Boone DN and Hann SR. The Myc-ARF-Egr1 Pathway: Unleashing Myc’s Apoptotic Power. Cell Cycle. 2011 Jul1;10(13):2043-4. PMC3234342
The c-Myc proto-oncogene encodes an enigmatic transcription factor that paradoxically has essential roles in the regulation of both proliferation and apoptosis. Deregulated c-myc expression combined with a loss of tumor suppressors, manifested in many types of human cancers, leads to tumorigenesis. Distinct threshold levels of c-Myc, which are regulated by various signaling pathways or deregulated in cancer, are correlated to different outcomes, such as cell cycle progression, transformation or apoptosis.1 But it is unclear whether elevated c-Myc leads to amplification of the same c-Myc target genes or whether an increase in c-Myc leads to regulation of additional targets. Considering that cell context also influences the biological outcomes initiated by elevated c-Myc, it is possible that additional cellular factors directly or indirectly modulate specific c-Myc target genes. Surprisingly, although c-Myc regulates thousands of genes, it is unclear which direct target genes mediate the different functions of c-Myc. In our recent report, we showed that a cofactor of c-Myc, the ARF tumor suppressor, switches the inherent function of c-Myc from a proliferative protein to an apoptotic protein by differentially controlling the regulation of specific direct target genes.