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Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, Illkirch, Communauté Urbaine de Strasbourg, France (P.G., P.C., H.G.); Max-Planck-Institute of Experimental Endocrinology, Hannover, Germany (G.E.); Howard Hughes Medical Institute, Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California (R.M.E.); Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and the Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (M.A.L.); Program in Molecular and Cellular Biology, Oregon State University, Corvallis, Oregon (M.L.); Departamento de Quimica Organica, Facultade de Quimica, Universidade de Vigo, Lagoas Marcosende, Vigo, Galicia, Spain (A.R.d.L.); Department of Thoracic/Head and Neck Medical Oncology-Unit 432, The University of Texas MD Anderson Cancer Center, Houston, Texas (R.L.); and Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas (D.J.M.)
Abstract
Abstract Introduction RARs Expression and Function of Retinoid Acid Receptors Natural Retinoids and Synthetic Analogs Diseases, Treatments, and Chemoprevention Ongoing Research
Retinoid is a term for compounds that bind to and activate retinoic acid receptors (RAR
, RAR
, and RAR
), members of the nuclear hormone receptor superfamily. The most important endogenous retinoid is all-trans-retinoic acid. Retinoids regulate a wide variety of essential biological processes, such as vertebrate embryonic morphogenesis and organogenesis, cell growth arrest, differentiation and apoptosis, and homeostasis, as well as their disorders. This review summarizes the considerable amount of knowledge generated on these receptors.
The retinoic acid receptors (RARs1) mediate both organismal and cellular effects of retinoids. "Retinoids" is a generic term that covers compounds including both naturally dietary vitamin A (retinol) metabolites and active synthetic analogs (Sporn et al., 1976
; Chambon, 2005). Both experimental and clinical studies have revealed that retinoids regulate a wide variety of essential biological processes, such as vertebrate embryonic morphogenesis and organogenesis, cell growth arrest, differentiation and apoptosis, and homeostasis, as well as their disorders (Sporn et al., 1976; Blomhoff, 1994; Sporn et al., 1994; Kastner et al., 1995; Chambon, 2005). All-trans-retinoic acid (ATRA), the most potent biologically active metabolite of vitamin A, can both prevent and rescue the main defects caused by vitamin A deficiency (VAD) in adult animals (Kastner et al., 1995). As early as 1925 preclinical studies demonstrated that VAD correlated with the development of squamous metaplasia in rodents (Wolbach and Howe, 1925). This and subsequent studies anticipated a strong rationale for the use of retinoids in the treatment and prevention of cancer (Hong and Sporn, 1997). The most impressive example of retinoid anticancer activity is the treatment of patients with acute promyelocytic leukemia (APL), a subtype of acute myelogenous leukemia, since upon addition of ATRA to the therapy approximately 72% of patients with APL can be cured (de The et al., 1990a; Degos and Wang, 2001; Lin et al., 1999).
Retinoids exert their pleiotropic effects through the three RAR subtypes [RAR (NR1B1), first identified in 1987 independently by Pierre Chambon's and Ron Evans's groups, RAR (NR1B2), and RAR (NR1B3)] that originate from three distinct genes (Giguere et al., 1987; Petkovich et al., 1987; Chambon, 1996). For each RAR subtype, several isoforms exist that differ from one another in their N-terminal region A. These isoforms arise from the differential usage of two promoters and alternative splicing. The downstream promoters, referred to as P2, are induced by retinoids owing to the presence of a retinoic acid response element (RARE, see below). There are two major isoforms for RAR (1 and 2) and for RAR (1 and 2) and four major isoforms for RAR (1 and 3 initiated at the P1 promoter and 2 and 4 initiated at the P2 promoter). RARs function as heterodimers with the three retinoid X receptors [RXR (NR2B1), RXR (NR2B2), and RXR (NR2B3)] (Mangelsdorf and Evans, 1995; Kastner et al., 1997; Mark et al., 1999). In vitro studies demonstrated that RXR-RAR heterodimers act as ligand-dependent transcriptional regulators by binding to the specific RARE DNA sequences found in the promoter region of retinoid target genes. RAREs correspond to direct repeats of polymorphic arrangements of the canonical motif 5'-PuG(G/T)TCA separated by five (generally referred to as DR5) or one (DR1) or two (DR2) nucleotides (Leid et al., 1992; Mangelsdorf and Evans, 1995). In DR5 and DR2 elements, RXRs occupy the 5' element, whereas RARs occupy the 3' element (5'-RXR-RAR-3'). In contrast, the polarity of heterodimers is reversed in DR1 elements (5'-RAR-RXR-3') (Kurokawa et al., 1994; Rastinejad et al., 2000; Rastinejad, 2001). Strikingly, and contrary to DR2 or DR5 context (see below), specific RAR agonists do not induce the dissociation of corepressors from the RAR-RXR heterodimer bound to a DR1 leading to repressive activity (Kurokawa et al., 1995). DR5 elements were identified in the promoters of genes such as the RAR2 gene (de The et al., 1990b), several Hox genes that are key players in the specification of the anteroposterior axis during development (Boncinelli et al., 1991; Tabin, 1995; Dupe et al., 1997), and the cytochrome P450RAI (CYP26) gene whose product is implicated in the catabolism of ATRA (Loudig et al., 2000). DR2 elements were found in the promoters of the cellular retinol binding protein I (Smith et al., 1991) and CRABPII (Durand et al., 1992) genes, CRABPs functioning in retinoid storage and intracellular transport (for other retinoid target genes, see McCaffery and Drager, 2000; Laudet and Gronemeyer, 2002).
