Normal and Neoplastic Growth Suppression by the Extended Myc Network

Abstract

Among the first discovered and most prominent cellular oncogenes is MYC, which encodes a bHLH-ZIP transcription factor (Myc) that both activates and suppresses numerous genes involved in proliferation, energy production, metabolism and translation. Myc belongs to a small group of bHLH-ZIP transcriptional regulators (the Myc Network) that includes its obligate heterodimerization partner Max and six “Mxd proteins” (Mxd1–4, Mnt and Mga), each of which heterodimerizes with Max and largely opposes Myc’s functions. More recently, a second group of bHLH-ZIP proteins (the Mlx Network) has emerged that bears many parallels with the Myc Network. It is comprised of the Myc-like factors ChREBP and MondoA, which, in association with the Max-like member Mlx, regulate smaller and more functionally restricted repertoires of target genes, some of which are shared with Myc. Opposing ChREBP and MondoA are heterodimers comprised of Mlx and Mxd1, Mxd4 and Mnt, which also structurally and operationally link the two Networks. We discuss here the functions of these “Extended Myc Network” members, with particular emphasis on their roles in suppressing normal and neoplastic growth. These roles are complex due to the temporal- and tissue-restricted expression of Extended Myc Network proteins in normal cells, their regulation of both common and unique target genes and, in some cases, their functional redundancy.

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

“…Together with the results of Figure 3 J , these findings support the idea that the binding of Myc, Mlx, or any other extended Myc Network factor to a target gene likely reflects only 1 aspect of the complex and integrative interplay among other network members that collectively dictates the gene’s expression level and downstream biological consequences. 20 …”

“…Recurrent MLX gene deletions are associated with at least 8 human cancer types and provide further reason to implicate the Mlx Network in the pathogenesis of hepatic adenomatosis ( https://portal.gdc.cancer.gov/genes/ENSG00000108788 ). 20 Genetic suppressors of hepatic adenomas and other benign tumors such as meningiomas, neurofibromas, and uterine fibroids are well documented but are distinct from more notorious counterparts such as TP53 , RB , PTEN , APC , and BRCA1 /2 that are associated with malignant tumors. 87 , 88 , 89 , 90 However, the role of Mlx and its members also may be more indirect and nuanced.…”

“… 13 , 14 , 15 , 16 , 17 Down-regulation of these genes, often occurring during cellular quiescence or differentiation, involves a reduction in Myc levels and a shift in E-box occupancy to heterodimers now comprising Max and members of the transcriptionally repressive bHLH-ZIP Mxd family, which includes Mxd1–4 and the less-related Mnt and Mga factors. 3 , 18 , 19 , 20 Together, their binding reverses the chromatin modifications mediated by Myc–Max binding and restores transcriptional repression. Negative regulation by Myc is more indirect and involves interaction with and inhibition of positively acting transcription factors such as Miz1 and Sp1.…”

“…The Myc Network crosstalks and shares considerable regulatory overlap with a structurally related but distinct group of bHLH-Zip transcription factors that comprise the so-called Mlx Network. 1 , 2 , 3 , 8 , 20 , 24 , 25 Classically believed to control target gene sets smaller and more functionally restricted than those overseen by Myc, the Myc-like equivalents of the Mlx Network include the transcription factors Carbohydrate response element (ChRE)-binding protein (ChREBP) and MondoA. Upon binding glucose and other nutrients, these cytoplasmic proteins translocate to the nucleus, heterodimerize with the Max-like protein Mlx, and bind to their target genes at carbohydrate response elements (ChoREs) comprising tandem E-boxes separated by 5 nucleotides.…”

“… 28 , 29 , 30 , 31 , 32 Although the Mlx Network is less widely implicated in tumorigenesis than the Myc Network, recurrent MLX gene deletions nevertheless occur in as many as 10%–20% of several human cancers, with the precise fraction correlating with the size of the deletion ( https://portal.gdc.cancer.gov/genes/ENSG00000108788 ). 1 , 2 , 3 , 13 , 20 , 33 …”