A model system to study the tumor suppressor APC

研究肿瘤抑制因子APC的模型系统

• 批准号: 6941713
• 负责人: Mark A. Peifer
• 金额: $ 22.71万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2008-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6941713
• 关键词: Drosophilidae; biological models; biological signal transduction; carcinogenesis; cell growth regulation; cellular polarity; cytoskeleton; gene mutation; microtubules; oncoproteins; protein binding; protein protein interaction; protein structure function; tumor suppressor proteins

DESCRIPTION (provided by applicant): Epithelial tissues are affected in many cancers. Cancer results from alterations in normal cell behavior, often due to changes in cell-cell communication. Cell-cell signals and their signal transduction pathways play fundamental roles in normal embryonic development and adult physiology, influencing many processes including gene expression and the cytoskeleton. To understand the disease process, we must first understand the normal role of the proteins affected. We focus on the tumor suppressor APC. Mutations in APC occur in >70% of all colon cancers. A key breakthrough in understanding APC function came from the discovery that it binds to the protein B-catenin. B-catenin and its Drosophila homolog Armadillo (Arm) are key effectors in the Wnt signal transduction pathway. This allowed scientists studying APC to take advantage of the knowledge gained from studying Wnt signaling in model organisms, and rapidly led to a model suggesting that APC negatively regulates Wnt signaling by heaping target Bi-catenin/Arm for phosphorylation and ultimate proteolytic destruction. We established a model system to explore Pac's functions. We utilize the fruit fly Drosophila, combining classical and molecular genetics with cell biology and biochemistry, and thus capitalizing on the speed of this model system and its synergy with vertebrate cell biology. We found that Drosophila APC2 is a negative regulator of Wnt signaling in the embryonic epidermis. We also found an unexpected role for APC2 in regulating the link between the actin and microtubule cytoskeletons during mitosis. We hypothesize that APC family proteins are multi-functional components of several different protein complexes that link signal transduction and the cytoskeleton. We will test this hypothesis, exploring the functions of fly APC2 as a model for human APC. Our specific aims are to: 1. Define the null phenotype of APC2 and assess redundancy between APC and APC2, 2. Define the contribution of individual protein domains to APC function, and use this information to test models for APC2 function in the destruction complex, 3. Determine APC2's role in cytoskeletal regulation, and 4. Use genetic and biochemical approaches to define new partners for APC2.

描述（由申请人提供）：上皮组织在许多癌症中受到影响。癌症是由正常细胞行为的改变引起的，通常是由于细胞间通讯的改变。细胞-细胞信号及其信号转导通路在正常胚胎发育和成人生理中起着重要作用，影响包括基因表达和细胞骨架在内的许多过程。要了解疾病过程，我们必须首先了解受影响的蛋白质的正常作用。我们专注于肿瘤抑制因子APC。APC突变发生在70%的结肠癌中。了解APC功能的一个关键突破来自于发现它与蛋白质b -连环蛋白结合。B-catenin及其果蝇同源物Armadillo （Arm）是Wnt信号转导通路中的关键效应因子。这使得研究APC的科学家能够利用在模式生物中研究Wnt信号所获得的知识，并迅速建立了一个模型，表明APC通过堆积靶Bi-catenin/Arm进行磷酸化和最终的蛋白水解破坏来负性调节Wnt信号。我们建立了一个模型系统来探索Pac的功能。我们利用果蝇，将经典和分子遗传学与细胞生物学和生物化学相结合，从而利用该模型系统的速度及其与脊椎动物细胞生物学的协同作用。我们发现果蝇APC2是胚胎表皮Wnt信号的负调控因子。我们还发现APC2在有丝分裂过程中调节肌动蛋白和微管细胞骨架之间的联系中具有意想不到的作用。我们假设APC家族蛋白是连接信号转导和细胞骨架的几种不同蛋白复合物的多功能组分。我们将验证这一假设，探索苍蝇APC2作为人类APC模型的功能。我们的具体目标是：1。定义APC2的空表型，并评估APC和APC2之间的冗余，2。定义单个蛋白结构域对APC功能的贡献，并使用这些信息来测试破坏复合体中APC2功能的模型，3。3 .确定APC2在细胞骨架调节中的作用；使用遗传和生化方法来定义APC2的新伙伴。