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: 7340360
• 负责人: NOA NOY
• 金额: $ 15.87万
• 依托单位: CASE WESTERN RESERVE 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7340360
• 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（由申请人提供）：视黄酸显示出多效性生物活性，这源于其调节多个靶基因转录速率的能力。这些化合物在细胞的分化和增殖中起关键作用，是致癌作用的有效抑制剂，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剂。这些激素的信号传导由两类核受体介导：类维生素A X受体（RXR）和视黄酸受体（RAR）。RXR是特别重要的，因为它也作为一个强制性的异源二聚化伴侣的一些其他核受体，因此是中央的多个信号事件，在基因组中收敛。除了类维生素A受体，视黄酸在细胞中结合细胞内脂质结合蛋白（iLBP）家族的成员，称为细胞视黄酸结合蛋白（CRABP）。这项工作的总体目标是描绘的亲脂性激素，如视黄酸的转录活性的分子机制，并澄清这些活动的功能后果。目前的建议有三个具体目标。(1)了解控制RXR在各种寡聚体之间分布的因素，RXR通过这些寡聚体发挥其转录活性，以及该受体在控制其异源二聚化伴侣的核定位中的作用。(2)最近的观察表明，RXR，不仅作为一个配体诱导的转录因子，但也可能通过调节DNA的几何形状来调节转录。我们计划表征RXR的这种新活性并探索其功能意义。(3)先前的工作表明，CRABP-II以及iLBP家族的其他两个成员通过将其各自的配体递送到细胞核来发挥作用，在那里它们直接将其递送到特定的核受体，从而显着增强受体的活性。我们建议探索CRABP-II的亚细胞定位，并描绘的结构特征，基础上的配体诱导的核进口的iLBP。从这些研究中获得的信息有望为涉及转录活性亲脂性激素的信号通路的调控特征提供新的见解，从而可能指向疾病治疗和预防的新干预工具。