Connecting PTEN and NF2 cancer predisposition syndromes

连接 PTEN 和 NF2 癌症易感综合征

• 批准号: 7236722
• 负责人: MARIA-MAGDALENA GEORGESCU
• 金额: $ 25.45万
• 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/7236722
• 关键词: 1-Phosphatidylinositol 3-Kinase; 3-Phosphoinositide Dependent Protein Kinase-1; Affect; Affinity; Animals; Binding; Cell membrane; Cells; Complex; Condition; Cultured Cells; Density Gradient Centrifugation; Development; Gel Chromatography; Genes; Growth; Hand; Homologous Gene; Immigration; Immunofluorescence Immunologic; Indium; Individual; Inherited; Knowledge; Laboratories; Laboratory Study; Link; Localized; Malignant Neoplasms; Malignant neoplasm of brain; Membrane; Molecular; Molecular Weight; Mus; Neoplasm Metastasis; Neurocutaneous Syndromes; Neurofibromatosis 2; Neurofibromin 2; Oncogenic; Organ; PTEN gene; Pathogenesis; Pathology; Pathway interactions; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphorylation; Predisposition; Protein Dephosphorylation; Proteins; Rate; Reading; Recruitment Activity; Regulation; Relative Risks; Research Personnel; Role; Signal Transduction; Syndrome; System; Testing; Tumor Suppression; Tumor Suppressor Proteins; base; cancer therapy; cell growth; cell motility; migration; programs; promoter; size; tumor; tumor progression

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性疾病，其中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（NF 2）是肿瘤抑制因子，其在体细胞癌和属于临床定义的组（phakomatoses）的癌症易感综合征中失活。 肿瘤抑制的机制仅对PTEN是已知的，并且依赖于其使磷酸肌醇去磷酸化和拮抗磷脂酰肌醇-3 OH（PI-3）激酶的生长促进作用的能力。 PTEN和NF 2（merlin）的调节尚未被理解，但它似乎取决于两种蛋白质向质膜的募集及其磷酸化。 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一个共同的途径中。 该项目的主要目的是表征PTEN和NF 2肿瘤抑制因子之间的分子联系。 新的发现，PTEN与衔接分子，以前被证明是结合到NF 2将构成本研究的主要重点。 具体的研究内容包括：（1）衔接分子在培养的基因缺陷细胞的细胞生长和迁移中的作用，以及在实验室已经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分析三种分子之间的复合物，通过凝胶过滤确定复合物的大小，通过密度梯度分离和免疫荧光确定膜共定位;以及（3）PTEN和NF 2在磷酸化、稳定性、Akt/PKB激酶和Rac GT酶激活方面的调节和信号传导的相互关系。 发现PTEN和NF 2肿瘤抑制因子之间的共同分子联系，决定了相似的癌症易感综合征，并经常在脑癌中失活，是理解癌症发病机制的基础，并构成了靶向癌症治疗的基础。