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.

Maxdeletion destabilizes MYC protein and abrogates Eμ-Myclymphomagenesis

“…Like MYC, MAX is a member of the basic region-helixloop-helix-zipper (bHLHZ) class of transcriptional regulators, and the association of MYC with MAX is mediated by heterodimerization between their two HLHZ domains. MYC-MAX heterodimers bind DNA through direct contact of each bHLHZ basic region with the major groove of E-box DNA sequences (CANNTG) (for reviews see (Conacci-Sorrell et al 2014) (Carroll et al 2018)). MYC does not homodimerize or bind DNA under physiological conditions and, aside from MAX, no other bHLHZ proteins have been compellingly demonstrated to dimerize with MYC.…”

MXD/MIZ1 complexes activate transcription of MYC-repressed genes

“…MYC-associated factor X (MAX) and its binding partners comprise a family of basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factors, which are implicated in the regulation of cell growth, proliferation, differentiation, apoptosis and tumorgenesis (Carroll et al, 2018;Conacci-Sorrell et al, 2014;Poole and van Riggelen, 2017).…”

“…Under physiological conditions MYC is expressed in response to mitogens and promotes cell growth and proliferation (Armelin et al, 1984;Carroll et al, 2018;Hasmall et al, 1997;Lutterbach and Hann, 1994;Wang et al, 2011). Elevated expression or activation of MYC is associated with uncontrolled cellular growth and proliferation and supports the development of cancer, and MYC or its homologues are overexpressed, amplified or deregulated in many cancer types (Dang, 2012;Kalkat et al, 2017).…”

“…The activation of genes by MYC/MAX is antagonized by the MAX-Dimerization (MXD) proteins, and MAX Network Transcriptional Repressor (MNT), henceforth collectively referred to as MXDs and MGA (Carroll et al, 2018). MXDs and MGA are bHLH transcription factors that form complexes with MAX and bind to the same E-boxes as MYC/MAX (Carroll et al, 2018;Conacci-Sorrell et al, 2014). MXDs recruit via their SID domain mSIN3-HDAC1/2 co-repressor complexes and repress transcription (Laherty et al, 1997;van Riggelen et al, 2010b).…”

MYC-associated factor MAX is an essential regulator of the clock core network

“…MYC is a transcription factor that can either activate or repress transcription depending on the interacting protein partners (Alderton, 2014; Carroll et al, 2018). As a heterodimer with the MYC-associated X-factor (MAX) protein, MYC stimulates transcription of diverse genes bearing promoter-proximal E-boxes, including important cell cycle and metabolic genes (Bretones et al, 2015; Wahlström and Henriksson, 2015) (Amati et al, 1992; Kretzner et al, 1992; Seoane et al, 2002).…”