Molecular Endocrinology, Vol 8, 757-770, Copyright © 1994 by Endocrine Society

ARTICLES

RZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers

C Carlberg, R Hooft van Huijsduijnen, JK Staple, JF DeLamarter and M Becker- Andre
Clinique de Dermatologie, Hopital Cantonal Universitaire, Geneva, Switzerland.

Members of the superfamily of nuclear receptors share the greatest homology in their DNA-binding domains. We have used reverse transcription-polymerase chain reaction and highly degenerate primers based on the amino acid sequence of the zinc finger motif of known nuclear receptors to identify novel members of the family. Starting with rat brain RNA, we have isolated an orphan receptor that we call RZR beta. The sequence of its nearly full-length complementary DNA shows great similarity to RZR alpha, a receptor we recently identified from human umbilical vein endothelial cells. These RZR subtypes represent members of a new family of orphan nuclear receptors that most likely regulate specific gene expression. Sequence comparison with other known nuclear receptors reveals great similarity for both RZR subtypes to retinoic acid and retinoid-X receptors. By Northern blot analyses, we found RZR beta messenger RNA only in brain, whereas RZR alpha is expressed in many tissues. We show here that the RZRs bind as monomers to natural retinoid response elements formed by (A/G)GGTCA half-sites. However, a T-residue in the -1 position of this motif greatly enhances the DNA binding affinity of RZRs, whereas the -2 position has no influence. We show that RZRs can bind as homodimers on response elements formed by palindromes, inverted palindromes, or direct repeats of two TAGGTCA half-sites. Interestingly, these response elements display dramatically reduced affinity for retinoic acid receptor-retinoid-X receptor heterodimers. Thus, the 5'-flanking sequence of hexameric half-sites appears to be crucial to direct the activity of several nuclear receptors. On monomeric as well as dimeric binding sites, RZRs show constitutive transactivational activity that can be enhanced by unidentified components of fetal calf serum.

This article has been cited by other articles:

				T. Wada, H. S. Kang, A. M. Jetten, and W. Xie The Emerging Role of Nuclear Receptor ROR{alpha} and Its Crosstalk with LXR in Xeno- and Endobiotic Gene Regulation Experimental Biology and Medicine, October 1, 2008; 233(10): 1191 - 1201. [Abstract] [Full Text] [PDF]

				S. Hummasti and P. Tontonoz Adopting New Orphans into the Family of Metabolic Regulators Mol. Endocrinol., August 1, 2008; 22(8): 1743 - 1753. [Abstract] [Full Text] [PDF]

				F. Madoux, X. Li, P. Chase, G. Zastrow, M. D. Cameron, J. J. Conkright, P. R. Griffin, S. Thacher, and P. Hodder Potent, Selective and Cell Penetrant Inhibitors of SF-1 by Functional Ultra-High-Throughput Screening Mol. Pharmacol., June 1, 2008; 73(6): 1776 - 1784. [Abstract] [Full Text] [PDF]

				T. Wada, H. S. Kang, M. Angers, H. Gong, S. Bhatia, S. Khadem, S. Ren, E. Ellis, S. C. Strom, A. M. Jetten, et al. Identification of Oxysterol 7{alpha}-Hydroxylase (Cyp7b1) as a Novel Retinoid-Related Orphan Receptor {alpha} (ROR{alpha}) (NR1F1) Target Gene and a Functional Cross-Talk between ROR{alpha} and Liver X Receptor (NR1H3) Mol. Pharmacol., March 1, 2008; 73(3): 891 - 899. [Abstract] [Full Text] [PDF]

				S. Raichur, P. Lau, B. Staels, and G. E O Muscat Retinoid-related orphan receptor {gamma} regulates several genes that control metabolism in skeletal muscle cells: links to modulation of reactive oxygen species production J. Mol. Endocrinol., July 1, 2007; 39(1): 29 - 44. [Abstract] [Full Text] [PDF]

				M. I. Masana, I. C. Sumaya, M. Becker-Andre, and M. L. Dubocovich Behavioral characterization and modulation of circadian rhythms by light and melatonin in C3H/HeN mice homozygous for the RORbeta knockout Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2007; 292(6): R2357 - R2367. [Abstract] [Full Text] [PDF]

				F. Molnar, M. Matilainen, and C. Carlberg Structural Determinants of the Agonist-independent Association of Human Peroxisome Proliferator-activated Receptors with Coactivators J. Biol. Chem., July 15, 2005; 280(28): 26543 - 26556. [Abstract] [Full Text] [PDF]

