The MYC transcription factor network: balancing metabolism, proliferation and oncogenesis

Abstract

Transcription factor networks have evolved in order to control, coordinate, and separate, the functions of distinct network modules spatially and temporally. In this review we focus on the MYC network (also known as the MAX-MLX Network), a highly conserved super-family of related basic-helix-loop-helix-zipper (bHLHZ) proteins that functions to integrate extracellular and intracellular signals and modulate global gene expression. Importantly the MYC network has been shown to be deeply involved in a broad spectrum of human and other animal cancers. Here we summarize molecular and biological properties of the network modules with emphasis on functional interactions among network members. We suggest that these network interactions serve to modulate growth and metabolism at the transcriptional level in order to balance nutrient demand with supply, to maintain growth homeostasis, and to influence cell fate. Moreover, oncogenic activation of MYC and/or loss of a MYC antagonist, results in an imbalance in the activity of the network as a whole, leading to tumor initiation, progression and maintenance.

Keywords: MAX; MLX; MYC; cancer; network; transcription.

Fig. 1

The MYC network showing the three modules from left to right—MYC; MXD/MNT/MGA; and MLXIP/MLXIPL and the dimerization interactions with MAX and/or MLX (indicated by double-headed arrows). The resulting heterodimers bind to E-box sequences in DNA.

Fig. 2

Crystal structures of the bHLHZ domains of (left) MYC-MAX heterodimer (PDB:INKP) and (right) MXD1-MAX heterodimer (PDB: INLW) bound to E-box DNA (5′-CACGTG-3′) at 19 nm and 2 nm resolution, respectively [1]. Image created with the PyMOL Molecular Graphics System, Version 1.5.0.4, Schrödinger, LLC.

Fig. 3

Organization of the MYC, MAX, MNT and MGA proteins. Heterodimers are formed by direct interaction of the basic-helix-loop-helix-zipper (bHLHZ) domain of MAX with the bHLH-Z domains of either MYC, MNTor MGA (blue lines). Number of residues in each protein indicated at C terminus. MYC: MBI–IV — conserved MYC boxes; PEST— region rich in proline, glutamic acid, serine and threonine; NLS— nuclear localization sequence; Calpain cleavage site—proteolytic cleavage to generate MYC-Nick [2]. MNT: SID — binding site for the mSIN3 co-repressor complex. MGA: repression mediated through assembly into a variant polycomb repressor complex (PRC1.6). Question mark indicates that the region of MGA that directly interacts with the complex is unknown. Protein lengths not to scale. See text for details.

Fig. 4

Organization of MLXIP (MondoA) and MLX. MLXIP: highly conserved regions proximal to the N terminus are thought to be responsible for binding to glucose metabolites. MLX interacts with MLXIP through their bHLHZ and DCD domains. MLX has 3 isoforms generated by alternative splicing: MLX-g (nuclear localized), MLX-α and MLX-β (both cytoplasmic).

Fig. 5

A hypothetical representation of two states of the MYC network and their impact on gene expression programs that influence growth, proliferation, differentiation, apoptosis and metabolism. (A) A balanced network in which gene expression is controlled through normal endogenous regulation of the MYC network. Transcriptional effects of MYC-MAX are balanced by MNT (heterodimerized with either MAX or MLX), MGA-MAX, and, under conditions of stress, by MLXIP-MLX or MLXIPL-MLX. (B) An unbalanced network due to deregulation of MYC expression. In this state MYC-MAX suppresses differentiation, reprograms metabolism, and triggers the apoptotic pathway. The suppressive effects of MGA-MAX and MNT-MAX/MLX on proliferation are overwhelmed by MYC-MAX which contributes to suppression of MYC-induced apoptosis. Increased nuclear accumulation of MLXIP-MLX (in response to deregulated MYC and/or metabolic stress) adjusts metabolic reprogramming by MYC-MAX and further reduces apoptosis. The effects on gene expression are presumed to occur through genomic binding and co-occupancy by network members. Green arrows, transcriptional activation; red arrows, transcriptional repression. Arrow width proportional to estimated transcriptional effect. Diagram adapted from [5].