Molecular mediators of tumor suppression for the PTPRD phosphatase in gliomas

胶质瘤中 PTPRD 磷酸酶的肿瘤抑制分子介质

• 批准号: 8545535
• 负责人: Berenice Ortiz
• 金额: $ 3.96万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-11 至 2014-06-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8545535
• 关键词: Astrocytes; Automobile Driving; Biochemistry; Biological; Biological Assay; Brain Neoplasms; CDKN2A gene; Cancer Cell Growth; Cell Cycle; Cell model; Collaborations; Core Facility; Cyclin-Dependent Kinase Inhibitor 2A; Data; Deletion Mutation; Development; Diagnosis; Diagnostic; Disease; Excision; Foundations; Frequencies; Genes; Genomics; Glioblastoma; Glioma; Goals; Head; Histopathology; Human; In Vitro; Knowledge; Malignant Neoplasms; Malignant neoplasm of brain; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Memorial Sloan-Kettering Cancer Center; Mentors; Microscopy; Modeling; Molecular; Molecular Biology; Molecular Mechanisms of Action; Molecular Target; Mus; Mutation; Oncogenic; Operative Surgical Procedures; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Peptides; Phosphoric Monoester Hydrolases; Phosphotyrosine; Platelet-Derived Growth Factor; Radiation; Research; STAT3 gene; Signal Pathway; Solid; Study Section; Therapeutic Intervention; Time; Tumor Suppression; Tumor Suppressor Proteins; Work; base; cancer genetics; delta protein; design; effective therapy; genetic analysis; human PTPRT protein; insight; metaplastic cell transformation; mouse model; novel; oncology; outcome forecast; research study; standard care; success; temozolomide; therapeutic target; tool; tumor; tumor initiation; tumor progression; tumorigenesis; tyrosine receptor

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.

描述（由申请方提供）：受体蛋白酪氨酸磷酸酶δ（PTPRD）是一种新型肿瘤抑制因子，在多形性胶质母细胞瘤和其他几种恶性肿瘤中广泛失活。PTPRD的作用机制和致癌背景在很大程度上仍不清楚。该建议的重点是定义介导PTPRD的肿瘤抑制功能的分子基础。遗传分析表明，PTPRD和CDKN2A，编码p16Ink4A细胞周期调节因子，经常失活。它们在人类胶质母细胞瘤中的一致丢失模式表明PTPRD可能在肿瘤发生期间与CDKN2A合作。我们将使用RCAS PDGF胶质瘤小鼠模型和体外人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。研究将集中于确定PTPRD失活单独或与CDKN2A缺失联合对肿瘤发生和进展、细胞转化以及对癌细胞生长重要的信号通路改变的协同作用。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存在其他底物。为了确定介导PTPRD的肿瘤抑制功能的分子机制，我们建议使用底物TRAP测定结合质谱法来全面表征PTPRD的底物谱。将研究经验证底物的生物学意义。随着该提案的完成，我们将更好地了解GBM中PTPRD肿瘤抑制因子的分子基础，并提供可能的治疗靶点和诊断分子工具的见解。