The RaLGTPase Regulatory Network

RaLGTPase 监管网络

• 批准号: 8117839
• 负责人: MICHAEL A. WHITE
• 金额: $ 6.49万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-07 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117839
• 关键词: Accounting; Adhesions; Animals; Biological Models; Cell Death; Cell Proliferation; Cell Survival; Cell physiology; Cells; Chronic; Family; GTP-Binding Proteins; Guanosine Triphosphate Phosphohydrolases; Mediating; Molecular; Nature; Oncogenic; Pathway interactions; Regulation; Signal Transduction; Xenograft procedure; base; cancer cell; ral A GTP-Binding Protein; restraint; tumor initiation; tumorigenic

DESCRIPTION (provided by applicant): Accumulating evidence from both cell and animal-based model systems indicates the Ras-like small GTP-binding proteins RalA and RalB are core components of a regulatory framework supporting tumorigenic transformation. Recently we have established discrete but interlocking contributions of these highly related G-proteins to the regulation of both cancer and cell proliferation and survival. Specifically, chronic activation of RalA is required to maintain anchorage-independent proliferation, while RalB is required to deflect cell-death checkpoint activation. This proposal is directed at defining the composition, organization, and function of cell regulatory networks engaged by Ral family G-proteins. Our focus is on the dominant RalA and RalB effector pathways that directly participate in oncogenic transformation. Our specific aims are 1) identification of the effector pathway(s) mediating RalA support of anchorage-independent proliferation, 2) defining the mechanistic contribution of RalB signaling to cancer cell survival, and 3) evaluating the consequences of perturbations in RalA/RalB signaling networks to tumor initiation and/or progression in xenograft and organotypic model systems.

描述（由申请人提供）：来自细胞和动物模型系统的积累证据表明，Ras 样小 GTP 结合蛋白 RalA 和 RalB 是支持致瘤转化的调控框架的核心组成部分。最近，我们已经确定了这些高度相关的 G 蛋白对癌症以及细胞增殖和存活的调节的离散但连锁的贡献。具体来说，需要长期激活 RalA 来维持锚定非依赖性增殖，而需要 RalB 来偏转细胞死亡检查点激活。该提案旨在定义 Ral 家族 G 蛋白参与的细胞调节网络的组成、组织和功能。我们的重点是直接参与致癌转化的主要 RalA 和 RalB 效应途径。我们的具体目标是 1) 鉴定介导 RalA 支持锚定非依赖性增殖的效应通路，2) 定义 RalB 信号传导对癌细胞存活的机制贡献，以及 3) 评估 RalA/RalB 信号传导扰动的后果异种移植和器官模型系统中肿瘤发生和/或进展的网络。