RGR--A NOVEL ONCOGENE IN THE RAL PATHWAY

RGR--RAL通路中的一种新型癌基因

• 批准号: 2619395
• 负责人: ANGEL PELLICER
• 金额: $ 25.28万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2619395
• 关键词: athymic mouse; cell differentiation; cell growth regulation; chemical carcinogen; chemical carcinogenesis; complementary DNA; gene induction /repression; genetically modified animals; guanine nucleotide binding protein; laboratory rabbit; neoplasm /cancer genetics; neoplastic growth; neoplastic process; nucleic acid sequence; oncogenes; skin neoplasms; squamous cell carcinoma; tissue /cell culture; transforming growth factors

The purpose of this application is to request continuing support to study the newly identified oncogene, rgr, that we have isolated during the previous funding period. This oncogene has 40 percent identity with Ral-GDS (Ral guanine nucleotide dissociation stimulator), and shows exchange activity for Ral (a member of the ras gene family involved in signal transduction). We named it rgr for ral-gds related. This is the first gene involved in the Ral pathway with tumorigenic activity, and therefore its analysis should provide important clues on the role of the Ral pathway in the control of cell proliferation. In addition, the Ral pathway has been shown to be interconnected with the Ras and Rho pathways, making it a crucial crossroads in cell signal transduction. We will analyze this novel oncogene by several approaches, for the molecular analysis, we will isolate the normal rabbit and mouse cDNA, we will determine the rgr pattern of expression, and we will analyze its function by gene inactivation and, if lethal embryonic, by using primary cultured embryonic cells and the cre/loxP approach to obtain tissue specific gene inactivation. For analysis of the signal mediated by Rgr, we will study its involvement in the Ras and Ral pathways to determine the functional impact of rgr function in those pathways given the hypothesized interactions between Rgr, Ras and Ral. Finally, we will analyze rgr-induced tumorigenesis by ascertaining the oncogene mechanism of activation and its in vivo potency and tumor spectrum by analyzing its ability to induce tumor development in transgenic mice. Molecular characterization of a novel oncogene involved in the Ral, Ras and Rho pathways should provide important information about the relationship between those pathways and tumorigenesis.

此申请的目的是请求持续支持 研究新发现的致癌基因 rgr，我们在 上一个资助期。 该癌基因与以下基因有 40% 的同一性： Ral-GDS（Ral 鸟嘌呤核苷酸解离刺激剂），并显示 Ral（参与 ras 基因家族的成员）的交换活动 信号转导）。我们将其命名为 rgr，表示与 ral-gds 相关。 这是 第一个参与具有致瘤活性的 Ral 途径的基因，以及 因此，其分析应该为了解该组织的作用提供重要线索。 Ral 通路控制细胞增殖。 此外，拉尔 通路已被证明与 Ras 和 Rho 相互关联 途径，使其成为细胞信号转导的关键十字路口。 我们将通过多种方法分析这种新的癌基因， 分子分析，我们将分离正常的兔子和小鼠的cDNA， 我们将确定 rgr 的表达模式，并分析其 通过基因失活来发挥功能，如果是致死胚胎，则通过使用初级 培养的胚胎细胞和 cre/loxP 方法获取组织 特定基因失活。 为了分析 Rgr 介导的信号， 我们将研究其参与 Ras 和 Ral 途径以确定 rgr 功能在这些途径中的功能影响 假设 Rgr、Ras 和 Ral 之间的相互作用。 最后，我们将 通过确定癌基因机制来分析 rgr 诱导的肿瘤发生 通过分析激活及其体内效力和肿瘤谱 它能够诱导转基因小鼠产生肿瘤。 分子 涉及 Ral、Ras 和 Rho 的新型癌基因的表征 路径应提供有关关系的重要信息 这些途径和肿瘤发生之间的关系。