Probing the multiple interactions of retinoid receptors

探讨类维生素A受体的多重相互作用

• 批准号: 7086204
• 负责人: NOA NOY
• 金额: $ 15.69万
• 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 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7086204
• 关键词: DNA footprinting; binding proteins; biological signal transduction; cell differentiation; cell proliferation; conformation; fluorescence spectrometry; gel mobility shift assay; genetic regulatory element; genetic transcription; ligands; nuclear receptors; nucleosomes; phosphorylation; posttranslational modifications; protein localization; protein protein interaction; protein transport; receptor binding; retinoate; retinoid binding proteins; retinoids; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Retinoic acids display pleiotropic biological activities which stem from their ability to regulate the rates of transcription of multiple target genes. These compounds play key roles in differentiation and proliferation of cells, are potent inhibitors of carcinogenesis, and are currently used as therapeutic and preventive agents in several clinical settings, ranging from dermatological disorders to cancer. Signalling by these hormones is mediated by two classes of nuclear receptors: the retinoid X receptors (RXR), and the retinoic acid receptors (RAR). RXR is of particular importance, because it also serves as an obligatory heterodimerization partner for a number of other nuclear receptors, and is thus central for multiple signalling events that converge at the genome. In addition to retinoid receptors, retinoic acid binds in cells to members of the family of intracellular lipid binding proteins (iLBP) known as cellular retinoic acid-binding proteins (CRABP). The overall goal of this work is to delineate the molecular mechanisms underlying the transcriptional activities of lipophilic hormones such as retinoic acids, and to clarify the functional consequences of these activities. The current proposal has three specific aims. (1) To understand the factors that control the distribution of RXR between the various oligomers through which it exerts its transcriptional activities, and the role of this receptor in governing the nuclear localization of its heterodimerization partners. (2) Recent observations suggest that RXR, not only acts as a ligand inducible transcription factor, but may also regulate transcription through modulation of DNA geometry. We plan to characterize this novel activity of RXR and to explore its functional significance. (3) Previous work revealed that CRABP-II, as well as two other members of the iLBP family, function by delivering their respective ligands to the nucleus, where they directly deliver them to particular nuclear receptors, thereby significantly enhancing the activities of the receptors. We propose to explore the subcellular localization of CRABP-II, and to delineate the structural features that underlie the ligand-induced nuclear import of iLBPs. The information obtained from these studies is expected to provide new insights into regulatory features of signaling pathways involving transcriptionally active lipophilic hormones, and thus may point at new intervention tools in therapy and prevention of diseases.

描述(申请人提供)：维甲酸表现出多效性生物活性，这源于它们调节多个靶基因的转录速率的能力。这些化合物在细胞分化和增殖中发挥关键作用，是有效的致癌抑制剂，目前在从皮肤病到癌症的多种临床环境中用作治疗和预防药物。这些激素的信号传递是由两类核受体介导的：视黄酸X受体(RXR)和维甲酸受体(RAR)。RXR具有特别重要的意义，因为它也是许多其他核受体的强制性异二聚化伙伴，因此对于汇聚在基因组的多个信号事件来说是核心的。除了维甲酸受体，维甲酸还与细胞内脂结合蛋白(ILBP)家族的成员结合，称为细胞维甲酸结合蛋白(CRABP)。这项工作的总体目标是描绘亲脂激素如维甲酸转录活性的分子机制，并阐明这些活性的功能后果。目前的提案有三个具体目标。(1)了解控制RXR在发挥转录活性的不同寡聚体之间分布的因素，以及该受体在调控其异源二聚体的核定位中的作用。(2)最近的研究表明，RXR不仅作为一种配体诱导转录因子发挥作用，还可能通过调节DNA几何构型来调控转录。我们计划对RXR的这一新活性进行表征，并探索其功能意义。(3)以前的工作表明，CRABP-II和iLBP家族的另外两个成员的功能是将各自的配体运送到细胞核，在那里他们直接将配体运送到特定的核受体，从而显著增强受体的活性。我们建议探索CRABP-II的亚细胞定位，并描述配体诱导的iLBPs核输入的结构特征。从这些研究中获得的信息有望为涉及转录活性亲脂激素的信号通路的调控特征提供新的见解，从而可能指向治疗和预防疾病的新的干预工具。