MYC and RAF: Key Effectors in Cellular Signaling and Major Drivers in Human Cancer

Abstract

The prototypes of the human MYC and RAF gene families are orthologs of animal proto-oncogenes that were originally identified as transduced alleles in the genomes of highly oncogenic retroviruses. MYC and RAF genes are now established as key regulatory elements in normal cellular physiology, but also as major cancer driver genes. Although the predominantly nuclear MYC proteins and the cytoplasmic RAF proteins have different biochemical functions, they are functionally linked in pivotal signaling cascades and circuits. The MYC protein is a transcription factor and together with its dimerization partner MAX holds a central position in a regulatory network of bHLH-LZ proteins. MYC regulates transcription conducted by all RNA polymerases and controls virtually the entire transcriptome. Fundamental cellular processes including distinct catabolic and anabolic branches of metabolism, cell cycle regulation, cell growth and proliferation, differentiation, stem cell regulation, and apoptosis are under MYC control. Deregulation of MYC expression by rearrangement or amplification of the MYC locus or by defects in kinase-mediated upstream signaling, accompanied by loss of apoptotic checkpoints, leads to tumorigenesis and is a hallmark of most human cancers. The critically controlled serine/threonine RAF kinases are central nodes of the cytoplasmic MAPK signaling cascade transducing converted extracellular signals to the nucleus for reshaping transcription factor controlled gene expression profiles. Specific mutations of RAF kinases, such as the prevalent BRAF(V600E) mutation in melanoma, or defects in upstream signaling or feedback loops cause decoupled kinase activities which lead to tumorigenesis. Different strategies for pharmacological interference with MYC- or RAF-induced tumorigenesis are being developed and several RAF kinase inhibitors are already in clinical use.

The brain acid‐soluble protein 1 (BASP1) interferes with the oncogenic capacity of MYC and its binding to calmodulin

“…A) (Raffeiner et al , ). In the absence of BASP1, the v‐Myc protein is quite stable presumably due to mutation of a critical threonine residue (corresponding to T58 in human MYC) in the amino‐terminal MYC box I (Stefan and Bister, ), rendering v‐Myc resistant toward GSK3β‐mediated phosphorylation and subsequent ubiquitin–proteasome‐mediated degradation as it occurs for c‐MYC (Farrell and Sears, ; Gregory and Hann, ; Stefan and Bister, ). This may explain the prolonged v‐Myc stability after CHX treatment in the absence of BASP1 (cf.…”

Differential regulation of myc homologs by Wnt/β‐Catenin signaling in the early metazoan Hydra

“…The recent identification of c-Myc to act as a possible general amplifier of gene expression controlling multiple transcriptional programs [8,[40][41][42][43] even enhances the complexity of Myc biology. Furthermore, several upstream signaling pathways like the mitogenic Ras/Raf cascade, or the Wnt/b-Catenin/ Tcf4 axis regulate c-Myc expression and activity in cell proliferation, but they are also relevant in malignant cell growth leading to aberrant c-myc activation [2,4,5,12].…”

“…The c-myc gene has been originally identified in the form of the transforming determinant of avian acute leukemia virus MC29 [1,2]. The highly oncogenic v-myc allele is derived from the cellular chicken c-myc protooncogene by retroviral transduction [1][2][3][4][5].…”

“…The c-myc gene has been originally identified in the form of the transforming determinant of avian acute leukemia virus MC29 [1,2]. The highly oncogenic v-myc allele is derived from the cellular chicken c-myc protooncogene by retroviral transduction [1][2][3][4][5]. The cellular c-myc proto-oncogene encodes the c-Myc protein, a transcription factor with oncogenic potential representing the central hub of a network controlling global gene expression and regulating fundamental cellular processes like growth, proliferation, differentiation, metabolism, and apoptosis [2,3,[5][6][7][8].…”

“…The highly oncogenic v-myc allele is derived from the cellular chicken c-myc protooncogene by retroviral transduction [1][2][3][4][5]. The cellular c-myc proto-oncogene encodes the c-Myc protein, a transcription factor with oncogenic potential representing the central hub of a network controlling global gene expression and regulating fundamental cellular processes like growth, proliferation, differentiation, metabolism, and apoptosis [2,3,[5][6][7][8]. c-Myc is a bHLHZip protein encompassing protein dimerization domains (helix-loop-helix, leucine zipper) and a DNA contact surface (basic region) that forms heterodimers with the Max (MAX) protein and binds typically to specific DNA sequence elements termed E-boxes (5 0 -CACGTG-3 0 ) [4,5].…”