Molecular characterization of the Myc oncoprotein

Myc is a multi-functional protein that can drive a diverse array of biological activities, including cell cycle progression, apoptosis, and cellular transformation. Myc orchestrates these events by functioning as a transcription factor, to activate or repress the expression of various genes, which then mediate its activities. However, the molecular mechanisms of Myc function are not well understood. There are a limited number of Myc regulated targets identified that can explain Myc activity and an understanding of the mechanism(s) of Myc activation and repression of gene transcription is just emerging. To characterize the function of the Myc protein we have taken three approaches. First, we have examined the structure-function relationship of the Myc N-terminal domain (NTD) through an analysis of Myc mutants. This study highlights the great complexity within the NTD with respect to the relationships between the different activities that Myc induces. Our second approach was to identify Myc regulated genes by microarray analysis. By assessing the expression of the putative targets in various cell systems we were able to isolate specific Myc regulated targets from those genes regulated as an indirect result of cellular activity. This study revealed 15 genes that fulfilled our criteria of a Myc regulated target and will provide useful tools for the study of the underlying mechanisms of Myc function in gene regulation and allow us to begin to understand how Myc exerts its biological activities through regulation of gene expression. Indeed, as a third approach, we further investigated the mechanism of transcriptional regulation of a newly identified Myc target. The mechanism of Myc repression at only a few targets has been investigated to date and interestingly, each has revealed a different mode of transcriptional repression. We investigated the mechanism of Myc repression of TMS-1 and a related family member TMS-2. Overall, these approaches have been useful in furthering our understanding of Myc function. By continuing to study the molecular activities of the Myc protein we will soon uncover how Myc is able to direct such a wide variety of cellular responses.