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Joseph L. Napoli - One of the best experts on this subject based on the ideXlab platform.
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cellular Retinoid binding proteins crbp crabp fabp5 effects on Retinoid metabolism function and related diseases
Pharmacology & Therapeutics, 2017Co-Authors: Joseph L. NapoliAbstract:Cellular binding-proteins (BP), including CRBP1, CRBP2, CRABP1, CRABP2, and FABP5, shepherd the poorly aqueous soluble Retinoids during uptake, metabolism and function. Holo-BP promote efficient use of retinol, a scarce but essential nutrient throughout evolution, by sheltering it and its major metabolite all-trans-retinoic acid from adventitious interactions with the cellular milieu, and by imposing specificity of delivery to enzymes, nuclear receptors and other partners. Apo-BP reflect cellular Retinoid status and modify activities of Retinoid metabolon enzymes, or exert non-canonical actions. High ligand binding affinities and the nature of ligand sequestration necessitate external factors to prompt Retinoid release from holo-BP. One or more of cross-linking, kinetics, and colocalization have identified these factors as RDH, RALDH, CYP26, LRAT, RAR and PPARβ/δ. Michaelis-Menten and other kinetic approaches verify that BP channel Retinoids to select enzymes and receptors by protein-protein interactions. Function of the BP and enzymes that constitute the Retinoid metabolon depends in part on Retinoid exchanges unique to specific pairings. The complexity of these exchanges configure retinol metabolism to meet the diverse functions of all-trans-retinoic acid and its ability to foster contrary outcomes in different cell types, such as inducing apoptosis, differentiation or proliferation. Altered BP expression affects Retinoid function, for example, by impairing pancreas development resulting in abnormal glucose and energy metabolism, promoting predisposition to breast cancer, and fostering more severe outcomes in prostate cancer, ovarian adenocarcinoma, and glioblastoma. Yet, the extent of BP interactions with Retinoid metabolon enzymes and their impact on Retinoid physiology remains incompletely understood.
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cis retinol androgen dehydrogenase isozyme 3 crad3 a short chain dehydrogenase active in a reconstituted path of 9 cis retinoic acid biosynthesis in intact cells
Biochemistry, 2002Co-Authors: Run Zhuang, Min Lin, Joseph L. NapoliAbstract:9-cis-Retinoic acid activates Retinoid X receptors, which serve as heterodimeric partners with other nuclear hormone receptors, yet the enzymology of its physiological generation remains unclear. Here, we report the identification and molecular/enzymatic characterization of a previously unknown member of the short-chain dehydrogenase/reductase family, CRAD3 (cis-Retinoid/androgen dehydrogenase, type 3), which catalyzes the first step in 9-cis-retinoic acid biosynthesis, the conversion of 9-cis-retinol into 9-cis-retinal. CRAD3 shares amino acid similarity with other Retinoid/steroid short-chain dehydrogenases/reductases: CRAD1, CRAD2, and RDH4. Relative to CRADI, CRAD3 has greater 9-cis-retinol/ all-trans-retinol discrimination and lower efficiency as an androgen dehydrogenase. CRAD3 has apparent efficiency (V/K m ) for 9-cis-retinol about equivalent to that for CRAD1 and 3 orders of magnitude greater than that for RDH4. (CRAD2 does not recognize 9-cis-retinol as a substrate). CRAD3 contributes to 9-cis-retinoic acid production in intact cells, in conjunction with each of three retinal dehydrogenases that recognize 9-cis-retinal (RALDH1/AHD2, RALDH2, and ALDH12). Liver and kidney, two tissues reportedly with the highest concentrations of 9-cis-Retinoids, show the most intense mRNA expression of CRAD3, but expression also occurs in testis, lung, small intestine, heart, and brain. These data are consistent with the participation of CRAD3 in the biogeneration of 9-cis-retinoic acid.
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Interactions of Retinoid binding proteins and enzymes in Retinoid metabolism.