A molecular mechanism by which RXR-RAR heterodimers regulate transcription of target genes has been proposed (Glass and Rosenfeld, 2000). In the absence of RAR agonist, the RXR-RAR heterodimer recruits the corepressor proteins NCoR or SMRT and associated factors such as histone deacetylases (HDACs) or DNA-methyl transferases that may lead to an inactive condensed chromatin structure, preventing transcription. Upon RAR agonist binding, corepressors are released, and coactivator complexes such as histone acetyltransferases or histone arginine methyltransferases are recruited to activate transcription (Nagy et al., 1997; Hu and Lazar, 2000; Aranda and Pascual, 2001; Privalsky, 2001; McKenna and O'Malley, 2002; Perissi and Rosenfeld, 2005). Recently, poly(ADP-ribose) polymerase 1, which can interact directly with RAR, has been shown to be indispensable to RAR-mediated transcription from the RAR2 promoter (Pavri et al., 2005).
Whereas RAR agonists can autonomously activate transcription through such heterodimers, RXRs are unable to respond to RXR-selective agonists (rexinoids) in the absence of RAR ligand. The molecular basis of this phenomenon, referred to as RXR subordination or silencing, has been dissected. Agonist binding to RXR is unable to induce the dissociation of corepressor from the RXR-RAR heterodimers, preventing coactivator recruitment (Westin et al., 1998; Germain et al., 2002). A synergistic transcriptional activation is observed when RAR and RXR partners are simultaneously bound to agonists, indicating that RXRs are not transcriptionally silent partners in RXR-RAR heterodimers (Lotan et al., 1995b).
The essential role of gene silencing by RARs has been demonstrated for two developmental processes, namely the skeletal development in the mouse and head formation in Xenopus (for a review, see Weston et al., 2003), and is underscored by the pathogenesis of APL in which an inappropriate repression by oncogenic RAR fusion proteins blocks myeloid differentiation leading to APL. The repressive model of unliganded heterodimers is based mainly on studies involving RAR, which can strongly interact with corepressors. However, recent findings suggest differences in cofactor stoichiometry and patterns of interactions among the distinct RAR subtypes, as unliganded RAR was shown to poorly associate corepressors and to be a significant transcriptional activator, contrasting with the strong repressing activity of unliganded RAR (Germain et al., 2002; Farboud et al., 2003; Hauksdottir et al., 2003).
RARs also integrate a variety of signaling pathways, notably through posttranslational modifications (Rochette-Egly and Chambon, 2001; Laudet and Gronemeyer, 2002; Rochette-Egly, 2003). Among these modifications, phosphorylation of RARs has been shown to play a critical role in the retinoid response. Both AF-1 domains and LBDs of RARs are substrates for various kinases activated by a variety of signals (Bastien and Rochette-Egly, 2004). Another particularly interesting feature of RARs has been revealed by the studies of several genes such as osteocalcin or collagenase showing the inhibition of the transcription factor complex activator protein-1 (AP-1)-driven transactivation by liganded RARs (Lafyatis et al., 1990; Nicholson et al., 1990; Schule et al., 1990; Chen et al., 1995; Resche-Rigon and Gronemeyer, 1998). However, the mechanism of this cross-talk remains elusive.
Expression and Function of Retinoid Acid Receptors
In situ hybridization revealed the expression of all three RARs during mouse embryonic development. Whereas RAR is present in most tissues, both RAR and RAR expressions are more selective (Dolle et al., 1990). These differences in tissue distribution suggest that RARs have distinct physiological functions.
The specific role of each RAR has been studied in great detail in the RA-responsive F9 murine embryonal carcinoma cell line. Interestingly, F9 cells represent a simple cell-autonomous model system for analyzing RAR signaling under in vitro conditions that mimics, at least to some extent, physiological processes occurring during early embryogenesis (for a review, see Rochette-Egly and Chambon, 2001). Both synthetic RAR isotype-selective ligands and knockouts of the individual RARs through homologous recombination followed by re-expression of wild-type or mutant RARs have been used. Overall these experiments revealed important insights regarding the complexity and the selectivity of retinoid signaling. In F9 cells RXR-RAR heterodimers are the functional units that selectively mediate the target gene expression and the differentiation and the growth arrest controlled by retinoids, and the AF-2 ligand-dependent transcriptional activity of RXRs is subordinated to their RAR heterodimeric partner. More specifically RXR-RAR heterodimers are necessary for growth arrest, visceral endodermal differentiation, and primitive endodermal differentiation, whereas RXR-RAR is required for parietal endodermal differentiation in the presence of cAMP. In addition the different roles of RAR phosphorylations have been revealed in the context of the differentiation induction in F9 cells. For instance, phosphorylation within the RAR AF-1 activation domain is required for primitive endodermal differentiation and for induction of retinoid target genes, but in a differential promoter-dependent manner, and for degradation of RXR-RAR heterodimers by the ubiquitin-proteasome system (Taneja et al., 1997) (for reviews, see Rochette-Egly, 2003; Bastien and Rochette-Egly, 2004). Furthermore, the RAR2-null F9 cell line exhibits no growth arrest in response to retinoids in contrast to wild-type, RAR-/-, and RAR-/- F9 cell lines (Faria et al., 1999). However, RAR knockouts may generate artifactual functional redundancies between individual RARs that do not exist under wild-type conditions (Taneja et al., 1996). Overall these investigations with the F9 cells and previous gene transfection studies demonstrated that the individual RAR subtypes can have distinct activities even within the same cell line. In the same line, in vitro studies have shown that, even though other RAR subtypes are also expressed, RAR agonists induce the inhibition of proliferation of some breast cancer cell lines and the differentiation of leukemic cells (Dawson et al., 1995; Chen et al., 1996).
