Abstract
Cellular signaling uses two main pathways, the membrane-associated and the nuclear receptors (NRs). The characteristic of the first is the use of water-soluble ligands which do not cross the membrane. Ligand binding at the cell surface induces, e.g., autophosphorylation of epidermal growth factor (EGF) receptor, starting a cascade of serine- or tyrosine-kinases, finally transducing the signal to the nucleus. NRs work very differently. Located in the nucleus they control the activity of their target genes directly by binding to specific DNA sequences called hormone response elements. They are activated by hydrophobic ligands, like the steroid hormones and retinoids, which reach their receptor in the cytoplasm or the nucleus by crossing the lipid bilayer of the cell membrane. Some of these ligands, such as retinoic acid, need to be metabolically modified, others are completely synthesized in the cell, as Prostaglandins.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Allegretto EA, McClurg MR, Lazarchik SB, Clemm DL, Kerner SA, Elgort MG, Boehm MF, White SK, Pike JW, Heyman RA (1993) Transactivation properties of retinoic acid and retinoid X receptors in mammalian cells and yeast. Correlation with hormone binding and effects of metabolism [published erratum appears in J Biol Chem 1994 Mar 11; 269 (10):7834]. J Biol Chem 268: 26625–26633
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
Bernard BA, Bernardon JM, Delescluse C, Martin B, Lenoir MC, Maignan J, Charpentier B, Pilgrim WR, Reichert U, Shroot B (1992) Identification of synthetic retinoids with selectivity for human nuclear retinoic acid receptor gamma. Biochem Biophys Res Commun 186: 977–983
Bourguet W, Ruff M, Chambon P, Gronemeyer H, Moras D (1995) Crystal structure of the ligand-binding domain of the human nuclear receptor RXRalpha. Nature 375: 377–382
Brzozowski AM, Pike ACW, Dauter Z, Hubbard RE, Bonn T, Engström O, 0h-man L, Greene GL, Gustafsson JA, Carlquist M (1997) Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389: 753–758
Chambon P (1996) A decade of molecular biology of retinoic acid receptors. FASEB J 10: 940–954
Chen JD, Evans RM (1995) A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377: 454–457
Chen JD, Umesono K, Evans RM (1996) SMRT isoforms mediate repression and anti-repression of nuclear receptor heterodimers. Proc Natl Acad Sci USA 93: 7567–7571
Dawson MI, Chao WR, Pine P, Jong L, Hobbs PD, Rudd CK, Quick TC, Niles RM, Zhang XK, Lombardo A et al (1995) Correlation of retinoid binding affinity to retinoic acid receptor alpha with retinoid inhibition of growth of estrogen receptor-positive MCF-7 mammary carcinoma cells. Cancer Res 55: 4446–4451
De Luca LM (1991) Retinoids and their receptors in differentiation, embryo-genesis, and neoplasia. FASEB J 5: 2924–2933
Driscoll JE, Seachord CL, Lupisella JA, Darveau RP, Reczek PR (1996) Ligand-induced conformational changes in the human retinoic acid receptor detected using monoclonal antibodies. J Biol Chem 271: 22969–22975
Escriva H, Safi R, Hänni C, Langlois MC, Saumitou-Laprade P, Stehelin D, Capron A, Pierce R, Laudet V (1997) Ligand binding was aquired during evolution of nuclear receptors. Proc Natl Acad Sci USA 94: 6803–6808
Evans SV (1993) Setor: hardware lighted three-dimensional solid model representations of macromolecules. J Mol Graphics 11: 134–138
Giguere V (1994) Retinoic acid receptors and cellular retinoid binding proteins: complex interplay in retinoid signaling. Endocr Rev 15: 61–79
Gronemeyer H, Moras D (1995) Nuclear receptors. How to finger DNA. Nature 375: 190–191
Hembree JR, Agarwal C, Beard RL, Chandraratna RA, Eckert R (1996) Retinoid X receptor-specific retinoids inhibit the ability of retinoic acid receptor-specific retinoids to increase the level of insulin-like growth factor binding protein-3 in human ectocervical epithelial cells. Cancer Res 56: 1794–1799
Horwitz KB, Jackson TA, Bain DL, Richer JK, Takimoto GS, Tung L (1996) Nuclear receptor coactivators and corepressors. Mol Endocrinol 10: 1167–1177
Hörlein AJ, Naar AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamei Y, Soderstrom M, Glass CK et al (1995) Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377: 397–404
Kastner P, Mark M, Chambon P (1995) Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 83: 859–869
Keidel S, Le Motte P, Apfel C (1994) Different agonist-and antagonist-induced conformational changes in retinoic acid receptors analyzed by protease mapping. Mol Cell Biol 14: 287–298
Klaholz BP, Renaud JP, Mitschler A, Zusi C, Chambon P, Gronemeyer H, Moras D (1998) Conformational adaptation of agonists to the human nuclear receptor RARy. Nat Struct Biol 5: 199–202
Kurokawa R, Di Renzo 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: 528–531
