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Retinoic Acid Receptors and Cellular Retinoid Binding Proteins: Complex Interplay in Retinoid Signaling^*

Division of Endocrinology, Research Institute, Hospital for Sick Children Toronto, Canada, M5G 1X8 Department of Molecular and Medical Genetics, University of Toronto Toronto, Canada M5S 1A8

Correspondence: Address requests for reprints to: Vincent Giguere, Ph.D., Division of Endocrinology, Research Institute, Hospital for Sick Children, 555 University Avenue, Toronto, Canada M5G 1X8.

Abstract

VITAMIN A and its biologically active derivatives, retinal and retinoic acid (RA), are essential for the health and survival of the individual. These natural compounds, together with a large repertoire of synthetic analogs, are collectively referred to as retinoids. In addition to their well known role in vision, retinoids are required for reproduction, act as morphogenetic agents during embryonic development, and regulate the growth and differentiation of a wide variety of cell types throughout the life of the organism. Although the role of 11-cis-retinal as the chromophore component of the photoreceptors in the visual cycle was elucidated three decades ago (1), the general mechanism by which RA influences cellular activities has been unraveled only relatively recently. In fact, our present understanding of how retinoids control cell functions stems directly from studies of steroid and thyroid hormones' action. These pioneering studies demonstrated that small hydrophobic ligands are able to cross passively biological membranes and control cell functions by using specific intracellular receptors as signal transducers.

Footnotes

^* This work was supported by grants from the National Cancer Institute of Canada and the Medical Research Council (MRC) of Canada. V. Giguère is a MRC Scholar.

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				X. Shan, A. Bourdeau, A. Rhoton, D. E. Wells, E. H. Cohen, B. E. Landgraf, and R. G. E. Palfree Characterization and Mapping to Human Chromosome 8q24.3 of Ly-6-Related Gene 9804 Encoding an Apparent Homologue of Mouse TSA-1 J. Immunol., January 1, 1998; 160(1): 197 - 208. [Abstract] [Full Text] [PDF]

				X. Chai, Y. Zhai, and J. L. Napoli cDNA Cloning and Characterization of a cis-Retinol/3alpha -Hydroxysterol Short-chain Dehydrogenase J. Biol. Chem., December 26, 1997; 272(52): 33125 - 33131. [Abstract] [Full Text] [PDF]

				S. Kersten, P. R. Reczek, and N. Noy The Tetramerization Region of the Retinoid X Receptor Is Important for Transcriptional Activation by the Receptor J. Biol. Chem., November 21, 1997; 272(47): 29759 - 29768. [Abstract] [Full Text] [PDF]

				T. Ikonen, J. J. Palvimo, and O. A. Janne Interaction between the Amino- and Carboxyl-terminal Regions of the Rat Androgen Receptor Modulates Transcriptional Activity and Is Influenced by Nuclear Receptor Coactivators J. Biol. Chem., November 21, 1997; 272(47): 29821 - 29828. [Abstract] [Full Text] [PDF]

				H. Chiba, J. Clifford, D. Metzger, and P. Chambon Specific and Redundant Functions of Retinoid X Receptor/Retinoic Acid Receptor Heterodimers in Differentiation, Proliferation, and Apoptosis of F9 Embryonal Carcinoma Cells J. Cell Biol., November 3, 1997; 139(3): 735 - 747. [Abstract] [Full Text] [PDF]

				G. I. Gorodeski, R. L. Eckert, D. Pal, W. H. Utian, and E. A. Rorke Retinoids regulate tight junctional resistance of cultured human cervical cells Am J Physiol Cell Physiol, November 1, 1997; 273(5): C1707 - C1713. [Abstract] [Full Text] [PDF]

				R. Y. Lee, J. Luo, R. M. Evans, V. Giguere, and H. M. Sucov Compartment-Selective Sensitivity of Cardiovascular Morphogenesis to Combinations of Retinoic Acid Receptor Gene Mutations Circ. Res., June 19, 1997; 80(6): 757 - 764. [Abstract] [Full Text]

				C. A. Hsu, A. K. Rishi, X. Su-Li, T. M. Gerald, M. I. Dawson, C. Schiffer, U. Reichert, B. Shroot, G. C. Poirer, and J. A. Fontana Retinoid Induced Apoptosis in Leukemia Cells Through a Retinoic Acid Nuclear Receptor-Independent Pathway Blood, June 15, 1997; 89(12): 4470 - 4479. [Abstract] [Full Text] [PDF]

				P. S. Attar, P. W. Wertz, M. McArthur, S. Imakado, J. R. Bickenbach, and D. R. Roop Inhibition of Retinoid Signaling in Transgenic Mice Alters Lipid Processing and Disrupts Epidermal Barrier Function Mol. Endocrinol., June 1, 1997; 11(6): 792 - 800. [Abstract] [Full Text]

				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]

				E. Guerin, M.-G. Ludwig, P. Basset, and P. Anglard Stromelysin-3 Induction and Interstitial Collagenase Repression by Retinoic Acid. THERAPEUTICAL IMPLICATION OF RECEPTOR-SELECTIVE RETINOIDS DISSOCIATING TRANSACTIVATION AND AP-1-MEDIATED TRANSREPRESSION J. Biol. Chem., April 25, 1997; 272(17): 11088 - 11095. [Abstract] [Full Text] [PDF]

