The Myc proto-oncogene has been studied for over 80 years and is implicated in over 70,000 cancer deaths each year. Myc proteins are bHLHZip transcription factors that bind consensus E-box sequences (CACGTG) and activate transcription of several genes that promote the G1/S transition and growth. Myc heterodimerizes with another bHLHZip protein, Max, and this interaction is required for the physiological and pathophysiological activities of Myc. Max also heterodimerizes with the Mad family of transcriptional repressors. Mad/Max heterodimers bind the same promoter sequences as Myc/Max heterocomplexes, and these overlapping biochemical activities allow for a developmental switch between proliferation (high Myc levels) and differentiation (high Mad levels). Some Mad family members also interact with a Max-like bHLHZip protein termed Mlx. Mad/Mlx heterodimers bind DNA and repress transcription similar to Mad/Max heterocomplexes. Mlx also interacts with the Mondo family of bHLHZip proteins. Mondo/Mlx heterodimers bind DNA and activate transcription from Myc/Max responsive promoters, suggesting the Myc and Mondo families may function similarly. In addition to redundancy between these families, each of the Myc, Mad, and Mondo families has at least two members, raising the possibility of functional redundancy within a family. In C. elegans, only one predicted gene (T20B12.6) has a high level of sequence identity to both Mondo (36%) and Myc (26%) family members, suggesting that it might possess Myc and Mondo-like functions. We have consequently named this gene
mml-1, for Myc and Mondo-like 1. Similarly, single Mad, Max, and Mlx orthologs are also present in C. elegans, demonstrating that the C. elegans network is simpler than the mammalian network. An MML-1::GFP translational fusion is constitutively expressed in the nuclei of hypodermal and intestinal cells throughout development and adulthood. MML-1::GFP is also transiently expressed in other tissues. The Mad, Max, and Mlx orthologs are also expressed in the same tissues where MML-1 is found. Animals carrying
mml-1::GFP arrays do not exhibit any hyperproliferation or growth phenotypes reminiscent of Myc overexpression in mammalian systems. Injection of dsRNA targeted against
mml-1 results in embryonic lethality, similar to that observed for c-myc or N-myc knockouts in mice. Furthermore, worms escaping embryonic lethality are smaller than wild type worms. Together, these data suggest a Myc-like role for MML-1 in cell growth and proliferation. Future experiments will focus on the functional cross-talk between the Mad-like and Myc-like arms of this transcriptional network.