Abstract
Vitamin A is essential for the formation and maintenance of many body tissues. It is also important for embryonic growth and development and can act as a teratogen at critical periods of development. Retinoic acid (RA) is the biologically active form of vitamin A and its signaling is mediated by the RA and retinoid X receptors. In addition to its role as an important molecule during development, RA has also been implicated in clinical applications, both as a potential anti-tumor agent as well as for the treatment of skin diseases. This review presents an overview of how dietary retinoids are converted to RA, hence presenting the major players in RA metabolism and signaling, and highlights examples of treatment applications of retinoids. Moreover, we discuss the origin and diversification of the retinoid pathway, which are important factors for understanding the evolution of ligand-specificity among retinoid receptors.
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Collins MD, Mao GE (1999) Teratology of retinoids. Annu Rev Pharmacol Toxicol 39:399–430
Morriss-Kay GM, Ward SJ (1999) Retinoids and mammalian development. Int Rev Cytol 188:73–131
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
Blomhoff R, Blomhoff HK (2006) Overview of retinoid metabolism and function. J Neurobiol 66:606–630
Sommer A (1998) Xerophthalmia and vitamin A status. Prog Retin Eye Res 17:9–31
Melhus H, Michaelsson K, Kindmark A, Bergstrom R, Holmberg L, Mallmin H, Wolk A, Ljunghall S (1998) Excessive dietary intake of vitamin A is associated with reduced bone mineral density and increased risk for hip fracture. Ann Intern Med 129:770–778
Silveira ER, Moreno FS (1998) Natural retinoids and β-carotene: from food to their actions on gene expression. J Nutr Biochem 9:446–456
Napoli JL (1996) Biochemical pathways of retinoid transport, metabolism, and signal transduction. Clin Immunol Immunopathol 80:S52–S62
Achkar CC, Derguini F, Blumberg B, Langston A, Levin AA, Speck J, Evans RM, Bolado J Jr, Nakanishi K, Buck J, Gudas LJ (1996) 4-Oxoretinol, a new natural ligand and transactivator of the retinoic acid receptors. Proc Natl Acad Sci USA 93:4879–4884
Buck J, Derguini F, Levi E, Nakanishi K, Hammerling U (1991) Intracellular signaling by 14-hydroxy-4,14-retro-retinol. Science 254:1654–1656
Moore T (1930) Vitamin A and carotene: the absence of the liver oil vitamin A from carotene. VI. The conversion of carotene to vitamin A in vivo. Biochem J 24:692–702
Karrer P, Helfenstein A, Wehrli H, Wettstein A (1930) Uber die Konstitution des Lycopins und Carotins. Helv Chim Acta 13
Simoes-Costa MS, Azambuja AP, Xavier-Neto J (2008) The search for non-chordate retinoic acid signaling: lessons from chordates. J Exp Zool B Mol Dev Evol 310:54–72
Holland LZ, Albalat R, Azumi K, Benito-Gutierrez E, Blow MJ, Bronner-Fraser M, Brunet F, Butts T, Candiani S, Dishaw LJ, Ferrier DE, Garcia-Fernandez J, Gibson-Brown JJ, Gissi C, Godzik A, Hallbook F, Hirose D, Hosomichi K, Ikuta T, Inoko H, Kasahara M, Kasamatsu J, Kawashima T, Kimura A, Kobayashi M, Kozmik Z, Kubokawa K, Laudet V, Litman GW, McHardy AC, Meulemans D, Nonaka M, Olinski RP, Pancer Z, Pennacchio LA, Pestarino M, Rast JP, Rigoutsos I, Robinson-Rechavi M, Roch G, Saiga H, Sasakura Y, Satake M, Satou Y, Schubert M, Sherwood N, Shiina T, Takatori N, Tello J, Vopalensky P, Wada S, Xu A, Ye Y, Yoshida K, Yoshizaki F, Yu JK, Zhang Q, Zmasek CM, de Jong PJ, Osoegawa K, Putnam NH, Rokhsar DS, Satoh N, Holland PW (2008) The amphioxus genome illuminates vertebrate origins and cephalochordate biology. Genome Res 18:1100–1111
von Lintig J, Hessel S, Isken A, Kiefer C, Lampert JM, Voolstra O, Vogt K (2005) Towards a better understanding of carotenoid metabolism in animals. Biochim Biophys Acta 1740:122–131
Chen H, Howald WN, Juchau MR (2000) Biosynthesis of all-trans-retinoic acid from all-trans-retinol: catalysis of all-trans-retinol oxidation by human P-450 cytochromes. Drug Metab Dispos 28:315–322
Albalat R (2009) The retinoic acid machinery in invertebrates: ancestral elements and vertebrate innovations. Mol Cell Endocrinol 313:23–35
Levin MS (1993) Cellular retinol-binding proteins are determinants of retinol uptake and metabolism in stably transfected Caco-2 cells. J Biol Chem 268:8267–8276
Ghyselinck NB, Bavik C, Sapin V, Mark M, Bonnier D, Hindelang C, Dierich A, Nilsson CB, Hakansson H, Sauvant P, Azais-Braesco V, Frasson M, Picaud S, Chambon P (1999) Cellular retinol-binding protein I is essential for vitamin A homeostasis. EMBO J 18:4903–4914
E X, Zhang L, Lu J, Tso P, Blaner WS, Levin MS, Li E (2002) Increased neonatal mortality in mice lacking cellular retinol-binding protein II. J Biol Chem 277:36617–36623
Piantedosi R, Ghyselinck N, Blaner WS, Vogel S (2005) Cellular retinol-binding protein type III is needed for retinoid incorporation into milk. J Biol Chem 280:24286–242892
Gottesman ME, Quadro L, Blaner WS (2001) Studies of vitamin A metabolism in mouse model systems. Bioessays 23:409–419
Herr FM, Ong DE (1992) Differential interaction of lecithin–retinol acyltransferase with cellular retinol binding proteins. Biochemistry 31:6748–6755
