Functional interactions among members of the MAX and MLX transcriptional network during oncogenesis

Abstract

The transcription factor MYC and its related family members MYCN and MYCL have been implicated in the etiology of a wide spectrum of human cancers. Compared to other oncoproteins, such as RAS or SRC, MYC is unique because its protein coding region is rarely mutated. Instead, MYC’s oncogenic properties are unleashed by regulatory mutations leading to unconstrained high levels of expression. Under both normal and pathological conditions MYC regulates multiple aspects of cellular physiology including proliferation, differentiation, apoptosis, growth and metabolism by controlling the expression of thousands of genes. How a single transcription factor exerts such broad effects remains a fascinating puzzle. Notably, MYC is part of a network of bHLHLZ proteins centered on the MYC heterodimeric partner MAX and its counterpart, the MAX-like protein MLX. This network includes MXD1-4, MNT, MGA, MONDOA and MONDOB proteins. With some exceptions, MXD proteins have been functionally linked to cell cycle arrest and differentiation, while MONDO proteins control cellular metabolism. Although the temporal expression patterns of many of these proteins can differ markedly they are frequently expressed simultaneously in the same cellular context, and potentially bind to the same, or similar DNA consensus sequence. Here we review the activities and interactions among these proteins and propose that the broad spectrum of phenotypes elicited by MYC deregulation is intimately connected to the functions and regulation of the other network members. Furthermore, we provide a meta-analysis of TCGA data suggesting that the coordinate regulation of the network is important in MYC driven tumorigenesis.

Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

“…Both MYC and MXD1 heterodimerize with MAX for DNA binding to target E-box motifs in gene promoters, and they mediate opposing effects on cells. MYC promotes cell proliferation and altered metabolism, while MXD1 promotes cell cycle arrest and differentiation (44). We found that KLF4 decreases MYC expression and decreases MYC downstream metabolic target genes in myeloid leukemia cells.…”

A novel role for the extended MYC network in cancer cell survival

“…Importantly, our recent review of the TCGA expression data indicated that multiple components of the network are simultaneously expressed in a wide range of both normal tissues and cancers, and that most tumor types show a specific expression pattern of MAX/MLX network members, arguing that each tissue has a distinct balance among members of the network. 9 In support of this hypothesis, Myc elicits alternative metabolic responses when overexpressed in murine lung or liver tissues, which predominantly express either MondoA or Chrebp. 10 Thus, evaluating the cell-or tissue-specific distribution and role of MAX/MLX network members, alone and in combination, will contribute to our understanding of both cancer cell metabolic flexibility and vulnerability.…”

Deregulated Myc Requires MondoA/Mlx for Metabolic Reprogramming and Tumorigenesis

“…A unique property of the Max/Mlx network is its capacity to sense and respond both to mitogenic signals and nutrient availability (Diolaiti et al, 2014; O’Shea and Ayer, 2013). In this study we provide evidence that the MondoA-Mlx heterodimer is required for Myc-driven transcriptional reprogramming of cellular metabolism and tumor growth.…”