BETA CATENIN IN PROSTATE CANCER

描述(申请人摘要)：β-连环蛋白是一种双功能分子 它介导了细胞表面黏附分子之间的连接 Ecadherin和作用细胞骨架，也是T细胞因子的伙伴 (Tcf)家族分子在形成异二聚体转录因子中的作用 介导来自Wnt受体的信号。β-连环蛋白信号在 许多癌症是由于β-连环蛋白突变或由于β-连环蛋白失活引起的 β-连环蛋白结合分子。这些致癌事件的影响是 减少胞质内降解，提高可利用性 β-连环蛋白实现其转录功能。我们发现了突变 β-连环蛋白基因在前列腺癌组织中的表达，从而表明 至少在某些前列腺中，β-连环蛋白信号转导被激活 癌症病例。β-连环蛋白激活的第二种潜在机制 前列腺癌是E-钙粘素表达缺失，发生在大约 一半的前列腺癌患者，与预后不良有关。我们的预赛 数据表明，β-连环素促进前列腺癌的一种机制 癌症的促进和进展是通过与雄激素受体相互作用来实现的。 以及通过必需激素雄激素提高转录活性 前列腺癌的生长。我们的假设是β-连环蛋白激活 促进前列腺癌进展的部分原因是 雄激素驱动的基因转录。这项提案的重点是确定 β-连环蛋白与雄激素受体的分子相互作用机制。 这些实验将试图证明一种直接相互作用 重组雄激素受体和β-连环蛋白。我们将绘制 通过缺失分析和定点突变获得相互作用的区域。我们 还将确定E-钙粘附素结合是否直接干扰该区域 与雄激素受体结合的β-连环蛋白。这些实验将 建立类固醇激素受体信号与WNT之间的联系 发信号。这将为更全面地研究 雄激素作用与Wnt信号通路的相互作用 由β-连环蛋白/TCFs介导的转录。

DESCRIPTION (Applicant's Abstract): Beta-Catenin is a bifunctional molecule that mediates the connection between the cell surface adhesion molecule Ecadherin and the acting cytoskeleton and also is a partner of T cell factor (TCF) family molecules in forming a heterodimeric transcription factor that mediates signaling from Wnt receptors. beta-Catenin signaling is activated in many cancers by mutation of beta-catenin or by inactivation of beta-catenin-binding molecules. The effects of these oncogenic events are to decrease intracytoplasmic degradation and increase the availability of beta-catenin to carry out its transcriptional function. We have found mutations of the beta-catenin gene in primary prostate cancer tissues, thereby showing that beta-catenin signal transduction is activated in at least some prostate cancer cases. A second potential mechanism for beta-catenin activation in prostate cancer is loss of E-cadherin expression that occurs in approximately half of prostate cancers and is associated with poor prognosis. Our preliminary data suggest that one mechanism by which beta-catenin contributes to prostate cancer promotion and progression is by interacting with the androgen receptor and increasing transcriptional activation by androgen, the essential hormone for prostate cancer growth. Our hypothesis is that beta-catenin activation contributes to prostate cancer progression in part by augmenting androgen-driven gene transcription. This proposal focuses on determining the mechanism of molecular interaction between beta-catenin and androgen receptor. The experiments will attempt to demonstrate a direct interaction between recombinant androgen receptor and beta-catenin proteins. We will map the regions of interaction by deletion analysis and site-directed mutagenesis. We will also determine if E-cadherin binding interferes directly with the region of beta-catenin that binds to androgen receptor. These experiments will establish a linkage between steroid hormone receptor signaling and Wnt signaling. This will set the stage for more comprehensive study of the interaction between androgen action and the Wnt signaling pathway that is mediated by beta-catenin/TCFdriven transcription.