Batten ML, Imanishi Y, Maeda T, Tu DC, Moise AR, Bronson D, Possin D, Van Gelder RN, Baehr W, Palczewski K (2004) Lecithin-retinol acyltransferase is essential for accumulation of all-trans-retinyl esters in the eye and in the liver. J Biol Chem 279:10422–10432
O’Byrne SM, Wongsiriroj N, Libien J, Vogel S, Goldberg IJ, Baehr W, Palczewski K, Blaner WS (2005) Retinoid absorption and storage is impaired in mice lacking lecithin:retinol acyltransferase (LRAT). J Biol Chem 280:35647–35657
Ross AC (1982) Retinol esterification by rat liver microsomes. Evidence for a fatty acyl coenzyme A: retinol acyltransferase. J Biol Chem 257:2453–2459
Blomhoff R, Green MH, Berg T, Norum KR (1990) Transport and storage of vitamin A. Science 250:399–404
Zanotti G, Berni R (2004) Plasma retinol-binding protein: structure and interactions with retinol, retinoids, and transthyretin. Vitam Horm 69:271–295
Soprano DR, Soprano KJ, Goodman DS (1986) Retinol-binding protein messenger RNA levels in the liver and in extrahepatic tissues of the rat. J Lipid Res 27:166–171
Kanai M, Raz A, Goodman DS (1968) Retinol-binding protein: the transport protein for vitamin A in human plasma. J Clin Invest 47:2025–2044
Quadro L, Blaner WS, Salchow DJ, Vogel S, Piantedosi R, Gouras P, Freeman S, Cosma MP, Colantuoni V, Gottesman ME (1999) Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein. EMBO J 18:4633–4644
Duester G (2008) Retinoic acid synthesis and signaling during early organogenesis. Cell 134:921–931
Niederreither K, Abu-Abed S, Schuhbaur B, Petkovich M, Chambon P, Dolle P (2002) Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development. Nat Genet 31:84–88
Kawaguchi R, Yu J, Honda J, Hu J, Whitelegge J, Ping P, Wiita P, Bok D, Sun H (2007) A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A. Science 315:820–825
Blaner WS (2007) STRA6, a cell-surface receptor for retinol-binding protein: the plot thickens. Cell Metab 5:164–166
Pasutto F, Sticht H, Hammersen G, Gillessen-Kaesbach G, Fitzpatrick DR, Nurnberg G, Brasch F, Schirmer-Zimmermann H, Tolmie JL, Chitayat D, Houge G, Fernandez-Martinez L, Keating S, Mortier G, Hennekam RC, von der Wense A, Slavotinek A, Meinecke P, Bitoun P, Becker C, Nurnberg P, Reis A, Rauch A (2007) Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation. Am J Hum Genet 80:550–560
Golzio C, Martinovic-Bouriel J, Thomas S, Mougou-Zrelli S, Grattagliano-Bessieres B, Bonniere M, Delahaye S, Munnich A, Encha-Razavi F, Lyonnet S, Vekemans M, Attie-Bitach T, Etchevers HC (2007) Matthew-Wood syndrome is caused by truncating mutations in the retinol-binding protein receptor gene STRA6. Am J Hum Genet 80:1179–1187
Pares X, Farres J, Kedishvili N, Duester G (2008) Medium- and short-chain dehydrogenase/reductase gene and protein families: medium-chain and short-chain dehydrogenases/reductases in retinoid metabolism. Cell Mol Life Sci 65:3936–3949
Molotkov A, Fan X, Deltour L, Foglio MH, Martras S, Farres J, Pares X, Duester G (2002) Stimulation of retinoic acid production and growth by ubiquitously expressed alcohol dehydrogenase Adh3. Proc Natl Acad Sci USA 99:5337–5342
Duester G, Mic FA, Molotkov A (2003) Cytosolic retinoid dehydrogenases govern ubiquitous metabolism of retinol to retinaldehyde followed by tissue-specific metabolism to retinoic acid. Chem Biol Interact 143–144:201–210
Molotkov A, Fan X, Duester G (2002) Excessive vitamin A toxicity in mice genetically deficient in either alcohol dehydrogenase Adh1 or Adh3. Eur J Biochem 269:2607–2612
Sandell LL, Sanderson BW, Moiseyev G, Johnson T, Mushegian A, Young K, Rey JP, Ma JX, Staehling-Hampton K, Trainor PA (2007) RDH10 is essential for synthesis of embryonic retinoic acid and is required for limb, craniofacial, and organ development. Genes Dev 21:1113–1124
Strate I, Min TH, Iliev D, Pera EM (2009) Retinol dehydrogenase 10 is a feedback regulator of retinoic acid signalling during axis formation and patterning of the central nervous system. Development 136:461–472
Albalat R, Canestro C (2009) Identification of Aldh1a, Cyp26 and RAR orthologs in protostomes pushes back the retinoic acid genetic machinery in evolutionary time to the bilaterian ancestor. Chem Biol Interact 178:188–196
Haselbeck RJ, Hoffmann I, Duester G (1999) Distinct functions for Aldh1 and Raldh2 in the control of ligand production for embryonic retinoid signaling pathways. Dev Genet 25:353–364
Niederreither K, Subbarayan V, Dolle P, Chambon P (1999) Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet 21:444–448
Niederreither K, Vermot J, Schuhbaur B, Chambon P, Dolle P (2000) Retinoic acid synthesis and hindbrain patterning in the mouse embryo. Development 127:75–85
Dupe V, Matt N, Garnier JM, Chambon P, Mark M, Ghyselinck NB (2003) A newborn lethal defect due to inactivation of retinaldehyde dehydrogenase type 3 is prevented by maternal retinoic acid treatment. Proc Natl Acad Sci USA 100:14036–14041
Lin M, Zhang M, Abraham M, Smith SM, Napoli JL (2003) Mouse retinal dehydrogenase 4 (RALDH4), molecular cloning, cellular expression, and activity in 9-cis-retinoic acid biosynthesis in intact cells. J Biol Chem 278:9856–9861
Campo-Paysaa F, Marletaz F, Laudet V, Schubert M (2008) Retinoic acid signaling in development: tissue-specific functions and evolutionary origins. Genesis 46:640–656
