R. P. Bissonnette
  • R. Cesario
  • K. Roegner
  • G. Shao
  • R. A. Heyman

There are no affiliations available

Personalised recommendations