The Role of b-catenin in EGFR-Related Tumor Development

b-连环蛋白在 EGFR 相关肿瘤发展中的作用

• 批准号: 7620969
• 负责人: ZHIMIN LU
• 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: 2005-08-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7620969
• 关键词: Adherens Junction; Binding; Binding Sites; Cell Line; Cells; DNA; Data; Development; Docking; Doctor of Philosophy; EGF gene; Endocytosis; Epidermal Growth Factor Receptor; Extracellular Signal Regulated Kinases; Gene Expression; Human Development; In Vitro; Intercellular Junctions; Knock-out; MAPK1 gene; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Mutation; Neoplasm Metastasis; Nuclear Translocation; Pathway interactions; Phosphopeptides; Phosphorylation; Phosphorylation Site; Play; Proteins; Ras/Raf; Regulation; Reporting; Research Personnel; Role; Signal Transduction; Signaling Molecule; Small Interfering RNA; Transactivation; Tumor Cell Invasion; base; beta catenin; cancer therapy; caveolin 1; cell growth; design; in vivo; neoplastic cell; novel; overexpression; programs; protein complex; response; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): EGF-induced signaling and increased beta-catenin transactivation have been reported separately to correlate with tumor formation and development. However, the exact relationship between EGF-induced signaling and increased beta-catenin transactivation is not clear. Our preliminary data show that EGF treatment disrupts cell-cell junctions of tumor cells overexpressing EGFR and increases beta-catenin transactivation. Moreover, EGF-induced beta-catenin transactivation is regulated through caveolin-1- and Ras/Raf/ERK-dependent pathways. ERK MAP kinase binds to beta-catenin, leading to our exploration into the mechanism of EGF-induced beta-catenin transactivation and its role in the development of human cancers that have aberrantly overexpress EGFR. In Aim 1, we will analyze the relationship between ERK and beta-catenin in response to EGF treatment and the role of this relationship in beta-catenin nuclear translocation and transactivation. Aim 2 focuses on understanding the mechanism of ERK-independent but caveolin-1-dependent regulation of beta-catenin transactivation and the mechanism of beta-catenin endocytosis in response to EGF stimulation. In Aim 3, we plan to determine the role of beta-catenin transactivation in EGFR-related tumor growth and metastasis. Understanding the interplay between EGFR and Wnt signaling components will provide an important basis for understanding tumor cell invasion and metastasis, which may provide novel targets and approaches for developing more effective cancer therapies.

描述（由申请人提供）：已分别报道EGF诱导的信号传导和增加的β-连环蛋白反式激活与肿瘤形成和发展相关。然而，EGF 诱导的信号传导与 β-连环蛋白反式激活增加之间的确切关系尚不清楚。我们的初步数据表明，EGF 治疗会破坏过度表达 EGFR 的肿瘤细胞的细胞连接，并增加 β-连环蛋白反式激活。此外，EGF 诱导的 β-catenin 反式激活通过 Caveolin-1 和 Ras/Raf/ERK 依赖性途径进行调节。 ERK MAP 激酶与 β-连环蛋白结合，促使我们探索 EGF 诱导的 β-连环蛋白反式激活机制及其在异常过度表达 EGFR 的人类癌症发展中的作用。在目标 1 中，我们将分析 ERK 和 β-catenin 之间的关系响应 EGF 治疗，以及这种关系在 β-catenin 核转位和反式激活中的作用。目标 2 重点了解不依赖 ERK 但依赖 Caveolin-1 的 β-catenin 反式激活调节机制，以及 β-catenin 内吞作用响应 EGF 刺激的机制。在目标 3 中，我们计划确定 β-catenin 反式激活在 EGFR 相关肿瘤生长和转移中的作用。了解EGFR和Wnt信号传导成分之间的相互作用将为了解肿瘤细胞侵袭和转移提供重要基础，这可能为开发更有效的癌症治疗提供新的靶点和方法。