Canestro C, Postlethwait JH, Gonzalez-Duarte R, Albalat R (2006) Is retinoic acid genetic machinery a chordate innovation? Evol Dev 8:394–406
Napoli JL (1996) Retinoic acid biosynthesis and metabolism. FASEB J 10:993–1001
Delva L, Bastie JN, Rochette-Egly C, Kraiba R, Balitrand N, Despouy G, Chambon P, Chomienne C (1999) Physical and functional interactions between cellular retinoic acid binding protein II and the retinoic acid-dependent nuclear complex. Mol Cell Biol 19:7158–7167
Dong D, Ruuska SE, Levinthal DJ, Noy N (1999) Distinct roles for cellular retinoic acid-binding proteins I and II in regulating signaling by retinoic acid. J Biol Chem 274:23695–23698
Lampron C, Rochette-Egly C, Gorry P, Dolle P, Mark M, Lufkin T, LeMeur M, Chambon P (1995) Mice deficient in cellular retinoic acid binding protein II (CRABPII) or in both CRABPI and CRABPII are essentially normal. Development 121:539–548
Jackman WR, Mougey JM, Panopoulou GD, Kimmel CB (2004) crabp and maf highlight the novelty of the amphioxus club-shaped gland. Acta Zool (Stockholm) 85:91–99
Petkovich PM (2001) Retinoic acid metabolism. J Am Acad Dermatol 45:S136–S142
Roberts ES, Vaz AD, Coon MJ (1992) Role of isozymes of rabbit microsomal cytochrome P-450 in the metabolism of retinoic acid, retinol, and retinal. Mol Pharmacol 41:427–433
Marill J, Capron CC, Idres N, Chabot GG (2002) Human cytochrome P450s involved in the metabolism of 9-cis- and 13-cis-retinoic acids. Biochem Pharmacol 63:933–943
White JA, Guo YD, Baetz K, Beckett-Jones B, Bonasoro J, Hsu KE, Dilworth FJ, Jones G, Petkovich M (1996) Identification of the retinoic acid-inducible all-trans-retinoic acid 4-hydroxylase. J Biol Chem 271:29922–29927
White JA, Beckett-Jones B, Guo YD, Dilworth FJ, Bonasoro J, Jones G, Petkovich M (1997) cDNA cloning of human retinoic acid-metabolizing enzyme (hP450RAI) identifies a novel family of cytochromes P450. J Biol Chem 272:18538–18541
White RJ, Schilling TF (2008) How degrading: Cyp26s in hindbrain development. Dev Dyn 237:2775–2790
Tanibe M, Michiue T, Yukita A, Danno H, Ikuzawa M, Ishiura S, Asashima M (2008) Retinoic acid metabolizing factor xCyp26c is specifically expressed in neuroectoderm and regulates anterior neural patterning in Xenopus laevis. Int J Dev Biol 52:893–901
Abu-Abed S, Dolle P, Metzger D, Beckett B, Chambon P, Petkovich M (2001) The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures. Genes Dev 15:226–240
White JA, Ramshaw H, Taimi M, Stangle W, Zhang A, Everingham S, Creighton S, Tam SP, Jones G, Petkovich M (2000) Identification of the human cytochrome P450, P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all-trans-retinoic acid metabolism. Proc Natl Acad Sci USA 97:6403–6408
Taimi M, Helvig C, Wisniewski J, Ramshaw H, White J, Amad M, Korczak B, Petkovich M (2004) A novel human cytochrome P450, CYP26C1, involved in metabolism of 9-cis and all-trans isomers of retinoic acid. J Biol Chem 279:77–85
Reijntjes S, Gale E, Maden M (2004) Generating gradients of retinoic acid in the chick embryo: Cyp26C1 expression and a comparative analysis of the Cyp26 enzymes. Dev Dyn 230:509–517
Uehara M, Yashiro K, Mamiya S, Nishino J, Chambon P, Dolle P, Sakai Y (2007) CYP26A1 and CYP26C1 cooperatively regulate anterior-posterior patterning of the developing brain and the production of migratory cranial neural crest cells in the mouse. Dev Biol 302:399–411
Hernandez RE, Putzke AP, Myers JP, Margaretha L, Moens CB (2007) Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development. Development 134:177–187
Laudet V, Gronemeyer H (2002) The nuclear receptor facts book. Academic, San Diego
Mangelsdorf DJ, Ong ES, Dyck JA, Evans RM (1990) Nuclear receptor that identifies a novel retinoic acid response pathway. Nature 345:224–229
Leid M, Kastner P, Chambon P (1992) Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci 17:427–433
Chambon P (2005) The nuclear receptor superfamily: a personal retrospect on the first two decades. Mol Endocrinol 19:1418–1428
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
Perlmann T, Umesono K, Rangarajan PN, Forman BM, Evans RM (1996) Two distinct dimerization interfaces differentially modulate target gene specificity of nuclear hormone receptors. Mol Endocrinol 10:958–966
Zechel C, Shen XQ, Chambon P, Gronemeyer H (1994) 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 (1994) 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
Balmer JE, Blomhoff R (2005) A robust characterization of retinoic acid response elements based on a comparison of sites in three species. J Steroid Biochem Mol Biol 96:347–354
Durand B, Saunders M, Leroy P, Leid M, Chambon P (1992) All-trans and 9-cis retinoic acid induction of CRABPII transcription is mediated by RAR-RXR heterodimers bound to DR1 and DR2 repeated motifs. Cell 71:73–85
Smith WC, Nakshatri H, Leroy P, Rees J, Chambon P (1991) A retinoic acid response element is present in the mouse cellular retinol binding protein I (mCRBPI) promoter. EMBO J 10:2223–2230
Perlmann T, Rangarajan PN, Umesono K, Evans RM (1993) Determinants for selective RAR and TR recognition of direct repeat HREs. Genes Dev 7:1411–1422
Predki PF, Zamble D, Sarkar B, Giguere V (1994) Ordered binding of retinoic acid and retinoid-X receptors to asymmetric response elements involves determinants adjacent to the DNA-binding domain. Mol Endocrinol 8:31–39