The above studies on F9 were complemented by genetic strategies in the mouse to determine the function of RARs under physiological conditions. This was mainly performed by Pierre Chambon's laboratory by knockout of the three RAR subtypes as well as the eight RAR isoforms (see above) through homologous recombination in embryonic stem cells. In combination with pharmacological approaches using RAR antagonists to block the retinoid signaling pathway, the generation of such germline mutations has provided many valuable insights on the developmental functions of RARs (for comprehensive reviews, see Mark et al., 2004, 2005). However, because of the functional redundancies observed between RARs artifactually generated by knockouts, the number of organs that need retinoids for their development might be underestimated, and these studies have failed to reveal many of the physiological functions of RARs, notably in adult animals. Despite this fact, they provided the genetic evidence that RARs transduced retinoid signals in vivo and revealed that the various RAR subtypes have distinct functionalities during embryogenesis. Briefly, all RAR single-null mutant mice are viable and altogether display some aspects of the postnatal and fetal VAD syndromes. Specifically, RAR-null mutant males are sterile as a result of a degeneration of the seminiferous epithelium that inhibits spermatogenesis (Li et al., 1993; Lufkin et al., 1993). RAR-null mice display abnormalities in the vitreous body in eyes (Grondona et al., 1996) and impaired abilities in locomotion and motor coordination (Krezel et al., 1998). RAR inactivation causes both skeletal and epithelial defects (Lohnes et al., 1993; Ghyselinck et al., 1997; Chapellier et al., 2002). In contrast to RAR single-null knockout mice, mutants lacking a pair of RAR subtypes (double-null mutants) or two or more isoforms belonging to distinct subtypes exhibit a number of defects leading to a dramatically reduced viability and all the known manifestations of the VAD syndrome. Also such genetic studies have revealed that retinoid signals are transduced by specific RXR-RAR(, , or ) heterodimers during development.
Natural Retinoids and Synthetic Analogs
Natural retinoids are produced in vivo from the oxidation of vitamin A. Synthesis of retinoic acid from retinol is a two-step process in which alcohol dehydrogenases perform the oxidation of vitamin A to all-trans-retinaldehyde, followed by oxidation of the latter to ATRA by retinaldehyde dehydrogenases (of which four have been characterized, RALDH1-4), which is the rate-limiting step in its production. ATRA is in turn metabolized by CYP26 to hydroxylated metabolites that can also activate all three RARs (Fujii et al., 1997; White et al., 1997). However, genetic approaches using the RALDH1a2 null mutation and the CYP26 null mutation demonstrated that the main function of CYP26 is to degrade endogenous ATRA and to protect cells from excess ATRA rather than to synthesize active hydroxylated retinoids (Niederreither et al., 2002). RARs bind with high affinity not only ATRA but also 9-cis retinoic acid (9CRA), an isomerization product of ATRA. Whereas ATRA can bind only to RARs, 9CRA can bind to both RAR and RXR. However, because 9CRA has not been consistently detected in mammalian cells unless the medium contained ATRA, the consideration of 9CRA as a natural bioactive retinoid remains controversial (see "LXIII. Retinoid X Receptors" on page 760 of this issue).
Given the importance of the retinoid signaling pathway, a major research effort has been directed to the identification of potent synthetic retinoids leading to the generation of a panel of modulators with activities ranging from agonists to inverse agonists (Klein et al., 1996; Thacher et al., 2000; Kagechika and Shudo, 2005). Such configurationally and/or conformationally restricted analogs of ATRA are valuable tools for dissecting the role of each RAR in several processes. Retinoids were also used as therapeutic agents for the treatment and prevention of cancer and hyperproliferative diseases (see below) (Thacher et al., 2000; Altucci and Gronemeyer, 2001; Clarke et al., 2004a; Dawson, 2004; Vivat-Hannah and Zusi, 2005). The crystal structures of the LBDs of all three RARs bound to various ligands have been solved, providing molecular details of the determinants of both subtype selectivity and the agonist/antagonist-induced structural changes (Renaud et al., 1995; Bourguet et al., 2000; Germain et al., 2004). These 3D structure determinations together with comparison of RAR sequences revealed only three divergent residues into the ligand-binding pockets of all three RARs that are critical for the recognition of subtype-specific ligands. This finding has been confirmed by swapping of these residues (Gehin et al., 1999). Accordingly, it has been possible to generate entirely subtype-selective ligands but also molecules that have complex activities such as ligands that are RAR and RAR antagonists and RAR agonists (Chen et al., 1995; Germain et al., 2004). Interestingly, selective retinoids that dissociate the inhibition of AP-1 activity from the classic RARE-dependent activation of transcription have been identified (Fanjul et al., 1994; Chen et al., 1995). Such compounds are promising therapeutic agents and provide valuable tools to address the mechanism of the RAR/AP-1 cross-talk, the importance of which for growth control and cancer is now established.
Diseases, Treatments, and Chemoprevention
The RARs have been associated with several diseases such as cancer or skin disorders on the basis of epidemiological, clinical, and experimental investigations in human and animals. Then retinoids are used in a variety of chemopreventive and chemotherapeutic settings. The recognized potential of the retinoids in skin disorders is demonstrated by the clinical use of ATRA, 9CRA, and 13-cis-retinoic acid for dermatological indications including acne, psoriasis, or photoaging (for reviews, see Thacher et al., 2000; Zouboulis, 2001; Dawson, 2004). In addition to these RA isomers, two synthetic retinoids are available for the treatment of stable plaque psoriasis [the RAR/-selective agonist tazarotene (AGN190168)] (Marks, 1997; McClelland, 1998) and for acne [adapalene (CD271)] (Galvin et al., 1998; Zhu et al., 2001).
Aberrant retinoid signaling mechanisms have been linked to cancer. The most direct implication of RAR in human disease is given by APL, which is caused by a reciprocal chromosomal translocation between RAR and promyelocyte leukemia protein (PML) human genes, leading to the alteration of the signaling of both RAR and PML (de The et al., 1990a). The resulting fusion protein PML-RAR displays increased binding efficiency to the transcriptional corepressors NCoR and SMRT compared with RAR, inducing the recruitment of HDAC complexes and the silencing of RAR target genes. This process, in turn, arrests myelopoiesis at the promyelocyte stage and prevents the differentiation of APL cells, which might normally occur in the presence of endogenous ATRA. Importantly, the use of supraphysiological doses of ATRA has led to remission in patients with APL, revealing the potential of retinoids for chemotherapeutic applications. This successful therapy is supposed to overcome the negative effects of PML-RAR by inducing the dissociation of silencing complexes from PML-RAR and then the activation of differentiation processes. In addition, high concentrations of ATRA can induce postmaturation apoptosis through the induction of the tumor-selective death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, also called Apo2L), a most promising molecule in cancer research (Altucci and Gronemeyer, 2001). However, with this therapy some patients with APL have a relapse and become resistant to ATRA. Interestingly, the RAR-selective agonist Am80 can induce complete remission in patients previously treated by ATRA who have had relapses, highlighting interest on the generation of even more selective retinoids (Kagechika et al., 1988; Tobita et al., 1997; Takeuchi et al., 1998).
