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

我们的长期目标是了解新的肿瘤抑制基因Sit和Sit的分子机制 USP33.我们以前的工作和初步数据表明，一种典型的神经元排斥剂，Sit，是一个重要的 肺癌的肿瘤抑制因子和Sit的表达预示着肺癌患者更好的预后。至 我们解剖了狭缝信号通路并研究了肺癌的肿瘤抑制机制 研究了信号转导分子如何与狭缝受体环形交叉路口(ROBO)相互作用。我们确定了 去泛素酶，USP33，肺癌Sit-Robo信号通路(S)的关键组成部分。这 该提案旨在用分子手段研究Sit-Robo-USP33介导的肺癌抑瘤作用。 生化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。我们的先导性深度测序研究支持Sit-Robo-2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这两个 实验和动物模型研究这一新发现的肿瘤抑制途径在肺癌中的作用 发展。我们计划使用这些集成的分子、细胞和遗传学方法来定义 Sit-Robo信号在抑制肺癌中的作用。我们提出的工作将有助于阐明分子机制 并确定Sit或USP33和USP33基因变异的作用 它们的下游基因与人类肺癌的发生有关。

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.