THE MOLECULAR MECHANISMS OF ONCOGENE ACTION

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Recent developments in the molecular genetics of 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 important 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 characterize the biochemical and molecular mechanisms by which the c-jun oncogene 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 and gene transactivation. Thus, the the ability of c-jun to transactivate correlates with its ability to transform cells. Therefore, c-jun appears to transform cells by regulating gene expression. Further, detailed mutation analysis of c-jun has demonstrated that phosphorlylation of cJun at serines 63/73 results in increased transactivation and ultimately transformation. The phosphorlyation of these sites is inpart 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 and may play a role in apoptosis. The mechanisms by which c-jun accomplishes this are now being explored. We have performed a similar analysis 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.