Connecting PTEN and NF2 cancer predisposition syndromes

连接 PTEN 和 NF2 癌症易感综合征

• 批准号: 6916850
• 负责人: MARIA-MAGDALENA GEORGESCU
• 金额: $ 26.84万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-12 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6916850
• 关键词: G protein; biological signal transduction; cancer risk; cell growth regulation; cell membrane; density gradient ultracentrifugation; genetic susceptibility; genetically modified animals; guanosinetriphosphatases; immunofluorescence technique; immunoprecipitation; kinase inhibitor; laboratory mouse; metastasis; molecular oncology; neoplasm /cancer genetics; neoplastic process; neurofibromatosis type 1 protein /gene; phosphatidylinositol 3 kinase; phosphorylation; preneoplastic state; protein protein interaction; protein tyrosine phosphatase; serine threonine protein kinase; sodium hydrogen exchanger; tissue /cell culture; tumor suppressor proteins

DESCRIPTION (provided by applicant): Cancer predisposition syndromes are autosomal dominantly inherited conditions in which the affected individuals have a high relative risk for developing cancer. PTEN and neurofibromatosis-2 (NF2) are tumor suppressors that are inactivated in both somatic cancers and in cancer predisposition syndromes that belong to a clinically defined group (phakomatoses). The mechanism for tumor suppression is known only for PTEN and relies on its ability to dephosphorylate phosphoinositides and antagonize the growth promoting effects of the phosphatidylinositol-3 OH (PI-3) kinase. The regulation of both PTEN and NF2 (merlin) is not yet understood, but it appears to depend on the recruitment of both proteins to the plasma membrane and on their phosphorylation. In spite of the similarities between these tumor suppressors, no previous study attempted to link them in a common pathway. The broad objective of this project is to characterize a molecular connection between PTEN and NF2 tumor suppressors. The new finding that PTEN associates with an adaptor molecule that was previously shown to bind to NF2 will constitute the major focus of this study. The detailed project attempts to cover the following topics: (1) the role of the adaptor molecule in cell growth and migration of cultured gene-deficient cells, and in tumor formation and metastasis in the gene-deficient animals already generated in the laboratory; (2) the analysis of the complex between the three molecules in terms of specific binding affinities, size of the complex by gel filtration and membrane co-localization by density gradient fractionation and immunofluorescence; and (3) interrelations in regulation and signaling between PTEN and NF2 in terms of phosphorylation, stability, Akt/PKB kinase and Rac GTP-ase activation. Finding a common molecular link between PTEN and NF2 tumor suppressors that determine similar cancer predisposition syndromes and are frequently inactivated in brain cancer is fundamental to the understanding of the pathogenesis of cancer and constitutes the basis of a targeted cancer therapy.

描述(由申请人提供)：癌症易感综合征是常染色体显性遗传疾病，受影响的个体患癌症的相对风险很高。PTEN和神经纤维瘤病-2(NF2)是两种肿瘤抑制基因，在体细胞癌和属于临床定义组(黑色素瘤病)的癌症易感综合征中都是失活的。抑制肿瘤的机制仅对PTEN已知，依赖于其对磷脂酰肌醇-3-羟基(PI-3)激酶的促生长作用和对磷脂酰肌醇-3-羟基(PI-3)激酶的去磷酸化能力。PTEN和NF2(Merlin)的调节尚不清楚，但它似乎依赖于这两种蛋白质在质膜上的募集和它们的磷酸化。尽管这些肿瘤抑制因子之间有相似之处，但以前没有研究试图将它们联系在共同的途径上。该项目的主要目标是表征PTEN和NF2肿瘤抑制因子之间的分子联系。PTEN与先前被证明与NF2结合的接头分子相关联的新发现将构成这项研究的主要焦点。这个详细的项目试图涵盖以下主题：(1)接头分子在培养的基因缺陷细胞的细胞生长和迁移中的作用，以及在实验室已产生的基因缺陷动物的肿瘤形成和转移中的作用；(2)根据特异性结合亲和力、凝胶过滤的复合体大小以及通过密度梯度分离和免疫荧光检测膜的共定位来分析三个分子之间的复合体；以及(3)PTEN和NF2在磷酸化、稳定性、Akt/PKB激酶和RAC GTP-ase激活方面的调控和信号传递中的相互关系。发现PTEN和NF2肿瘤抑制因子之间的共同分子联系是理解癌症发病机制的基础，也是靶向癌症治疗的基础。PTEN和NF2肿瘤抑制因子决定了相似的癌症易感综合征，并且在脑癌中经常被失活。