RESUMO
The discovery of retinoic acid receptors arose from research into how vitamins are essential for life. Early studies indicated that Vitamin A was metabolized into an active factor, retinoic acid (RA), which regulates RNA and protein expression in cells. Each step forward in our understanding of retinoic acid in human health was accomplished by the development and application of new technologies. Development cDNA cloning techniques and discovery of nuclear receptors for steroid hormones provided the basis for identification of two classes of retinoic acid receptors, RARs and RXRs, each of which has three isoforms, α, ß and É£. DNA manipulation and crystallographic studies revealed that the receptors contain discrete functional domains responsible for binding to DNA, ligands and cofactors. Ligand binding was shown to induce conformational changes in the receptors that cause release of corepressors and recruitment of coactivators to create functional complexes that are bound to consensus promoter DNA sequences called retinoic acid response elements (RAREs) and that cause opening of chromatin and transcription of adjacent genes. Homologous recombination technology allowed the development of mice lacking expression of retinoic acid receptors, individually or in various combinations, which demonstrated that the receptors exhibit vital, but redundant, functions in fetal development and in vision, reproduction, and other functions required for maintenance of adult life. More recent advancements in sequencing and proteomic technologies reveal the complexity of retinoic acid receptor involvement in cellular function through regulation of gene expression and kinase activity. Future directions will require systems biology approaches to decipher how these integrated networks affect human stem cells, health, and disease.
Assuntos
Receptores do Ácido Retinoico/história , Receptores X de Retinoides/história , Tretinoína/metabolismo , Vitamina A/metabolismo , Animais , Clonagem Molecular , Regulação da Expressão Gênica , História do Século XX , História do Século XXI , Humanos , Camundongos , Camundongos Knockout , Isoformas de Proteínas/genética , Isoformas de Proteínas/história , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Elementos de Resposta , Receptores X de Retinoides/genética , Receptores X de Retinoides/metabolismo , Transdução de Sinais , Tretinoína/química , Vitamina A/químicaAssuntos
RNA Polimerases Dirigidas por DNA/história , Família Multigênica/genética , Receptores do Ácido Retinoico/história , Receptor X Retinoide alfa/história , Transcrição Gênica/fisiologia , RNA Polimerases Dirigidas por DNA/química , História do Século XX , História do Século XXI , Regiões Promotoras Genéticas/genética , Receptores de Estrogênio/química , Receptores do Ácido Retinoico/química , Receptor X Retinoide alfa/química , Receptor gama de Ácido RetinoicoRESUMO
This review presents a historical overview of the discoveries of retinoic acid receptor (RAR) and retinoid X receptor (RXR) class- and subtype-selective synthetic retinoids. These synthetic retinoids are conformationally restricted by having aromatic rings in place of the tetraene bond systems of all-trans- and 9-cis-retinoic acids. Events leading to the design and synthesis of such retinoid transcriptional agonists as RAR subtype beta,gamma-selective 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-naph-thalenecarboxylic acid (TTNN), the RARgamma-selective Z-oxime of 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenylcarbonyl)-2-naphthalenecarboxylic acid (SR11254), RAR-selective 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid (TTAB), RXR-selective 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-cyclopropyl] benzoic acid (SR11246), RXR-selective 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-2-methylpropenyl]benzoic acid (SR11345), and RARgamma-selective retinoid transcriptional antagonist 2-(6-carboxy-2-naphthalenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1,3-dithiolane (SR11253) are described.
