BETA CATENIN IN PROSTATE CANCER

β-连环蛋白在前列腺癌中的作用

• 批准号: 6190700
• 负责人: Edward P Gelmann
• 金额: $ 15.6万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6190700
• 关键词: androgen receptor; cadherins; cell line; immunoprecipitation; prostate neoplasms; protein structure function; recombinant proteins; site directed mutagenesis; transfection; transfection /expression vector; western blottings

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.

描述（申请人摘要）：β-连环蛋白是一种双功能分子 介导细胞表面粘附分子之间的连接 Ecadherin 和作用细胞骨架，也是 T 细胞因子的伙伴 (TCF) 家族分子形成异二聚体转录因子 介导 Wnt 受体的信号传导。 β-连环蛋白信号被激活 许多癌症是由 β-连环蛋白突变或 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 减少胞质内降解并增加 β-连环蛋白执行其转录功能。我们发现了突变 原发性前列腺癌组织中β-连环蛋白基因的变化，从而表明 β-连环蛋白信号转导至少在某些前列腺中被激活 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-钙粘蛋白表达缺失，大约发生在 一半的前列腺癌，且与不良预后相关。我们的初步 数据表明，β-连环蛋白有助于前列腺的一种机制 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 并增加雄激素（必需激素）的转录激活 促进前列腺癌的生长。我们的假设是 β-连环蛋白激活 部分通过增强前列腺癌的进展 雄激素驱动的基因转录。该提案的重点是确定 β-连环蛋白和雄激素受体之间的分子相互作用机制。 实验将试图证明之间的直接相互作用 重组雄激素受体和β-连环蛋白。我们将绘制地图 通过缺失分析和定点突变确定相互作用区域。我们 还将确定 E-钙粘蛋白结合是否直接干扰该区域 β-连环蛋白与雄激素受体结合。这些实验将 建立类固醇激素受体信号传导与 Wnt 之间的联系 发信号。这将为更全面的研究奠定基础 雄激素作用与 Wnt 信号通路之间的相互作用 由 β-catenin/TCF 驱动的转录介导。