RETINOID RECEPTOR INTERACTION

维甲酸-受体相互作用项目的目标由 阐明维甲酸分子机制的主题 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A酸类化合物具有深刻的 对细胞分化、动态平衡和脊椎动物的影响 开发并在临床上用于治疗几种 癌症和皮肤病的种类。这两个班级 维甲酸(RAR)和维甲酸X(RXR)核受体 受体通过作用介导其细胞功能的多效性效应 作为RXR/RAR形式的配体依赖的转录因子 异源二聚体调节维甲酸类靶基因的表达。 配体诱导的维甲酸受体构象改变 作为分子开关的角色，隐藏转录不活跃 受体进入复合体，有效地相互作用(激活)或 抑制(抑制)转录机制或拮抗 AP-1介导的转录激活与 调节维甲酸的抗增殖作用。这些回应 似乎涉及维甲酸受体与其他 被称为转录中介因子的细胞蛋白质， 它们起到协同激活剂或协同抑制因子的作用。因为 视黄醇(S)在这些过程中的核心作用，理解 配体与维甲酸受体的相互作用及其结构 作为配体结合的结果，受体的变化是 具有至关重要的意义。AIM III.1的目标是映射维甲酸 作为结果经历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 有限的蛋白质分解和质谱学。的表达 视黄酸受体β2(RARbeta2)基因受 维甲酸受体复合体以配位体的形式。这个 RARbeta2蛋白与乳腺癌细胞生长有关 抑制和细胞凋亡。AIM III.2的目标是开发一个智能网 调控RARbeta2基因的体外转录系统 可以通过对促进剂的研究来确定其作用机制(S 配基维甲酸受体激活这一启动子及其作用 其他转录因子，如pEA3，对这些调控因子 流程。合成维甲酸6-[3-(1-金刚烷基)-4- 羟苯基]-2-萘甲酸(AHPN)诱导 乳腺癌细胞凋亡的独立机制(S) RAR和RXR。AIM III的目标是提纯AHPN 受体，并克隆编码该蛋白的cDNAs以帮助 了解AHPN的作用机制。

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.