Principles for modulation of the nuclear receptor superfamily

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Abstract

Nuclear receptors are major targets for drug discovery and have key roles in development and homeostasis, as well as in many diseases such as obesity, diabetes and cancer. This review provides a general overview of the mechanism of action of nuclear receptors and explores the various factors that are instrumental in modulating their pharmacology. In most cases, the response of a given receptor to a particular ligand in a specific tissue will be dictated by the set of proteins with which the receptor is able to interact. One of the most promising aspects of nuclear receptor pharmacology is that it is now possible to develop ligands with a large spectrum of full, partial or inverse agonist or antagonist activities, but also compounds, called selective nuclear receptor modulators, that activate only a subset of the functions induced by the cognate ligand or that act in a cell-type-selective manner.

Key Points

  • Many factors have a role in defining the pharmacological profile of the nuclear receptor family of drug targets.

  • The response to a given ligand will be dictated by the set of proteins (from DNA-binding partners to transcriptional coregulators and transcription factors involved in crosstalk) with which this receptor will interact.

  • The potential of developing new ligands with tissue-specific and/or promoter-specific activities, called selective nuclear receptor modulators (SNuRMs), is becoming an attractive prospect for drug discovery.

  • Consideration of the evolution of nuclear receptors and developing an established nomenclature system should aid our understanding of the complex pharmacology of this receptor superfamily.

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Figure 1: Nuclear receptors in action.
Figure 2: Ligand binding induces a conformational change of the ligand-binding domain structure of nuclear receptors.
Figure 3: Comparative view of the ligand-binding pockets of the oestrogen receptor-α and -β.
Figure 4: Structural basis of antagonist action.

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References

  1. 1

    Laudet, V. & Gronemeyer, H. The Nuclear Receptors Factbooks (Academic, San Diego, 2001).

  2. 2

    Gehin, M. et al. Structural basis for engineering of retinoic acid receptor isotype-selective agonists and antagonists. Chem. Biol. 6, 519–529 (1999).

  3. 3

    Germain, P., Iyer, J., Zechel, C. & Gronemeyer, H. Co-regulator recruitment and the mechanism of retinoic acid receptor synergy. Nature 415, 187–192 (2002). This study demonstrates how receptor–coregulator interactions can be modulated by different types of ligand, and reveals the mechanism of RXR subordination.

  4. 4

    Chen, J. Y. et al. RAR-specific agonist/antagonists which dissociate transactivation and AP1 transrepression inhibit anchorage-independent cell proliferation. EMBO J. 14, 1187–1197 (1995).

  5. 5

    Coghlan, M. J. et al. A novel antiinflammatory maintains glucocorticoid efficacy with reduced side effects. Mol. Endocrinol. 17, 860–869 (2003).

  6. 6

    Herrlich, P. Cross-talk between glucocorticoid receptor and AP-1. Oncogene 20, 2465–2475 (2001).

  7. 7

    Jordan, V. C. Antioestrogens and selective oestrogen receptor modulators as multifunctional medicines. 1. Receptor interactions. J. Med. Chem. 46, 883–908 (2003).

  8. 8

    Jordan, V. C. Antioestrogens and selective oestrogen receptor modulators as multifunctional medicines. 2. Clinical considerations and new agents. J. Med. Chem. 46, 1081–1111 (2003).

  9. 9

    Shang, Y. & Brown, M. Molecular determinants for the tissue specificity of SERMs. Science 295, 2465–2468 (2002). A demonstration of the promoter-selective action of SERMs by chromatin immunoprecipitation.

  10. 10

    Hafezi-Moghadam, A. et al. Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nature Med. 8, 473–479 (2002).

  11. 11

    Simoncini, T. et al. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407, 538–541 (2000).

  12. 12

    Kumar, R. et al. A naturally occurring MTA1 variant sequesters oestrogen receptor-α in the cytoplasm. Nature 418, 654–657 (2002).

  13. 13

    Altucci, L. et al. Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nature Med. 7, 680–686 (2001). This study links the known cancer therapeutic and cancer preventive action of retinoids to the induction a death receptor ligand that is known to kill tumour but not normal cells.

