BETA CATENIN IN PROSTATE CANCER

β-连环蛋白在前列腺癌中的作用

基本信息

批准号：
6378100
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
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-07-01 至 2003-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6378100
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

项目摘要

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（申请人的摘要）：β-catenin是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细胞因子的合作伙伴（TCF）在形成异二聚体转录因子中的家族分子介导WNT受体的信号传导。 β-catenin信号在许多癌症是通过β-catenin的突变或失活的 β-catenin结合分子。这些致癌事件的影响是减少胞质内降解并增加可用性 β-catenin以执行其转录功能。我们发现突变原发性前列腺癌组织中的β-catenin基因，从而显示至少在一些前列腺中激活该β-catenin信号转导。癌症病例。 β-catenin激活的第二个潜在机制前列腺癌是在大约发生的E-钙粘蛋白表达的丧失前列腺癌的一半，与预后不良有关。我们的初步数据表明，β-catenin有助于前列腺的一种机制癌症促进和进展是通过与雄激素受体相互作用并增加雄激素的转录激活，必需激素前列腺癌的生长。我们的假设是β-catenin激活通过增强有助于前列腺癌的进展雄激素驱动的基因转录。该提议着重于确定 β-catenin和雄激素受体之间分子相互作用的机制。实验将尝试证明重组雄激素受体和β-catenin蛋白。我们将映射通过缺失分析和定向诱变的相互作用区域。我们还将确定E-钙粘蛋白结合是否直接干扰该区域与雄激素受体结合的β-catenin。这些实验会建立类固醇激素受体信号和Wnt之间的联系信号。这将为更全面的研究奠定了基础雄激素作用与Wnt信号通路之间的相互作用由β-catenin/tcf驱动转录介导。