Molecular mediators of tumor suppression for the PTPRD phosphatase in gliomas

描述(申请人提供)：受体蛋白酪氨酸磷酸酶增量(PTPRD)是一种新的肿瘤抑制因子，在多形性胶质母细胞瘤和其他几种恶性肿瘤中广泛失活。作用机制(S)和PTPRD作用的致癌背景在很大程度上仍不清楚。本研究的重点在于明确PTPRD抑制肿瘤功能的分子基础。遗传分析表明，编码p16INK4a细胞周期调节因子的PTPRD和CDKN2A经常失活。它们在人脑胶质母细胞瘤中的丢失模式一致，提示PTPRD在肿瘤发生过程中可能与CDKN2A协同作用。我们将使用RCAS PDGF小鼠胶质瘤模型和体外人脑星形胶质细胞模型来剖析PTPRD和CDKN2A在肿瘤发生过程中的功能关系。研究重点将集中在确定PTPRD失活单独或与CDKN2A缺失一起对肿瘤的启动和进展、细胞转化以及对癌细胞生长至关重要的信号通路的改变的协同作用。我们的初步数据表明，STAT3是PTPRD磷酸酶的底物，我们实验室最近的工作表明，可能还存在其他底物。为了确定PTPRD抑制肿瘤功能的分子机制，我们建议使用底物捕获分析结合质谱法来综合表征PTPRD的底物谱。验证过的底物的生物学意义将被调查。随着这一建议的完成，我们将更好地了解PTPRD肿瘤抑制因子在GBM中的分子基础，并为可能的治疗靶点和诊断分子工具提供洞察力。 与公共卫生相关：我们为多形性胶质母细胞瘤寻找有效治疗方法的挑战是了解推动肿瘤发生的分子变化及其作用机制(S)。本项目的目的是研究PTPRD基因的肿瘤抑制功能的分子机制，PTPRD基因是GBM中最常见的失活基因之一。这项工作将为该病的诊断和治疗干预提供可能的靶点。

DESCRIPTION (provided by applicant): Receptor protein tyrosine phosphatase delta (PTPRD) is a novel tumor suppressor that is widely inactivated in glioblastoma multiforme and several other malignancies. The mechanism(s) of action and the oncogenic context in which PTPRD acts remains largely unknown. This proposal focuses on defining the molecular foundations mediating the tumor suppressive function of PTPRD. Genetic analysis demonstrates that PTPRD and CDKN2A, which encodes the p16Ink4A cell cycle regulator, are frequently inactivated. Their concordant patterns of loss within human glioblastomas suggest that PTPRD may cooperate with CDKN2A during tumorigenesis. We will dissect the functional relationship of PTPRD and CDKN2A during tumorigenesis using the RCAS PDGF glioma mouse model and in vitro human astrocyte models. Studies will focus on determining the cooperative effects of PTPRD inactivation alone or in combination with CDKN2A deletion on tumor initiation and progression, cellular transformation, and alterations in signaling pathways important for cancer cell growth. Our preliminary data shows that STAT3 is a substrate of the PTPRD phosphatase, and recent work in our lab suggests that other substrates may exist. In order to define the molecular mechanisms mediating the tumor suppressive function of PTPRD, we propose to comprehensively characterize the substrate profile of PTPRD using a substrate TRAP assay in conjunction with mass spectrometry. The biological significance of the validated substrates will be investigated. With the completion of this proposal we will gain a better understanding of the molecular foundations of the PTPRD tumor suppressor in GBM, and provide insight into possible therapeutic targets and molecular tools for diagnosis. PUBLIC HEALTH RELEVANCE: Our challenge for finding effective treatments for Glioblastoma multiforme (GBM), the most common and aggressive form of brain cancer, is to understand the molecular alterations that are driving tumorigenesis and their mechanism(s) of action. The goal of this project is to characterize the molecular mechanisms mediating the tumor suppressive function of PTPRD, one of the most frequently inactivated genes in GBM. This work will provide insight into possible targets for diagnostic and therapeutic intervention of this disease.