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 371:528–531
Giguere V, Ong ES, Segui P, Evans RM (1987) Identification of a receptor for the morphogen retinoic acid. Nature 330:624–629
Petkovich M, Brand NJ, Krust A, Chambon P (1987) A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature 330:444–450
Mark M, Ghyselinck NB, Chambon P (2009) Function of retinoic acid receptors during embryonic development. Nucl Recept Signal 7:e002
Brand N, Petkovich M, Krust A, Chambon P, de The H, Marchio A, Tiollais P, Dejean A (1988) Identification of a second human retinoic acid receptor. Nature 332:850–853
Dejean A, Bougueleret L, Grzeschik KH, Tiollais P (1986) Hepatitis B virus DNA integration in a sequence homologous to v-erb-A and steroid receptor genes in a hepatocellular carcinoma. Nature 322:70–72
Peng X, Maruo T, Cao Y, Punj V, Mehta R, Das Gupta TK, Christov K (2004) A novel RARβ isoform directed by a distinct promoter P3 and mediated by retinoic acid in breast cancer cells. Cancer Res 64:8911–8918
Zelent A, Mendelsohn C, Kastner P, Krust A, Garnier JM, Ruffenach F, Leroy P, Chambon P (1991) Differentially expressed isoforms of the mouse retinoic acid receptor β generated by usage of two promoters and alternative splicing. EMBO J 10:71–81
Liao WL, Tsai HC, Wang HF, Chang J, Lu KM, Wu HL, Lee YC, Tsai TF, Takahashi H, Wagner M, Ghyselinck NB, Chambon P, Liu FC (2008) Modular patterning of structure and function of the striatum by retinoid receptor signaling. Proc Natl Acad Sci USA 105:6765–6770
Krezel W, Ghyselinck N, Samad TA, Dupe V, Kastner P, Borrelli E, Chambon P (1998) Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science 279:863–867
Krust A, Kastner P, Petkovich M, Zelent A, Chambon P (1989) A third human retinoic acid receptor, hRARγ. Proc Natl Acad Sci USA 86:5310–5314
Zelent A, Krust A, Petkovich M, Kastner P, Chambon P (1989) Cloning of murine α and β retinoic acid receptors and a novel receptor γ predominantly expressed in skin. Nature 339:714–717
Lohnes D, Kastner P, Dierich A, Mark M, LeMeur M, Chambon P (1993) Function of retinoic acid receptor γ in the mouse. Cell 73:643–658
Williams JA, Kondo N, Okabe T, Takeshita N, Pilchak DM, Koyama E, Ochiai T, Jensen D, Chu ML, Kane MA, Napoli JL, Enomoto-Iwamoto M, Ghyselinck N, Chambon P, Pacifici M, Iwamoto M (2009) Retinoic acid receptors are required for skeletal growth, matrix homeostasis and growth plate function in postnatal mouse. Dev Biol 328:315–327
Lohnes D, Mark M, Mendelsohn C, Dolle P, Dierich A, Gorry P, Gansmuller A, Chambon P (1994) Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants. Development 120:2723–2748
Mendelsohn C, Lohnes D, Decimo D, Lufkin T, LeMeur M, Chambon P, Mark M (1994) Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development 120:2749–2771
Hamada K, Gleason SL, Levi BZ, Hirschfeld S, Appella E, Ozato K (1989) H-2RIIBP, a member of the nuclear hormone receptor superfamily that binds to both the regulatory element of major histocompatibility class I genes and the estrogen response element. Proc Natl Acad Sci USA 86:8289–8293
Kastner P, Messaddeq N, Mark M, Wendling O, Grondona JM, Ward S, Ghyselinck N, Chambon P (1997) Vitamin A deficiency and mutations of RXRα, RXRβ and RARα lead to early differentiation of embryonic ventricular cardiomyocytes. Development 124:4749–4758
Sucov HM, Izpisua-Belmonte JC, Ganan Y, Evans RM (1995) Mouse embryos lacking RXRα are resistant to retinoic-acid-induced limb defects. Development 121:3997–4003
Nugent P, Sucov HM, Pisano MM, Greene RM (1999) The role of RXRα in retinoic acid-induced cleft palate as assessed with the RXRα knockout mouse. Int J Dev Biol 43:567–570
Kastner P, Mark M, Leid M, Gansmuller A, Chin W, Grondona JM, Decimo D, Krezel W, Dierich A, Chambon P (1996) Abnormal spermatogenesis in RXRβ mutant mice. Genes Dev 10:80–92
Krezel W, Dupe V, Mark M, Dierich A, Kastner P, Chambon P (1996) RXRγ null mice are apparently normal and compound RXRα +/−/RXRβ −/−/RXRγ −/− mutant mice are viable. Proc Natl Acad Sci USA 93:9010–9014
Brown NS, Smart A, Sharma V, Brinkmeier ML, Greenlee L, Camper SA, Jensen DR, Eckel RH, Krezel W, Chambon P, Haugen BR (2000) Thyroid hormone resistance and increased metabolic rate in the RXR-γ-deficient mouse. J Clin Invest 106:73–79
Schug TT, Berry DC, Shaw NS, Travis SN, Noy N (2007) Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell 129:723–733
Berry DC, Noy N (2007) Is PPARβ/δ a retinoid receptor? PPAR Res 2007:73256
Shaw N, Elholm M, Noy N (2003) Retinoic acid is a high affinity selective ligand for the peroxisome proliferator-activated receptor β/δ. J Biol Chem 278:41589–41592
Di-Poi N, Tan NS, Michalik L, Wahli W, Desvergne B (2002) Antiapoptotic role of PPARβ in keratinocytes via transcriptional control of the Akt1 signaling pathway. Mol Cell 10:721–733
Tan NS, Michalik L, Desvergne B, Wahli W (2004) Peroxisome proliferator-activated receptor-β as a target for wound healing drugs. Expert Opin Ther Targets 8:39–48
Wolf G (2008) Retinoic acid as cause of cell proliferation or cell growth inhibition depending on activation of one of two different nuclear receptors. Nutr Rev 66:55–59
Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud JP, Moras D, Schule R (2003) All-trans retinoic acid is a ligand for the orphan nuclear receptor RORβ. Nat Struct Biol 10:820–825
Park JI, Tsai SY, Tsai MJ (2003) Molecular mechanism of chicken ovalbumin upstream promoter-transcription factor (COUP-TF) actions. Keio J Med 52:174–181
Pereira FA, Qiu Y, Zhou G, Tsai MJ, Tsai SY (1999) The orphan nuclear receptor COUP-TFII is required for angiogenesis and heart development. Genes Dev 13:1037–1049
Kruse SW, Suino-Powell K, Zhou XE, Kretschman JE, Reynolds R, Vonrhein C, Xu Y, Wang L, Tsai SY, Tsai MJ, Xu HE (2008) Identification of COUP-TFII orphan nuclear receptor as a retinoic acid-activated receptor. PLoS Biol 6:e227
Allenby G, Janocha R, Kazmer S, Speck J, Grippo JF, Levin AA (1994) Binding of 9-cis-retinoic acid and all-trans-retinoic acid to retinoic acid receptors α, β, and γ. Retinoic acid receptor γ binds all-trans-retinoic acid preferentially over 9-cis-retinoic acid. J Biol Chem 269:16689–16695
Chambon P (1996) A decade of molecular biology of retinoic acid receptors. FASEB J 10:940–954
Repa JJ, Hanson KK, Clagett-Dame M (1993) All-trans-retinol is a ligand for the retinoic acid receptors. Proc Natl Acad Sci USA 90:7293–7297
Pijnappel WW, Hendriks HF, Folkers GE, van den Brink CE, Dekker EJ, Edelenbosch C, van der Saag PT, Durston AJ (1993) The retinoid ligand 4-oxo-retinoic acid is a highly active modulator of positional specification. Nature 366:340–344
Schuchardt JP, Wahlstrom D, Ruegg J, Giese N, Stefan M, Hopf H, Pongratz I, Hakansson H, Eichele G, Pettersson K, Nau H (2009) The endogenous retinoid metabolite S-4-oxo-9-cis-13, 14-dihydro-retinoic acid activates retinoic acid receptor signalling both in vitro and in vivo. FEBS J 276:3043–3059
Matsumoto A, Mizukami H, Mizuno S, Umegaki K, Nishikawa J, Shudo K, Kagechika H, Inoue M (2007) β-Cryptoxanthin, a novel natural RAR ligand, induces ATP-binding cassette transporters in macrophages. Biochem Pharmacol 74:256–264
Altucci L, Leibowitz MD, Ogilvie KM, de Lera AR, Gronemeyer H (2007) RAR and RXR modulation in cancer and metabolic disease. Nat Rev Drug Discov 6:793–810
Boehm MF, Zhang L, Badea BA, White SK, 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 37:2930–2941
de Lera AR, Bourguet W, Altucci L, Gronemeyer H (2007) Design of selective nuclear receptor modulators: RAR and RXR as a case study. Nat Rev Drug Discov 6:811–820
Kistler A (1987) Limb bud cell cultures for estimating the teratogenic potential of compounds. Validation of the test system with retinoids. Arch Toxicol 60:403–414
Pignatello MA, Kauffman FC, Levin AA (1997) Multiple factors contribute to the toxicity of the aromatic retinoid, TTNPB (Ro 13–7410): binding affinities and disposition. Toxicol Appl Pharmacol 142:319–327
Germain P, Gaudon C, Pogenberg V, Sanglier S, Van Dorsselaer A, Royer CA, Lazar MA, Bourguet W, Gronemeyer H (2009) Differential action on coregulator interaction defines inverse retinoid agonists and neutral antagonists. Chem Biol 16:479–489
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 68:397–406
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 6:329–344
Wolf G (2006) Is 9-cis-retinoic acid the endogenous ligand for the retinoic acid-X receptor? Nutr Rev 64:532–538
Dmetrichuk JM, Carlone RL, Jones TR, Vesprini ND, Spencer GE (2008) Detection of endogenous retinoids in the molluscan CNS and characterization of the trophic and tropic actions of 9-cis retinoic acid on isolated neurons. J Neurosci 28:13014–13024
Nowickyj SM, Chithalen JV, Cameron D, Tyshenko MG, Petkovich M, Wyatt GR, Jones G, Walker VK (2008) Locust retinoid X receptors: 9-cis retinoic acid in embryos from a primitive insect. Proc Natl Acad Sci USA 105:9540–9545
Hopkins P (2001) Limb regeneration in the fiddler crab, Uca pugilator: hormonal and growth factor control. Am Zool 41:389–398
Viviano CM, Horton CE, Maden M, Brockes JP (1995) Synthesis and release of 9-cis retinoic acid by the urodele wound epidermis. Development 121:3753–3762
Bourguet W, Vivat V, Wurtz JM, Chambon P, Gronemeyer H, Moras D (2000) Crystal structure of a heterodimeric complex of RAR and RXR ligand-binding domains. Mol Cell 5:289–298
de Urquiza AM, Liu S, Sjoberg M, Zetterstrom RH, Griffiths W, Sjovall J, Perlmann T (2000) Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science 290:2140–2144
Goldstein JT, Dobrzyn A, Clagett-Dame M, Pike JW, DeLuca HF (2003) Isolation and characterization of unsaturated fatty acids as natural ligands for the retinoid-X receptor. Arch Biochem Biophys 420:185–193
Tocchini-Valentini GD, Rochel N, Escriva H, Germain P, Peluso-Iltis C, Paris M, Sanglier-Cianferani S, Van Dorsselaer A, Moras D, Laudet V (2009) Structural and functional insights into the ligand-binding domain of a nonduplicated retinoid X nuclear receptor from the invertebrate chordate amphioxus. J Biol Chem 284:1938–1948
Lehmann JM, Jong L, Fanjul A, Cameron JF, Lu XP, Haefner P, Dawson MI, Pfahl M (1992) Retinoids selective for retinoid X receptor response pathways. Science 258:1944–1946
Boehm MF, Zhang L, Zhi L, McClurg MR, Berger E, Wagoner M, Mais DE, Suto CM, Davies JA, Heyman RA, Nadzan AM (1995) Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells. J Med Chem 38:3146–3155
