TR2 nuclear receptor in vitamin A signaling

维生素 A 信号转导中的 TR2 核受体

• 批准号: 8010070
• 负责人: Li-Na Wei
• 金额: $ 13.25万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010070
• 关键词: Acetylation; Address; Affect; Apolipoprotein E; Binding; Biochemical; Biological; Biological Assay; Cell Culture Techniques; Cell Cycle Progression; Cell Nucleus; Chromatin; Complex; Cyclin D1; Cyclins; DNA; DNA Binding; Detection; Dimerization; Endocrine system; Event; Family; Funding; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Histones; Hormonal; In Vitro; Kinetics; Ligands; Methylation; Modification; Molecular Conformation; Nature; Nuclear; Nuclear Receptors; Nucleic Acid Regulatory Sequences; Nucleosomes; Orphan; Pathway interactions; Phosphorylation; Plasma; Play; Positioning Attribute; Post-Translational Protein Processing; Property; Proteomics; RXR; Recruitment Activity; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Surface; System; Testing; Transcriptional Activation; Tretinoin; Vitamin A; base; cell type; chromatin immunoprecipitation; chromatin remodeling; histone modification; human NRIP1 protein; in vivo; lipid metabolism; novel; orphan nuclear receptor TR2; promoter; receptor; Acetylation; Address; Affect; Apolipoprotein E; Binding; Biochemical; Biological; Biological Assay; Cell Culture Techniques; Cell Cycle Progression; Cell Nucleus; Chromatin; Complex; Cyclin D1; Cyclins; DNA; DNA Binding; Detection; Dimerization; Endocrine system; Event; Family; Funding; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Histones; Hormonal; In Vitro; Kinetics; Ligands; Methylation; Modification; Molecular Conformation; Nature; Nuclear; Nuclear Receptors; Nucleic Acid Regulatory Sequences; Nucleosomes; Orphan; Pathway interactions; Phosphorylation; Plasma; Play; Positioning Attribute; Post-Translational Protein Processing; Property; Proteomics; RXR; Recruitment Activity; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Surface; System; Testing; Transcriptional Activation; Tretinoin; Vitamin A; base; cell type; chromatin immunoprecipitation; chromatin remodeling; histone modification; human NRIP1 protein; in vivo; lipid metabolism; novel; orphan nuclear receptor TR2; promoter; receptor

The long-term goal of this project is to understandhow vitamin A signaling is modulated by orphannuclear receptors belonged to the TR2 and TR4 family. Previous studiesfocused on the repressive mechanisms of TR2 that include i) directly recruitingco-repressors like histone deacetylases (HDACs), receptor interacting protein 140 (RIP140) and SMRT (an active mechanism), and ii) competing with RA receptors (RARs) and retinoid X receptor (RXR) for DNA binding (a passive mechanism).By extending from these conclusions and based upon recent studies, this renewal proposal focuses on novel ligand-independent signaling pathways that can modify the property and activity of TR2 and TR4 for the regulation of RAR|32, cyclin D1 and apoE genes. Three hypotheses will be tested: i) the biological activity of TR2 and TR4 can be modulated by protein modification (biochemical factors) and their interaction with coregulators (kinetic factors), ii) the physiologically relevant receptor activity is manifested through their interaction with, or recruitment of, specific coregulators onto the regulatory region of the target gene (dynamic factors), and iii)the ligand- independently activated receptor complex can contribute to chromatin remodeling of target gene to activate transcription. Aim I will address the first and second hypotheses by examining the mechanisms of ligand- independent modulation of receptor activity elicited through protein modifications (using a proteomic approach) that affect: i) the biochemical nature of receptors, ii) the general property of receptors, iii) receptor- coregulator interaction kinetics and iv) dynamics of TR2 and TR4 coregularory complex on target genes. Aim II will address the third hypothesis in physiologically relevant cell cultures by manipulatingTR2 and TR4, and determiningthe effects of their modification on target genes. The biological effects to be examined include the formation of coregulatory complexes and alteration in chromatin conformation (remodeling) or histone modification on the target gene promoters (RAR|32, cyclin Dl and apoE) and theirbiological activities in P19 cell cycle progression as well as transcription efficiency of target genes. Results from both in vitro (aim 1) and in vivo (aim 2) systems will be integrated to construct a comprehensive overview of the mechanisms underlyingthe modulation of vitamin A signalingpathways by these orphan receptors, specifically with respect to signals generated from protein modifications of receptors.

该项目的长期目标是了解维生素A信号传导是由Orphannuclear调节的 受体属于TR2和TR4家族。以前的研究专注于抑制性机制 TR2包括i）直接招募Co-Repressor，例如组蛋白脱乙酰基酶（HDAC），受体相互作用 蛋白质140（RIP140）和SMRT（一种主动机制），以及II）与RA受体（RARS）竞争（RARS）和 视网膜类动物X受体（RXR）用于DNA结合（一种被动机制）。从这些结论中延伸 并基于最近的研究，该更新建议着重于新型配体无关的信号传导途径 可以修改TR2和TR4的属性和活动，以调节RAR | 32，Cyclin D1和ApoE 基因。将测试三个假设：i）TR2和TR4的生物学活性可以通过蛋白质调节 修饰（生化因子）及其与核心节的相互作用（动力学因素），ii） 生理上相关的受体活性通过与募集或募集的相互作用而表现出来 特定的核心节剂到靶基因的调节区域（动态因子），iii）配体 - 独立活化的受体复合物可以有助于靶基因的染色质重塑以激活 转录。目的我将通过检查配体的机制来解决第一和第二个假设。 通过蛋白质修饰引起的受体活性的独立调节（使用蛋白质组学 影响：i）受体的生化性质，ii）受体的一般特性，iii）受体 - 核心测量器的相互作用动力学和IV）靶基因上TR2和TR4 Coregularory复合物的动力学。目的 II将通过manipulatingtr2和tr4来解决生理相关细胞培养的第三个假设， 并确定其修饰对靶基因的影响。要检查的生物学作用 包括形成核调节络合物的形成和染色质构象（重塑）或 靶基因启动子（RAR | 32，Cyclin dl和apoE）及其生物学上的组蛋白修饰 p19细胞周期进程的活性以及靶基因的转录效率。两者的结果 体外（AIM 1）和体内（AIM 2）系统将集成，以构建有关该系统的全面概述 这些孤儿受体对维生素A信号路径调节的基础机制， 特别是根据受体蛋白质修饰产生的信号。