Connecting PTEN and NF2 cancer predisposition syndromes

连接 PTEN 和 NF2 癌症易感综合征

• 批准号: 7913486
• 负责人: MARIA-MAGDALENA GEORGESCU
• 金额: $ 30.8万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-09-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913486
• 关键词: 1-Phosphatidylinositol 3-Kinase; 3-Phosphoinositide Dependent Protein Kinase-1; Affect; Affinity; Animals; Binding; Cell membrane; Cells; Complex; Cultured Cells; Density Gradient Centrifugation; Development; Gel Chromatography; Genes; Growth; Hand; Homologous Gene; Immigration; Immunofluorescence Immunologic; Indium; Individual; Inherited; Knowledge; Laboratories; Laboratory Study; Link; 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; 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; 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）：癌症易感综合症是常染色体显性遗传病，受影响的个体患癌症的相对风险较高。 PTEN 和神经纤维瘤病-2 (NF2) 是肿瘤抑制因子，在体细胞癌症和属于临床定义组（斑状细胞瘤病）的癌症易感综合征中均失活。 仅 PTEN 的肿瘤抑制机制已知，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 NF2 (merlin) 的调节尚不清楚，但它似乎取决于两种蛋白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，但之前没有研究试图将它们连接到一个共同的通路中。 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 与先前显示与 NF2 结合的接头分子相关的新发现将构成本研究的主要焦点。 该详细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，以及在实验室已经产生的基因缺陷动物的肿瘤形成和转移中的作用； (2)通过特异性结合亲和力、通过凝胶过滤的复合物的大小以及通过密度梯度分级和免疫荧光的膜共定位来分析三个分子之间的复合物； (3) PTEN 和 NF2 之间在磷酸化、稳定性、Akt/PKB 激酶和 Rac GTP 酶激活方面的调节和信号传导相互关系。 寻找 PTEN 和 NF2 肿瘤抑制因子之间的共同分子联系，决定类似的癌症易感综合征，并且在脑癌中经常失活，对于了解癌症的发病机制至关重要，并构成靶向癌症治疗的基础。

项目成果

PTEN Tumor Suppressor Network in PI3K-Akt Pathway Control.

• DOI: 10.1177/1947601911407325
• 发表时间: 2010-12-01
• 期刊: Genes & cancer
• 作者: Georgescu, Maria-Magdalena

NHERF1/EBP50 and NF2 as diagnostic markers for choroid plexus tumors.

• DOI: 10.1186/s40478-016-0329-0
• 发表时间: 2016-05-27
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1
• 作者: Georgescu MM;Mobley BC;Orr BA;Shang P;Lehman NL;Zhu X;O'Neill TJ;Rajaram V;Hatanpaa KJ;Timmons CF;Raisanen JM
• 通讯作者: Raisanen JM

NHERF1/EBP50 is an organizer of polarity structures and a diagnostic marker in ependymoma.

• DOI: 10.1186/s40478-015-0197-z
• 发表时间: 2015-03-08
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1
• 作者: Georgescu MM;Yell P;Mobley BC;Shang P;Georgescu T;Wang SH;Canoll P;Hatanpaa KJ;White CL 3rd;Raisanen JM
• 通讯作者: Raisanen JM

PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase.

• DOI: 10.18632/oncotarget.1774
• 发表时间: 2014-02-15
• 期刊: Oncotarget
• 作者: Agarwal NK;Zhu X;Gagea M;White CL 3rd;Cote G;Georgescu MM
• 通讯作者: Georgescu MM

Loss of PTEN binding adapter protein NHERF1 from plasma membrane in glioblastoma contributes to PTEN inactivation.

• DOI: 10.1158/0008-5472.can-10-1271
• 发表时间: 2010-09-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Molina JR;Morales FC;Hayashi Y;Aldape KD;Georgescu MM
• 通讯作者: Georgescu MM