Minucci S, Leid M, Toyama R, Saint-Jeannet JP, Peterson VJ, Horn V, Ishmael JE, Bhattacharyya 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 17:644–655
Balmer JE, Blomhoff R (2002) Gene expression regulation by retinoic acid. J Lipid Res 43:1773–1808
Astrom A, Pettersson U, Chambon P, Voorhees JJ (1994) Retinoic acid induction of human cellular retinoic acid-binding protein-II gene transcription is mediated by retinoic acid receptor-retinoid X receptor heterodimers bound to one far upstream retinoic acid-responsive element with 5-base pair spacing. J Biol Chem 269:22334–22339
McGinnis W, Krumlauf R (1992) Homeobox genes and axial patterning. Cell 68:283–302
Kessel M (1992) Respecification of vertebral identities by retinoic acid. Development 115:487–501
Kessel M, Gruss P (1991) Homeotic transformations of murine vertebrae and concomitant alteration of Hox codes induced by retinoic acid. Cell 67:89–104
Marletaz F, Holland LZ, Laudet V, Schubert M (2006) Retinoic acid signaling and the evolution of chordates. Int J Biol Sci 2:38–47
Langston AW, Thompson JR, Gudas LJ (1997) Retinoic acid-responsive enhancers located 3′ of the Hox A and Hox B homeobox gene clusters. Functional analysis. J Biol Chem 272:2167–2175
Manzanares M, Wada H, Itasaki N, Trainor PA, Krumlauf R, Holland PW (2000) Conservation and elaboration of Hox gene regulation during evolution of the vertebrate head. Nature 408:854–857
Wada H, Escriva H, Zhang S, Laudet V (2006) Conserved RARE localization in amphioxus Hox clusters and implications for Hox code evolution in the vertebrate neural crest. Dev Dyn 235:1522–1531
Kanda M, Wada H, Fujiwara S (2009) Epidermal expression of Hox1 is directly activated by retinoic acid in the Ciona intestinalis embryo. Dev Biol 335:454–463
Feng L, Hernandez RE, Waxman JS, Yelon D, Moens CB (2010) Dhrs3a regulates retinoic acid biosynthesis through a feedback inhibition mechanism. Dev Biol 338:1–14
Hua S, Kittler R, White KP (2009) Genomic antagonism between retinoic acid and estrogen signaling in breast cancer. Cell 137:1259–1271
Chen N, Onisko B, Napoli JL (2008) The nuclear transcription factor RARα associates with neuronal RNA granules and suppresses translation. J Biol Chem 283:20841–20847
Poon MM, Chen L (2008) Retinoic acid-gated sequence-specific translational control by RARα. Proc Natl Acad Sci USA 105:20303–20308
Liao YP, Ho SY, Liou JC (2004) Non-genomic regulation of transmitter release by retinoic acid at developing motoneurons in Xenopus cell culture. J Cell Sci 117:2917–2924
Liou JC, Ho SY, Shen MR, Liao YP, Chiu WT, Kang KH (2005) A rapid, nongenomic pathway facilitates the synaptic transmission induced by retinoic acid at the developing synapse. J Cell Sci 118:4721–4730
Masia S, Alvarez S, de Lera AR, Barettino D (2007) Rapid, nongenomic actions of retinoic acid on phosphatidylinositol-3-kinase signaling pathway mediated by the retinoic acid receptor. Mol Endocrinol 21:2391–2402
Fanjul A, Dawson MI, Hobbs PD, Jong L, Cameron JF, Harlev E, Graupner G, Lu XP, Pfahl M (1994) A new class of retinoids with selective inhibition of AP-1 inhibits proliferation. Nature 372:107–111
Baeuerle PA, Baltimore D (1996) NF-κB: ten years after. Cell 87:13–20
Austenaa LM, Carlsen H, Ertesvag A, Alexander G, Blomhoff HK, Blomhoff R (2004) Vitamin A status significantly alters nuclear factor-κB activity assessed by in vivo imaging. FASEB J 18:1255–1257
Austenaa LM, Carlsen H, Hollung K, Blomhoff HK, Blomhoff R (2009) Retinoic acid dampens LPS-induced NF-κB activity: results from human monoblasts and in vivo imaging of NF-κB reporter mice. J Nutr Biochem 20:726–734
Aggarwal S, Kim SW, Cheon K, Tabassam FH, Yoon JH, Koo JS (2006) Nonclassical action of retinoic acid on the activation of the cAMP response element-binding protein in normal human bronchial epithelial cells. Mol Biol Cell 17:566–575
Ochoa WF, Torrecillas A, Fita I, Verdaguer N, Corbalan-Garcia S, Gomez-Fernandez JC (2003) Retinoic acid binds to the C2-domain of protein kinase Cα. Biochemistry 42:8774–8779
Farrar NR, Dmetrichuk JM, Carlone RL, Spencer GE (2009) A novel, nongenomic mechanism underlies retinoic acid-induced growth cone turning. J Neurosci 29:14136–14142
Escriva H, Holland ND, Gronemeyer H, Laudet V, Holland LZ (2002) The retinoic acid signaling pathway regulates anterior/posterior patterning in the nerve cord and pharynx of amphioxus, a chordate lacking neural crest. Development 129:2905–2916
Holland LZ, Holland ND (1996) Expression of AmphiHox-1 and AmphiPax-1 in amphioxus embryos treated with retinoic acid: insights into evolution and patterning of the chordate nerve cord and pharynx. Development 122:1829–1838
Schubert M, Yu JK, Holland ND, Escriva H, Laudet V, Holland LZ (2005) Retinoic acid signaling acts via Hox1 to establish the posterior limit of the pharynx in the chordate amphioxus. Development 132:61–73
Onai T, Lin HC, Schubert M, Koop D, Osborne PW, Alvarez S, Alvarez R, Holland ND, Holland LZ (2009) Retinoic acid and Wnt/β-catenin have complementary roles in anterior/posterior patterning embryos of the basal chordate amphioxus. Dev Biol 332:223–233
Schubert M, Holland ND, Laudet V, Holland LZ (2006) A retinoic acid-Hox hierarchy controls both anterior/posterior patterning and neuronal specification in the developing central nervous system of the cephalochordate amphioxus. Dev Biol 296:190–202
