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Introduction to the Myc family
The Myc family of human transcription factors was identified after discovering homology between an oncogene carried by the Avian virus, Myelocytomatosis (v-myc), and cellular Myc (c-Myc), a human gene that is often over-expressed in several cancers. Two further transcription factors, n-Myc and l-Myc, were later added to the family.
Structure of c-Myc
c-Myc is a 62 kDa protein (439 amino acids) and belongs to the basic helix-loop-helix zipper (bHLHZip) class of transcription factors. The N-terminal transactivation domain (NTD) contains the transcription activation domain (TAD) and two MYC boxes, MBI and MBII, which are highly conserved sequence elements involved in transcription regulation and protein stability1. The central portion of c-Myc contains a nuclear localization signal and two further conserved sequence elements, MBIII and MBIV. The C-terminal domain contains the bHLHZip motif, which remains partially unstructured until it dimerizes with another bHLHZip protein, MAX. It then forms an ordered alpha-helix structure, which is subject to multiple post-translational modifications and protein interactions that regulate the function of c-Myc 1.
Function and regulation of c-Myc
c-Myc has been implicated in multiple cellular processes, including proliferation, differentiation, apoptosis and metabolism2. The four-helix structure of c-Myc and MAX binds to DNA sequences, such as E-box motifs (5’-CACGTG -3’), to control transcription of specific genes. These genes have been reported to be involved in chromatin modification, DNA replication, and ribosome and mitochondrial biogenesis2.
Due to its involvement in a variety of cellular functions, it is critical for c-Myc to be tightly regulated. Transcription of c-Myc is controlled by developmental or mitogenic signals. As the mRNA of c-Myc is short-lived, with a half-life of around 30 min, levels of c-Myc protein can be quickly reduced if positive regulatory signals decrease3. c-Myc can also be phosphorylated, which directs the protein towards degradation via the ubiquitin proteasome pathway4.
c-Myc and cancer
Although c-Myc expression is often upregulated in tumors, its involvement in the apoptosis pathway can help to mitigate its oncogenic effect. Nevertheless, it is still a contributing cause of around 40% of tumors, including Burkitt's lymphoma, epithelial tumors and B-cell lymphoma. This is due to c-Myc being not only a critical regulator of cell proliferation but also a regulator of other metabolic processes, including glycolysis. Tumor cells are known to favor glycolysis, known as the Warburg effect, and c-Myc increases the levels of glucose transporters as well as glycolytic enzymes4.
As a master regulator of many of the processes associated with cancer, c-Myc is an attractive therapeutic target. Several avenues are currently being explored, including antisense oligonucleotides, histone deacetylase inhibitors and targeting closely related pathways, such as the HIF-1 pathway 4.
1. Sammak, S. et al. Crystal Structures and Nuclear Magnetic Resonance Studies of the Apo Form of the c-MYC:MAX bHLHZip Complex Reveal a Helical Basic Region in the Absence of DNA. Biochemistry 58, 3144-3154 (2019).