Lee MS, Kliewer SA, Provencal J, Wright PE, Evans RM (1993) Structure of the retinoid X receptor alpha DNA binding domain: a helix required for homodimeric DNA binding. Science 260: 1117–1121
Leid M (1994) Ligand-induced alteration of the protease sensitivity of retinoid X receptor alpha. J Biol Chem 269: 14175–14181
Leng X, Tsai SY, O’Malley BW, Tsai MJ (1993) Ligand-dependent conformational changes in thyroid hormone and retinoic acid receptors are potentially enhanced by heterodimerization with retinoic X receptor. J Steroid Biochem Mol Biol 46: 643–661
Leng X, Blanco J, Tsai SY, Ozato K, O’Malley BW, Tsai MJ (1995) Mouse retinoid X receptor contains a separable ligand-binding and transactivation domain in its E region. Mol Cell Biol 15: 255–263
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 RXR alpha. Nature 355: 359–361
Lotan R (1997) Retinoids and chemoprevention of aerodigestive tract cancers. Cancer Metastasis Rev 16: 349–356
Luisi BF, Xu WX, Otwinowski Z, Freedman LP, Yamamoto KR, Sigler PB (1991) Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA. Nature 352: 497–505
Mader S, Chen JY, Chen Z, White J, Chambon P, Gronemeyer H (1993) The patterns of binding of RAR, RXR and TR homo-and heterodimers to direct repeats are dictated by the binding specificites of the DNA binding domains. EMBO J 12: 5029–5041
Mangelsdorf DJ, Evans RM (1995) The RXR heterodimers and orphan receptors. Cell 83: 841–850
Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P et al (1995) The nuclear receptor superfamily: the second decade. Cell 83: 835–839
McInerney EM, Tsai MJ, O’Malley BW, Katzenellenbogen BS (1996) Analysis of estrogen receptor transcriptional enhancement by a nuclear hormone receptor coactivator. Proc Natl Acad Sci USA 93: 10069–10073
Napoli JL (1996) Retinoic acid biosynthesis and metabolism. FASEB J 10: 993–1001
Nicholls A, Sharp KA, Honig B (1991) Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins 11: 281–286
Niles RM (1995) Use of vitamins A and D in chemoprevention and therapy of cancer: control of nuclear receptor expression and function. Vitamins, cancer and receptors. Adv Exp Med Biol 375: 1–15
Orate SA, Tsai SY, Tsai MJ, O’Malley BW (1995) Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270: 1354–1357
Rastinejad F, Perlmann T, Evans RM, Sigler PB (1995) Structural determinants of nuclear receptor assembly on DNA direct repeats. Nature 375: 203–211
Renaud JP, Rochel N, Ruff M, Vivat V, Chambon P, Gronemeyer H, Moras D (1995) Crystal structure of the RAR-gamma ligand-binding domain bound to all-trans retinoic acid. Nature 378: 681–689
Rochette-Egly C, Adam S, Rossignol M, Egly JM, Chambon P (1997) Stimulation of RAR-alpha activation function AF-1 through binding to the general transcription factor TFIIH and phosphorylation by cdk7. Cell 90: 97–107
Schwabe JWR, Chapman L, Finch JT, Rhodes D, Neuhaus D (1993) DNA recognition by the oestrogen receptor: from solution to the crystal. Structure 1: 187–204
Tallman MS, Wiernik PH (1992) Retinoids in cancer treatment. J Clin Pharmacol 32: 868–888
Voegel JJ, Heine MJ, Zechel C, Chambon P, Gronemeyer H (1996) TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO J 15: 3667–3675
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: 690–697
Wurtz JM, Bourguet W, Renaud JP, Vivat V, Chambon P, Moras D, Gronemeyer H (1996) A canonical structure for the ligand-binding domain of nuclear receptors. Nat Struct Biol 3: 87–94
Ylikomi T, Bocquel MT, Berry M, Gronemeyer H, Chambon P (1992) Cooperation of proto-signals for nuclear accumulation of estrogen and progesterone receptors. EMBO J 11: 3681–3694
Zechel C, Shen XQ, Chambon P, Gronemeyer H (1994a) Dimerization interfaces formed between the DNA binding domains determine the cooperative binding of RXR/RAR and RXR/TR heterodimers to DR5 and DR4 elements. EMBO J 13: 1414–1424
Zechel C, Shen XQ, Chen JY, Chen ZP, Chambon P, Gronemeyer H (1994b) The dimerization interfaces formed between the DNA binding domains of RXR, RAR and TR determine the binding specificity and polarity of the full-length receptors to direct repeats. EMBO J 13: 1425–1433
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1998 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Klaholz, B.P., Moras, D. (1998). A Structural View of the Retinoid Nuclear Receptors. In: Gronemeyer, H., Fuhrmann, U., Parczyk, K. (eds) Molecular Basis of Sex Hormone Receptor Function. Ernst Schering Research Foundation Workshop, vol 24. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-03689-1_8
Download citation
DOI: https://doi.org/10.1007/978-3-662-03689-1_8
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-03691-4
Online ISBN: 978-3-662-03689-1
eBook Packages: Springer Book Archive