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.
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