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Review
. 2022 Dec 8;11(24):3974.
doi: 10.3390/cells11243974.

Regulation of Normal and Neoplastic Proliferation and Metabolism by the Extended Myc Network

Edward V Prochownik  1   2   3   4
Affiliations
Review

Regulation of Normal and Neoplastic Proliferation and Metabolism by the Extended Myc Network

Edward V Prochownik. Cells. .

Abstract

The Myc Network, comprising a small assemblage of bHLH-ZIP transcription factors, regulates many hundreds to thousands of genes involved in proliferation, energy metabolism, translation and other activities. A structurally and functionally related set of factors known as the Mlx Network also supervises some of these same functions via the regulation of a more limited but overlapping transcriptional repertoire. Target gene co-regulation by these two Networks is the result of their sharing of three members that suppress target gene expression as well as by the ability of both Network's members to cross-bind one another's consensus DNA sites. The two Networks also differ in that the Mlx Network's control over transcription is positively regulated by several glycolytic pathway intermediates and other metabolites. These distinctive properties, functions and tissue expression patterns potentially allow for sensitive control of gene regulation in ways that are differentially responsive to environmental and metabolic cues while allowing for them to be both rapid and of limited duration. This review explores how such control might occur. It further discusses how the actual functional dependencies of the Myc and Mlx Networks rely upon cellular context and how they may differ between normal and neoplastic cells. Finally, consideration is given to how future studies may permit a more refined understanding of the functional interrelationships between the two Networks.

Keywords: ChREBP; Mlx; Mnt; MondoA; Mxd; TXNIP; hepatoblastoma; hepatocellular carcinoma.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
The Myc and Mlx Networks. Inactive as a monomer and unable to homodimerize under physiologic conditions, Myc binds to target gene consensus E-boxes (CACGTG) only after heterodimerizing with Max [9,22]. This leads to the de novo acetylation and methylation of specific histone residues, the relaxing of chromatin structure and target gene transcriptional activation following the Myc-dependent recruitment of scores of transcriptional cofactors [9,23,24,25]. Although Max homodimerizes and binds DNA well in its unmodified form, its ability to do so within cells is low due to inhibitory casein kinase II-mediated phosphorylation [26,27]. Transcriptional silencing is mediated by six “Mxd proteins” (Mxd [1,2,3,4], Mnt and Mga), which compete with Myc for Max, displace Myc-Max heterodimers from E-boxes, recruit histone deacetylases and reverse the above-described histone modifications [9,18,23]. In the Mlx Network, the Myc-like factors ChREBP and MondoA homodimerize poorly but heterodimerize well with the Max-like factor Mlx. However, they enter the nucleus and engage E box-related ChoRE sites (CAYGNGN5CNCRTG) only after binding glucose, glucose-6-phosphate, fructose-2,6-bisphosphate, lactate or adenosine [9,28,29,30,31,32,33,34,35,36]. The reversal of ChREBP/MondoA target gene activation is mediated by heterodimers between Mlx and Mxd1, Mxd4 and Mnt, thus allowing communication with the Myc Network. Further cross-talk derives from the fact that Myc and Mlx Network members may bind one another’s target genes under certain circumstances [9,28,37].
Figure 2
Figure 2
Co-regulation of common target genes by Myc and Mlx Network members. Possible transcriptional scenarios in response to binding by Myc and/or Mlx Network members. On the left, a hypothetical gene bearing an E box that is either of high- or low-affinity for Myc (++++ and +, respectively) (small gray box). It also contains a ChoRE of similar affinities for MondoA/ ChREBP-Mlx (large gray box). The gene is expressed at a low basal level in the absence of Myc and MondoA/ChREBP as might occur in quiescent cells maintained in low glucose. (A). In a low glucose environment, Myc may be induced in response to a normal proliferative signal. Myc-Max heterodimers bind to the high-affinity E box but not to the ChoRE and activate transcription in a glucose-independent manner. (B). In quiescent cells in a high glucose environment, MondoA/ChREBP-Mlx heterodimers enter the nucleus, bind to the high-affinity ChoRE but not to the E-box and activate transcription in a glucose-dependent manner. (C). In tumor cells that express excessively high Myc levels, Myc binds to both the high affinity E box and the low-affinity ChoRE. In the latter case, Myc-Max levels may be sufficiently high so as to exclude MondoA/ChREBP-Mlx binding entirely despite their otherwise high affinities for this site and particularly if they are expressed at low levels. Gene expression is now again glucose-independent. (D). In quiescent cells in which MondoA and/or ChREBP are particularly high, they may bind to both high-affinity ChoREs and low-affinity E boxes and regulate gene expression in a manner that is now glucose-dependent and Myc-independent. (E). In response to a normal proliferative stimulus and high-glucose, the gene is induced to a high level as a result of Myc-Max and MondoA/ChREBP-Mlx heterodimers each binding their respective high-affinity sites.
Figure 3
Figure 3
The Myc and Mlx Networks cross-talk to modulate TXNIP and glycolysis. The G6P-mediated cytoplasmic → nuclear transport of MondoA-Mlx heterodimers (and probably ChREBP-Mlx heterodimers as well) facilitates their binding to tandem ChoREs in the TXNIP gene’s promoter and up-regulates its expression [30,32,85,88]. Among the functions of TXNIP is to enhance endocytosis of the Glut1 and Glut4 glucose receptors encoded by SLCA1 and SLC2A4 genes [86,89]. Myc down-regulates TXNIP in part by displacing MondoA/ChREBP-Mlx heterodimers at ChoREs [87]. Myc also directly facilitates glucose uptake via binding to E boxes in the proximal promoters of the SLC2A1 and SLC2A4 genes and further drives glycolysis by a similar induction of the H2K gene, whose encoded protein, hexokinase 2, is one of the rate-limiting enzymes of glycolysis [52,65]. Genes that are direct targets for members of the Myc and/or Mlx Networks are shown in red.
Figure 4
Figure 4
Use of the FAH model of HT to assess long-term hepatocyte proliferation. HT is caused by mutations in the FAH gene, which leads to accumulation of toxic tyrosine products, hepatocyte death and eventual liver failure [107]. Blocking the upstream enzyme HPD with Nitisinone (NTBC) prevents the formation of these catabolites and preserves hepatocyte viability and function. The disease process can also be reversed by transplanting donor Fah+/+ hepatocytes via intrasplenic administration. Over 3–4 months, during which time Nitisinone is periodically discontinued and then resumed, recipient hepatocytes succumb to their accumulated toxic tyrosine by-products and are replaced by migrant donor hepatocytes. After a 50–100-fold expansion, donor cells typically replace as much as 70–80% of the recipient’s liver and allow for Nitisinone-free survival. The model also permits the delivery of two or more populations of competing donor hepatocytes whose ability to repopulate the recipient liver can be directly compared within the same animal. Abbreviations: TAT: tyrosine aminotransferase; HPD: 4-Hydroxyphenylpyruvate dioxygenase; HGD: Homogentisate 1,2-Dioxygenase; MAI: 4-Maleylacetoacetate isomerse; FAH: Fumarylacetoacetate hydrolase.
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