Schubert M, Holland ND, Escriva H, Holland LZ, Laudet V (2004) Retinoic acid influences anteroposterior positioning of epidermal sensory neurons and their gene expression in a developing chordate (amphioxus). Proc Natl Acad Sci USA 101:10320–10325
Hinman VF, Degnan BM (1998) Retinoic acid disrupts anterior ectodermal and endodermal development in ascidian larvae and postlarvae. Dev Genes Evol 208:336–345
Katsuyama Y, Saiga H (1998) Retinoic acid affects patterning along the anterior-posterior axis of the ascidian embryo. Dev Growth Differ 40:413–422
Fujiwara S (2006) Retinoids and nonvertebrate chordate development. J Neurobiol 66:645–652
Yagi K, Makabe KW (2002) Retinoic acid differently affects the formation of palps and surrounding neurons in the ascidian tadpole. Dev Genes Evol 212:288–292
Rinkevich Y, Paz G, Rinkevich B, Reshef R (2007) Systemic bud induction and retinoic acid signaling underlie whole body regeneration in the urochordate Botrylloides leachi. PLoS Biol 5:e71
Sciarrino S, Matranga V (1995) Effects of retinoic acid and dimethylsulfoxide on the morphogenesis of the sea urchin embryo. Cell Biol Int 19:675–680
Dmetrichuk JM, Carlone RL, Spencer GE (2006) Retinoic acid induces neurite outgrowth and growth cone turning in invertebrate neurons. Dev Biol 294:39–49
Fields AL, Soprano DR, Soprano KJ (2007) Retinoids in biological control and cancer. J Cell Biochem 102:886–898
Wolbach SB, Howe PR (1925) Tissue changes following deprivation of fat-soluble A vitamin. Nutr Rev 36:16–19
Dragnev KH, Rigas JR, Dmitrovsky E (2000) The retinoids and cancer prevention mechanisms. Oncologist 5:361–368
Niles RM (2000) Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer. Nutrition 16:1084–1089
Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L, Gu LJ, Wang ZY (1988) Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72:567–572
Borrow J, Goddard AD, Sheer D, Solomon E (1990) Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. Science 249:1577–1580
de The H, Chomienne C, Lanotte M, Degos L, Dejean A (1990) The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor α gene to a novel transcribed locus. Nature 347:558–561
de The H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A (1991) The PML-RARα fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66:675–684
Kakizuka A, Miller WH Jr, Umesono K, Warrell RP Jr, Frankel SR, Murty VV, Dmitrovsky E, Evans RM (1991) Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARα with a novel putative transcription factor, PML. Cell 66:663–674
Kastner P, Perez A, Lutz Y, Rochette-Egly C, Gaub MP, Durand B, Lanotte M, Berger R, Chambon P (1992) Structure, localization and transcriptional properties of two classes of retinoic acid receptor alpha fusion proteins in acute promyelocytic leukemia (APL): structural similarities with a new family of oncoproteins. EMBO J 11:629–642
Hummel JL, Zhang T, Wells RA, Kamel-Reid S (2002) The retinoic acid receptor α (RARα) chimeric proteins PML-, PLZF-, NPM-, and NuMA-RARα have distinct intracellular localization patterns. Cell Growth Differ 13:173–183
Fenaux P, Chevret S, Guerci A, Fegueux N, Dombret H, Thomas X, Sanz M, Link H, Maloisel F, Gardin C, Bordessoule D, Stoppa AM, Sadoun A, Muus P, Wandt H, Mineur P, Whittaker JA, Fey M, Daniel MT, Castaigne S, Degos L (2000) Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. European APL group. Leukemia 14:1371–1377
Tallman MS, Nabhan C, Feusner JH, Rowe JM (2002) Acute promyelocytic leukemia: evolving therapeutic strategies. Blood 99:759–767
Brown D, Kogan S, Lagasse E, Weissman I, Alcalay M, Pelicci PG, Atwater S, Bishop JM (1997) A PMLRARα transgene initiates murine acute promyelocytic leukemia. Proc Natl Acad Sci USA 94:2551–2556
Licht JD (2006) Reconstructing a disease: What essential features of the retinoic acid receptor fusion oncoproteins generate acute promyelocytic leukemia? Cancer Cell 9:73–74
Seewaldt VL, Johnson BS, Parker MB, Collins SJ, Swisshelm K (1995) Expression of retinoic acid receptor β mediates retinoic acid-induced growth arrest and apoptosis in breast cancer cells. Cell Growth Differ 6:1077–1088
Sun SY, Lotan R (2002) Retinoids and their receptors in cancer development and chemoprevention. Crit Rev Oncol Hematol 41:41–55
Castillo L, Milano G, Santini J, Demard F, Pierrefite V (1997) Analysis of retinoic acid receptor β expression in normal and malignant laryngeal mucosa by a sensitive and routine applicable reverse transcription-polymerase chain reaction enzyme-linked immunosorbent assay method. Clin Cancer Res 3:2137–2142
Picard E, Seguin C, Monhoven N, Rochette-Egly C, Siat J, Borrelly J, Martinet Y, Martinet N, Vignaud JM (1999) Expression of retinoid receptor genes and proteins in non-small-cell lung cancer. J Natl Cancer Inst 91:1059–1066
Widschwendter M, Berger J, Daxenbichler G, Muller-Holzner E, Widschwendter A, Mayr A, Marth C, Zeimet AG (1997) Loss of retinoic acid receptor β expression in breast cancer and morphologically normal adjacent tissue but not in the normal breast tissue distant from the cancer. Cancer Res 57:4158–4161
Berard J, Gaboury L, Landers M, De Repentigny Y, Houle B, Kothary R, Bradley WE (1994) Hyperplasia and tumours in lung, breast and other tissues in mice carrying a RARβ4-like transgene. EMBO J 13:5570–5580
