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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA050434-13
Application #
6512652
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Perry, Mary Ellen
Project Start
1989-08-01
Project End
2005-03-31
Budget Start
2002-04-01
Budget End
2005-03-31
Support Year
13
Fiscal Year
2002
Total Cost
$271,600
Indirect Cost
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10016
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Osei-Sarfo, K; Martello, L; Ibrahim, S et al. (2011) The human Rgr oncogene is overexpressed in T-cell malignancies and induces transformation by acting as a GEF for Ras and Ral. Oncogene 30:3661-71
Martello, Laura A; Pellicer, Angel (2006) Biochemical and biological analyses of Rgr RalGEF oncogene. Methods Enzymol 407:115-28
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Perez de Castro, Ignacio; Bivona, Trever G; Philips, Mark R et al. (2004) Ras activation in Jurkat T cells following low-grade stimulation of the T-cell receptor is specific to N-Ras and occurs only on the Golgi apparatus. Mol Cell Biol 24:3485-96
Hernandez-Munoz, Inmaculada; Benet, Marta; Calero, Miguel et al. (2003) rgr oncogene: activation by elimination of translational controls and mislocalization. Cancer Res 63:4188-95
Leonardi, Peter; Kassin, Ezra; Hernandez-Munoz, Inmaculada et al. (2002) Human rgr: transforming activity and alteration in T-cell malignancies. Oncogene 21:5108-16
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Hernandez-Munoz, I; Malumbres, M; Leonardi, P et al. (2000) The Rgr oncogene (homologous to RalGDS) induces transformation and gene expression by activating Ras, Ral and Rho mediated pathways. Oncogene 19:2745-57

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