TRANSCRIPTION ACTIVATION BY MYC AND MAX - FLANKING SEQUENCES TARGET ACTIVATION TO A SUBSET OF CACGTG MOTIFS IN-VIVO

The Myc oncoprotein has been implicated in control of cell growth, div ision and differentiation. Although Myc contains a bHLH-LZ motif, it f ails to bind DNA atone but can do so by forming heterodimers with an u nrelated bHLH-LZ protein, Max. Max homodimers and Myc-Max heterodimers share the ability to bind CACGTG or CATGTG elements. Current models, based on experimentally induced overexpression of Myc and Max in mamma lian cells, propose that Max-Max homodimers repress while Myc-Max hete rodimers activate transcription through CACGTG binding sites. The inte rpretation of the results using mammalian celts is complicated by the presence of numerous unrelated CACGTG binding transcription activators and the existence of two alternative Max dimerization partners, Mad a nd Mxi-1. Thus, the mechanism whereby overexpression of Max leads to t ranscriptional repression remains to be established. Using a yeast sys tem we show that Max homodimers have the potential to activate transcr iption through CACGTG motifs. Activation by Max requires DNA binding a nd amino acids outside the bHLH-LZ domain but is reduced compared with activation by Myc-Max heterodimers. Moreover, transcriptional activat ion by Myc-Max heterodimers, but not Max-Max homodimers, is strongly i nhibited in vivo by specific sequences flanking the core CACGTG bindin g motif, presumably reflecting reduced DNA binding affinity. These res ults suggest a mechanism for directing the Myc-Max complex to a specif ic subset of CACGTG-containing target genes.