C-myc transcriptional repression is linked to cell transformation

The c-Myc oncoprotein is a transcription factor known to participate in cell proliferation, apoptosis, and cell transformation. It is widely believed that c-Myc promotes oncogenesis by transactivating genes that regulate cell growth. Recently cMyc mediated repression of promoters containing an initiator element (Inr) has also been reported but its relevance to cell transformation remains unknown. The Inr is a pyrimidine-rich DNA sequence found in several TATA-less promoters of genes that are regulated during differentiation. We chose to delineate c-Myc transcriptional repression through the Inr in transient transfection assays using the adenoviral major late {adML) promoter which contains two Myc binding sites and an Inr. Methods/Results: We observed that c-Myc represses the adML promoter through the initiator element. To determine which functional domains of the c-Myc protein are necessary for transcriptional repression, we used Myc deletion mutants in similar experiments and found that amino acids 106-143 of the c-Myc transactivation domain and the dimerization motif are required for transcriptional repression. We then examined the transcription and transformation properties of a lymphoma-derived mutant, MycB2, that contains a mutation (115-Phe) within one region critical for repression. This mutant repressed transcription to a greater extent than wild-type cMyc. The mutant also conferred a greater cell growth potential than wild-type c-Myc in soft-anchorage independent growth and ras cotransformation assays. Conclusion: These findings link c-Myc transcriptional repression with cell transformation, thus posing an additional mechanism by which c-Myc could potentially transform cells.