Mutual regulation of PTEN and P-REX2a in normal and cancer cells

正常细胞和癌细胞中 PTEN 和 P-REX2a 的相互调节

• 批准号: 8025381
• 负责人: Ramon E Parsons
• 金额: $ 33.3万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8025381
• 关键词: Ablation; Address; Apoptosis; Attenuated; Binding; Biochemistry; Brain; Cancer Biology; Catalytic Domain; Cell Migration Inhibition function; Cell Proliferation; Cells; Cellular biology; Complex; Development; Disease; Enzymes; Equilibrium; Fibroblasts; Genetic; Goals; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate; Human; In Vitro; Kinetics; Lipids; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Molecular; Monomeric GTP-Binding Proteins; Mus; Mutate; Mutation; Neoplasm Metastasis; Neurons; Normal Cell; Oncogenic; Output; PH Domain; PIK3CA gene; PTEN gene; Pathway interactions; Phenotype; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Proteins; Proto-Oncogene Proteins c-akt; Receptor Activation; Regulation; Research; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Tail; Testing; Time; Tumor Suppressor Proteins; base; cancer cell; cell growth; cell motility; expectation; in vitro activity; inhibitor/antagonist; interest; migration; mouse model; mutant; neoplastic cell; overexpression; receptor; research study; second messenger; theories; therapeutic target; tumor

DESCRIPTION (provided by applicant): PTEN is a tumor suppressor that is deregulated in a large number of human cancers to activate the oncogenic phosphoinositide-3 kinase (PI3K) pathway. Inactivation of PTEN leads to multiple cancer related phenotypes including enhanced cellular proliferation, migration, and survival. We have recently determined that PREX2 is an inhibitor of PTEN phosphatase activity. PREX2 is over expressed in human cancers with wild type PTEN. Moreover, PREX2 is often over expressed in cancers that harbor mutations in the PIK3CA gene, which encodes the catalytic subunit of PI3K. We have shown that mutant PIK3CA and PREX2 can stimulate cell growth in vitro, and that reduced expression of PREX2 inhibits tumor cell growth in a setting of wild type PTEN. PREX2 encodes an enzyme that catalyzes the loading of GTP onto the small GTPase RAC1 and is a mediator of cell migration and normal development in the brain. We propose that PTEN is likely to function to inhibit migration through PREX2; thus, PREX2 and PTEN are candidate mutual inhibitors. This application will use a combination of biochemistry, cell biology, mouse genetics, and cancer biology to address the following goals: 1) determine the molecular mechanism through which PREX2 inhibits PTEN phosphatase activity in vitro and activates the PI3K pathway in cells, 2) define the genetic relationships between PTEN and PREX2 in fibroblasts and the brain, 3) assess the contribution of PREX2 to PIK3CA mediated tumor formation, 4) define the mechanism through which PTEN inhibits PREX2-induced cell migration. PUBLIC HEALTH RELEVANCE: The PI3K pathway causes the formation of cancer. Analysis of human tumors has shown that it is one of the most frequently activated pathways in many forms of human malignancy. In many cases, pathway activation in cancer cannot be explained. Here we will define an important mechanism of PTEN inhibition via PREX2 that appears to be a common mechanism for activating the PI3K pathway. PREX2 represents a target for therapeutic inhibition of the PI3K pathway in disease.

描述（由申请人提供）：PTEN是一种肿瘤抑制因子，其在大量人类癌症中失调以激活致癌性磷酸肌醇-3激酶（PI 3 K）途径。PTEN的失活导致多种癌症相关表型，包括增强的细胞增殖、迁移和存活。我们最近确定PREX 2是PTEN磷酸酶活性的抑制剂。PREX 2在具有野生型PTEN的人类癌症中过表达。此外，PREX 2通常在PIK 3CA基因中含有突变的癌症中过度表达，PIK 3CA基因编码PI 3 K的催化亚基。我们已经表明突变体PIK 3CA和PREX 2可以在体外刺激细胞生长，并且PREX 2的表达减少在野生型PTEN的情况下抑制肿瘤细胞生长。PREX 2编码一种酶，催化GTP加载到小GTP酶RAC 1上，并且是大脑中细胞迁移和正常发育的介导剂。我们认为，PTEN可能通过PREX 2发挥抑制迁移的作用，因此，PREX 2和PTEN是候选的相互抑制剂。该应用程序将使用生物化学，细胞生物学，小鼠遗传学和癌症生物学的组合，以解决以下目标：1）确定PREX 2在体外抑制PTEN磷酸酶活性并激活细胞中PI 3 K通路的分子机制，2）确定成纤维细胞和脑中PTEN和PREX 2之间的遗传关系，3）评估PREX 2对PIK 3CA介导的肿瘤形成的贡献，4）定义PTEN抑制PREX 2诱导的细胞迁移的机制。 公共卫生相关性：PI 3 K通路导致癌症的形成。对人类肿瘤的分析表明，它是许多形式的人类恶性肿瘤中最频繁激活的途径之一。在许多情况下，癌症中的通路激活无法解释。在这里，我们将定义通过PREX 2抑制PTEN的重要机制，PREX 2似乎是激活PI 3 K通路的常见机制。PREX 2代表疾病中PI 3 K通路的治疗性抑制的靶标。