A LINK BETWEEN C-MYC-MEDIATED TRANSCRIPTIONAL REPRESSION AND NEOPLASTIC TRANSFORMATION

Recent studies indicate that the transcription factor c-Myc contribute s to oncogenesis by altering the expression of genes involved in cell proliferation, but its precise function in neoplasia remains ambiguous . The ability of c-Myc to bind the sequence CAC(G/A)TG and transactiva te appears to be linked to its transforming activity; however, c-Myc a lso represses transcription in vitro through a pyrimidine-rich cis ele ment termed the initiator (Inr). In transfection experiments using the adenoviral major late (adML) promoter, which contains two Myc binding sites and an Inr, we determined that c-Myc represses transcription th rough the initiator in vivo, This activity requires the dimerization d omain and amino acids 106 to 143, which are located within the transac tivation domain and are necessary for neoplastic transformation, We st udied a lymphoma-derived c-Myc substitution mutation at 115-Phe, which is within the region required for transcriptional suppression, and fo und the mutant more effective than wild-type c-Myc in transforming rod ent fibroblasts and in suppressing the adML promoter, Our studies of b oth loss-of-function and gain-of-function c-Myc mutations suggest a li nk between c-Myc-mediated neoplastic transformation and transcriptiona l repression through the Inr.