The RAR gene can translocate with other genes, such as the promyelocytic leukemia zinc finger (PLZF) gene product, that are insensitive to ATRA. In the case of the PLZF-RAR fusion protein, the PLZF moiety is constitutively associated to corepressor complexes independently of ATRA, which is supposed to lead to the ATRA insensitivity.
Strong evidence supports the idea that retinoids pharmacologically prevent carcinogenesis in a variety of tissues. Retinoids are used as chemopreventive agents for the treatment of preneoplastic diseases such as oral leukoplakia, cervical dysplasia, and xeroderma pigmentosum (Lotan, 1996; Lippman and Lotan, 2000; Sun and Lotan, 2002). However, the promises of preclinical studies demonstrating the efficacy of retinoids did not consistently translate into clinical response for the treatment of other solid tumors. Interestingly, both experimental investigations and analyses of the natural course of solid human tumor development suggest that RAR may act as a potential tumor suppressor. Indeed, its expression is selectively lost in many neoplastic tissues, including non-small cell lung cancer, squamous cell carcinomas of the head and neck, and breast cancer (Castillo et al., 1997; Widschwendter et al., 1997; Xu et al., 1997a,b; Picard et al., 1999). The restoration of RAR expression with concomitant retinoic treatment was associated with a clinical response of oral leukoplakia (Lotan et al., 1995a). Furthermore, a recently identified novel RAR isoform, referred to as RAR1', which apparently arises from an alternative splicing of RAR1, may function as a tumor suppressor gene in the lung with biological functions distinct from those of previously known RAR isoforms (Petty et al., 2005).
Despite their promising therapeutic value for various indications, the administration of retinoids is strongly limited by severe associated toxic side effects due to the pleiotropic functions of these agents. These effects include teratogenicity, increases in serum triglycerides, mucocutaneous cytotoxicity, headache, and bone toxicity. Therefore, research in progress on retinoid therapy is focused on overcoming both the unwanted side effects of currently used retinoids in the clinic and intrinsic or acquired ATRA resistance in patients and their consequences (Freemantle et al., 2003). First, more work is required to understand better the molecular pathways induced by RARs, notably those underlying the antiproliferative and anticancer activities of retinoids, even though multiple mechanisms that modulate the complex retinoid signaling pathways and their cross-reactions are gradually being elucidated. For instance, the increased understanding of the regulation of RAR activities through phosphorylation should provide new insights in the developmental processes and in cancer (Bastien and Rochette-Egly, 2004).
Second, combinations with other chemopreventive agents that may also enhance the clinical efficacy of retinoids are increasingly sought. Indeed, increased understanding of epigenetic dysregulations that occur during the development of carcinogenesis suggest that ATRA resistance might be combatted by the use of epigenetic modifying agents such as HCAC inhibitors or DNA methyl transferase inhibitors in combination with retinoids, some of which are in clinical trials (Bachman et al., 2003; Egger et al., 2004; Feinberg and Tycko, 2004; Altucci et al., 2005). Several studies revealed other candidates for combinations treatment such as tumor necrosis factor or TRAIL (Altucci and Gronemeyer, 2001; Zusi et al., 2002). Interestingly the recent demonstration of retinoid-induced tumor suppression activities through a network involving the tumor suppressor interferon-regulator factor 1 and TRAIL provides new avenues for the therapeutic combination of retinoids and interferons that is already being tested clinically (Lippman et al., 1997; Clarke et al., 2004b, 2005).
Lastly, the improved use of retinoids in therapy will require the generation of novel synthetic RAR ligands harboring increased selective properties both to decrease the adverse effects associated with retinoid treatments and to overcome resistance to retinoids. Among the novel compounds, atypical retinoids, such as N-(4-hydroxyphenyl) retinamide or CD437, have emerged as potential anticancer agents because of their antiproliferative and apoptotic actions with little toxicity compared with classic retinoids (Ortiz et al., 2002; Dawson, 2004). Despite these compounds being classified as retinoids because of their binding to RARs, their antitumoral effects, at least in part, seem to be independent of the RXR-RAR heterodimer function (Holmes et al., 2000). Furthermore, the development of RAR-selective ligands will be of prime importance because of the tumor-suppression potential of RAR.
Tables 1, 2, 3 summarize the major molecular, physiological, and pharmacological properties of RAR subtypes.
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Address correspondence to: Dr. Pierre Germain, Department of Cell Biology and Signal Transduction, Institut de Genetique et de Biologie Moleculaire et Cellulaire, 1 rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, France. E-mail: germain{at}titus.u-strasbg.fr
Article, publication date, and citation information can be found http://pharmrev.aspetjournals.org.
1 Abbreviations: RAR, retinoic acid receptor; ATRA, all-trans-retinoic acid; VAD, vitamin A deficiency; APL, acute promyelocytic leukemia; RARE, retinoic acid response element; RXR, retinoid X receptor; DR, direct repeat; NCoR, nuclear receptor corepressor; SMRT, silencing mediator for retinoid and thyroid hormone receptors; CRABP, cellular retinoic acid-binding protein; HCAC, histone deacetylase; AF, activation function; AP-1, activator protein-1; 9CRA, 9-cis retinoic acid; RA, retinoic acid; PML, promyelocyte leukemia protein; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; PLZF, promyelocytic leukemia zinc finger. 
