A NOVEL MECHANISM OF ANDROGEN RECEPTOR ACTION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 前列腺癌最关键的方面是进展到晚期疾病，这与从雄激素依赖性状态到雄激素非依赖性状态的转换一致。 我们最近证明，细胞表面胰岛素样生长因子-I（IGF-I）受体（IGF-IR）的水平在转移性与非转移性肿瘤样品和前列腺癌细胞系中降低。 重要的是，转移性前列腺癌细胞系中IGF-IR水平的恢复减弱了裸鼠异种移植物中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。 我们现在已经发现，将野生型雄激素受体（AR）导入M12转移性前列腺癌细胞系导致伴随的肿瘤发生性降低和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、配体非依赖性的作用，并且可能与进展为晚期疾病时雄激素反应性的丧失有关。 具体目标：（1）评估AR对IGF-IR mRNA的多聚体加载和异源IGF-IR 5 ′-UTR/荧光素酶融合构建体的表达的影响，（2）确定AR介导的翻译控制所必需的IGF-IR 5 ′-UTR序列的结构组分，（3）确定参与翻译调节的AR结构域，和（4）使用微阵列分析鉴定AR的其它翻译靶。

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.