  14. 14

    Wrange, Ö. & Gustafsson, J. -Å. Separation of the hormone- and DNA-binding sites of the hepatic glucocorticoid receptor by means of proteolysis. J. Biol. Chem. 253, 856–865 (1978). This is the first paper to provide solid evidence for the modular structure of nuclear receptors.

  15. 15

    Bourguet, W., Germain, P. & Gronemeyer, H. Nuclear receptor ligand-binding domains: 3D structures, molecular interactions and pharmacological implications. Trends Pharmacol. Sci. 21, 381–388 (2000).

  16. 16

    Wurtz, J. M. et al. A canonical structure for the ligand-binding domain of nuclear receptors. Nature Struct. Biol. 3, 87–94 (19996) The first generalization of the structural principles governing the conformational change induced by the ligand in the LBD of nuclear receptors.

  17. 17

    He, B. et al. Dependence of selective gene activation on the androgen receptor NH2- and COOH-terminal interaction. J. Biol. Chem. 277, 25631–25639 (2002).

  18. 18

    Glass, C. K. & Rosenfeld, M. G. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 14, 121–141 (2000).

  19. 19

    McKenna, N. J., Lanz, R. B. & O'Malley, B. W. Nuclear receptor coregulators: cellular and molecular biology. Endocrine Rev. 20, 321–344 (1999).

  20. 20

    Métivier, R. et al. Estrogen receptor-α directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 115, 751–763 (2003). An amazingly laborious study that reveals, in great detail, the cyclo-temporal interaction of a plethora of transcription factors and molecular machinery with an oestrogen receptor target gene before and after hormone induction.

  21. 21

    Laudet, V., Hänni, C., Coll, J., Catzeflis, F. & Stéhelin, D. Evolution of the nuclear receptor superfamily. EMBO J. 11, 1003–1013 (1992). The first evolutionary analysis of the nuclear receptor superfamily, and the first classification of the superfamily into several subfamilies.

  22. 22

    Escriva, H., Bertrand, S. & Laudet, V. The evolution of the nuclear receptor superfamily. Essays Biochem. 40, 11–26 (2004).

  23. 23

    Kuiper, G. G., Enmark, E., Pelto-Huikko, M., Nilsson, S. & Gustafsson, J. -Å. Cloning of a novel receptor expressed in rat prostate and ovary. Proc. Natl Acad. Sci. USA 93, 5925–5230 (1996). This paper is the first report on the novel oestrogen receptor-β. This discovery has led to a paradigm shift in our understanding of oestrogen signalling.

  24. 24

    Gustafsson, J. -Å. What pharmacologists can learn from recent advances in oestrogen signaling. Trends Pharmacol. Sci. 24, 479–485 (2003). The author summarizes the pharmaceutical potential of oestrogen receptor-β-targeted drugs.

  25. 25

    Katzenellenbogen, B. S. et al. Structure-function relationships in oestrogen receptors and the characterization of novel selective oestrogen receptor modulators with unique pharmacological profiles. Ann. NY Acad. Sci. 949, 6–15 (2001).

  26. 26

    Matt, N., Ghyselinck, N. B., Wendling, O., Chambon, P. & Mark, M. Retinoic acid-induced developmental defects are mediated by RARβ/RXR heterodimers in the pharyngeal endoderm. Development 130, 2083–2093 (2003).

  27. 27

    Massaro, G. D., Massaro, D. & Chambon, P. Retinoic acid receptor-α regulates pulmonary alveolus formation in mice after, but not during, perinatal period. Am. J. Physiol. Lung Cell. Mol. Physiol. 284, L431–L433 (2003).

  28. 28

    Chiang, M. Y. et al. An essential role for retinoid receptors RARβ and RXRγ in long-term potentiation and depression. Neuron 21, 1353–1361 (1998).

  29. 29

    Kastner, P. et al. Positive and negative regulation of granulopoiesis by endogenous RARα. Blood 97, 1314–1320 (2001).

  30. 30

    Li, M. et al. Skin abnormalities generated by temporally controlled RXRα mutations in mouse epidermis. Nature 407, 633–636 (2000).