				Z. H. Yan, A. Medvedev, T. Hirose, H. Gotoh, and A. M. Jetten Characterization of the Response Element and DNA Binding Properties of the Nuclear Orphan Receptor Germ Cell Nuclear Factor/Retinoid Receptor-related Testis-associated Receptor J. Biol. Chem., April 18, 1997; 272(16): 10565 - 10572. [Abstract] [Full Text] [PDF]

				P. G. Walfish, T. Yoganathan, Y.-F. Yang, H. Hong, T. R. Butt, and M. R. Stallcup Yeast hormone response element assays detect and characterize GRIP1 coactivator-dependent activation of transcription by thyroid and retinoid nuclear receptors PNAS, April 15, 1997; 94(8): 3697 - 3702. [Abstract] [Full Text] [PDF]

				J. Botling, D. S. Castro, F. Oberg, K. Nilsson, and T. Perlmann Retinoic Acid Receptor/Retinoid X Receptor Heterodimers Can Be Activated through Both Subunits Providing a Basis for Synergistic Transactivation and Cellular Differentiation J. Biol. Chem., April 4, 1997; 272(14): 9443 - 9449. [Abstract] [Full Text] [PDF]

				B. R. Haugen, N. S. Brown, W. M. Wood, D. F. Gordon, and E. C. Ridgway The Thyrotrope-Restricted Isoform of the Retinoid-X Receptor-{gamma}1 Mediates 9-cis-Retinoic Acid Suppression of Thyrotropin-{beta} Promoter Activity Mol. Endocrinol., April 1, 1997; 11(4): 481 - 489. [Abstract] [Full Text]

				G. Csaba and A. Gaal Effect of perinatal vitamin A or retinoic acid treatment (hormonal imprinting) on the sexual behavior of adult rats Human and Experimental Toxicology, April 1, 1997; 16(4): 193 - 197. [Abstract] [PDF]

				S. E. Blutt, E. A. Allegretto, J. W. Pike, and N. L. Weigel 1,25-Dihydroxyvitamin D3 and 9-cis-Retinoic Acid Act Synergistically to Inhibit the Growth of LNCaP Prostate Cells and Cause Accumulation of Cells in G1 Endocrinology, April 1, 1997; 138(4): 1491 - 1497. [Abstract] [Full Text] [PDF]

				Y.-s. Piao, H. Peltoketo, A. Jouppila, and R. Vihko Retinoic Acids Increase 17{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression in JEG-3 and T47D Cells, but the Stimulation Is Potentiated by Epidermal Growth Factor, 12-O-Tetradecanoylphorbol-13-Acetate, and Cyclic Adenosine 3',5'-Monophosphate Only in JEG-3 Cells Endocrinology, March 1, 1997; 138(3): 898 - 904. [Abstract] [Full Text] [PDF]

				D. E. Cash, C. B. Bock, K. Schughart, E. Linney, and T. M. Underhill Retinoic Acid Receptor {alpha} Function in Vertebrate Limb Skeletogenesis: a Modulator of Chondrogenesis J. Cell Biol., January 27, 1997; 136(2): 445 - 457. [Abstract] [Full Text] [PDF]

				M Plateroti, J. Freund, C Leberquier, and M Kedinger Mesenchyme-mediated effects of retinoic acid during rat intestinal development J. Cell Sci., January 5, 1997; 110(10): 1227 - 1238. [Abstract] [PDF]

				D. K. Scott, J. A. Mitchell, and D. K. Granner The Orphan Receptor COUP-TF Binds to a Third Glucocorticoid Accessory Factor Element within the Phosphoenolpyruvate Carboxykinase Gene Promoter J. Biol. Chem., December 13, 1996; 271(50): 31909 - 31914. [Abstract] [Full Text] [PDF]

				L. Panariello, L. Quadro, S. Trematerra, and V. Colantuoni Identification of a Novel Retinoic Acid Response Element in the Promoter Region of the Retinol-binding Protein Gene J. Biol. Chem., October 11, 1996; 271(41): 25524 - 25532. [Abstract] [Full Text] [PDF]

				X. Cao, S. L. Teitelbaum, H.-J. Zhu, L. Zhang, X. Feng, and F. P. Ross Competition for a Unique Response Element Mediates Retinoic Acid Inhibition of Vitamin D3-stimulated Transcription J. Biol. Chem., August 23, 1996; 271(34): 20650 - 20654. [Abstract] [Full Text] [PDF]

				X. Wang, P. Penzes, and J. L. Napoli Cloning of a cDNA Encoding an Aldehyde Dehydrogenase and Its Expression in Escherichia coli. RECOGNITION OF RETINAL AS SUBSTRATE J. Biol. Chem., July 5, 1996; 271(27): 16288 - 16293. [Abstract] [Full Text] [PDF]

				J. Grondona, P Kastner, A Gansmuller, D Decimo, P Chambon, and M Mark Retinal dysplasia and degeneration in RARbeta2/RARgamma2 compound mutant mice Development, July 1, 1996; 122(7): 2173 - 2188. [Abstract] [PDF]