Myc-dependent apoptosis as a tumor-suppressive mechanism: how do cells discriminate between physiological and oncogenic levels of Myc expression?

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Deregulated expression of Myc is observed in the majority of all human tumors and is universal in some tumor entities. A plethora of tissue culture and transgenic experiments documents that deregulated expression of Myc elicits multiple characteristics of transformed cells and contributes to tumorigenesis. Surprisingly, ectopic expression of Myc in primary cells induces apoptosis and this is thought to be a major failsafe mechanism that protects organisms from tumorigenesis. Current concepts suggest that tumors can only arise when secondary mutations block Myc-induced apoptosis. Despite many studies, the molecular mechanisms that allow cells to discriminate physiological from supra-physiological levels of Myc remain unresolved.Myc proteins are transcription factors that bind to the majority of open promoters in the genome. Some models assume that all binding sites are functionally equivalent and see Myc proteins as universal "amplifiers" of transcription. This contrasts with experiments showing that Myc activates and represses specific genes.We have shown previously that Myc forms a complex with the Zn-finger protein Miz1 and inhibits Miz1-dependent transcription. This is critical for Myc-induced tumorigenesis. We have now performed extensive ChIp-sequencing and found that Miz1 co-binds the majority of Myc target promoters; hence, target promoters of Myc bind a mixture of activating and repressive complexes. We have identified the consensus Miz1 binding sequence and shown that Myc and Miz1 recruit each other to their cognate target sites. As a result, the topology, relative proportion of Myc and Miz1 bound, and the response to Myc differs among promoters. The resulting model sees Myc as a specific regulator of transcription rather than a general transcriptional amplifier.Genes with consensus Miz1 binding motifs sites are not targets for repression by Myc. Promoters of repressed genes are characterized by the absence of consensus E-boxes and Miz1 binding motifs and by binding relatively low amounts of both proteins, suggesting that their occupancy changes with varying Myc levels. In a parallel work, we have found that induction of apoptosis by Myc in epithelial cells depends on association of Myc with Miz1 and identified a group of genes that are regulated by Myc in a Miz1-dependent manner. These genes are required for epithelial cell integrity and Myc specifically suppresses growth of epithelial, but not of stem cells. Strikingly, these genes are selectively regulated in response to supra-physiological levels of Myc. Collectively, the data suggest that the relative affinities of Myc/Miz1 complexes to different target promoters allow cells to discriminate physiological from supra-physiological levels of Myc. Here we propose to test this hypothesis and study the underlying biochemical mechanisms. We believe that this study will open the way for a biochemical and, ultimately, quantitative understanding of Myc-induced apoptosis.