				A. Genoux, H. Dehondt, A. Helleboid-Chapman, C. Duhem, D. W. Hum, G. Martin, L. A. Pennacchio, B. Staels, J. Fruchart-Najib, and J.-C. Fruchart Transcriptional Regulation of Apolipoprotein A5 Gene Expression by the Nuclear Receptor ROR{alpha} Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1186 - 1192. [Abstract] [Full Text] [PDF]

				A. Slominski, J. Wortsman, and D. J. Tobin The cutaneous serotoninergic/melatoninergic system: securing a place under the sun FASEB J, February 1, 2005; 19(2): 176 - 194. [Abstract] [Full Text] [PDF]

				C. V. Rider, T. A. Gorr, A. W. Olmstead, B. A. Wasilak, and G. A. LeBlanc Stress signaling: coregulation of hemoglobin and male sex determination through a terpenoid signaling pathway in a crustacean J. Exp. Biol., January 1, 2005; 208(1): 15 - 23. [Abstract] [Full Text] [PDF]

				I. Dzhagalov, V. Giguere, and Y.-W. He Lymphocyte Development and Function in the Absence of Retinoic Acid-Related Orphan Receptor {alpha} J. Immunol., September 1, 2004; 173(5): 2952 - 2959. [Abstract] [Full Text] [PDF]

				P. Lau, S. J. Nixon, R. G. Parton, and G. E. O. Muscat ROR{alpha} Regulates the Expression of Genes Involved in Lipid Homeostasis in Skeletal Muscle Cells: CAVEOLIN-3 AND CPT-1 ARE DIRECT TARGETS OF ROR J. Biol. Chem., August 27, 2004; 279(35): 36828 - 36840. [Abstract] [Full Text] [PDF]

				N. Miki, M. Ikuta, and T. Matsui Hypoxia-induced Activation of the Retinoic Acid Receptor-related Orphan Receptor {alpha}4 Gene by an Interaction between Hypoxia-inducible Factor-1 and Sp1 J. Biol. Chem., April 9, 2004; 279(15): 15025 - 15031. [Abstract] [Full Text] [PDF]

				F. Boukhtouche, J. Mariani, and A. Tedgui The "CholesteROR" Protective Pathway in the Vascular System Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 637 - 643. [Abstract] [Full Text] [PDF]

				H. Ino Immunohistochemical Characterization of the Orphan Nuclear Receptor ROR{alpha} in the Mouse Nervous System J. Histochem. Cytochem., March 1, 2004; 52(3): 311 - 324. [Abstract] [Full Text] [PDF]

				C. Frank, M. M. Gonzalez, C. Oinonen, T. W. Dunlop, and C. Carlberg Characterization of DNA Complexes Formed by the Nuclear Receptor Constitutive Androstane Receptor J. Biol. Chem., October 31, 2003; 278(44): 43299 - 43310. [Abstract] [Full Text] [PDF]

				E. Raspe, G. Mautino, C. Duval, C. Fontaine, H. Duez, O. Barbier, D. Monte, J. Fruchart, J.-C. Fruchart, and B. Staels Transcriptional Regulation of Human Rev-erbalpha Gene Expression by the Orphan Nuclear Receptor Retinoic Acid-related Orphan Receptor alpha J. Biol. Chem., December 13, 2002; 277(51): 49275 - 49281. [Abstract] [Full Text] [PDF]

				P. Delerive, W. W. Chin, and C. S. Suen Identification of Reverbalpha as a Novel RORalpha Target Gene J. Biol. Chem., September 13, 2002; 277(38): 35013 - 35018. [Abstract] [Full Text] [PDF]

				Y.-W. He Orphan nuclear receptors in T lymphocyte development J. Leukoc. Biol., September 1, 2002; 72(3): 440 - 446. [Abstract] [Full Text] [PDF]

				E. Ueda, S. Kurebayashi, M. Sakaue, M. Backlund, B. Koller, and A. M. Jetten High Incidence of T-Cell Lymphomas in Mice Deficient in the Retinoid-related Orphan Receptor ROR{gamma} Cancer Res., February 1, 2002; 62(3): 901 - 909. [Abstract] [Full Text] [PDF]

				D. Roy, N. L. Angelini, H. Fujieda, G. M. Brown, and D. D. Belsham Cyclical Regulation of GnRH Gene Expression in GT1-7 GnRH-Secreting Neurons by Melatonin Endocrinology, November 1, 2001; 142(11): 4711 - 4720. [Abstract] [Full Text] [PDF]

