Cables and the colonocyte

描述(申请人提供)：结肠癌是导致男性和女性癌症的第二大原因，在普通人群中总的终生风险为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的KRAS突变作为早期事件。紧随其后的是人类染色体18q的缺失和p53肿瘤抑制基因的突变。染色体18q缺失所针对的基因还没有很好的定义。我们最近的研究表明，CABLES是一种新的调节蛋白，定位于人类染色体18q，在结肠癌中丢失的频率很高。我们发现，在大约60%的结肠癌和三分之一的结肠腺瘤中，电缆减少或丢失。电缆似乎在参与细胞增殖和肿瘤形成的重要蛋白质之间起到了电缆或纽带的作用。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，调节细胞周期的进程，最终调节细胞增殖。CABLES与CDK2相互作用，增强抑制的CDK2酪氨酸磷酸化，从而导致激酶活性降低和细胞增殖减少。CABLES还与P53肿瘤抑制基因相互作用，增强P53诱导的细胞凋亡。相反，电缆的丢失可能会导致细胞生长失控，促进肿瘤形成。这一提议的假设是，电缆的丢失或减少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小鼠结肠癌发生模型中的肿瘤抑制功能；2)确定CABLES基因在原发结肠肿瘤中失活的机制。我们已经创造了一种电缆缺陷的小鼠，这种小鼠是可行的，而且容易患结肠癌。这项提案中的研究将有助于确定哪些基因改变会导致电缆丢失，以及电缆是否是结肠癌中常见的染色体18q缺失的关键目标。如果这是真的，那么恢复电缆功能的治疗方法就可以被开发出来，并且可以研究在有或没有电缆丢失的情况下对肿瘤治疗的预后和/或反应。

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.