THE ALTERNATIVELY INITIATED C-MYC PROTEINS DIFFERENTIALLY REGULATE TRANSCRIPTION THROUGH A NONCANONICAL DNA-BINDING SITE

The myc proto-oncogene family has been implicated in multiple cellular processes, including proliferation, differentiation, and apoptosis. T he Myc proteins, as heterodimers with Max protein, have been shown to function as activators of transcription through an E-box DNA-binding e lement, CACGTG. We have now found that the c-Myc proteins regulate tra nscription through another, noncanonical, DNA sequence. The non-AUG in itiated form of the c-Myc protein, c-Myc 1, strongly and specifically activates transcription of the C/EBP sequences within the EFII enhance r element of the Rous sarcoma virus long terminal repeat. In contrast, comparable amounts of the AUG-initiated form, c-Myc 2, fail to signif icantly affect enhancer activity. However, both c-Myc proteins trans-a ctivate the CACGTG sequence comparably. In addition, Myc/Max heterodim ers, but not Max homodimers, bind to the EFII enhancer sequence in vit ro. finally, c-Myc 1 overexpression, but not c-Myc 2 overexpression, s ignificantly inhibits cell growth. These results reveal new transcript ional activities for the Myc proteins and demonstrate that the differe nt farms of the Myc protein are functionally distinct. These results a lso suggest an interplay between two different growth regulatory trans cription factor families.