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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.
Highlights
Coupled with a previous finding that Mxd3 protected against γ-radiation-induced cell death in primary thymocytes and neural progenitor cells [55], these findings suggested that Mxd3 functions in ways that are both distinct from other Mxd members and potentially pro-oncogenic
At least in the cell lines examined, was primarily centered around Myc targets. These results indicated that, in several normal and neoplastic cell types, DNA-binding complexes comprised of Mga, Max and E2F6 interact with members of the PRC1 complex, compete with Myc–Max complexes for binding to Myc-activated targets and repress their expression
Identified by yeast two-hybrid screening as a bHLH-ZIP binding partner for Max-like protein X (Mlx), MondoA was quickly determined to be a paralog of ChREBP, albeit with a wider tissue distribution pattern including high expression in skeletal muscle, where it is required for normal development [31,56,88,89,374]
Summary
The findings indicated that high levels of mitotic signaling mediated by the PI3-kinase/Akt/S6K and MAP kinase/RSK pathways converge on Mxd so as to fine-tune its stability, its association with Max and its DNA binding activity, allowing for competing Myc-mediated cell cycle-promoting processes to proceed. Mxd2−/− MEFs replicated faster in vitro than their wild-type counterparts and were 3–5-fold more transformable by MYC+RAS oncogenes These findings suggested that Mxd gene silencing was associated with broadly similar outcomes in prostatic epithelium, MEFs and T cells that involved a dysregulation of both. Other than the presence of T-boxes, what determines the relative strength and dominance of these effects and how does cross-talk with other Myc Network members bound at nearby sites fine tune them?
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