Biochimica et Biophysica Acta, 1999Co-Authors: Joseph L. NapoliAbstract:Abstract Naturally occurring Retinoids (vitamin A or retinol and its active metabolites) are vital for vision, controlling the differentiation program of epithelial cells in the digestive tract and respiratory system, skin, bone, the nervous system, the immune system, and for hematopoiesis. Retinoids are essential for growth, reproduction (conception and embryonic development), and resistance to and recovery from infection. The functions of Retinoids in the embryo begin soon after conception and continue throughout the lifespan of all vertebrates. Both naturally occurring and synthetic Retinoids are used in the therapy of various skin diseases, especially acne, for augmenting the treatment of diabetes, and as cancer chemopreventive agents. Retinol metabolites serve as ligands that activate specific transcription factors in the superfamily of steroid/Retinoid/thyroid/vitamin D/orphan receptors and thereby control gene expression. Additionally, Retinoids may also function through non-genomic actions. Various Retinoid binding proteins serve as partners in Retinoid function. These binding proteins show high specificity and affinity for specific Retinoids and seem to control Retinoid metabolism in vivo qualitatively and quantitatively by reducing ‘free’ Retinoid concentrations, protecting Retinoids from non-specific interactions, and chaperoning access of metabolic enzymes to Retinoids. Implementation of the physiological effects of Retinoids depends on the spatial-temporal expressions of binding proteins, receptors and metabolic enzymes. This review will discuss current understanding of the enzymes that catalyze retinol and retinoic acid metabolism and their unique and integral relationship to Retinoid binding proteins.
Huijeong Jang - One of the best experts on this subject based on the ideXlab platform.
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Retinoid production using metabolically engineered escherichia coli with a two phase culture system
Microbial Cell Factories, 2011Co-Authors: Huijeong Jang, Sanghwal Yoon, Chonglong Wang, Deok-kun OhAbstract:Background Retinoids are lipophilic isoprenoids composed of a cyclic group and a linear chain with a hydrophilic end group. These compounds include retinol, retinal, retinoic acid, retinyl esters, and various derivatives of these structures. Retinoids are used as cosmetic agents and effective pharmaceuticals for skin diseases. Retinal, an immediate precursor of Retinoids, is derived by β-carotene 15,15'-mono(di)oxygenase (BCM(D)O) from β-carotene, which is synthesized from the isoprenoid building blocks isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Retinoids are chemically unstable and biologically degraded via retinoic acid. Although extensive studies have been performed on the microbial production of carotenoids, Retinoid production using microbial metabolic engineering has not been reported. Here, we report Retinoid production using engineered Escherichia coli that express exogenous BCM(D)O and the mevalonate (MVA) pathway for the building blocks synthesis in combination with a two-phase culture system using a dodecane overlay.
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Retinoid production using metabolically engineered escherichia coli with a two phase culture system
Microbial Cell Factories, 2011Co-Authors: Huijeong Jang, Sanghwal Yoon, Chonglong Wang, Heekyung Ryu, Junghun Kim, Jaeyean Kim, Seonwon KimAbstract:Retinoids are lipophilic isoprenoids composed of a cyclic group and a linear chain with a hydrophilic end group. These compounds include retinol, retinal, retinoic acid, retinyl esters, and various derivatives of these structures. Retinoids are used as cosmetic agents and effective pharmaceuticals for skin diseases. Retinal, an immediate precursor of Retinoids, is derived by β-carotene 15,15'-mono(di)oxygenase (BCM(D)O) from β-carotene, which is synthesized from the isoprenoid building blocks isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Retinoids are chemically unstable and biologically degraded via retinoic acid. Although extensive studies have been performed on the microbial production of carotenoids, Retinoid production using microbial metabolic engineering has not been reported. Here, we report Retinoid production using engineered