The purpose of the present continuing application is to pursue our long-term goal to understand the role of N-ras in physiology and tumor development. We will address first the specificity of N-ras in transducing the signal initiated after T cell receptor (TCR) activation, following our observations of specific N-ras activation in TCR-stimulated Jurkat cells. We will investigate the structural requirements of N-ras to carry that signal and the specificity of the exchange factor involved in N-ras activation. After performing those experiments in Jurkat cells, we will then confirm their relevance in primary T cells and subsequently in mice. The second topic that we will be addressing in this application is the functional interaction between N-ras and p15INK4b in the development of thymic lymphomas. We have observed in the previous period of the award that p15INK4b plays a very important role in the development of those lymphomas. We will probe the role of p15 in T cell precursors to determine if the absence of p15 in the presence of activated Ras is deleterious for those precursors, indicating a role of p15INK4b in the homeostasis of the T cell lineage. Moreover, we will determine if this role is specific and cannot be substituted by p16INK4a. We have observed in the course of the previous award that wild type N-ras can be involved in tumor development but also has tumor inhibitory activity. These interesting results will be also pursued to determine the range of tumor inhibitory activity that N-ras possess and then we will investigate the molecular mechanisms that mediate this tumor inhibitory activity. The characterization of N-ras signal transduction specificity, of its role in lymphoma development opposed by p15INK4b, and of its tumor inhibitory activity should provide a comprehensive picture of the role of this important gene.
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