MYC explained

MYC proto-oncogene, bHLH transcription factor is a protein that in humans is encoded by the MYC gene^[1] which is a member of the Myc family of transcription factors. The protein contains basic helix-loop-helix (bHLH) structural motif.

Function

This gene is a proto-oncogene and encodes a nuclear phosphoprotein that plays a role in cell cycle progression, apoptosis and cellular transformation. The encoded protein forms a heterodimer with the related transcription factor MAX. This complex binds to the E box DNA consensus sequence and regulates the transcription of specific target genes. Amplification of this gene is frequently observed in numerous human cancers. Translocations involving this gene are associated with Burkitt lymphoma and multiple myeloma in human patients. There is evidence to show that translation initiates both from an upstream, in-frame non-AUG (CUG) and a downstream AUG start site, resulting in the production of two isoforms with distinct N-termini. [provided by RefSeq, Aug 2017].

As a drug target

Under normal circumstances, c-Myc through its bHLHZip domain heterodimerizes with other transcription factors such as MAD, MAX, and MNT. Myc/Max dimers activate gene transcription, while Mad/Max and Mnt/Max dimers inhibit the activity of Myc.^[2] c-MYC is over expressed in the majority of human cancers and in cancers where it is overexpressed, it drives proliferation of cancer cells.^{[3] [4]}

A recombinant form of c-Myc called Omomyc in which four residues are mutated has been produced.^[5] Omomyc heterodimers with c-Myc and inhibits c-Myc transcriptional activity. When the mouse cancer cell line NIH3T3 is treated with Omomyc, it inhibits proliferation. In a mouse model of cancer in which cancer cells were genetically engineered to conditionally express Omomyc, Omomyc triggered tumor regression which was accompanied by reduced proliferation and increased apoptosis of the tumor tissue.^[6]

The Omomyc displays high affinity for MAX (Myc-associated protein X) and for enhancer box element CACGTG DNA sequences, that result in the uncoupling of cellular proliferation from normal growth factor regulation and contribute to many of the phenotypic hallmarks of cancer.^[7]

The recombinantly produced Omomyc miniprotein has been developed as a drug (OMO-103) and is currently in clinical trials.^[8]

Further reading

• Hann SR, King MW, Bentley DL, Anderson CW, