PROBING THE MULTIPLE INTERACTIONS OF RETINOID RECEPTORS

探索类维生素A受体的多重相互作用

• 批准号: 2748810
• 负责人: NOA NOY
• 金额: $ 20.79万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2748810
• 关键词: DNA footprinting; biological signal transduction; chemical aggregate; chemical association; chemical kinetics; conformation; dimer; fluorescence spectrometry; fluorescent dye /probe; gel mobility shift assay; genetic regulatory element; genetic transcription; hormone receptor; laboratory rat; ligands; nucleosomes; phosphorylation; posttranslational modifications; protein kinase; receptor binding; retinoid binding proteins; retinoids; thermodynamics; thyroid hormones; transcription factor

Retinoids exert pleiotropic effects on mammalian physiology. They play a key role in epithelial cell differentiation, have profound effects on limb and nervous system morphogenesis, are potent inhibitors of carcinogenesis, and are currently used as chemopreventive and therapeutic agents in several types of cancer. Signalling by these hormones is mediated by two classes of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs) which bind all trans- and 9 cis-retinoic acids, respectively. These receptors usually associate with regulatory elements upstream from speCific target genes and act as ligand-inducible transcription factors. The proposed project is designed to clarify the factors that modulate the multiple interactions of retinoid nuclear receptors and obtain insights into the mechanisms by which signalling by retinoids may be regulated. The processes of self- association of receptor proteins and their interactions with their ligands and with cognate DNA will be studied. Binding affinities characterizing these interactions as well as the kinetic parameters leading to the formation of receptor-ligand-DNA complexes will be investigated using quantitative methods. The interactions of the retinoid X receptors with the thyroid hormone receptor will be studied to better understand the mechanisms by which signalling pathways by thyroid hormone and by retinoids may converge to affect gene transcription. To clarify one aspect of the mechanisms by which retinoids may suppress carcinogenesis, the interactions of retinoid receptors with the proton- oncogene products c-Fos and c-Jun (AP-1 transcription factor) and the effects of retinoid receptors on binding of the AP-1 factor to its cognate DNA will be investigated. The roles of post-translational modification of receptor proteins in modulating their various interactions will be examined in order to better understand the mechanisms underlying the regulation of retinoid receptor function in the cell.

维甲酸对哺乳动物的生理作用具有多效性。他们打球 在上皮细胞分化中的关键作用，对 肢体和神经系统的形态发生，是有效的抑制 致癌，目前被用作化学预防和治疗 治疗几种癌症的药物。这些激素发出的信号是 由两类核受体介导，维甲酸受体 (RARs)和维甲酸X受体(RXRs)结合所有反式和9 顺式维甲酸。这些受体通常与 调控元件位于特定靶基因的上游，并起到 配体诱导转录因子。建议的项目是设计的 为了弄清调节多种相互作用的因素 并通过以下方式深入了解其机制 维甲酸的信号转导可能受到调控。自我发展的过程 受体蛋白的相互作用及其相互作用 配基和同源DNA将被研究。结合亲和力 表征这些相互作用以及动力学参数 导致受体-配体-DNA复合体的形成 使用定量的方法进行调查。维甲酸的相互作用 X受体与甲状腺激素受体的研究将更好地 了解甲状腺激素信号转导途径的机制 而类维A酸可能会聚集在一起，影响基因转录。为了澄清 维甲酸可能抑制的机制的一个方面 致癌，维甲酸受体与质子相互作用- 癌基因产物c-Fos和c-jun(AP-1转录因子)和 视黄酸受体对AP-1因子与其结合的影响 将对同源DNA进行调查。后翻译的作用 受体蛋白在调节其各种变化中的修饰 为了更好地理解 视黄醇受体功能调节机制的研究进展 手机。