Role of c-Cbl in Colon cancer

描述（由申请人提供）：结直肠癌的主要挑战之一包括对调节其发生和进展的因素的理解不足。由于APC肿瘤抑制基因的缺失或β连环蛋白的突变，由过量活性β连环蛋白驱动的过度活跃的Wnt信号传导被认为是绝大多数结直肠癌患者中的激发事件。虽然这种信号通路的许多组成部分是已知的，但调节活性β连环蛋白的机制仍然不完全清楚。我们最近描述了c-Cbl，一种已知的肿瘤抑制因子，作为Wnt信号传导的新型抑制剂和活性核β连环蛋白的E3泛素连接酶。利用这一发现，在结直肠癌细胞中，c-Cbl也可以抑制磷酸化抗性S33 A突变体β连环蛋白和APC失活导致的活性β连环蛋白，这是腺瘤形成的关键触发因素，这项研究旨在研究c-Cbl在结直肠癌肿瘤发生中的作用。我们将利用生物化学、遗传学、细胞和分子生物学方法，研究c-Cbl如何调节大肠癌细胞的基本生物学功能和抑制β连环蛋白介导的核转录。我们将使用小鼠异种移植和敲除动物模型验证这些观察结果，并进一步了解多步骤结直肠癌发病机制。我们将在人类结直肠癌组织中进一步验证我们的发现。这一系列实验将为c-Cbl在结直肠癌中的独特调控作用提供一个窗口，并为进一步的转化研究铺平道路。

DESCRIPTION (provided by applicant): One of the major challenges in colorectal cancer includes poor understanding of the factors regulating its initiation and progression. Hyperactive Wnt signaling driven by excess active beta catenin due to either loss of the APC tumor suppressor gene or mutation of beta catenin is considered as an inciting event in vast majority of colorectal cancer patients. Although many of the components of this signaling pathway are known, the mechanisms that regulate the active beta catenin remain incompletely understood. We have recently described c-Cbl, a known tumor suppressor, as a novel inhibitor of Wnt signaling and an E3 ubiquitin ligase for active nuclear beta catenin. Leveraging the findings that in colorectal cancer cells, c-Cbl can also suppresses the phospho-resistant S33A mutant beta catenin and the active beta catenin resulting from APC inactivation, the crucial triggers for adenoma formation, this grant seeks to examine the role of c-Cbl in colorectal cancer tumorigenesis. Using biochemical, genetic, cellular and molecular biology approaches, we will examine how c- Cbl regulates the fundamental colorectal cancer cell biological functions and inhibits the beta catenin-mediated transcription in nucleus. We will validate these observations and gain further mechanistic understanding in the multistep colorectal cancer pathogenesis using mouse xenograft and knock out animal models. We will further validate our findings in human colorectal cancer tissues. This series of experiments will provide a window into the unique regulatory role of c-Cbl in colorectal cancer and pave the road for further translational studies.