Cables and the colonocyte

电缆和结肠细胞

• 批准号: 6965250
• 负责人: LAWRENCE R ZUKERBERG
• 金额: $ 29.97万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6965250
• 关键词: carcinogenesis; cell differentiation; cell growth regulation; cell proliferation; colon neoplasms; colon polyp; cyclin dependent kinase; gastrointestinal epithelium; genetically modified animals; human tissue; laboratory mouse; neoplasm /cancer genetics; protein protein interaction; protein structure function; regulatory gene; tissue /cell culture; tumor suppressor proteins

DESCRIPTION (provided by applicant): Colon cancer is the second leading cause of cancer in men and women combined, and the overall lifetime risk in the general population is six percent. A stepwise model of colon cancer includes mutations of the adenomatous polyposis tumor suppressor gene and oncogenic KRAS mutations as early events. These are followed by deletions on human chromosome 18q and mutation of the p53 tumorsuppressor gene. The gene targeted by chromosome 18q deletions has not been well defined. Our recent studies have demonstrated that Cables, a novel regulatory protein, maps to human chromosome 18q and is lost at a high frequency in colon cancer. We find decreased or loss of Cables in approximately 60% of colon cancer and one-third of colonic adenomas. Cables appear to act as a cable or link between important proteins involved in cell proliferation and tumorigenesis. Cyclin dependent kinase (cdk) 2 is a serine/threonine protein kinase that regulates progression through the cell cycle and ultimately cell proliferation. Cables interacts with cdk2 and enhances an inhibitory cdk2 tyrosine phosphorylation, which leads to decreased kinase activity and decreased cell proliferation. Cables also interacts with the p53 tumor-suppressor gene and augments p53 induced apoptosis. Conversely, loss of Cables may cause uncontrolled cell growth and enhance tumor formation. The hypothesis for this proposal is that loss of or reduced levels of Cables is one of the important events in the pathways to colon cancer formation. To study the role of Cables in colon cancer we plan to: 1) define the tumor-suppressor function of Cables in primary colonic epithelial cells and in mouse models of colonic tumorigenesis; 2) determine the mechanism of Cables gene inactivation in primary colon tumors. We have already created a Cables deficient mouse, which is viable and is prone to the development of colon cancer. The studies in this proposal will help determine what genetic alterations lead to Cables loss and if Cables is a key target of the chromosome 18q deletions commonly seen in colon cancer. If this is true than therapeutics to restore Cables function could be developed and the prognostic implications and/or response to treatment of tumors with or without Cables loss could be studied.

描述（由申请人提供）：结肠癌是男性和女性合并的第二大癌症原因，一般人群的总体终生风险为6%。结肠癌的逐步模型包括腺瘤性息肉病肿瘤抑制基因突变和致癌KRAS突变作为早期事件。随后是人类染色体18 q的缺失和p53肿瘤抑制基因的突变。染色体18 q缺失所靶向的基因尚未得到很好的定义。我们最近的研究表明，电缆，一种新的调节蛋白，映射到人类染色体18 q，并在结肠癌中以高频率丢失。我们发现大约60%的结肠癌和三分之一的结肠腺瘤中Cables减少或丢失。电缆似乎作为一个电缆或参与细胞增殖和肿瘤发生的重要蛋白质之间的联系。细胞周期蛋白依赖性激酶（cdk）2是一种丝氨酸/苏氨酸蛋白激酶，通过细胞周期和最终细胞增殖调节进程。线缆与cdk 2相互作用并增强抑制性cdk 2酪氨酸磷酸化，这导致激酶活性降低和细胞增殖降低。Cables还与p53肿瘤抑制基因相互作用并增强p53诱导的细胞凋亡。相反，电缆的损失可能会导致不受控制的细胞生长和增强肿瘤的形成。该建议的假设是，Cables的丢失或水平降低是结肠癌形成途径中的重要事件之一。为了研究Cables在结肠癌中的作用，我们计划：1）确定Cables在原代结肠上皮细胞和结肠肿瘤发生的小鼠模型中的肿瘤抑制功能; 2）确定Cables基因在原代结肠肿瘤中失活的机制。我们已经创造了一个电缆缺陷的小鼠，这是可行的，容易发展结肠癌。这项提案中的研究将有助于确定哪些遗传改变导致Cables丢失，以及Cables是否是结肠癌中常见的染色体18 q缺失的关键目标。如果这是真的，那么可以开发恢复线缆功能的治疗剂，并且可以研究具有或不具有线缆损失的肿瘤的预后意义和/或对治疗的响应。