  31. 31

    Zusi, F. C., Lorenzi, M. V. & Vivat-Hannah, V. Selective retinoids and rexinoids in cancer therapy and chemoprevention. Drug Discov. Today 7, 1165–1174 (2002).

  32. 32

    Chen, J. Y. et al. Two distinct actions of retinoid-receptor ligands. Nature 382, 819–822 (1996).

  33. 33

    Nagy, L. et al. Activation of retinoid X receptors induces apoptosis in HL-60 cell lines. Mol. Cell. Biol. 15, 3540–3551 (1995).

  34. 34

    Renaud, J. P. et al. Crystal structure of the RAR-γ ligand-binding domain bound to all-trans retinoic acid. Nature 378, 681–689 (1995).

  35. 35

    Klaholz, B. P., Mitschler, A. & Moras, D. Structural basis for isotype selectivity of the human retinoic acid nuclear receptor. J. Mol. Biol. 302, 155–170 (2000).

  36. 36

    Klaholz, B. P. et al. Conformational adaptation of agonists to the human nuclear receptor RAR-γ. Nature Struct. Biol. 5, 199–202 (1998).

  37. 37

    Billas, I. M. L. et al. Structural adaptability in the ligand-binding pocket of the ecdysone hormone receptor. Nature 426, 91–96 (2003).

  38. 38

    Färnegardh, M. et al. The three-dimensional structure of the liver X receptor-β reveals a flexible ligand-binding pocket that can accommodate fundamentally different ligands. J. Biol. Chem. 278, 38821–38828 (2003)

  39. 39

    Paech, K. et al. Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science 277, 1508–1510 (1997). A landmark study that describes the paradoxical agonist activity of ligands interacting with oestrogen receptor-β on AP1 response element.

  40. 40

    Berry, M., Metzger, D. & Chambon, P. Role of the two activating domains of the oestrogen receptor in the cell-type and promoter-context dependent agonistic activity of the anti-oestrogen 4-hydroxytamoxifen. EMBO J. 9, 2811–2818 (1990).

  41. 41

    Kushner, P. J., et al. Estrogen receptor pathways to AP-1. J. Steroid Biochem. Mol. Biol. 74, 311–317 (2000).

  42. 42

    Saville, B, et al. Ligand-, cell-, and estrogen receptor subtype (α/β)-dependent activation at GC-rich (Sp1) promoter elements. J. Biol. Chem. 275, 5379–5387 (2000).

  43. 43

    Liu, M. M. et al. Opposing action of estrogen receptors α and β on cyclin D1 gene expression. J. Biol. Chem. 277, 24353–24360 (2002).

  44. 44

    Chen, H., Tini, M. & Evans, R. M. HATs on and beyond chromatin. Curr. Opin. Cell. Biol. 13, 218–224 (2001).

  45. 45

    Shang, Y., Hu, X., Di Renzo, J., Lazar, M. A. & Brown, M. Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 103, 843–852 (2000). The first report of the cyclic interaction of transcription factors with a hormone-inducible promoter.

  46. 46

    Ikura, T. et al. Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell 102, 463–473 (2000).

  47. 47

    Katzenellenbogen, B. S. & Katzenellenbogen, J. A. Defining the 'S' in SERMs. Science 295, 2380–2381 (2002).

  48. 48

    Bocquel, M. T., Kumar, V., Stricker, C., Chambon, P. & Gronemeyer, H. The contribution of the N- and C-terminal regions of steroid receptors to activation of transcription is both receptor and cell-specific. Nucleic Acids Res. 17, 2581–2595 (1989). On the basis of squelching experiments, the authors predict the existence of transcriptional intermediary factors for nuclear receptors, now referred to as coregulators, which act in a receptor and cell-type-specific manner.

  49. 49

    Sporn, M. B., Suh, N. & Mangelsdorf, D. J. Prospects for prevention and treatment of cancer with selective PPARγ modulators (SPARMs). Trends Mol. Med. 7, 395–400 (2001).

  50. 50

    Negro-Vilar, A. Selective androgen receptor modulators (SARMs): a novel approach to androgen therapy for the new millennium. J. Clin. Endocrinol. Metab. 84, 3459–3462 (1999).

