RGR--A NOVEL ONCOGENE IN THE RAL PATHWAY

此应用程序的目的是请求继续支持 研究新发现的癌基因RGR，这是我们在 上一个资助期。这种癌基因与40%的 Ral-GDS(Ral鸟嘌呤核苷酸解离刺激物)，并显示 与ral的交换活性(ras基因家族中的一员，参与 信号转导)。我们将其命名为RGR，以表示与al-GDS相关。这是 第一个涉及具有致癌活性的Ral途径的基因，以及 因此，它的分析应该为了解 RAL通路在细胞增殖调控中的作用此外，雷亚尔 途径已被证明与RAS和RHO相互连接 途径，使其成为细胞信号转导的关键十字路口。 我们将通过几种方法分析这个新的癌基因，因为 分子分析，我们将分离正常的兔和小鼠的cdna， 我们将确定RGR的表达模式，并分析其 通过基因失活发挥功能，如果是致命的胚胎，则通过使用初级 胚胎细胞培养及cre/loxP方法获取组织 特定基因失活。为了分析RGR介导的信号， 我们将研究它在RAS和RAR通路中的参与情况，以确定 RGR功能在这些通路中的功能影响 假设RGR、RAS和RAL之间的相互作用。最后，我们会 从癌基因机制分析RGR诱导的肿瘤发生 通过分析激活及其体内效力和肿瘤谱 其在转基因小鼠体内诱导肿瘤发展的能力。分子 一个与ral、RAS和RHO相关的新癌基因的鉴定 路径应提供有关关系的重要信息 在这些途径和肿瘤发生之间。

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.