Proto-oncogene c-abl is a normal constituent of the vertebrate genomes. Three lines of evidence indicate the importance of this gene in the regulation of cell growth and development: (a) viral derivatives of the c-abl gene can induce cancers in mice and cats; (b) human c-abl gene is consistently translocated in the Philadelphia chromosome of chronic myclogenous leukemia to generate an altered c-abl proteins; (c) the expression of c-abl gene is modulated during embryogenesis and spermatogenesis. Our research goals are to elucidate the normal function of c-able and to understand the mechanism of tumorogenesis induced by the oncogenic derivatives of the c-abl gene. We have succeeded in isolating cDNA clones of the normal c-abl RNA, monoclonal antibodies that reach with the c-abl proteins and antibodies that recognize phosphotyrosine. The analyses of our cDNA clones revealed an unexpected finding that several RNAs with different 5'-sequences are generated from the mouse c-abl gene. In this proposal, we will determine the 5'-structure of the c-abl gene and the molecular mechanism for the generation of the heterogeneous c-abl RNAs. We will examine the possible regulation of the expression of these RNAs by tumorogenic processes, by development, and by mitogenic stimulation. The heterogenous regions of these c-abl RNAs contain protein coding sequences. We will define the protein product of each of these RNAs in vitro. Each of the c-abl cDNAs will be expressed in mouse cells at high levels so that the properties and the enzymatic activity of the cellular c-abl proteins can be analyzed. We will study the tyrosine kinase activity of the c-abl proteins; compare them to the oncogenic v-abl protein; and examine the regulation of the c-abl tyrosine kinase activity in mouse cells and in a bacterial expression system. The analyses of the c-abl tyrosine kinase activity, which is crucial to the function of the c-abl protein, will be facilitated by the anti-phosphotyrosine antibodies we have isolated. The proposed studiew will define the structure of the c-abl gene, the regulation of the generation of different c-abl RNAs and the structures and enzymatic functions of the c-abl proteins. These results will form the basis for future studies leading to the understanding of c-abl gene function in cell growth and differentiation.
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