The ras family of oncogenes have been implicated in a substantial fraction of human and animal cancers. Normal ras genes encode membrane proteins of 21,000 daltons (p21ras) that in vitro bind guanine nucleotides and have GTPase activity. Although the role of p21ras proteins in normal cell physiology is incompletely known, it is clear that both quantitative and qualitative changes in their expression can cause neoplastic transformation of some target cells. Despite the evolutionary divergence of the three known mammalian ras genes (rasH, rasN, rasK), the polypeptides they encode are very similar in amino acid sequence, except for a variable segment of 15 residues located near the carboxyl terminus. This C-terminus of p21ras may be cleaved after translation, though our studies do not confirm this hypothesis. The major objectives of the proposed study are: (1) to develop reagents necessary to study the expression and processing of the different ras gene products independently and (2) to use these reagents to attempt to determine the significance of the structural heterogeneity of p21ras proteins. In order to achieve these objectives we propose to produce polyclonal antisera and monoclonal antibodies that distinguish ras gene products; to determine, utilizing specific antisera and nucleic acid probes, if the distinct ras gene products are expressed differentially as a function of cell type; to purify p21ras from mammalian brain in order to determine which rasgenes are active in this tissue and to obtain fully processed protein for enzymatic studies and for comparison with p21ras produced by bacteria by recombinant DNA techniques. Studies of the expression of p21ras in transformed cells should ultimately have diagnostic and/or prognostic value in the clinical evaluation of cancer. (X)
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