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Role of c-Cbl in Colon cancer

c-Cbl 在结肠癌中的作用

基本信息

批准号：
9062392
负责人：
Vipul C Chitalia
金额：
$ 36.11万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9062392
关键词：
APC gene Adenomatous Polyposis Coli Animal Model Animals Armadillo Repeat Binding Biochemical Biochemical Genetics Biological Assay Biological Process Boston Cancer Patient Cell Nucleus Cell Proliferation Clinical Colon Carcinoma Colorectal Cancer Cytosol Data Development Diagnosis Diagnostic tests Disease Disease model EMSA Endothelial Cells Event Future Gene Expression Gene Targeting Genetic Transcription Goals Grant Growth Health Healthcare Human In Vitro Investigation Lead Ligands Manuscripts Mediating Medical center Molecular Molecular and Cellular Biology Mus Mutation Normal Cell Nuclear Outcome Pathogenesis Pathologic Predisposition Prognostic Marker Receptor Protein-Tyrosine Kinases Regulation Resistance Risk Risk Factors Role Series Signal Pathway Signal Transduction Staging Suppressor Mutations Tamoxifen Techniques Testing Time Tissues Tumor Burden Tumor Suppressor Genes Tumor Suppressor Proteins United States Work Xenograft Model Xenograft procedure adenoma beta catenin beta-Transducin Repeat-Containing Proteins c-myc Genes cancer cell cancer initiation cell type chromatin immunoprecipitation colon cancer patients colon tumorigenesis inhibitor/antagonist knockout animal leukemia mutant new therapeutic target novel promoter research study targeted treatment therapeutic target translational study tumor growth tumor progression tumorigenesis tumorigenic ubiquitin-protein ligase

项目摘要

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.

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了解甚少。由于 APC 肿瘤抑制基因缺失或 β 连环蛋白突变，由过量的活性 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的诱发事件。尽管该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。利用结直肠癌细胞中 c-Cbl 还可以抑制磷酸抗性 S33A 突变型 β 连环蛋白和 APC 失活产生的活性 β 连环蛋白（腺瘤形成的关键触发因素）的发现，这项资助旨在研究 c-Cbl 在结直肠癌肿瘤发生中的作用。利用生化、遗传、细胞和分子生物学方法，我们将研究c-Cbl如何调节结直肠癌细胞的基本生物学功能并抑制β连环蛋白介导的细胞核转录。我们将使用小鼠异种移植和敲除动物模型来验证这些观察结果并进一步了解结直肠癌多步骤发病机制。我们将进一步验证我们在人类结直肠癌组织中的发现。这一系列实验将为了解c-Cbl在结直肠癌中的独特调节作用提供一个窗口，并为进一步的转化研究铺平道路。