Altucci L, Clarke N, Nebbioso A, Scognamiglio A, and Gronemeyer H (2005) Acute myeloid leukemia: therapeutic impact of epigenetic drugs. Int J Biochem Cell Biol 37: 1752-1762.[CrossRef][Medline]
Altucci L and Gronemeyer H (2001) The promise of retinoids to fight against cancer. Nat Rev Cancer 1: 181-193.[CrossRef][Medline]
Aranda A and Pascual A (2001) Nuclear hormone receptors and gene expression. Physiol Rev 81: 1269-1304.
Bachman KE, Park BH, Rhee I, Rajagopalan H, Herman JG, Baylin SB, Kinzler KW, and Vogelstein B (2003) Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 3: 89-95.[CrossRef][Medline]
Bastien J and Rochette-Egly C (2004) Nuclear retinoid receptors and the transcription of retinoid-target genes. Gene 328: 1-16.[CrossRef][Medline]
Blomhoff R (1994) Transport and metabolism of vitamin A. Nutr Rev 52: S13-23.[Medline]
Boncinelli E, Simeone A, Acampora D, and Mavilio F (1991) HOX gene activation by retinoic acid. Trends Genet 7: 329-334.[Medline]
Bourguet W, Vivat V, Wurtz JM, Chambon P, Gronemeyer H, and Moras D (2000) Crystal structure of a heterodimeric complex of RAR and RXR ligand-binding domains. Mol Cell 5: 289-298.[CrossRef][Medline]
Castillo L, Milano G, Santini J, Demard F, and Pierrefite V (1997) Analysis of retinoic acid receptor 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.[Abstract]
Chambon P (1996) A decade of molecular biology of retinoic acid receptors. FASEB J 10: 940-954.[Abstract]
Chambon P (2005) The nuclear receptor superfamily: a personal retrospect on the first two decades. Mol Endocrinol 19: 1418-1428.
Chapellier B, Mark M, Messaddeq N, Calleja C, Warot X, Brocard J, Gerard C, Li M, Metzger D, Ghyselinck NB, et al. (2002) Physiological and retinoid-induced proliferations of epidermis basal keratinocytes are differently controlled. EMBO (Eur Mol Biol Organ) J 21: 3402-3413.[CrossRef][Medline]
Chen JY, Clifford J, Zusi C, Starrett J, Tortolani D, Ostrowski J, Reczek PR, Chambon P, and Gronemeyer H (1996) Two distinct actions of retinoid-receptor ligands. Nature (Lond) 382: 819-822.[CrossRef][Medline]
Chen JY, Penco S, Ostrowski J, Balaguer P, Pons M, Starrett JE, Reczek P, Chambon P, and Gronemeyer H (1995) RAR-specific agonist/antagonists which dissociate transactivation and AP1 transrepression inhibit anchorage-independent cell proliferation. EMBO (Eur Mol Biol Organ) J 14: 1187-1197.[Medline]
Clarke N, Germain P, Altucci L, and Gronemeyer H (2004a) Retinoids: potential in cancer prevention and therapy. Expert Rev Mol Med 6: 1-23.[Medline]
Clarke N, Jimenez-Lara AM, Voltz E, and Gronemeyer H (2004b) Tumor suppressor IRF-1 mediates retinoid and interferon anticancer signaling to death ligand TRAIL. EMBO (Eur Mol Biol Organ) J 23: 3051-3060.[CrossRef][Medline]
Clarke N, Nebbioso A, Altucci L, and Gronemeyer H (2005) TRAIL: at the center of drugable anti-tumor pathways. Cell Cycle 4: 914-918.[Medline]
Dawson MI (2004) Synthetic retinoids and their nuclear receptors. Curr Med Chem Anti-Cancer Agents 4: 199-230.[Medline]
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 with retinoid inhibition of growth of estrogen receptor-positive MCF-7 mammary carcinoma cells. Cancer Res 55: 4446-4451.
de The H, Chomienne C, Lanotte M, Degos L, and Dejean A (1990a) The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor gene to a novel transcribed locus. Nature (Lond) 347: 558-561.[CrossRef][Medline]
de The H, Vivanco-Ruiz MM, Tiollais P, Stunnenberg H, and Dejean A (1990b) Identification of a retinoic acid responsive element in the retinoic acid receptor gene. Nature (Lond) 343: 177-180.[CrossRef][Medline]
Degos L and Wang ZY (2001) All trans retinoic acid in acute promyelocytic leukemia. Oncogene 20: 7140-7145.[CrossRef][Medline]
Dolle P, Ruberte E, Leroy P, Morriss-Kay G, and Chambon P (1990) Retinoic acid receptors and cellular retinoid binding proteins. I. A systematic study of their differential pattern of transcription during mouse organogenesis. Development 110: 1133-1151.
Dupe V, Davenne M, Brocard J, Dolle P, Mark M, Dierich A, Chambon P, and Rijli FM (1997) In vivo functional analysis of the Hoxa-1 3' retinoic acid response element (3'RARE). Development 124: 399-410.[Abstract]
Durand B, Saunders M, Leroy P, Leid M, and 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.[CrossRef][Medline]
Egger G, Liang G, Aparicio A, and Jones PA (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature (Lond) 429: 457-463.[CrossRef][Medline]
Fanjul A, Dawson MI, Hobbs PD, Jong L, Cameron JF, Harlev E, Graupner G, Lu XP, and Pfahl M (1994) A new class of retinoids with selective inhibition of AP-1 inhibits proliferation. Nature (Lond) 372: 107-111.[CrossRef][Medline]
Farboud B, Hauksdottir H, Wu Y, and Privalsky ML (2003) Isotype-restricted corepressor recruitment: a constitutively closed helix 12 conformation in retinoic acid receptors and interferes with corepressor recruitment and prevents transcriptional repression. Mol Cell Biol 23: 2844-2858.
Faria TN, Mendelsohn C, Chambon P, and Gudas LJ (1999) The targeted disruption of both alleles of RAR2 in F9 cells results in the loss of retinoic acid-associated growth arrest. J Biol Chem 274: 26783-26788.
