RETINOID RECEPTOR INTERACTION

类维生素A受体相互作用项目的目标是统一的， 阐明维甲酸分子机制的主题 在乳腺癌细胞中的作用，以确定更有效的治疗方法 治疗这种毁灭性疾病的药物。 维甲酸具有深刻的 对细胞分化、稳态和脊椎动物的影响 发展，并在临床上用于治疗几个 癌症和皮肤病的类型。 这两类 视黄酸和视黄酸X核受体 受体介导其细胞功能的多效性效应， 作为RXR/RAR形式的配体依赖性转录因子 异二聚体来调节类视色素靶基因的表达。 配体诱导的类维生素A受体构象的改变 作为分子开关， 受体转化为复合物，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， 调节类维生素A的抗增殖作用。 这些响应 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， 其作为共激活子或共抑制子起作用。 因为 类维生素A在这些过程中的中心作用， 配体与类维生素A受体的相互作用及其结构 由于配体结合而发生的受体改变， 至关重要。 目标III.1的目标是绘制类维生素A图谱 受体区域发生结构改变， 配体（激动剂和拮抗剂）结合的技术， 有限的蛋白水解和质谱分析。 表达 视黄酸受体β 2（RAR β 2）基因受 类维生素A受体复合物以韧带=de[emememt]的方式。 的 RAR β 2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RAR β 2的调节 可以研究助催化剂以确定 配体类维生素A受体激活该启动子， 其他转录因子，如pEA 3，对这些调节 流程.合成类维生素A 6-[3-（1-金刚烷基）-4- 羟苯基]-2-萘甲酸（AHPN）诱导 乳腺癌细胞凋亡通过独立于 RAR和RXR。 目标III.3的目标是纯化AHPN 受体，并克隆编码这种蛋白质的cDNA，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.