Regulation of Ras and Rho Family GTPases in Lung Cancer

Ras 和 Rho 家族 GTP 酶在肺癌中的调控

• 批准号: 7781653
• 负责人: Carol Lucille Williams
• 金额: $ 31.54万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7781653
• 关键词: Affect; Agar; Biological Assay; C-terminal; Cell Line; Cell Proliferation; Cell Survival; Cell membrane; Cell physiology; Development; Doxycycline; Endoplasmic Reticulum; Epithelial Cells; Family; Guanine Nucleotide Exchange Factors; Guanine Nucleotides; Guanosine Triphosphate Phosphohydrolases; Human; Image; In Vitro; Laboratories; Lead; Life; Lung; Lung Neoplasms; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Measures; Messenger RNA; Modeling; Monomeric GTP-Binding Proteins; Mus; Names; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Pathway interactions; Patients; Process; Proliferating; Proteins; RNA Splicing; Recombinant Proteins; Regulation; Reporting; Research; Signal Transduction; Small Interfering RNA; Structure of parenchyma of lung; Testing; Therapeutic; Time; Variant; base; cancer cell; design; in vivo; malignant phenotype; migration; mutant; novel; novel strategies; novel therapeutic intervention; prenylation; public health relevance; research study; rho; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Activation of multiple small GTPases in the Ras and Rho families promotes the proliferation and migration of non-small cell lung carcinoma (NSCLC) cells, which contributes to NSCLC tumorigenesis and metastasis. Surprisingly little is known about how small GTPases are activated in NSCLC cells to promote tumorigenesis and metastasis. Our research indicates that the unique guanine nucleotide exchange factor known as SmgGDS is a major regulator of small GTPase activity in NSCLC. SmgGDS uniquely activates multiple small GTPases in the Ras and Rho families. We previously reported that SmgGDS is expressed at high levels in NSCLC tumors and stimulates the proliferation and migration of NSCLC cells. We recently discovered that NSCLC cells express several forms of SmgGDS. Our results support the model that different forms of SmgGDS promote post-translational processing of the small GTPases K-Ras, Rac1, RhoA, Rap1A, and Rap1B. This model will be tested in the following aims. Aim1: Define the expression of different forms of SmgGDS in NSCLC tumors from patients and in NSCLC cell lines. Aim 2: Determine which form of SmgGDS and which of the small GTPases that interact with SmgGDS contribute the most to NSCLC cell proliferation, migration, tumorigenesis, and experimental metastasis. Aim 3: Characterize how different forms of SmgGDS regulate the activity, post-translational processing, and subcellular localization of different small GTPases in NSCLC. This research will define the unique ability of SmgGDS to regulate the activities of K-Ras, Rac1, RhoA, Rap1A, and Rap1A in NSCLC, and will help determine the therapeutic potential of these proteins in lung cancer. PUBLIC HEALTH RELEVANCE: Lung cancer cells make a group of proteins called "small GTPases". When these small GTPases are activated in lung cancer cells, they induce the lung cancer cells to proliferate and migrate, which promotes tumorigenesis and metastasis. Our laboratory is investigating how these small GTPases are activated in lung cancer, because this information will help us design new ways to stop the activation of small GTPases, and thereby stop lung cancer tumorigenesis and metastasis. We found that a protein called SmgGDS activates small GTPases in lung cancer cells and is made in high amounts in lung tumors from patients. Our proposed research will define how SmgGDS activates different small GTPases in lung cancer. This research may discover how small GTPases are activated in lung cancer and thus may identify new approaches to stop these proteins from promoting lung cancer tumorigenesis and metastasis.

描述（由申请人提供）：RAS和RHO家族中多个小GTP酶的激活促进了非小细胞肺癌（NSCLC）细胞的增殖和迁移，这有助于NSCLC肿瘤发生和转移。令人惊讶的是，对于如何在NSCLC细胞中激活小的GTPase以促进肿瘤发生和转移，知之甚少。我们的研究表明，称为SMGGDS的独特鸟嘌呤核苷酸交换因子是NSCLC中小GTPase活性的主要调节剂。 SMGGD唯一激活了RAS和RHO家族中的多个小型GTPase。我们先前报道说，SMGGD在NSCLC肿瘤中以高水平表达，并刺激NSCLC细胞的增殖和迁移。我们最近发现NSCLC细胞表达了几种形式的SMGGD。我们的结果支持了不同形式的SMGGD促进小型GTPASES K-RAS，RAC1，RHOA，RAP1A和RAP1B的翻译后处理的模型。该模型将在以下目标中进行测试。 AIM1：定义来自患者和NSCLC细胞系中NSCLC肿瘤中不同形式的SMGGD的表达。目标2：确定与SMGGDS相互作用的哪种形式的SMGGDS以及哪种小型GTP酶对NSCLC细胞增殖，迁移，肿瘤发生和实验转移最大的贡献。 AIM 3：表征不同形式的SMGGD如何调节NSCLC中不同小GTPases的活性，翻译后处理和亚细胞定位。这项研究将定义SMGGD在NSCLC中调节K-RAS，RAC1，RHOA，RAP1A和RAP1A活性的独特能力，并将有助于确定这些蛋白质在肺癌中的治疗潜力。 公共卫生相关性：肺癌细胞使一组称为“小GTPases”的蛋白质。当这些小的GTPase在肺癌细胞中被激活时，它们会诱导肺癌细胞增殖和迁移，从而促进肿瘤发生和转移。我们的实验室正在研究这些小型GTPases如何在肺癌中激活，因为此信息将有助于我们设计新的方法来停止小型GTP酶的激活，从而停止肺癌肿瘤发生和转移。我们发现一种称为SMGGD的蛋白质会激活肺癌细胞中的小GTPase，并在患者的肺肿瘤中大量生产。我们提出的研究将定义SMGGD如何激活肺癌中不同的小GTPase。这项研究可能会发现如何在肺癌中激活小的GTPases，因此可以确定阻止这些蛋白质促进肺癌肿瘤发生和转移的新方法。