Role of first exon/intron sequences in the regulation of myc family oncogenic potency.

cis-Acting sequence elements that participate in the regulation of myc family gene expression in normal tissues and that serve as potential targets for the deregulation of expression in tumors have been localized to the first exon/intron region of all three myc family genes. To test directly the importance of these cis elements in the tumor-associated deregulation of myc family gene expression, we have compared the oncogenic activities of complete (exons 1, 2 and 3) and truncated (exons 2 and 3 only) c-, N- and L-myc expression constructs in the rat embryo fibroblast (REF) cooperation assay. Removal of the first exon/intron region from each construct was associated with a dramatic increase in oncogenic potency by several criteria. Analysis of N-myc/ras-transformed cell lines demonstrated (i) fewer transfected N-myc gene copies and an overall higher level of steady-state N-myc mRNA with the truncated N-myc expression construct and (ii) the presence of a significant block to transcriptional elongation in the first exon of the complete N-myc expression construct. These results indicate that the first exon of N-myc plays an important role in governing oncogenic potency, possibly through transcriptional control mechanisms.