Escherichia coli that express exogenous BCM(D)O and the mevalonate (MVA) pathway for the building blocks synthesis in combination with a two-phase culture system using a dodecane overlay. Among the BCM(D)O tested in E. coli, the synthetic Retinoid synthesis protein (SR), based on bacteriorhodopsin-related protein-like homolog (Blh) of the uncultured marine bacteria 66A03, showed the highest β-carotene cleavage activity with no residual intracellular β-carotene. By introducing the exogenous MVA pathway, 8.7 mg/L of retinal was produced, which is 4-fold higher production than that of augmenting the MEP pathway (dxs overexpression). There was a large gap between retinal production and β-carotene consumption using the exogenous MVA pathway; therefore, the retinal derivatives were analyzed. The derivatives, except for retinoic acid, that formed were identified, and the levels of retinal, retinol, and retinyl acetate were measured. Amounts as high as 95 mg/L Retinoids were obtained from engineered E. coli DH5α harboring the synthetic SR gene and the exogenous MVA pathway in addition to dxs overexpression, which were cultured at 29°C for 72 hours with 2YT medium containing 2.0% (w/v) glycerol as the main carbon source. However, a significant level of intracellular degradation of the Retinoids was also observed in the culture. To prevent degradation of the intracellular Retinoids through in situ extraction from the cells, a two-phase culture system with dodecane was used. The highest level of Retinoid production (136 mg/L) was obtained after 72 hours with 5 mL of dodecane overlaid on a 5 mL culture. In this study, we successfully produced 136 mg/L Retinoids, which were composed of 67 mg/L retinal, 54 mg/L retinol, and 15 mg/L retinyl acetate, using a two-phase culture system with dodecane, which produced 68-fold more Retinoids than the initial level of production (2.2 mg/L). Our results demonstrate the potential use of E. coli as a promising microbial cell factory for Retinoid production.
Miguel Machado Santos - One of the best experts on this subject based on the ideXlab platform.
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Differences in Retinoid levels and metabolism among gastropod lineages: imposex-susceptible gastropods lack the ability to store Retinoids in the form of retinyl esters.
Aquatic toxicology (Amsterdam Netherlands), 2013Co-Authors: Manuel Gesto, L Filipe C Castro, Miguel Machado SantosAbstract:The presence of a complex Retinoid system was long believed to be a chordate/vertebrate novelty. However, recent findings indicate otherwise since the gastropod mollusk Osilinus lineatus was found to have the capacity to store Retinoids in the form of retinyl esters (REs), a key feature to maintain a homeostatic control of Retinoid levels. Here, we investigated whether such a complex Retinoid system is widely distributed among gastropod lineages. Additionally, since one of the most spectacular examples of endocrine disruption in the wild, the masculinization of female gastropods (imposex) by the Retinoid X receptor (RXR) agonist, tributyltin (TBT), has been linked with perturbed Retinoid signaling, we also investigated if Retinoid storage mechanisms in the form of retinyl esters were present in imposex-susceptible gastropods. Initially, we determined the presence of both polar (active retinoic acid isomers) and nonpolar Retinoids (retinol, REs) in selected gastropod species: the limpet Patella depressa and the imposex-susceptible whelks Nucella lapillus and Nassarius reticulatus. Although all species presented active Retinoid forms, N. lapillus and N. reticulatus were shown to lack nonpolar Retinoids. The absence of REs, which are the common Retinoid storage form found in vertebrates and in O. lineatus suggest that those species are unable to use them to maintain a homeostatic control of their Retinoid levels. In order to further clarify the Retinoid metabolic pathways in imposex-susceptible gastropods, a Retinoid exposure study was carried out with N. lapillus. The results demonstrate that although N. lapillus is able to metabolize several Retinoid precursors, it lacks the capacity to store Retinoids as REs. Whether the lack of Retinoid storage mechanisms in the form of REs in imposex-susceptible gastropods plays an important role in the susceptibility to RXR agonists warrants additional studies.
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retinol metabolism in the mollusk osilinus lineatus indicates an ancient origin for retinyl ester storage capacity
PLOS ONE, 2012Co-Authors: Manuel Gesto, Filipe L. C. Castro, M A Reishenriques, Miguel Machado SantosAbstract:Although Retinoids have been reported to be present and active in vertebrates and invertebrates, the presence of mechanisms for Retinoid storage in the form of retinyl esters, a key feature to maintain whole-organism Retinoid homeostasis, have been considered to date a vertebrate innovation. Here we demonstrate for the first time the presence of retinol and retinyl esters in an invertebrate lophotrochozoan species, the gastropod mollusk Osilinus lineatus. Furthermore, through a pharmacological approach consisting of intramuscular injections of different Retinoid precursors, we also demonstrate that the retinol esterification pathway is active in vivo in this species. Interestingly, retinol and retinyl esters were only detected in males, suggesting a gender-specific role for these compounds in the testis. Females, although lacking detectable levels of retinol or retinyl esters, also have the biochemical capacity to esterify retinol, but at a lower rate than males. The occurrence of retinyl ester storage capacity, together with the presence in males and females of active Retinoids, i.e., retinoic acid isomers, indicates that O. lineatus has a well developed Retinoid system. Hence, the present data strongly suggest that the capacity to maintain Retinoid homeostasis has arisen earlier in Bilateria evolution than previously thought.
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Retinol Metabolism in the Mollusk Osilinus lineatus Indicates an Ancient Origin for Retinyl Ester Storage Capacity
2012Co-Authors: Manuel Gesto, L. Filipe, C. Castro, Maria Arm, A Reis-henriques, Miguel Machado SantosAbstract:Although Retinoids have been reported to be present and active in vertebrates and invertebrates, the presence of mechanisms for Retinoid storage in the form of retinyl esters, a key feature to maintain whole-organism Retinoid homeostasis, have been considered to date a vertebrate innovation. Here we demonstrate for the first time the presence of retinol and retinyl esters in an invertebrate lophotrochozoan species, the gastropod mollusk Osilinus lineatus. Furthermore, through a pharmacological approach consisting of intramuscular injections of different Retinoid precursors, we also demonstrate that the retinol esterification pathway is active in vivo in this species. Interestingly, retinol and retinyl esters were only detected in males, suggesting a gender-specific role for these compounds in the testis. Females, although lacking detectable levels of retinol or retinyl esters, also have the biochemical capacity to esterify retinol, but at a lower rate than males. The occurrence of retinyl ester storage capacity, together with the presence in males and females of active Retinoids, i.e., retinoic acid isomers, indicates that O. lineatus has a well developed Retinoid system. Hence, the present data strongl
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Overview of the Retinoid metabolism in vertebrates
2012Co-Authors: Manuel Gesto, Filipe L. C. Castro, Maria Armanda Reis-henriques, Miguel Machado SantosAbstract:. A. Major pathways in Retinoid metabolism. In the intestine, Retinoids and carotenoids taken in the diet (from animal and vegetable sources, respectively) are mainly converted to REs, which are incorporated into chylomicrons and taken to the liver trough the lymph and general circulation. In the liver the REs are taken up by hepatocytes and hydrolyzed to ROL which is bound to RBP for transport to storage or target cells. ROL could be stored as REs in liver stellate cells. When required, the ROL is bound to RBP and mobilized from hepatocytes or stellate cells to circulation, where is bound to TTR to avoid glomerular filtration in the kidney and to ensure delivery to target cells. Once in the target cell, free ROL is oxidized to RAL and then to RA, which enters the nucleus and activates RXRs and/or RARs, regulating gene transcription. For a complete description of Retinoid metabolism see references [2] and [3].B: Main biochemical routes involved in the Retinoid system. (9cRA), 9-cis-retinoic acid; (ADHs) alcohol dehydrogenases (medium-chain dehydrogenases/reductases family); (ALDHs) aldehyde dehydrogenases; (ARAT) acyl-CoA:retinol acyltransferase; (atRA), all-trans-retinoic acid; (BCO I), □, □-carotene-15,15′-monooxygenase; (BCO II), □, □-carotene 9′,10′-dioxygenase; (LRAT), lecithin:retinol acyltransferase; (RA), retinoic acid; (RAL), retinaldehyde; (RARs), retinoic acid receptors; (RBP), retinol binding protein; (REHs), retinyl ester hydrolases; (REs), retinyl esters; (ROL), retinol; (RXRs), Retinoid X receptors; (SDRs) short-chain dehydrogenases/reductases; (TTR), transthyretin.