Feinberg AP and Tycko B (2004) The history of cancer epigenetics. Nat Rev Cancer 4: 143-153.[Medline]
Freemantle SJ, Spinella MJ, and Dmitrovsky E (2003) Retinoids in cancer therapy and chemoprevention: promise meets resistance. Oncogene 22: 7305-7315.[CrossRef][Medline]
Fujii H, Sato T, Kaneko S, Gotoh O, Fujii-Kuriyama Y, Osawa K, Kato S, and Hamada H (1997) Metabolic inactivation of retinoic acid by a novel P450 differentially expressed in developing mouse embryos. EMBO (Eur Mol Biol Organ) J 16: 4163-4173.[CrossRef][Medline]
Galvin SA, Gilbert R, Baker M, Guibal F, and Tuley MR (1998) Comparative tolerance of adapalene 0.1% gel and six different tretinoin formulations. Br J Dermatol 139 (Suppl 52): 34-40.[Medline]
Gehin M, Vivat V, Wurtz JM, Losson R, Chambon P, Moras D, and Gronemeyer H (1999) Structural basis for engineering of retinoic acid receptor isotype—selective agonists and antagonists. Chem Biol 6: 519-529.[CrossRef][Medline]
Germain P, Iyer J, Zechel C, and Gronemeyer H (2002) Coregulator recruitment and the mechanism of retinoic acid receptor synergy. Nature (Lond) 415: 187-192.[CrossRef][Medline]
Germain P, Kammerer S, Perez E, Peluso-Iltis C, Tortolani D, Zusi FC, Starrett J, Lapointe P, Daris JP, Marinier A, et al. (2004) Rational design of RAR-selective ligands revealed by RAR crystal stucture. EMBO (Eur Mol Biol Organ) Rep 5: 877-882.
Ghyselinck NB, Dupe V, Dierich A, Messaddeq N, Garnier JM, Rochette-Egly C, Chambon P, and Mark M (1997) Role of the retinoic acid receptor (RAR) during mouse development. Int J Dev Biol 41: 425-447.[Medline]
Giguere V, Ong ES, Segui P, and Evans RM (1987) Identification of a receptor for the morphogen retinoic acid. Nature (Lond) 330: 624-629.[CrossRef][Medline]
Glass CK and Rosenfeld MG (2000) The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev 14: 121-141.
Grondona JM, Kastner P, Gansmuller A, Decimo D, Chambon P, and Mark M (1996) Retinal dysplasia and degeneration in RARb2/RAR2 compound mutant mice. Development 122: 2173-2188.[Abstract]
Hauksdottir H, Farboud B, and Privalsky ML (2003) Retinoic acid receptors and do not repress, but instead activate target gene transcription in both the absence and presence of hormone ligand. Mol Endocrinol 17: 373-385.
Holmes WF, Dawson MI, Soprano RD, and Soprano KJ (2000) Induction of apoptosis in ovarian carcinoma cells by AHPN/CD437 is mediated by retinoic acid receptors. J Cell Physiol 185: 61-67.[CrossRef][Medline]
Hong WK and Sporn MB (1997) Recent advances in chemoprevention of cancer. Science (Wash DC) 278: 1073-1077.
Hu X and Lazar MA (2000) Transcriptional repression by nuclear hormone receptors. Trends Endocrinol Metab 11: 6-10.[CrossRef][Medline]
Kagechika H, Kawachi E, Hashimoto Y, Himi T, and Shudo K (1988) Retinobenzoic acids. 1. Structure-activity relationships of aromatic amides with retinoidal activity. J Med Chem 31: 2182-2192.[CrossRef][Medline]
Kagechika H and Shudo K (2005) Synthetic retinoids: recent developments concerning structure and clinical utility. J Med Chem 48: 5875-5883.[CrossRef][Medline]
Kastner P, Mark M, and Chambon P (1995) Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 83: 859-869.[CrossRef][Medline]
Kastner P, Mark M, Ghyselinck N, Krezel W, Dupe V, Grondona JM, and Chambon P (1997) Genetic evidence that the retinoid signal is transduced by heterodimeric RXR/RAR functional units during mouse development. Development 124: 313-326.[Abstract]
Klein ES, Pino ME, Johnson AT, Davies PJ, Nagpal S, Thacher SM, Krasinski G, and Chandraratna RA (1996) Identification and functional separation of retinoic acid receptor neutral antagonists and inverse agonists. J Biol Chem 271: 22692-22696.
Krezel W, Ghyselinck N, Samad TA, Dupe V, Kastner P, Borrelli E, and Chambon P (1998) Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science (Wash DC) 279: 863-867.
Kurokawa R, DiRenzo J, Boehm M, Sugarman J, Gloss B, Rosenfeld MG, Heyman RA, and Glass CK (1994) Regulation of retinoid signalling by receptor polarity and allosteric control of ligand bindig. Nature (Lond) 371: 528-531.[CrossRef][Medline]
Kurokawa R, Soderstrom M, Horlein A, Halachmi S, Brown M, Rosenfeld MG, and Glass CK (1995) Polarity-specific activities of retinoic acid receptors determined by a co-repressor. Nature (Lond) 377: 451-454.[CrossRef][Medline]
Lafyatis R, Kim SJ, Angel P, Roberts AB, Sporn MB, Karin M, and Wilder RL (1990) Interleukin-1 stimulates and all-trans-retinoic acid inhibits collagenase gene expression through its 5' activator protein-1-binding site. Mol Endocrinol 4: 973-980.[Abstract]
Laudet V and Gronemeyer H (2002) The Nuclear Receptor Facts Book, Academic Press, San Diego.
Leid M, Kastner P, and Chambon P (1992) Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci 17: 427-433.[CrossRef][Medline]
Li E, Sucov HM, Lee KF, Evans RM, and Jaenisch R (1993) Normal development and growth of mice carrying a targeted disruption of the 1 retinoic acid receptor gene. Proc Natl Acad Sci USA 90: 1590-1594.
Lin RJ, Egan DA, and Evans RM (1999) Molecular genetics of acute promyelocytic leukemia. Trends Genet 15: 179-184.[Medline]
Lippman SM and Lotan R (2000) Advances in the development of retinoids as chemopreventive agents. J Nutr 130: 479S-482S.
