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The role of deubiquitinating enzyme USP33 in Slit-Robo signaling in lung cancer

去泛素化酶 USP33 在肺癌 Slit-Robo 信号传导中的作用

基本信息

批准号：
8632559
负责人：
JANE Y WU
金额：
$ 45.67万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2014-03-07 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8632559
关键词：
Affect Alpha 1 Casein Kinase 1 Animal Genetics Animal Model Biochemical Biological Biological Assay Cancer Control Cancer Patient Cell Death Cell Proliferation Cells Data Deubiquitinating Enzyme Development Disease Drosophila sli protein Enzymes GTPase-Activating Proteins Gene Targeting Genes Genetic Genetic Variation Goals Human Human Development In Vitro Lead Ligands Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Methods Methylation Microscopy Molecular Mutate Mutation Neoplasm Metastasis Neurons Pathway interactions Patients Play Publishing Research Role Sampling Sequence Analysis Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule TP53 gene Testing Time Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins Work angiogenesis cancer cell cancer type cell motility chemokine deep sequencing design enzyme activity extracellular in vitro Assay in vivo lung tumorigenesis migration mutant neuronal guidance new therapeutic target novel outcome forecast protein function public health relevance receptor research study tumor tumorigenesis wound

项目摘要

Our long-term goal is to understand molecular mechanisms underlying novel tumor suppressor genes Slit and USP33. Our previous work and preliminary data suggest that a prototypical neuronal repellent, Slit, is an important tumor suppressor for lung cancer and that Slit expression predicts better prognosis in lung cancer patients. To dissect Slit signaling pathways and examine mechanisms underlying tumor suppression in lung cancer, we examined how signal-transducing molecules interacted with Slit receptor Roundabout (Robo). We identified the deubiquitinating enzyme, USP33, as a critical component in Slit-Robo signaling pathway(s) in lung cancer. This proposal aims to examine Slit-Robo-USP33 mediated tumor suppression in lung cancer using molecular, biochemical and cell biological methods in combination with animal models and sequence analyses of human lung cancer samples. Our pilot deep-sequencing studies support the tumor suppressive function of Slit-Robo- USP33 pathway and the involvement of the downstream signaling molecules. We have established both in vitro assays and animal models to study the role of this newly uncovered tumor suppression pathway in lung cancer development. We plan to use these integrated molecular, cellular and genetic approaches to define the role of Slit-Robo signaling in suppressing lung cancer. Our proposed work will help elucidate molecular mechanisms underlying Slit and USP33 tumor suppressors and determine the role of genetic variations in Slit or USP33 and their downstream genes in development of human lung cancer.

我们的长期目标是了解新型肿瘤抑制基因 Slit 和 Slit 的分子机制 USP33。我们之前的工作和初步数据表明，典型的神经元驱虫剂 Slit 是一种重要的驱虫剂。 Slit 表达可预测肺癌患者更好的预后。到剖析 Slit 信号通路并检查肺癌肿瘤抑制的机制，我们研究了信号转导分子如何与 Slit 受体 Roundabout (Robo) 相互作用。我们确定了去泛素化酶 USP33，作为肺癌 Slit-Robo 信号通路的关键成分。这该提案旨在利用分子、生物化学和细胞生物学方法与动物模型和人类序列分析相结合肺癌样本。我们的试点深度测序研究支持 Slit-Robo 的肿瘤抑制功能 USP33途径和下游信号分子的参与。我们已经在体外建立了检测和动物模型来研究这种新发现的肿瘤抑制途径在肺癌中的作用发展。我们计划使用这些综合的分子、细胞和遗传方法来定义 Slit-Robo 信号传导抑制肺癌。我们提出的工作将有助于阐明分子机制潜在的 Slit 和 USP33 肿瘤抑制因子，并确定 Slit 或 USP33 中遗传变异的作用和它们的下游基因在人类肺癌的发展中。