Pierre Chambon - One of the best experts on this subject based on the ideXlab platform.
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regulation of cd8 t lymphocyte effector function and macrophage inflammatory cytokine production by retinoic acid receptor γ
Journal of Immunology, 2007Co-Authors: Ivan Dzhagalov, Pierre ChambonAbstract:Vitamin A and its derivatives regulate a broad array of immune functions. The effects of these Retinoids are mediated through members of retinoic acid receptors (RARs) and Retinoid X receptors. However, the role of individual Retinoid receptors in the pleiotropic effects of Retinoids remains unclear. To dissect the role of these receptors in the immune system, we analyzed immune cell development and function in mice conditionally lacking RARγ, the third member of the RAR family. We show that RARγ is dispensable for T and B lymphocyte development, the humoral immune response to a T-dependent Ag and in vitro Th cell differentiation. However, RARγ-deficient mice had a defective primary and memory CD8 + T cell response to Listeria monocytogenes infection. Unexpectedly, RARγ-deficient macrophages exhibited impaired inflammatory cytokine production upon TLR stimulation. These results suggest that under physiological condition, RARγ is a positive regulator of inflammatory cytokine production.
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international union of pharmacology lx retinoic acid receptors
Pharmacological Reviews, 2006Co-Authors: Pierre Chambon, Reuben Lotan, Mark Leid, Pierre Germain, Gregor Eichele, Ronald M Evans, Mitchell A Lazar, Angel R De Lera, David J MangelsdorfAbstract:Retinoid is a term for compounds that bind to and activate retinoic acid receptors (RARα, RARβ, and RARγ), 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.
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Retinoid status and responsiveness to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking Retinoid binding protein or Retinoid receptor forms.
Chemico-biological interactions, 2005Co-Authors: Pi Hoegberg, Heinz Nau, Carsten K. Schmidt, Nicholas Fletcher, Charlotte B. Nilsson, Christina Trossvik, A. Gerlienke Schuur, Abraham Brouwer, Norbert B. Ghyselinck, Pierre ChambonAbstract:We have investigated the role of Vitamin A (Retinoid) proteins in hepatic Retinoid processing under normal conditions and during chemical stress induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a chemical known to interfere with Retinoid turnover and metabolism. Three separate studies were performed in wildtype control mice and transgenic mice that lack one or more isoforms of retinoic acid receptors (RAR), Retinoid X receptors (RXR), or intracellular Retinoid-binding proteins (CRABP I, CRABP II, CRBP I). Body and organ weight development was monitored from 2 weeks of age to adult, and hepatic levels of retinyl esters, retinol, and retinoic acid were investigated. In addition, hepatic concentrations of 9-cis-4-oxo-13,14-dihydro-retinoic acid, a recently discovered Retinoid metabolite that has proven sensitive to both TCDD exposure and Vitamin A status, were also determined. Mice absent in the three proteins CRBP I, CRABP I, and CRABP II (CI/CAI/CAII-/-) displayed significantly lower hepatic retinyl ester, retinol, and all-trans-retinoic acid levels compared to wildtype mice, whereas the liver concentrations of 9-cis-4-oxo-13,14-dihydro-retinoic acid was considerably higher. After treatment with TCDD, hepatic total Retinoids were almost entirely depleted in the CI/CAI/CAII-/- mice, whereas wildtype mice and mice lacking CRABP I, and CRABP II (CAI/CAII-/-) retained approximately 60-70% of their Vitamin A content compared to controls at 28 days. RAR and RXR knockout mice responded similarly to wildtype mice with respect to TCDD-induced Retinoid disruption, with the exception of RXRbeta-/- mice which showed no decrease in hepatic Vitamin A concentration, suggesting that the role of RXRbeta in TCDD-induced Retinoid disruption should be further investigated. Overall, the abnormal Retinoid profile in the triple knockout mice (CI/CAI/CAII-/-), but not double knockout (CAI/CAII-/-) mice, suggests that a loss of CRBP I may account for the difference in Retinoid profile in CI/CAI/CAII-/- mice, and is likely to result in an increased susceptibility to hepatic Retinoid depletion following dioxin exposure.
