TRANSCRIPTIONAL ACTIVATION BY MYC IS UNDER NEGATIVE CONTROL BY THE TRANSCRIPTION FACTOR AP-2

The Myc protein binds to and transactivates the expression of genes vi a E-box elements containing a central CAC(G/A)TG sequence. The transcr iptional activation function of Myc is required for its ability to ind uce cell cycle progression, cellular transformation and apoptosis. Her e we show that transactivation by Myc is under negative control by the transcription factor AP-2. AP-2 inhibits transactivation by Myc via t wo distinct mechanisms. First, high affinity binding sites for AP-2 ov erlap Myc-response elements in two bona fide target genes of Myc, prot hymosin-alpha and ornithine decarboxylase. On these sites, AP-2 compet es for binding of either Myc/Max heterodimers or Max/Max homodimers. T he second mechanism involves a specific interaction between C-terminal domains of AP-2 and the BR/HLH/LZ domain of Myc, but not Max or Mad. Binding of AP-2 to Myc does not preclude association of Myc with Max, but impairs DNA binding of the Myc/Max complex and inhibits transactiv ation by Myc even in the absence of an overlapping AP-2 binding site. Taken together, our data suggest that AP-2 acts as a negative regulato r of transactivation by Myc.