An overview of c-Myc: structure, function and regulation

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. 

References

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).

2.    Stoelzle, T., Schwarb, P., Trumpp, A. & Hynes, N. c-Myc affects mRNA translation, cell proliferation and progenitor cell function in the mammary gland. BMC Biology 7, 63 (2009).

3.    Kato, G. & Dang, C. Function of the c‐Myc oncoprotein. The FASEB Journal 6, 3065-3072 (1992).

4.    Miller, D., Thomas, S., Islam, A., Muench, D. & Sedoris, K. c-Myc and Cancer Metabolism. Clinical Cancer Research 18, 5546-5553 (2012).