C-MYC TARGETS IN THE PATHOGENESIS OF HUMAN CANCERS

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The role of the c-myc oncogene appears to be pivotal in the genesis of a number of human cancers. The c-Myc protein contribute positively to cell proliferation; however, the molecular mechanisms underlying the activities of c-Myc in human cancers remain largely unknown. Although significant advances, including identification of various functional domains of c-Myc and the discovery of a Myc partner protein Max, have been achieved in understanding Myc function, numerous critical questions remain unanswered. Our long term objective is to understand the mechanisms by which c-Myc may contribute to the pathogenesis of human cancers so that potential rational approaches to cancer therapy might be generated. To reach our objective, we propose specific aims to address the following questions: 1) What are the proteins that influence the ability of c-Myc to activate or suppress transcription? The amino-terminal domain of c-Myc is necessary for its function including neoplastic transformation. Using our c-myc mutants and an extensive collection of chimeric c-myc genes capable of producing chimeric proteins, we found that this region of c-Myc contains a transcriptional activation domain. The activation domain of c-Myc augments transcription in a model system through factors which are distinct from those utilized by the VP16 acidic activation domain. We propose strategies to identify proteins that interact with and modulate the transcriptional activation potential of c-Myc. 2) What is the role of Max in neoplastic transformation? We have constructed various expression vectors capable of expressing Max in either sense or anti-sense directions. Experiments are proposed to delineate the role of exogenous and endogenous Max in neoplastic cellular transformation caused by Myc and an activated Ras. 3) What are the genes, which play critical roles in cell proliferation, that are regulated by Myc? We have shown that the c-Myc basic region within the DNA binding domain can functionally substitute for the homologous region of the yeast protein CBF1 in a novel genetic system in yeast. Myc and Max will be expressed in yeast to further characterize their transcriptional regulatory function in vivo. Using this genetic system in conjunction with in vitro DNA binding assays, we propose a strategy to identify DNA sites in the human genome that are relevant to Myc-Max mediated neoplastic transformation. 4) Are there other molecules that might interact with the Myc or Max oligomerization domains? To study protein-protein interactions in vivo, we have developed a selection system capable of identifying cDNAs encoding protein domains that oligomerize with a known target. This system will be used to identify cDNAs that encode other proteins which interact with Myc or Max. The findings from the proposed studies should provide significant insights into the molecular mechanisms underlying the normal function of c-Myc and its role in the pathogenesis of human cancers. In addition, it is hoped that the understanding of these mechanisms will provide a rational molecular approach to potential cancer therapeutics.