Lippman SM, Lotan R, and Schleuniger U (1997) Retinoid-interferon therapy of solid tumors. Int J Cancer 70: 481-483.[CrossRef][Medline]
Lohnes D, Kastner P, Dierich A, Mark M, LeMeur M, and Chambon P (1993) Function of retinoic acid receptor in the mouse. Cell 73: 643-658.[CrossRef][Medline]
Lotan R (1996) Retinoids in cancer chemoprevention. FASEB J 10: 1031-1039.[Abstract]
Lotan R, Dawson MI, Zou CC, Jong L, Lotan D, and Zou CP (1995a) Enhanced efficacy of combinations of retinoic acid- and retinoid X receptor-selective retinoids and alpha-interferon in inhibition of cervical carcinoma cell proliferation. Cancer Res 55: 232-236.
Lotan R, Xu XC, Lippman SM, Ro JY, Lee JS, Lee JJ, and Hong WK (1995b) Suppression of retinoic acid receptor- in premalignant oral lesions and its up-regulation by isotretinoin. N Engl J Med 332: 1405-1410.
Loudig O, Babichuk C, White J, Abu-Abed S, Mueller C, and Petkovich M (2000) Cytochrome P450RAI(CYP26) promoter: a distinct composite retinoic acid response element underlies the complex regulation of retinoic acid metabolism. Mol Endocrinol 14: 1483-1497.
Lufkin T, Lohnes D, Mark M, Dierich A, Gorry P, Gaub MP, LeMeur M, and Chambon P (1993) High postnatal lethality and testis degeneration in retinoic acid receptor mutant mice. Proc Natl Acad Sci USA 90: 7225-7229.
Mangelsdorf DJ and Evans RM (1995) The RXR heterodimers and orphan receptors. Cell 83: 841-850.[CrossRef][Medline]
Mark M, Ghyselinck NB, and Chambon P (2004) Retinoic acid signalling in the development of branchial arches. Curr Opin Genet Dev 14: 591-598.[CrossRef][Medline]
Mark M, Ghyselinck NB, and Chambon P (2006) Function of retinoid nuclear receptors: lessons from genetic and pharmacological dissections of the retinoic acid signalling pathway during mouse embryogenesis. Annu Rev Pharmacol Toxicol 46: 451-480.[CrossRef][Medline]
Mark M, Ghyselinck NB, Wendling O, Dupe V, Mascrez B, Kastner P, and Chambon P (1999) A genetic dissection of the retinoid signalling pathway in the mouse. Proc Nutr Soc 58: 609-613.[Medline]
Marks R (1997) Clinical safety of tazarotene in the treatment of plaque psoriasis. J Am Acad Dermatol 37: S25-S32.[Medline]
McCaffery P and Drager UC (2000) Regulation of retinoic acid signaling in the embryonic nervous system: a master differentiation factor. Cytokine Growth Factor Rev 11: 233-249.[CrossRef][Medline]
McClelland PB (1998) Obtaining the optimal treatment outcome with tazarotene. Dermatol Nurs 10: 343-348.[Medline]
McKenna NJ and O'Malley BW (2002) Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 108: 465-474.[CrossRef][Medline]
Nagy L, Kao HY, Chakravarti D, Lin RJ, Hassig CA, Ayer DE, Schreiber SL, and Evans RM (1997) Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell 89: 373-380.[CrossRef][Medline]
Nicholson RC, Mader S, Nagpal S, Leid M, Rochette-Egly C, and Chambon P (1990) Negative regulation of the rat stromelysin gene promoter by retinoic acid is mediated by an AP1 binding site. EMBO (Eur Mol Biol Organ) J 9: 4443-4454.[Medline]
Niederreither K, Abu-Abed S, Schuhbaur B, Petkovich M, Chambon P, and 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.[Medline]
Ortiz MA, Bayon Y, Lopez-Hernandez FJ, and Piedrafita FJ (2002) Retinoids in combination therapies for the treatment of cancer: mechanisms and perspectives. Drug Resist Updat 5: 162-175.[CrossRef][Medline]
Pavri R, Lewis B, Kim TK, Dilworth FJ, Erdjument-Bromage H, Tempst P, de Murcia G, Evans R, Chambon P, and Reinberg D (2005) PARP-1 determines specificity in a retinoid signaling pathway via direct modulation of mediator. Mol Cell 18: 83-96.[CrossRef][Medline]
Perissi V and Rosenfeld MG (2005) Controlling nuclear receptors: the circular logic of cofactor cycles. Nat Rev Mol Cell Biol 6: 542-554.[CrossRef][Medline]
Petkovich M, Brand NJ, Krust A, and Chambon P (1987) A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature (Lond) 330: 444-450.[CrossRef][Medline]
Petty WJ, Li N, Biddle A, Bounds R, Nitkin C, Ma Y, Dragnev KH, Freemantle SJ, and Dmitrovsky E (2005) A novel retinoic acid receptor isoform and retinoid resistance in lung carcinogenesis. J Natl Cancer Inst 97: 1645-1651.
Picard E, Seguin C, Monhoven N, Rochette-Egly C, Siat J, Borrelly J, Martinet Y, Martinet N, and Vignaud JM (1999) Expression of retinoid receptor genes and proteins in non-small-cell lung cancer. J Natl Cancer Inst 91: 1059-1066.
