Beta Catenin in Prostate Cancer

前列腺癌中的β连环蛋白

• 批准号: 6779148
• 负责人: Edward P Gelmann
• 金额: $ 22.12万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-15 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6779148
• 关键词: androgen receptor; biological signal transduction; cadherins; chimeric proteins; gene expression; glutathione transferase; human genetic material tag; ligands; mutant; prostate neoplasms; prostate specific antigen; radiotracer; receptor binding; recombinant proteins; tissue /cell culture; transcription factor; transfection; transfection /expression vector

DESCRIPTION (provided by applicant): Beta-catenin is a component of the Wnt signaling pathway that is disrupted by oncogenic mutations in many cancer types. We first demonstrated that beta-catenin was mutated in a subset of prostate cancer specimens. Emerging data from other laboratories have confirmed our findings and identified mutations in other components of the Wnt signaling pathway such as APC in prostate cancer. In prostate cancer cells mutant beta-catenin can potentiate androgen receptor (AR) signaling and broaden ligand specificity. Since increased AR activity and response to an expanded range of steroid hormones is a hallmark of advanced prostate cancer, beta-catenin mutations appear to be an additional mechanism by which prostate cancer cells enhance AR activity. This finding may have clinical implications for determining apropriate second-line hormonal therapy for prostate cancer patients. We now propose to elucidate the details of the direct intermolecular interactions between beta-catenin and androgen receptor. Our preliminary data indicate that beta-catenin binds to the AR ligand-binding domain. Moreover, LXXLL peptide motifs in the beta-catenin armadillo repeat region that resemble motifs in p160 steroid hormone coactivator molecules are important for beta-catenin/ AR interaction. Using a mammalian two-hybrid assay we will determine the regions of androgen receptor bound by beta-catenin and we will determine the regions of beta-catenin that bind androgen receptor. Using recombinant proteins we will demonstrate the direct physical interaction between AR and beta-catenin. We will also determine the ligand-dependence of this binding and the spectrum of ligands that support the interaction. We will determine if beta-catenin affects the interaction of androgen receptor with ligand by measuring dissociation of different ligands from androgen receptor. Lastly, we will determine the mechanism by which beta-catenin synergizes with p160 steroid receptor coactivator proteins to increase AR activity. These experiments will clearly establish as interaction between the Wnt signaling and steroid receptor pathways and thereby describe a new mechanism for prostate cancer progression, which is often dependent on enhancement of AR activity.

描述（由申请人提供）：β-连环蛋白是 Wnt 信号通路的一个组成部分，在许多癌症类型中，该通路会被致癌突变破坏。我们首先证明β-连环蛋白在前列腺癌样本的子集中发生突变。来自其他实验室的新数据证实了我们的发现，并确定了 Wnt 信号通路其他组件（例如前列腺癌中的 APC）的突变。在前列腺癌细胞中，突变的 β-连环蛋白可以增强雄激素受体 (AR) 信号传导并扩大配体特异性。由于 AR 活性增加和对范围扩大的类固醇激素的反应是晚期前列腺癌的标志，β-连环蛋白突变似乎是前列腺癌细胞增强 AR 活性的另一种机制。这一发现可能对确定前列腺癌患者合适的二线激素治疗具有临床意义。我们现在建议阐明β-连环蛋白和雄激素受体之间直接分子间相互作用的细节。我们的初步数据表明 β-连环蛋白与 AR 配体结合域结合。此外，β-连环蛋白犰狳重复区域中的 LXXLL 肽基序与 p160 类固醇激素共激活剂分子中的基序相似，对于 β-连环蛋白/ AR 相互作用非常重要。使用哺乳动物双杂交测定，我们将确定与 β-联蛋白结合的雄激素受体区域，并且我们将确定与雄激素受体结合的 β-联蛋白区域。使用重组蛋白，我们将证明 AR 和 β-连环蛋白之间的直接物理相互作用。我们还将确定这种结合的配体依赖性以及支持相互作用的配体谱。我们将通过测量不同配体与雄激素受体的解离来确定β-连环蛋白是否影响雄激素受体与配体的相互作用。最后，我们将确定 β-catenin 与 p160 类固醇受体辅激活蛋白协同作用以增加 AR 活性的机制。这些实验将清楚地确定 Wnt 信号传导和类固醇受体途径之间的相互作用，从而描述前列腺癌进展的新机制，该机制通常依赖于 AR 活性的增强。