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: 6641226
• 负责人: Mark A. Peifer
• 金额: $ 23.9万
• 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 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6641226
• 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。癌症是由于正常细胞行为的改变而导致的，通常是由于细胞 - 细胞通信的变化所致。细胞 - 细胞信号及其信号转导途径在正常的胚胎发育和成人生理学中起着基本作用，影响了许多过程，包括基因表达和细胞骨架。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APC。 APC中的突变发生在所有结肠癌的70％中。理解APC函数的关键突破来自于发现它与蛋白质B-catenin结合的发现。 B-catenin及其果蝇同源物臂甲（ARM）是Wnt信号转导途径中的关键效应子。这使研究APC的科学家可以利用从研究模型生物中的Wnt信号传导所获得的知识，并迅速导致模型表明APC通过堆积靶靶Bi-catenin/ARM来磷酸化和最终的蛋白水解破坏来负面调节Wnt信号传导。我们建立了一个模型系统来探索PAC的功能。我们利用果蝇果蝇，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以及与脊椎动物细胞生物学的协同作用。我们发现果蝇APC2是胚胎表皮中Wnt信号的负调节剂。我们还发现APC2在调节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发挥了意外作用。我们假设APC家族蛋白是将信号转导和细胞骨架连接的几种不同蛋白质复合物的多功能组件。我们将检验这一假设，探索Fly APC2作为人APC模型的功能。我们的具体目的是：1。定义APC2的无效表型，并评估APC和APC2之间的冗余性，2。定义单个蛋白质域对APC功能的贡献，并使用此信息来测试APC2在破坏性综合体中的APC2功能，3。确定APC2在Cytoskeletal consenner中的作用，并使用4。Apcpanfc for apc and and apc and。