RGR--A NOVEL ONCOGENE IN THE RAL PATHWAY

本申请的目的是请求继续支持， 研究新发现的癌基因，rgr，我们已经分离， 上一个融资期。 这个致癌基因与 Ral-GDS（Ral鸟嘌呤核苷酸解离刺激剂），并显示 Ral（ras基因家族的一个成员，参与 信号转导）。我们将其命名为rgr，以表示ral-gds相关。 这是 参与具有致瘤活性的Ral途径的第一基因，和 因此，它的分析应该提供重要线索的作用， Ral通路在细胞增殖调控中的作用。 此外，Ral 已经证明，这一途径与Ras和Rho相互关联 这使得它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种新的癌基因， 分子分析，我们将分离正常的兔和小鼠cDNA， 我们将确定rgr的表达模式，并分析其 通过基因失活和，如果致命的胚胎，通过使用初级 培养的胚胎细胞和cre/loxP方法获得组织 特异性基因失活。 为了分析Rgr介导的信号， 我们将研究它在Ras和Ral通路中的作用， 在这些途径中RGR功能的功能影响， 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分析RGR诱导的肿瘤发生 的激活及其体内效力和肿瘤谱，通过分析 其在转基因小鼠中诱导肿瘤发展的能力。 分子 一个新的癌基因参与Ral、Ras和Rho的特性 路径应该提供有关关系的重要信息， 和肿瘤发生之间的联系

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.