  51. 51

    Giannoukos, G., Szapary, D., Smith, C. L., Meeker, J. E. & Simons, S. S. New antiprogestins with partial agonist activity: potential selective progesterone receptor modulators (SPRMs) and probes for receptor- and coregulator-induced changes in progesterone receptor induction properties. Mol. Endocrinol. 15, 255–270 (2001).

  52. 52

    Rocchi, et al. A unique PPARγ ligand with potent insulin-sensitizing yet weak adipogenic activity. Mol. Cell 8, 737–747 (2001).

  53. 53

    Olive, D. L. Role of progesterone antagonists and new selective progesterone receptor modulators in reproductive health. Obstet. Gynecol. Surv. 57, S55–S63 (2002).

  54. 54

    Brower, V. A second chance for hormone replacement therapy? EMBO Rep. 4, 1112–1115 (2003).

  55. 55

    de Urquiza, A. M. et al. Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science 290, 2140–2144 (2000). Using a clever genetic strategy, the authors identified docosahexenoic acid as a potential endogenous RXR ligand.

  56. 56

    Kurokawa, R. et al. Regulation of retinoid signalling by receptor polarity and allosteric control of ligand binding. Nature 371, 528–531 (1994).

  57. 57

    Chen, Z. et al. Ligand- and DNA-induced dissociation of RXR tetramers. J. Mol. Biol. 275, 55–65 (1998).

  58. 58

    Kersten, S., Dawson, M. I., Lewis, B. A. & Noy, N. Individual subunits of heterodimers comprised of retinoic acid and retinoid X receptors interact with their ligands independently. Biochemistry 35, 3816–3824 (1996).

  59. 59

    Minucci, S. et al. Retinoid X receptor (RXR) within the RXR-retinoic acid receptor heterodimer binds its ligand and enhances retinoid-dependent gene expression. Mol. Cell. Biol. 17, 644–655 (1997).

  60. 60

    Altucci, L. & Gronemeyer, H. The promise of retinoids to fight against cancer. Nature Rev. Cancer 1, 181–193 (2001).

  61. 61

    Germain, P. et al. Rational design of RAR selective ligands revealed by RARβ crystal structure. EMBO Rep. 5, 877–882 (2004).

  62. 62

    Blumberg, B. & Evans, R. M. Orphan nuclear receptors — new ligands and new possibilities. Genes Dev. 12, 3149–3155 (1998).

  63. 63

    Wiebel, F. F., Steffensen, K. R., Treuter, E., Feltkamp, D. & Gustafsson, J. -Å. Ligand-independent coregulator recruitment by the triply activatable OR1/Retinoid X receptor-α nuclear receptor heterodimer. Mol. Endocrinol. 13, 1105–1118 (1999).

  64. 64

    Esteva, F. J. et al. Multicenter phase II study of oral bexarotene for patients with metastatic breast cancer. J. Clin. Oncol. 21, 999–1006 (2003).

  65. 65

    Mukherjee, R. et al. Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists. Nature 386, 407–410 (1997).

  66. 66

    Michellys, P. Y. et al. Novel (2E,4E,6Z)-7-(2-alkoxy-3,5-dialkylbenzene)-3-methylocta-2,4,6-trienoic acid retinoid X receptor modulators are active in models of type 2 diabetes. J. Med. Chem. 46, 2683–2696 (2003).

  67. 67

    Duvic, M. et al. Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II–III trial results. J. Clin. Oncol. 19, 2456–2471 (2001).

  68. 68

    Krathen, R. A., Ward, S. & Duvic, M. Bexarotene is a new treatment option for lymphomatoid papulosis. Dermatology 206, 142–147 (2003).

  69. 69

    Aboulafia, D. M. et al. 9-cis-retinoic acid capsules in the treatment of AIDS-related Kaposi sarcoma: results of a phase 2 multicenter clinical trial. Arch. Dermatol. 139, 178–186 (2003)

  70. 70

    Benoit, G. et al. RAR-independent RXR signaling induces t(15;17) leukemia cell maturation. EMBO J. 18, 7011–7018 (1999).

  71. 71

    Dawson, M. I. Synthetic retinoids and their nuclear receptors. Curr. Med. Chem. Anti-Canc. Agents 4, 199–230 (2004).

