A NOVEL MECHANISM OF ANDROGEN RECEPTOR ACTION

雄激素受体作用的新机制

• 批准号: 7715989
• 负责人: Charles T Roberts
• 金额: $ 5.55万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715989
• 关键词: Androgen Receptor; Androgens; Attenuated; Cell surface; Computer Retrieval of Information on Scientific Projects Database; Disease; Disease Progression; Funding; Grant; Institution; Insulin-Like-Growth Factor I Receptor; Ligands; Luciferases; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Microarray Analysis; Neoplasm Metastasis; Nude Mice; PC3 cell line; Research; Research Personnel; Resources; Sampling; Source; Transcriptional Activation; Translational Regulation; United States National Institutes of Health; Untranslated Regions; Up-Regulation; Xenograft procedure; mRNA Expression; non-genomic; novel; restoration

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The most critical aspect of prostate cancer is the progression to advanced disease, which is coincident with the conversion from an androgen-dependent to an androgen-independent state. We have recently demonstrated that the levels of the cell-surface insulin-like growth factor-I (IGF-I) receptor (IGF-IR) are reduced in metastatic vs. non-metastatic tumor samples and prostate cancer cell lines. Importantly, restoration of IGF-IR levels in the metastatic prostate cancer cell lines attenuates tumorigenecity and metastatic potential in nude mouse xenografts. These studies suggest that the decrease in IGF-IR expression is a critical aspect of disease progression. We have now found that introduction of a wild-type androgen receptor (AR) into the M12 metastatic prostate cancer cell line results in concomitant reduced tumorigenecity and up-regulation of IGF-IR expression. We hypothesize that the upregulation of IGF-IR expression represents an entirely novel, nongenomic, ligand-independent action of the AR, and one that may be relevant to the loss of androgen responsiveness in the progression to advanced disease. Specific Aims: (1) Assess the effect of the AR on polysomal loading of IGF-IR mRNA and the expression of heterologous IGF-IR 5'-UTR/luciferase fusion constructs, (2) define the structural components of the IGF-IR 5'-UTR sequence that are necessary for AR-mediated translational control, (3) define the domains of the AR that are involved in translational regulation, and (4) identify additional translational targets of the AR using microarray analysis.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 前列腺癌最关键的方面是进展为晚期疾病，这与从雄激素依赖状态向雄激素非依赖状态的转变同时发生。 我们最近证明，与非转移性肿瘤样本和前列腺癌细胞系相比，细胞表面胰岛素样生长因子-I (IGF-I) 受体 (IGF-IR) 的水平降低。 重要的是，转移性前列腺癌细胞系中IGF-IR水平的恢复可减弱裸鼠异种移植物的致瘤性和转移潜力。 这些研究表明 IGF-IR 表达的减少是疾病进展的一个关键方面。 我们现在发现，将野生型雄激素受体 (AR) 引入 M12 转移性前列腺癌细胞系会导致肿瘤发生性降低和 IGF-IR 表达上调。 我们假设 IGF-IR 表达的上调代表了 AR 的一种全新的、非基因组的、配体独立的作用，并且可能与晚期疾病进展过程中雄激素反应性的丧失有关。 具体目标：(1) 评估 AR 对 IGF-IR mRNA 多核糖体负载和异源 IGF-IR 5'-UTR/荧光素酶融合构建体表达的影响，(2) 定义 AR 介导的翻译控制所需的 IGF-IR 5'-UTR 序列的结构成分，(3) 定义参与翻译调节的 AR 结构域，以及 (4) 确定 使用微阵列分析的 AR 的其他翻译目标。