RETINOID RECEPTOR INTERACTION

视黄醇受体相互作用

• 批准号: 6491804
• 负责人: MARK E LEID
• 金额: $ 25.62万
• 依托单位: MOLECULAR MEDICINE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6491804
• 关键词: antineoplastics; breast neoplasms; genetic transcription; molecular cloning; neoplasm /cancer nutrition therapy; protein sequence; receptor binding; retinoids; tissue /cell culture; vitamin receptor; vitamin therapy

The goals of Project Retinoid-Receptor Interactions are united by the theme of elucidating the molecular mechanisms of retinoid action in breast cancer cells to identify more effective therapeutic agents to treat this devastating disease. Retinoids have profound effects on cell differentiation, homeostasis, and vertebrate development and are clinically useful in the treatment of several types of cancer and dermatological diseases. The two classes of nuclear retinoid receptors retinoic acid (RAR) and retinoid X (RXR) receptors mediate their pleiotropic effects of cell function by acting as ligand-dependent transcription factors in the form of RXR/RAR heterodimers to regulate the expression of retinoid target genes. Ligand-induced alterations of retinoid receptor conformation have roles as molecular switches that covert transcriptionally inactive receptors into complexes that interact productively (activate) or inhibit (repress) the transcriptional machinery or antagonize transcriptional activation mediated by AP-1 all functions with modulate the antiproliferative effects of retinoids. These responses appear to be involve the interaction of retinoid receptors with other cellular proteins known as transcriptional intermediary factors, which function as co-activators or co-repressor. Because of the central role of retinoid(s) in these processes, an understanding of ligand interactions with retinoid receptors and the structural alterations in the receptors that occur as a result of ligand binding is of critical importance. The goal of Aim III.1 is to map retinoid receptor regions that undergo structural alteration as a consequence of ligand (agonist and antagonist) binding using the techniques of limited proteolysis and mass spectrometry. Expression of the retinoic acid receptor beta2 (RARbeta2) gene is regulated by retinoid receptor complexes in a ligamd=de[ememt manner. The RARbeta2 protein has been implicated in breast cancer cell growth inhibition and apoptosis. The goal of Aim III.2 is to develop an in vitro transcription system in which regulation of the RARbeta2 promoter can be studied to determine the mechanism(s) by which liganded retinoid receptors activate this promoter and the effect of other transcription factors, such as pEA3, on these regulatory processes. The synthetic retinoid 6-[3-(1-adamantyl)-4- hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN) induces breast cancer cell apoptosis through mechanism(s) independent of the RARs and RXRs. The goal of Aim III.3 is to purify the AHPN receptor and clone the cDNA encoding this protein to aid in the understanding of the mechanism of action of AHPN.

类维生素A-受体相互作用项目的目标是 阐明类维生素A分子机制的主题 对乳腺癌细胞的作用以确定更有效的治疗方法 治疗这种毁灭性疾病的药物。 类维生素A具有深远的 对细胞分化、体内平衡和脊椎动物的影响 的发展并在临床上可用于治疗多种 癌症和皮肤病的类型。 两个类的 核视黄酸受体视黄酸 (RAR) 和视黄酸 X (RXR) 受体通过作用介导细胞功能的多效性 作为 RXR/RAR 形式的配体依赖性转录因子 异二聚体调节类维生素A靶基因的表达。 配体诱导的类维生素A受体构象改变 作为隐藏转录失活的分子开关的作用 受体形成复合物，有效地相互作用（激活）或 抑制（抑制）转录机制或拮抗 由 AP-1 介导的转录激活的所有功能 调节类维生素A的抗增殖作用。 这些回应 似乎涉及类维生素A受体与其他受体的相互作用 称为转录中介因子的细胞蛋白质， 其功能为共激活子或共抑制子。 因为 类维生素A在这些过程中的核心作用，了解 配体与类维生素A受体的相互作用和结构 由于配体结合而发生的受体改变是 至关重要。 目标 III.1 的目标是绘制类维生素A图谱 结果发生结构改变的受体区域 使用以下技术的配体（激动剂和拮抗剂）结合 有限的蛋白水解和质谱分析。 的表达 视黄酸受体β2 (RARbeta2) 基因受调节 类维生素A受体复合物以配体=去[ememt]的方式。 这 RARbeta2 蛋白与乳腺癌细胞生长有关 抑制和凋亡。 目标 III.2 的目标是开发一种 体外转录系统，其中 RARbeta2 的调节 可以研究启动子以确定其机制 配体视黄醇受体激活该启动子以及 其他转录因子，例如 pEA3，对这些调节 流程。合成类维生素A 6-[3-(1-金刚烷基)-4- 羟基苯基]-2-萘甲酸 (AHPN) 诱导 乳腺癌细胞凋亡通过独立于 RAR 和 RXR。 目标 III.3 的目标是净化 AHPN 受体并克隆编码该蛋白的 cDNA 以帮助 了解 AHPN 的作用机制。