History of Retinoic Acid Receptors
History of Retinoic Acid Receptors
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DOI：
10.1007/978-94-017-9050-5_1
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发表时间：
2014-01-01
期刊：
影响因子：
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通讯作者：
Asson-Batres, Mary Ann
中科院分区：
文献类型：
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作者：
Benbrook, Doris M.;Chambon, Pierre;Asson-Batres, Mary Ann
视黄酸受体的发现源于对维生素对于生命的重要性的研究。早期研究表明，维生素 A 被代谢为活性因子视黄酸 (RA)，可调节细胞中 RNA 和蛋白质的表达。我们对视黄酸对人类健康的理解的每一步进步都是通过新技术的开发和应用来实现的。 cDNA 克隆技术的发展和类固醇激素核受体的发现为鉴定两类视黄酸受体 RAR 和 RXR 提供了基础，每种受体都有三种亚型：α、β 和 γ DNA 操作和晶体学研究表明，这些受体包含负责与 DNA、配体和辅因子结合的离散功能域。研究表明，配体结合可诱导受体发生构象变化，从而导致辅阻遏物的释放和共激活物的募集，从而形成功能复合物，该复合物与称为视黄酸反应元件 (RARE) 的共有启动子 DNA 序列结合，并导致染色质打开和相邻基因转录。同源重组技术使得缺乏视黄酸受体表达的小鼠得以发育，无论是单独的还是以各种组合的形式，这证明这些受体在胎儿发育以及视力、生殖和维持成年生命所需的其他功能中表现出重要但多余的功能。测序和蛋白质组学技术的最新进展揭示了视黄酸受体通过调节基因表达和激酶活性参与细胞功能的复杂性。未来的方向将需要系统生物学方法来破译这些集成网络如何影响人类干细胞、健康和疾病。
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, alpha, beta and gamma 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.