Coordinated Cross-Talk Between the Myc and Mlx Networks in Liver Regeneration and Neoplasia

The Myc bHLH-ZIP transcription factor is deregulated by most cancers. As a heterodimer with the bHLH-ZIP protein Max, Myc regulates target genes that contribute to metabolism and proliferation. This "Myc Network" cross-talks with the "Mlx Network" comprised of the Myc-like bHLH-ZIP proteins MondoA and ChREBP and the Max-like bHLH-ZIP protein Mlx. This "Extended Myc Network" regulates genes with both common and distinct functions. We have generated hepatocytes lacking Mlx (mlxKO) or Mlx+Myc (double KO or DKO) and quantified their abilities to replace dying hepatocytes in a murine model of Type I tyosinemia. We find that this function deteriorates as the Extended Myc Network is progressively dismantled. Genes dysregulated in mlxKO and DKO hepatocytes include those involved in translation and mitochondrial function. The Myc and Mlx Networks thus cross-talk with the latter playing a disproportionate role. mycKO and mlxKO mice also develop non-alcoholic fatty liver disease and mlxKO and DKO mice develop extensive hepatic adenomatosis not observed in wild-type, mycKO, chrebpKO or mycKOxchrebpKO mice. In addition to demonstrating cooperation between the Myc and Mlx Networks, this study reveals the latter to be more important in maintaining metabolic and translational homeostasis, while concurrently serving as a suppressor of benign tumorigenesis.