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Retinoids regulate survival and antigen presentation by immature dendritic cells
Journal of Experimental Medicine, 2003Co-Authors: Frederic Geissmann, Patrick Revy, Nicole Brousse, Yves Lepelletier, Claudia Folli, Anne Durandy, Pierre ChambonAbstract:Maturation of dendritic cells (DCs) is a critical step for the induction of an immune response. We have examined the role of Retinoid nuclear receptor pathways in this process. Retinoids induce DC apoptosis, in the absence of inflammatory signals, through retinoic acid receptor (RAR)α/retinoic X receptor (RXR) heterodimers. In contrast, via a cross talk with inflammatory cytokines, Retinoids increase DNA binding activity of nuclear factor κB in DCs, trigger membrane major histocompatibility complex class II and costimulatory molecule expression, induce the differentiation of immature DCs into mature DCs, and enhance antigen-specific T cell response. This maturation of DCs is mediated via a RXR-dependent/RAR-independent pathway and via an RARα/RXR pathway distinct from the one responsible for apoptosis. Apoptosis and activation, mediated through distinct nuclear Retinoid receptor pathways, can be dissociated from each other with selective synthetic Retinoids. We identify a novel cellular function for Retinoids and suggest that selective Retinoids might be of interest for controlling antigen presentation.
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Mouse P450RAI (CYP26) Expression and Retinoic Acid-inducible Retinoic Acid Metabolism in F9 Cells Are Regulated by Retinoic Acid Receptor γ and Retinoid X Receptor α
The Journal of biological chemistry, 1998Co-Authors: Suzan Abu-abed, Pierre Chambon, Barbara R. Beckett, Hideki Chiba, James V. Chithalen, Glenville Jones, Daniel Metzger, Martin PetkovichAbstract:We have cloned a mouse cDNA homolog of P450RAI, a cytochrome P450 belonging to a new family (CYP26), which has previously been isolated from zebrafish and human cDNAs and found to encode a retinoic acid-inducible retinoic acid hydroxylase activity. The cross-species conservation of the amino acid sequence is high, particularly between the mouse and the human enzymes, in which it is over 90%. Like its human and zibrafish counterparts, the mouse P450RAI cDNA catalyzes metabolism of retinoic acid into 4-OH-retinoic acid, 4-oxo-retinoic acid, 18-OH-retinoic acid, and unidentified water-soluble metabolites when transfected into COS-1 cells. Retinoic acid-inducible retinoic acid metabolism has previously been observed in F9 murine embryonal carcinoma cells and some derivatives lacking Retinoid receptors. We were interested in determining whether P450RAI could be responsible for retinoic acid metabolism in F9 cells and in studying the effect of Retinoid receptor ablation on P450RAI expression. In wild-type F9 cells and derivatives lacking RAR gamma, RAR alpha, and/or RXR alpha, we observed a direct relationship between the level of retinoic acid metabolic activity and retinoic acid-induced P450RAI mRNA. These experiments, as well as others using synthetic receptor subtype-specific Retinoids, suggest that the RAR gamma and RXR alpha receptors mediate the effects of retinoic acid on the expression of the P450RAI gene.
Reuben Lotan - One of the best experts on this subject based on the ideXlab platform.
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international union of pharmacology lx retinoic acid receptors
Pharmacological Reviews, 2006Co-Authors: Pierre Chambon, Reuben Lotan, Mark Leid, Pierre Germain, Gregor Eichele, Ronald M Evans, Mitchell A Lazar, Angel R De Lera, David J MangelsdorfAbstract:Retinoid is a term for compounds that bind to and activate retinoic acid receptors (RARα, RARβ, and RARγ), 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.
