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

• 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
• 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

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Slit和USP 33的分子机制。我们以前的工作和初步数据表明，原型神经元排斥剂，Slit，是一个重要的肺癌肿瘤抑制因子，Slit表达预测肺癌患者的预后更好。为了剖析Slit信号通路并研究肺癌中肿瘤抑制的潜在机制，我们研究了信号转导分子如何与Slit受体Roundabout（Robo）相互作用。我们鉴定了去泛素化酶USP 33作为肺癌中Slit-Robo信号通路的关键组分。该提案旨在使用分子，生物化学和细胞生物学方法结合动物模型和人类肺癌样本的序列分析来检查Slit-Robo-USP 33介导的肺癌肿瘤抑制。我们的初步深度测序研究支持Slit-Robo-USP 33通路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试验和动物模型来研究这种新发现的肿瘤抑制途径在肺癌发展中的作用。我们计划使用这些整合的分子，细胞和遗传方法来确定Slit-Robo信号转导在抑制肺癌中的作用。我们的工作将有助于阐明Slit和USP 33肿瘤抑制因子的分子机制，并确定Slit或USP 33及其下游基因的遗传变异在人类肺癌发展中的作用。