  72. 72

    Hong, W. K. & Sporn, M. B. Recent advances in chemoprevention of cancer. Science 278, 1073–1077 (1997).

  73. 73

    Sudbo, J. et al. Molecular based treatment of oral cancer. Oral Oncol. 39, 749–758 (2003).

  74. 74

    Sun, S. Y. & Lotan, R. Retinoids and their receptors in cancer development and chemoprevention. Crit. Rev. Oncol. Hematol. 41, 41–55 (2002).

  75. 75

    Shin, D. M. et al. Accumulation of p53 protein and retinoic acid receptor-β in retinoid chemoprevention. Clin. Cancer Res. 3, 875–880 (1997).

  76. 76

    Kurie, J. M. et al. Treatment of former smokers with 9-cis-retinoic acid reverses loss of retinoic acid receptor-β expression in the bronchial epithelium: results from a randomized placebo-controlled trial. J. Natl Cancer Inst. 95, 206–214 (2003).

  77. 77

    Clarke, N. et al. Tumor suppressor IRF1 mediates retinoid and interferon anti-cancer signalling to death ligand TRAIL. EMBO J. 23, 3051–3060 (2004).

  78. 78

    Giguere, V., Yang, N., Segui, P. & Evans, R. M. Identification of a new class of steroid hormone receptors. Nature 331, 91–94 (1988). This paper provides the first description of an orphan receptor.

  79. 79

    Tremblay, G. B. et al. Diethylstilbestrol regulates trophoblast stem cell differentiation as a ligand of orphan nuclear receptor ERRβ. Genes Dev. 15, 833–888 (2001).

  80. 80

    Coward, P., Lee, D., Hull, M. V. & Lehmann, J. M. 4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor-γ. Proc. Natl Acad. Sci. USA 98, 8880–8884 (2001).

  81. 81

    Horard, B. & Vanacker, J. -M. ERRs: orphan receptors desperately seeking ligand. J. Mol. Endocrinol. 31, 349–357 (2003).

  82. 82

    Vanacker, J. M., Pettersson, K., Gustafsson, J. -Å. & Laudet, V. Transcriptional targets shared by estrogen-receptor related receptors (ERRs) and estrogen receptors (ER)α but not by ERβ. EMBO J. 18, 4270–4279 (1999).

  83. 83

    Bonnelye, E. et al. The ERR-1 orphan receptor is a transcriptional activator expressed during bone formation. Mol. Endocrinol. 11, 905–916 (1997).

  84. 84

    Bonnelye, E. & Aubin, J. E. Differential expression of estrogen receptor-related receptor-α and estrogen receptors α and β in osteoblasts in vivo and in vitro. J. Bone Miner. Res. 17, 1392–1400 (2002).

  85. 85

    Chawla, A., Repa, J. J., Evans, R. M. & Mangelsdorf, D. J. Nuclear receptors and lipid physiology: opening the X-files. Science 294, 1866–1870 (2001).

  86. 86

    Lee, C. H., Olson, P. & Evans, R. M. Lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology 144, 2201–2207 (2003).

  87. 87

    Solomin, L. et al. Retinoid-X receptor signalling in the developing spinal cord. Nature 395, 398–402 (1998).

  88. 88

    Conneely, O. M., Mulac-Jericevic, B., Lydon, J. P. & de Mayo, F. J. Reproductive functions of the progesterone receptor isoforms: lessons from knock-out mice. Mol. Cell. Endocrinol. 179, 97–103 (2001).

  89. 89

    Kliewer, S. A. et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92, 73–82 (1998).

  90. 90

    Dotzlaw, H., Leygue, E., Watson, P. & Murphy, L. C. The human orphan receptor PXR messenger RNA is expressed in both normal and neoplastic breast tissue. Clin. Cancer Res. 5, 2103–2107 (1999).

  91. 91

    De Bosscher, K., Vanden Berghe, W. & Haegeman, G. Glucocorticoid repression of AP-1 is not mediated by competition for nuclear coactivators. Mol. Endocrinol. 15, 219–227 (2001).

  92. 92

    Kassel, O. et al. A nuclear isoform of the focal adhesion LIM domain protein Trip6 integrates activating and repressing signals at AP-1- and NF-κB-regulated promoters. Genes Dev. 18, 2518–2528 (2004).

