THE MOLECULAR MECHANISMS OF ONCOGENE ACTION

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Recent development in the application of molecular biology to epithelial cancers has led to the identification of specific genetic lesions resulting in either activation or inactivation of key target genes. These genes, called oncogenes, are involved in various aspects in the regulation of cell growth and as such play major roles in the early carcinogenic processes of "initiation" and "promotion." It is now critical to understand the precise mechanism by which these genes function, so molecular or pharmacologic agents can be derived to alter or repress their effects. The purpose of this project is to elucidate the biochemical and molecular mechanisms by which oncogenes transform mammalian cells. To this end, we have performed structure/function analysis on members of the jun oncogene family. This study has revealed various structural aspects of these proteins which are necessary and sufficient for transformation and transcriptional regulation. Our studies of the c-jun oncogene revealed that in addition to the DNA binding and dimerization domains, the N-terminal transactivation domain is required for cellular transformation. In addition, the ability of c-jun appears to transform cells by regulating gene expression. Further, detailed mutation analysis of c-jun has demonstrated that phosphorylation of c-Jun at serines 63/73 results in increased transactivation and ultimately transformation. The phosphorylation of these sites is in part through a ras/raf dependent pathway which provides an important biochemical link between these oncogenes. More recent studies suggest that c-jun transforms cells by altering specific portions of the cell cycle The mechanisms by which c-jun accomplishes this are now being explored. We have performed similar studies on Jun B. Jun B is an inhibitor of c- jun induced transactivation. Using a series of deletion mutants, we have mapped the regions critical for this inhibitory action to include the leucine zipper, DNA binding domain and a transrepression domain just 5' of the DNA binding domain. Future studies are aimed at defining the biologic functions of these mutants, the molecular action of the transrepression domain and the collaborating proteins required for the inhibitory activity of Jun B.