Wang Z, Boudjelal M, Kang S, Voorhees JJ, Fisher GJ (1999) Ultraviolet irradiation of human skin causes functional vitamin A deficiency, preventable by all-trans retinoic acid pre-treatment. Nat Med 5:418–422
De Luca LM (1991) Retinoids and their receptors in differentiation, embryogenesis, and neoplasia. FASEB J 5:2924–2933
Lee JS, Newman RA, Lippman SM, Huber MH, Minor T, Raber MN, Krakoff IH, Hong WK (1993) Phase I evaluation of all-trans-retinoic acid in adults with solid tumors. J Clin Oncol 11:959–966
Reynolds CP (2000) Differentiating agents in pediatric malignancies: retinoids in neuroblastoma. Curr Oncol Rep 2:511–518
Rigas JR, Dragnev KH (2005) Emerging role of rexinoids in non-small cell lung cancer: focus on bexarotene. Oncologist 10:22–33
So PL, Fujimoto MA, Epstein EH Jr (2008) Pharmacologic retinoid signaling and physiologic retinoic acid receptor signaling inhibit basal cell carcinoma tumorigenesis. Mol Cancer Ther 7:1275–1284
Yen A, Fenning R, Chandraratna R, Walker P, Varvayanis S (2004) A retinoic acid receptor β/γ-selective prodrug (tazarotene) plus a retinoid X receptor ligand induces extracellular signal-regulated kinase activation, retinoblastoma hypophosphorylation, G0 arrest, and cell differentiation. Mol Pharmacol 66:1727–1737
Kraemer KH, DiGiovanna JJ, Peck GL (1992) Chemoprevention of skin cancer in xeroderma pigmentosum. J Dermatol 19:715–718
Tanaka T, De Luca LM (2009) Therapeutic potential of “rexinoids” in cancer prevention and treatment. Cancer Res 69:4945–4947
Tanaka T, Suh KS, Lo AM, De Luca LM (2007) p21WAF1/CIP1 is a common transcriptional target of retinoid receptors: pleiotropic regulatory mechanism through retinoic acid receptor (RAR)/retinoid X receptor (RXR) heterodimer and RXR/RXR homodimer. J Biol Chem 282:29987–29997
Crowe DL, Chandraratna RA (2004) A retinoid X receptor (RXR)-selective retinoid reveals that RXRα is potentially a therapeutic target in breast cancer cell lines, and that it potentiates antiproliferative and apoptotic responses to peroxisome proliferator-activated receptor ligands. Breast Cancer Res 6:R546–R555
Mukherjee R, Davies PJ, 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 retinoid X receptor agonists. Nature 386:407–410
Singh Ahuja H, Liu S, Crombie DL, Boehm M, Leibowitz MD, Heyman RA, Depre C, Nagy L, Tontonoz P, Davies PJ (2001) Differential effects of rexinoids and thiazolidinediones on metabolic gene expression in diabetic rodents. Mol Pharmacol 59:765–773
Benoit G, Altucci L, Flexor M, Ruchaud S, Lillehaug J, Raffelsberger W, Gronemeyer H, Lanotte M (1999) RAR-independent RXR signaling induces t(15;17) leukemia cell maturation. EMBO J 18:7011–7018
Ruchaud S, Duprez E, Gendron MC, Houge G, Genieser HG, Jastorff B, Doskeland SO, Lanotte M (1994) Two distinctly regulated events, priming and triggering, during retinoid-induced maturation and resistance of NB4 promyelocytic leukemia cell line. Proc Natl Acad Sci USA 91:8428–8432
Liby K, Royce DB, Risingsong R, Williams CR, Wood MD, Chandraratna RA, Sporn MB (2007) A new rexinoid, NRX194204, prevents carcinogenesis in both the lung and mammary gland. Clin Cancer Res 13:6237–6243
Wu K, Kim HT, Rodriquez JL, Hilsenbeck SG, Mohsin SK, Xu XC, Lamph WW, Kuhn JG, Green JE, Brown PH (2002) Suppression of mammary tumorigenesis in transgenic mice by the RXR-selective retinoid, LGD1069. Cancer Epidemiol Biomarkers Prev 11:467–474
Wu K, Zhang Y, Xu XC, Hill J, Celestino J, Kim HT, Mohsin SK, Hilsenbeck SG, Lamph WW, Bissonette R, Brown PH (2002) The retinoid X receptor-selective retinoid, LGD1069, prevents the development of estrogen receptor-negative mammary tumors in transgenic mice. Cancer Res 62:6376–6380
Klopper JP, Sharma V, Berenz A, Hays WR, Loi M, Pugazhenthi U, Said S, Haugen BR (2009) Retinoid and thiazolidinedione therapies in melanoma: an analysis of differential response based on nuclear hormone receptor expression. Mol Cancer 8:16
Rendi MH, Suh N, Lamph WW, Krajewski S, Reed JC, Heyman RA, Berchuck A, Liby K, Risingsong R, Royce DB, Williams CR, Sporn MB (2004) The selective estrogen receptor modulator arzoxifene and the rexinoid LG100268 cooperate to promote transforming growth factor β-dependent apoptosis in breast cancer. Cancer Res 64:3566–3571
Acknowledgments
The authors would like to thank Gabriel V. Markov, Jasmin Schulz, and Gérard Benoit for critical reading of the manuscript, and the ANR (ANR-07-BLAN-0038 and ANR-09-BLAN-0262-02), the CNRS, and CRESCENDO (a European Union Integrated Project of FP6) for providing financial support. Furthermore, we would like to apologize to all colleagues, whose original work and contributions could not be cited in this article due to space limitations.
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An erratum to this article can be found at http://dx.doi.org/10.1007/s00018-010-0361-3
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Theodosiou, M., Laudet, V. & Schubert, M. From carrot to clinic: an overview of the retinoic acid signaling pathway. Cell. Mol. Life Sci. 67, 1423–1445 (2010). https://doi.org/10.1007/s00018-010-0268-z
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DOI: https://doi.org/10.1007/s00018-010-0268-z