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: 6350180
• 负责人: NOA NOY
• 金额: $ 23.44万
• 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 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6350180
• 关键词: DNA footprinting; antisense nucleic acid; biological signal transduction; cell differentiation; conformation; fluorescence spectrometry; gel mobility shift assay; genetic regulatory element; genetic transcription; ligands; nuclear receptors; nucleosomes; phosphorylation; posttranslational modifications; protein kinase; receptor binding; retinoate; retinoid binding proteins; retinoids; tissue /cell culture; transcription factor

Retinoids play key roles in regulating cell proliferation and differentiation and are used as therapeutic agents in clinical settings ranging from dermatological disorders to cancer. Signaling by these hormones is mediated by two classes of ligand-activated transcription factors, the retinoic acid- and the retinoid X-receptors (RAR and RXR), which are activated by all trans- and 9 cis-retinoic acids, respectively (RA and 9cra). Because of its unique ability to heterodimerize with other nuclear receptors, RCR is involved in multiple signaling pathways and is thus sometimes termed a 'master regulator'. RXR is also unique in that, in the absence of 9cRA, it sequesters itself into transcriptionally inactive tetramers. Hence, RXR acts as an 'auto-silencer', and the first step in its activation seems to compromise ligand-induced dissociation of tetramers into active dimers and monomers. This application proposes to delineate the roles of the oligomerization behavior of RxR and the presence of various cognate ligands in governing the distribution of RXR between the multiple molecular complexes in which it may be involved in vivo. The functional consequences of the physical-chemical properties of the various RCR-containing oligomers for the transcriptional activity of RXR in cells, and the possible functional outcomes of DNA-binding by RXR tetramers will then be explored. In addition to retinoid receptors, two intracellular binding proteins for RA (CRABP-I and CRABP-II) are known to exist. The exact roles of CRABPs in the biology of RA and the functional differences between the two isoforms are not well defined. Our recent studies suggest that CRABP-II, but not CRABP-1, directly 'channels' retinoic acid to RAR, thereby enhancing the transcriptional activity of this receptor. These observations point at a novel role for CRABP-II in regulating retinoid signaling. We propose to study the CRABP-II.RAR interactions that allow for channeling of RA between them, and to address the physiological significance of these interactions by investigating the effect of CRABP-II on RA-induced stem cell differentiation. Overall, these studies are designed to clarify the factors that modulate the multiple interactions of retinoic nuclear receptors and to obtain insights into the mechanisms by which signaling by retinoids is regulated.

类维生素A在调节细胞增殖和分化中起关键作用，并在从皮肤病到癌症的临床环境中用作治疗剂。这些激素的信号传导由两类配体激活的转录因子介导，即视黄酸和类视黄酸X受体（RAR和RXR），它们分别由所有反式和9顺式视黄酸（RA和9 cra）激活。由于其与其他核受体异二聚化的独特能力，RCR参与多种信号传导途径，因此有时被称为“主调节剂”。RXR的独特之处还在于，在不存在9 cRA的情况下，它将自身隔离成转录失活的四聚体。因此，RXR作为一个“自动沉默器”，其激活的第一步似乎损害了配体诱导的四聚体解离成活性二聚体和单体。 本申请提出描述RXR的寡聚化行为和各种同源配体的存在在控制RXR在多个分子复合物之间的分布中的作用，其中RXR可能在体内参与。然后将探讨各种含RCR的寡聚体的理化性质对细胞中RXR转录活性的功能后果，以及RXR四聚体与DNA结合的可能功能结果。除了类维生素A受体，已知存在两种RA的细胞内结合蛋白（CRABP-I和CRABP-II）。CRABPs在RA生物学中的确切作用以及两种亚型之间的功能差异尚未明确。我们最近的研究表明，CRABP-II，而不是CRABP-1，直接“通道”视黄酸RAR，从而增强这种受体的转录活性。这些观察结果指出了CRABP-II在调节类维生素A信号传导中的新作用。我们建议研究的CRABP-II.RAR的相互作用，使通道之间的RA，并解决这些相互作用的生理意义，通过调查的影响，CRABP-II RA诱导的干细胞分化。总体而言，这些研究旨在阐明调节维甲酸核受体的多种相互作用的因素，并深入了解类维生素A调节信号传导的机制。