				K. Gawlas and H. G. Stunnenberg Differential transcription of the orphan receptor ROR{beta} in nuclear extracts derived from Neuro2A and HeLa cells Nucleic Acids Res., August 15, 2001; 29(16): 3424 - 3432. [Abstract] [Full Text] [PDF]

				A. Aranda and A. Pascual Nuclear Hormone Receptors and Gene Expression Physiol Rev, July 1, 2001; 81(3): 1269 - 1304. [Abstract] [Full Text] [PDF]

				M. Kostrouchova, M. Krause, Z. Kostrouch, and J. E. Rall Nuclear hormone receptor CHR3 is a critical regulator of all four larval molts of the nematode Caenorhabditis elegans PNAS, June 19, 2001; 98(13): 7360 - 7365. [Abstract] [Full Text] [PDF]

				S. Kurebayashi, E. Ueda, M. Sakaue, D. D. Patel, A. Medvedev, F. Zhang, and A. M. Jetten Retinoid-related orphan receptor gamma (RORgamma ) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis PNAS, August 29, 2000; 97(18): 10132 - 10137. [Abstract] [Full Text] [PDF]

				S. A. Ross, P. J. McCaffery, U. C. Drager, and L. M. De Luca Retinoids in Embryonal Development Physiol Rev, July 1, 2000; 80(3): 1021 - 1054. [Abstract] [Full Text] [PDF]

				V. Giguère Orphan Nuclear Receptors: From Gene to Function Endocr. Rev., October 1, 1999; 20(5): 689 - 725. [Abstract] [Full Text]

				J. R. McWhirter, S. T. C. Neuteboom, E. V. Wancewicz, B. P. Monia, J. R. Downing, and C. Murre Oncogenic homeodomain transcription factor E2A-Pbx1 activates a novel WNT gene in pre-B acute lymphoblastoid leukemia PNAS, September 28, 1999; 96(20): 11464 - 11469. [Abstract] [Full Text] [PDF]

				J. A. Roth, B.-G. Kim, W.-L. Lin, and M.-I. Cho Melatonin Promotes Osteoblast Differentiation and Bone Formation J. Biol. Chem., July 30, 1999; 274(31): 22041 - 22047. [Abstract] [Full Text] [PDF]

				A. GARCÍA RATO, J. GARCÍA PEDRERO, M. A. MARTÍNEZ, B. DEL RIO, P. S. LAZO, and S. RAMOS Melatonin blocks the activation of estrogen receptor for DNA binding FASEB J, May 1, 1999; 13(8): 857 - 868. [Abstract] [Full Text]

				A. N. Moraitis and V. Giguère Transition from Monomeric to Homodimeric DNA Binding by Nuclear Receptors: Identification of RevErbA{alpha} Determinants Required for ROR{alpha} Homodimer Complex Formation Mol. Endocrinol., March 1, 1999; 13(3): 431 - 439. [Abstract] [Full Text]

				A. Mamontova, S. Seguret-Mace, B. Esposito, C. Chaniale, M. Bouly, N. Delhaye-Bouchaud, G. Luc, B. Staels, N. Duverger, J. Mariani, et al. Severe Atherosclerosis and Hypoalphalipoproteinemia in the Staggerer Mouse, a Mutant of the Nuclear Receptor ROR{alpha} Circulation, December 15, 1998; 98(24): 2738 - 2743. [Abstract] [Full Text] [PDF]

				C. J. Winrow, J. P. Capone, and R. A. Rachubinski Cross-talk between Orphan Nuclear Hormone Receptor RZRalpha and Peroxisome Proliferator-activated Receptor alpha  in Regulation of the Peroxisomal Hydratase-Dehydrogenase Gene J. Biol. Chem., November 20, 1998; 273(47): 31442 - 31448. [Abstract] [Full Text] [PDF]

				G. W. Anderson, R. J. Larson, D. R. Oas, C. R. Sandhofer, H. L. Schwartz, C. N. Mariash, and J. H. Oppenheimer Chicken Ovalbumin Upstream Promoter-Transcription Factor (COUP-TF) Modulates Expression of the Purkinje Cell Protein-2 Gene. A POTENTIAL ROLE FOR COUP-TF IN REPRESSING PREMATURE THYROID HORMONE ACTION IN THE DEVELOPING BRAIN J. Biol. Chem., June 26, 1998; 273(26): 16391 - 16399. [Abstract] [Full Text] [PDF]

				I. Wiesenberg, M. Chiesi, M. Missbach, C. Spanka, W. Pignat, and C. Carlberg Specific Activation of the Nuclear Receptors PPARgamma and RORA by the Antidiabetic Thiazolidinedione BRL 49653 and the Antiarthritic Thiazolidinedione Derivative CGP 52608 Mol. Pharmacol., June 1, 1998; 53(6): 1131 - 1138. [Abstract] [Full Text]