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a crucial role for cellular retinol binding protein i in Retinoid signaling
Journal of the National Cancer Institute, 2005Co-Authors: Reuben LotanAbstract:Retinol (the prototypic vitamin A) and its metabolites called Retinoids play important physiologic roles in embryonal development, vision, maintenance of epithelial differentiation, immune functions, and reproduction (1). Many of these functions are mediated by retinol metabolites such as all-trans-retinoic acid (ATRA) (2). ATRA modulates gene expression by means of nuclear receptors that are members of the steroid hormone gene superfamily. These receptors, retinoic acid receptors (RARs) and Retinoid X receptors (RXRs), appear in at least three subtypes, designated , , and . The receptors function as ligand-activated heterodimeric DNA-binding transcription enhancing factors and regulate the transcription of various genes, which play important roles during development and in adult tissues. Abberant expression and function of specific Retinoid receptors, primarily RAR , have been associated with cancer development and progression (3,4). However, recent studies have highlighted additional mechanisms for abrogation of Retinoid signaling in carcinogenesis. These involve abnormalities located upstream of retinoic acid and its nuclear receptors. These defects interfere with retinol storage and its metabolism to retinoic acid and result in a localized Retinoid deficiency. Interestingly, we have suggested that decreased levels of RAR may be, at least in part, caused by local vitamin A deficiency (5). Dietary retinol is stored in the liver in specialized cells and delivered to various target tissues via a retinol-binding protein
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Retinoids and their receptors in cancer development and chemoprevention
Critical Reviews in Oncology Hematology, 2002Co-Authors: Shiyong Sun, Reuben LotanAbstract:Retinoids play an important role in regulating the growth and differentiation of normal, premalignant and malignant cell types, especially epithelial cells, mainly through interaction with two types of nuclear receptors: retinoic acid receptors (RARalpha, beta and gamma) and Retinoid X receptors (RXRalpha, beta and gamma). Vitamin A deficiency in experimental animals has been associated with a higher incidence of cancer and with increased susceptibility to chemical carcinogens. This is in agreement with the epidemiological studies indicating that individuals with a lower dietary vitamin A intake are at a higher risk to develop cancer. At the molecular level, aberrant expression and function of nuclear Retinoid receptors have been found in various types of cancer including premalignant lesions. Thus, aberrations in Retinoid signaling are early events in carcinogenesis. Retinoids at pharmacological doses exhibit a variety of effects associated with cancer prevention. They suppress transformation of cells in vitro, inhibit carcinogenesis in various organs in animal models, reduce premalignant human epithelial lesions and prevent second primary tumors following curative therapy for epithelial malignancies such as head and neck, lung, liver, and breast cancer.
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Differential effects of chromosome 3p deletion on the expression of the putative tumor suppressor RARβ and on Retinoid resistance in human squamous carcinoma cells
Oncogene, 2001Co-Authors: Chang-ping Zou, Emile M Youssef, Chang-chun Zou, Thomas E Carey, Reuben LotanAbstract:Retinoids' effects on cell growth and differentiation are mediated by nuclear Retinoid receptors, which are ligand-activated transcription enhancing factors. Because the expression of the retinoic acid receptor β (RARβ) gene, which is located on chromosome 3p24, is diminished in premalignant and malignant tissues it has been proposed that it acts as a tumor suppressor. To test the hypothesis that RARβ loss leads to Retinoid resistance, we studied several karyotyped head and neck squamous carcinoma (HNSCC) cell lines (UMSCC-17A, -17B, -22A, -22B, and -38) with deletion of one chromosome 3p arm. RARβ mRNA was neither detected nor induced by retinoic acid in these cells, whereas it was expressed and induced by retinoic acid in two other HNSCC cell lines (1483 and 183) without 3p deletion. Methylation of the RARβ gene promoter was detected in the 17B and 22B cells that failed to express RARβ but no methylation was found in 183A cells that did express RARβ mRNA. Responsiveness of HNSCC cells to several Retinoids in assays of growth inhibition and colony formation, was rank ordered as: 22B>1483>38>183>17B. Additionally, Retinoid response elements were transactivated in 22B more efficiently than in 17B cells. These results indicate that loss of RARβ expression does not necessarily lead to loss of growth inhibition by Retinoids or to a block of Retinoid signaling.
