c‐Myc represses transcription in vivo by a novel mechanism dependent on the initiator element and Myc box II.

We show that c‐Myc, in addition to activating transcription through E‐box Myc binding sites (Ems), also represses transcription by a mechanism dependent on initiator (Inr) elements of the basal promoters of susceptible genes. Repression was first observed as a component of c‐Myc biphasic regulation of the adenovirus‐2 major late promoter (MLP), which contains both Inr and Ems sequences. Two differentiation‐specific genes containing Inr, the C/EBP alpha and albumin genes, are repressed through their basal promoters by c‐Myc, but are activated by the related B‐HLH‐LZ factor, USF. Repression requires both the B‐HLH‐LZ and Myc box II (MBII) domains. Significantly, a MBII deletion mutant which is deficient in repression, but transactivates normally, fails to cooperate with an activated ras gene to transform primary fibroblasts. Thus Myc‐dependent transactivation is insufficient for Ras cooperation and the novel transcription repression function is implicated in Ras cooperation as well as the suppression of Inr‐dependent genes.