				M. Steinmayr, E. Andre, F. Conquet, L. Rondi-Reig, N. Delhaye-Bouchaud, N. Auclair, H. Daniel, F. Crepel, J. Mariani, C. Sotelo, et al. staggerer phenotype in retinoid-related orphan receptor alpha -deficient mice PNAS, March 31, 1998; 95(7): 3960 - 3965. [Abstract] [Full Text] [PDF]

				M Kostrouchova, M Krause, Z Kostrouch, and J. Rall CHR3: a Caenorhabditis elegans orphan nuclear hormone receptor required for proper epidermal development and molting Development, January 5, 1998; 125(9): 1617 - 1626. [Abstract] [PDF]

				D. P. Wade, L. H. Puckey, B. L. Knight, F. Acquati, A. Mihalich, and R. Taramelli Characterization of Multiple Enhancer Regions Upstream of the Apolipoprotein(a) Gene J. Biol. Chem., November 28, 1997; 272(48): 30387 - 30399. [Abstract] [Full Text] [PDF]

				N. Vu-Dac, P. Gervois, T. Grotzinger, P. De Vos, K. Schoonjans, J.-C. Fruchart, J. Auwerx, J. Mariani, A. Tedgui, and B. Staels Transcriptional Regulation of Apolipoprotein A-I Gene Expression by the Nuclear Receptor RORalpha J. Biol. Chem., September 5, 1997; 272(36): 22401 - 22404. [Abstract] [Full Text] [PDF]

				M. Becker-Andre, I. Wiesenberg, N. Schaeren-Wiemers, E. Andre, M. Missbach, J.-H. Saurat, and C. Carlberg Additions and Corrections to Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J. Biol. Chem., June 27, 1997; 272(26): 16707 - 16707. [Full Text] [PDF]

				S. Kersten, H. Gronemeyer, and N. Noy The DNA Binding Pattern of the Retinoid X Receptor Is Regulated by Ligand-dependent Modulation of Its Oligomeric State J. Biol. Chem., May 9, 1997; 272(19): 12771 - 12777. [Abstract] [Full Text] [PDF]

				M. Schrader, C. Danielsson, I. Wiesenberg, and C. Carlberg Identification of Natural Monomeric Response Elements of the Nuclear Receptor RZR/ROR. THEY ALSO BIND COUP-TF HOMODIMERS J. Biol. Chem., August 16, 1996; 271(33): 19732 - 19736. [Abstract] [Full Text] [PDF]

				M. Missbach, B. Jagher, I. Sigg, S. Nayeri, C. Carlberg, and I. Wiesenberg Thiazolidine Diones, Specific Ligands of the Nuclear Receptor Retinoid Z Receptor/Retinoid Acid Receptor-related Orphan Receptor alpha with Potent Antiarthritic Activity J. Biol. Chem., June 7, 1996; 271(23): 13515 - 13522. [Abstract] [Full Text] [PDF]

				M. Tini, R. A. Fraser, and V. Giguère Functional Interactions between Retinoic Acid Receptor-related Orphan Nuclear Receptor (RORalpha) and the Retinoic Acid Receptors in the Regulation of the [IMAGE]F-Crystallin Promoter J. Biol. Chem., August 25, 1995; 270(34): 20156 - 20161. [Abstract] [Full Text] [PDF]

				D. Steinhilber, M. Brungs, O. Werz, I. Wiesenberg, C. Danielsson, J.-P. Kahlen, S. Nayeri, M. Schräder, and C. Carlberg The Nuclear Receptor for Melatonin Represses 5-Lipoxygenase Gene Expression in Human B Lymphocytes J. Biol. Chem., March 31, 1995; 270(13): 7037 - 7040. [Abstract] [Full Text] [PDF]

				E. Raspe, H. Duez, P. Gervois, C. Fievet, J.-C. Fruchart, S. Besnard, J. Mariani, A. Tedgui, and B. Staels Transcriptional Regulation of Apolipoprotein C-III Gene Expression by the Orphan Nuclear Receptor RORalpha J. Biol. Chem., January 19, 2001; 276(4): 2865 - 2871. [Abstract] [Full Text] [PDF]

				T. Meyer, M. Kneissel, J. Mariani, and B. Fournier In vitro and in vivo evidence for orphan nuclear receptor RORalpha function in bone metabolism PNAS, August 1, 2000; 97(16): 9197 - 9202. [Abstract] [Full Text] [PDF]