  93. 93

    Reichardt, H. M., Tronche, F., Berger, S., Kellendonk, C. & Schutz, G. New insights into glucocorticoid and mineralocorticoid signaling: lessons from gene targeting. Adv. Pharmacol. 47, 1–21 (2000).

  94. 94

    Vayssiere, B. M. et al. Synthetic glucocorticoids that dissociate transactivation and AP-1 transrepression exhibit antiinflammatory activity in vivo. Mol. Endocrinol. 11, 1245–1255 (1997).

  95. 95

    Van den Berghe, W., Francesconi, E., De Bosscher, K., Resche-Rigon, M. & Haegeman, G. Dissociated glucocorticoids with anti-inflammatory potential repress interleukin-6 gene expression by a nuclear factor-κB-dependent mechanism. Mol. Pharmacol. 56, 797–806 (1999).

  96. 96

    Fu, M. et al. Androgen receptor acetylation governs trans activation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function. Mol. Cell. Biol. 22, 3373–3388 (2002).

  97. 97

    Wang, C. et al. Direct acetylation of the oestrogen receptor-α hinge region by p300 regulates transactivation and hormone sensitivity. J. Biol. Chem. 276, 18375–18383 (2001).

  98. 98

    Couse, J. F. & Korach, K. S. Oestrogen receptor null mice: what have we learned and where will they lead us? Endocr. Rev. 20, 358–417 (1999).

  99. 99

    Michalides, R. et al. Tamoxifen resistance by a conformational arrest of the estrogen receptor a after PKA activation in breast cancer. Cancer Cell 5, 597–605 (2004).

  100. 100

    Chambliss, K. L. & Shaul, P. W. Oestrogen modulation of endothelial nitric oxide synthase. Endocr. Rev. 23, 665–686 (2002).

  101. 101

    Kousteni, S. et al. Nongenotropic, sex-nonspecific signaling through the oestrogen or androgen receptors: dissociation from transcriptional activity. Cell 104, 719–730 (2001).

  102. 102

    Stehlin-Gaon, C. et al. All-trans retinoic acid is a ligand for the orphan nuclear receptor RORβ. Nature Struct. Biol. 10, 820–825 (2003).

  103. 103

    Shaw, N., Elholm, M. & Noy, N. Retinoic acid is a high affinity selective ligand for the peroxisome proliferator-activated receptorβ/δ. J. Biol. Chem. 278, 41589–41592 (2003).

  104. 104

    Escriva, H. et al. Ligand binding was acquired during evolution of nuclear receptors. Proc. Natl Acad. Sci. USA 94, 6803–6808 (1997). The authors demonstrate that nuclear receptors are specific to metazoans. This paper also suggests that the first nuclear receptor was an orphan receptor and that liganded receptors gained ligand-binding capactities independently and at a later stage.

  105. 105

    Grasso, L. C. et al. The evolution of nuclear receptors: evidence from the coral Acropora. Mol. Phylogenet. Evol. 21, 93–102 (2001).

  106. 106

    Kostrouch, Z. et al. Retinoic acid X receptor in the diploblast, Tripedalia cystophora. Proc. Natl Acad. Sci. USA 95, 13442–13447 (1998). The suggestion that RXR is a very ancient receptor, and that the RXR from early metazoans can bind 9- cis retinoic acid in vitro , is put forward by the authors in this paper.

  107. 107

    Wiens, M., Batel, R., Korzhev, M. & Muller, W. E. Retinoid X receptor and retinoic acid response in the marine sponge Suberites domuncula. J. Exp. Biol. 206, 3261–3271 (2003).

  108. 108

    Thornton, J. W., Need, E. & Crews, D. Resurrecting the ancestral steroid receptor: ancient origin of estrogen signaling. Science 301, 1714–1717 (2003).

  109. 109

    Ohtake, F. et al. Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature 423, 545–550 (2003). This study reveals that the dioxin receptor can signal through ERα and ERβ through direct interaction of AhR/Arnt with ERα and ERβ, thereby explaining the oestrogen-related actions of dioxins.

