BIOLOGIC CHARACTERIZATION OF A NOVEL SHC-LIKE GENE

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The ras oncogene encodes a small, molecular weight GTPase involved in a plethora of signaling pathways. Mutation of ras is a recurring theme in human malignancies. Approximately 30% of human tumors harbor mutant ras alleles with greater than 90% of pancreatic cancers positive for ras mutations. Therefore, understanding the regulation of the Ras signal is important for the design of potential therapeutic treatments of ras-positive tumors. Recently, a number of Ras regulatory proteins have been isolated. These include GTPase activating proteins (GAPs), guanine nucleotide exchange or releasing factors (GEFs) and adapter proteins such as Grb2 and Shc which link Ras to its upstream regulators. The objective of this proposal is to characterize a novel Shc-like gene (Sli) which I have recently identified and determine its role in the regulation of the Ras signal transduction cascade. The goals of this proposal are to (1) determine the similarities and differences between Sli and Shc in terms of their sequence and expression patterns; (2) determine the biochemical redundancy between Sli and Shc; (3) examine the role of Sli in transformation and differentiation; (4) examine the role of Sli in developmental processes through knocking out the gene by homologous recombination. The studies proposed here will begin to elucidate the function of a potentially novel Ras regulatory protein, Sli, furthering our understanding of Ras signaling. This, in turn, and may lead to a more rational design of therapeutic treatments for cancer.