A NOVEL MECHANISM OF ANDROGEN RECEPTOR ACTION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 前列腺癌最关键的方面是进展到晚期疾病，这与雄激素依赖状态向雄激素非依赖状态的转变是一致的。我们最近已经证明，在转移性和非转移性肿瘤样本和前列腺癌细胞系中，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水平的恢复可以降低裸鼠移植瘤的成瘤性和转移潜能。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，会导致肿瘤成瘤性降低和IGF-IR表达上调。我们推测，IGF-IR的表达上调代表了AR的一种全新的、非基因组的、不依赖于配体的作用，可能与进展为晚期疾病过程中雄激素反应性的丧失有关。 具体目的：(1)评估AR对IGF-IR mRNA多聚体负载和异源IGF-IR 5‘-UTR/荧光素酶融合构建体表达的影响，(2)确定AR介导的翻译调控所必需的IGF-IR 5’-UTR序列的结构成分，(3)定义参与翻译调控的AR的结构域，以及(4)利用微阵列分析确定AR的其他翻译靶点。

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.