  110. 110

    Norris, J. D. et al. Peptide antagonists of the human estrogen receptor. Science 285, 744–746 (1999).

  111. 111

    Ferrara, F. F. et al. Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia. Cancer Res. 61, 2–7 (2001). A demonstration that HDAC inhibitors can restore antiproliferative retinoic acid signalling in acute myeloid leukaemia cells that are otherwise unresponsive to retinoids. This is an important argument for the development of combination therapies in which one drug prepares the target tissue for the action of the other.

  112. 112

    Nuclear Receptor Nomenclature Committee. A unified nomenclature system for the nuclear receptors superfamily. Cell 97, 161–163 (1999).

  113. 113

    Rochette-Egly, C. Nuclear receptors: integration of multiple signalling pathways through phosphorylation. Cell Signal. 15, 355–366 (2003).

  114. 114

    Bertrand, S. et al. Evolutionary genomics of nuclear receptors: from 25 ancestral genes to derived endocrine systems Mol. Biol. Evol. 21, 1923–1937 (2004). The most recent evolutionary analysis of the nuclear receptor superfamily based on the evolution of all complete genome sequences available. It suggests that in addition to gene duplication, gene loss has had an important role in nuclear receptor evolution.

  115. 115

    Elger, W. et al. International patent application WO-03045396.

  116. 116

    Robinson-Rechavi, M. Escriva-Garcia, H. & Laudet, V. The nuclear receptor superfamily. J. Cell Sci. 116, 585–586 (2003).

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Acknowledgements

V.L. thanks S. Watson, J. Samarut and M. Schubert for critical reading of the manuscript as well as H. Escriva and J. Katzenellenbogen for help in preparation. H.G. would like to thank the members of his and D. Moras' lab for discussions and figures. J.-Å.G. also thanks K. Koehler for discussions and for figures. Work in our laboratories is supported by grants from the Association for International Cancer Research, the Association pour la Recherche contre le Cancer, the Fondation de France, the European Community, Bristol-Myers Squibb, The Swedish Cancer Fund, The Swedish Science Council, KaroBio AB, Centre National de la Recherche Scientifique, Ministère de la Recherche et de la Technologie, and Région Rhône-Alpes. This publication is supported by the CASCADE network of excellence of the European Community.

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Correspondence to Vincent Laudet.

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AP1

AR

CAR

CARM1

DAX1

eNOS

EP300

NCOA1

NCOA2

NCOR1

NCOR2

PCAF

PXR

RAR

RXR

SF1

SP1

THR

VDR

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Glossary

INVERSE (ANT)AGONIST

A ligand that stabilizes an inactive conformation of a receptor — for example, by increasing corepressor interaction, thereby decreasing signalling below basal levels.

SELECTIVE NUCLEAR RECEPTOR MODULATORS

(SNuRMS). Ligands that selectively modulate different receptor subtypes and/or act in a cell-selective manner.

NON-GENOMIC ACTION

Action of a ligand that does not involve the activation of the target genes of its cognate receptor.

TRANSACTIVATION

Activation of transcription by the binding of a transcription factor to a DNA regulatory sequence.

BIO-ISOSTERIC REPLACEMENT

The creation of a new compound with similar biological properties to the parent compound by exchanging an atom or a group of atoms with another, broadly similar atom or group of atoms.

ALL-TRANS RETINOIC ACID SYNDROME

A side effect that occurs in 10–15% of patients that is preceded by increasing leukocyte count and that includes fever, respiratory distress, weight gain and oedema of the lower extremities and which is fatal in at least 10% of cases.

LYMPHOMATOID PAPULOSIS

A chronic lymphoproliferative disease of the skin.

TRANSREPRESSION

Repression of transcription through a mechanism in which a transcriptional activator, such as a nuclear receptor, represses the transcriptional activation potential of another transactivator, such as AP1, without binding to DNA or altering the DNA-binding activity of AP1. Several mechanisms have been proposed (see text), but none explains all of the experimental observations.

APTAMERS

Protein-based recognition agents that block protein–protein interactions.

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Gronemeyer, H., Gustafsson, J. & Laudet, V. Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3, 950–964 (2004) doi:10.1038/nrd1551

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