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：
8819521
负责人：
JANE Y WU
金额：
$ 44.31万
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/8819521
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 Variation Goals Health 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 genetic approach in vitro Assay in vivo lung tumorigenesis migration mutant neuronal guidance new therapeutic target novel outcome forecast protein function receptor research study tumor tumorigenesis wound

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：我们的长期目标是了解新型肿瘤抑制基因狭缝和USP33的分子机制。我们以前的工作和初步数据表明，典型的神经脱位术SLIT是肺癌的重要肿瘤抑制剂，并且狭缝表达预测肺癌患者的预后更好。为了剖析缝隙信号通路并检查肺癌肿瘤抑制的机制，我们检查了信号传递分子如何与缝隙受体roundabout（ROBO）相互作用。我们确定去泛素化酶USP33，是肺癌中缝隙 - robo信号通路中的关键成分。该提案旨在使用分子，生化和细胞生物学方法与动物模型以及人类肺癌样品的序列分析一起使用分子，生化和细胞生物学方法来检查肺癌介导的肿瘤抑制。我们的飞行员深入序列研究支持狭缝-ROBO-USP33途径的肿瘤抑制功能以及下游信号分子的参与。我们已经建立了体外测定和动物模型，以研究这种新发现的肿瘤抑制途径在肺癌发育中的作用。我们计划使用这些综合分子，细胞和遗传方法来定义狭缝 - 摩布信号传导在抑制肺癌中的作用。我们提出的工作将有助于阐明裂缝和USP33肿瘤抑制子的分子机制，并确定遗传变异在SLIT或USP33及其下游基因在人肺癌发展中的作用。