Privalsky ML (2001) Regulation of SMRT and N-CoR corepressor function. Curr Top Microbiol Immunol 254: 117-136.[Medline]
Rastinejad F (2001) Retinoid X receptor and its partners in the nuclear receptor family. Curr Opin Struct Biol 11: 33-38.[CrossRef][Medline]
Rastinejad F, Wagner T, Zhao Q, and Khorasanizadeh S (2000) Structure of the RXR-RAR DNA-binding complex on the retinoic acid response element DR1. EMBO (Eur Mol Biol Organ) J 19: 1045-1054.[CrossRef][Medline]
Renaud JP, Rochel N, Ruff M, Vivat V, Chambon P, Gronemeyer H, and Moras D (1995) Crystal structure of the RAR- ligand-binding domain bound to all-trans retinoic acid. Nature (Lond) 378: 681-689.[CrossRef][Medline]
Resche-Rigon M and Gronemeyer H (1998) Therapeutic potential of selective modulators of nuclear receptor action. Curr Opin Chem Biol 2: 501-507.[CrossRef][Medline]
Rochette-Egly C (2003) Nuclear receptors: integration of multiple signalling pathways through phosphorylation. Cell Signal 15: 355-366.[CrossRef][Medline]
Rochette-Egly C and Chambon P (2001) F9 embryocarcinoma cells: a cell autonomous model to study the functional selectivity of RARs and RXRs in retinoid signaling. Histol Histopathol 16: 909-922.[Medline]
Schule R, Umesono K, Mangelsdorf DJ, Bolado J, Pike JW, and Evans RM (1990) Jun-Fos and receptors for vitamins A and D recognize a common response element in the human osteocalcin gene. Cell 61: 497-504.[CrossRef][Medline]
Smith WC, Nakshatri H, Leroy P, Rees J, and Chambon P (1991) A retinoic acid response element is present in the mouse cellular retinol binding protein I (mCRBPI) promoter. EMBO (Eur Mol Biol Organ) J 10: 2223-2230.[Medline]
Sporn MB, Dunlop NM, Newton DL, and Smith JM (1976) Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc 35: 1332-1338.[Medline]
Sporn MB, Roberts AB, and Goodman DS (1994) The Retinoids: Biology, Chemistry and Medicine, Raven Press, New York.
Sun SY and Lotan R (2002) Retinoids and their receptors in cancer development and chemoprevention. Crit Rev Oncol Hematol 41: 41-55.[Medline]
Tabin C (1995) The initiation of the limb bud: growth factors, Hox genes, and retinoids. Cell 80: 671-674.[CrossRef][Medline]
Takeuchi M, Yano T, Omoto E, Takahashi K, Kibata M, Shudo K, Harada M, Ueda R, and Ohno R (1998) Relapsed acute promyelocytic leukemia previously treated with all-trans retinoic acid: clinical experience with a new synthetic retinoid, Am-80. Leuk Lymphoma 31: 441-451.[Medline]
Taneja R, Rochette-Egly C, Plassat JL, Penna L, Gaub MP, and Chambon P (1997) Phosphorylation of activation functions AF-1 and AF-2 of RAR and RAR is indispensable for differentiation of F9 cells upon retinoic acid and cAMP treatment. EMBO (Eur Mol Biol Organ) J 16: 6452-6465.[CrossRef][Medline]
Taneja R, Roy B, Plassat JL, Zusi CF, Ostrowski J, Reczek PR, and Chambon P (1996) Cell-type and promoter-context dependent retinoic acid receptor (RAR) redundancies for RAR2 and Hoxa-1 activation in F9 and P19 cells can be artefactually generated by gene knockouts. Proc Natl Acad Sci USA 93: 6197-6202.
Thacher SM, Vasudevan J, and Chandraratna RA (2000) Therapeutic applications for ligands of retinoid receptors. Curr Pharm Des 6: 25-58.[CrossRef][Medline]
Tobita T, Takeshita A, Kitamura K, Ohnishi K, Yanagi M, Hiraoka A, Karasuno T, Takeuchi M, Miyawaki S, Ueda R, et al. (1997) Treatment with a new synthetic retinoid, Am80, of acute promyelocytic leukemia relapsed from complete remission induced by all-trans retinoic acid. Blood 90: 967-973.
Vivat-Hannah V and Zusi FC (2005) Retinoids as therapeutic agents: today and tomorrow. Mini Rev Med Chem 5: 755-760.[CrossRef][Medline]
Westin S, Kurokawa R, Nolte RT, Wisely GB, McInerney EM, Rose DW, Milburn MV, Rosenfeld MG, and Glass CK (1998) Interactions controlling the assembly of nuclear-receptor heterodimers and co-activators. Nature (Lond) 395: 199-202.[CrossRef][Medline]
Weston AD, Blumberg B, and Underhill TM (2003) Active repression by unliganded retinoid receptors in development: less is sometimes more. J Cell Biol 161: 223-228.
White JA, Beckett-Jones B, Guo YD, Dilworth FJ, Bonasoro J, Jones G, and 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.
Widschwendter M, Berger J, Daxenbichler G, Muller-Holzner E, Widschwendter A, Mayr A, Marth C, and Zeimet AG (1997) Loss of retinoic acid receptor 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.
Wolbach SB and Howe PR (1925). Tissue changes following deprivation of fat-soluble A vitamin. J Exp Med 43: 753-777.
Xu XC, Sneige N, Liu X, Nandagiri R, Lee JJ, Lukmanji F, Hortobagyi G, Lippman SM, Dhingra K, and Lotan R (1997a) Progressive decrease in nuclear retinoic acid receptor messenger RNA level during breast carcinogenesis. Cancer Res 57: 4992-4996.
Xu XC, Sozzi G, Lee JS, Lee JJ, Pastorino U, Pilotti S, Kurie JM, Hong WK, and Lotan R (1997b) Suppression of retinoic acid receptor in non-small-cell lung cancer in vivo: implications for lung cancer development. J Natl Cancer Inst 89: 624-629.
Zhu XJ, Tu P, Zhen J, and Duan YQ (2001) Adapalene gel 0.1%: effective and well tolerated in the topical treatment of acne vulgaris in Chinese patients. Cutis 68: 55-59.[Medline]
Zouboulis CC (2001) Retinoids—which dermatological indications will benefit in the near future? Skin Pharmacol Appl Skin Physiol 14: 303-315.[CrossRef][Medline]
Zusi FC, Lorenzi MV, and Vivat-Hannah V (2002) Selective retinoids and rexinoids in cancer therapy and chemoprevention. Drug Discov Today 7: 1165-1174.[CrossRef][Medline]
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