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Phorbol Ester Response and Resistance in Thymoma Cells

胸腺瘤细胞中的佛波酯反应和耐药性

基本信息

批准号：
7345369
负责人：
Kathryn E Meier
金额：
$ 22.53万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-16 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7345369
关键词：
1,2-diacylglycerol Abbreviations Acetates Address Adhesions Affect Apoptotic Appendix Binding Biological Models Cell Adhesion Cell Cycle Arrest Cell Line Cell Proliferation Cell Survival Cell model Cells Cessation of life Complex Coupling Diglycerides Docking Event Family member Focal Adhesion Kinase 1 Generations Goals Growth Growth Factor Immunologics Interleukin-2 Knowledge Laboratories MAP Kinase Gene Mediating Mitogen-Activated Protein Kinases Modeling Molecular Mus Pathway interactions Phenotype Phorbol Phorbol Esters Phorbols Phosphorylation Phosphotransferases Play Proliferating Protein Tyrosine Kinase Proteins Research Personnel Resistance Role Series Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Protein Src homology 2 domain-containing, transforming protein 1 Stimulation of Cell Proliferation Testing Thymoma Transfection Tumor Cell Biology Tumor Promoters Tumorigenicity Variant Work cell type in vivo neoplastic cell novel novel therapeutics paxillin phorbol ester receptor phorbol-12-myristate programs protein expression protein protein interaction ras Guanine Nucleotide Exchange Factors response tumor tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Proliferation and survival of tumor cells involves a complex interplay between cell adhesion and mitogenic signal transduction cascades. EL4, a murine thymoma cell line, is a unique model system in which to investigate the molecular steps involved in these events. EL4 cells exist in two basic phenotypes, PMA-sensitive and PMA-resistant. These phenotypes refer to the ability of the cells to survive and proliferate in the presence of phorbol 12-myristate 13-acetate (PMA), a tumor promoter. Characterization of signal transduction and protein expression in the two cell types has revealed that PMA-resistant cells are unable to fully activate the Erk mitogen-activated protein kinase cascade in response to PMA. Erk activation is required for PMA-induced growth arrest in PMA-sensitive cells. Additional findings are that only PMA-resistant cells express focal adhesion kinase (FAK), while PMA-sensitive cells express higher levels of Pyk2, a FAK-related kinase. In addition, PMA-sensitive cells express higher levels of RasGRP, a guanine nucleotide exchange factor for Ras, than do resistant cells. RasGRP is a phorbol ester receptor that induces activation of Ras when bound to PMA. The proposed work tests two hypotheses that have arisen from these previous observations. The first is that, in EL4 cells, phorbol ester-mediated ERK activation occurs via proteins that regulate activation of Ras. The second is that expression of FAK enhances attachment, survival, and tumorigenicity of EL4 thymoma cells. The Specific Aims are: 1) To examine the effects of PKC activation on proteins upstream of Ras in EL4 cells, 2) To determine the roles of RasGRP and Pyk2 in PMA-induced Erk activation, 3) To define the roles of adhesion proteins in PMA response in EL4 cells, and 4) To examine the role of FAK and PMA sensitivity in tumorigenesis of EL4 cells in vivo. The proposed work will utilize a series of clonal EL4 cell lines. The alterations in protein expression that occur in these cells mimic those occurring in some tumors. EL4 cells provide a particularly novel model in which to study the roles of adhesion proteins in signaling. The long-term goal of this work is to delineate major pathways for response to phorbol ester and diglycerides. The information gained will suggest new therapeutic approaches to inhibit tumor cell progression.

描述（由申请人提供）：肿瘤细胞的增殖和存活涉及细胞粘附和有丝分裂信号转导级联之间的复杂相互作用。EL4是一种小鼠胸腺瘤细胞系，是一种独特的模型系统，用于研究参与这些事件的分子步骤。EL4细胞存在两种基本表型：pma敏感型和pma耐药型。这些表型是指细胞在肿瘤启动子phorbol 12-肉豆蔻酸13-醋酸酯（PMA）存在下存活和增殖的能力。对两种细胞类型的信号转导和蛋白表达的表征表明，PMA抗性细胞无法完全激活Erk丝裂原激活的蛋白激酶级联反应以响应PMA。在pma敏感细胞中，pma诱导的生长停滞需要Erk激活。其他发现是，只有pma耐药细胞表达局灶黏附激酶（FAK），而pma敏感细胞表达更高水平的Pyk2，一种FAK相关的激酶。此外，pma敏感细胞比耐药细胞表达更高水平的RasGRP （Ras的鸟嘌呤核苷酸交换因子）。RasGRP是一种磷酯受体，当与PMA结合时可诱导Ras活化。这项提议的工作检验了从这些先前的观察中产生的两个假设。首先，在EL4细胞中，磷酯介导的ERK激活通过调节Ras激活的蛋白质发生。其次，FAK的表达增强了EL4胸腺瘤细胞的附着、存活和致瘤性。具体目的是：1)研究PKC活化对EL4细胞Ras上游蛋白的影响；2)确定RasGRP和Pyk2在PMA诱导的Erk活化中的作用；3)明确粘附蛋白在EL4细胞PMA应答中的作用；4)研究FAK和PMA敏感性在EL4细胞体内肿瘤发生中的作用。这项工作将利用一系列克隆EL4细胞系。在这些细胞中发生的蛋白质表达的改变类似于在某些肿瘤中发生的改变。EL4细胞为研究粘附蛋白在信号传导中的作用提供了一个特别新颖的模型。这项工作的长期目标是描绘对佛波酯和甘油三酯反应的主要途径。获得的信息将提示新的治疗方法来抑制肿瘤细胞的进展。