The expression of the c-myc oncogene is tightly controlled in normal cells, and its deregulation appears to underlie the pathogenesis of a wide range of human cancers. During the post funding period, the work supported by this grant has led to the identification of a number of critical properties of the c-Myc protein that are involved in neoplastic transformation. We have characterized the molecular functions of several Myc domains, including those mediating transcriptional activation and DNA-binding. The discovery of Max as a heterodimeric partner for Myc has led us to find that specific DNA binding by Myc requires Max, an that the ability of the Myc/Max heterodimer to activate transcription resides in amino-terminal Myc sequences. Furthermore, we have found that in transient transfection studies, Myc can both activate and suppress transcription from reporter constructs bearing myc-specific DNA binding sites. Studies on the interaction of myc and Max with DNA have demonstrated distinct DNA bending by these proteins. Our preliminary results suggest that Myc regulation of cyclin A gene expression is correlated with the ability of Myc to induce diametrically opposite cell fates of proliferation or apoptosis. Additional preliminary observations suggest that mutations in the Myc transcription activation domain found in patient-derived lymphomas cause resistance to p107 inhibition of c-Myc transcriptional activation. In this proposal, we will pursue the molecular characterization of Myc transcriptional properties as they relate to cellular transformation by posing the following questions: 1) What are the molecular components required for transcriptional inhibition by c-Myc? 2) Does DNA bending by c-Myc/Max affect transcriptional regulation by c-Myc? 3) What is the mechanism by which c-Myc up regulates cyclin A gene expression and thereby affect cell proliferation or induce apoptosis: 4) The answers to these and related questions will yield a view of c-Myc function in neoplasia that may provide a rational basis for future therapeutics.
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