ROLE OF 1ST 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 localiz ed to the first exon/intron region of all three myc family genes. To t est directly the importance of these cis elements in the tumor-associa ted deregulation of myc family gene expression, we have compared the o ncogenic activities of complete (exons 1, 2 and 3) and truncated (exon s 2 and 3 only) c-, N- and L-myc expression constructs in the rat embr yo fibroblast (REF) cooperation assay. Removal of the first exon/intro n region from each construct was associated with a dramatic increase i n oncogenic potency by several criteria. Analysis of N-myc/ras-transfo rmed cell lines demonstrated (i) fewer transfected N-myc gene copies a nd an overall higher level of steady-state N-myc mRNA with the truncat ed N-myc expression construct and (ii) the presence of a significant b lock 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, possi bly through transcriptional control mechanisms.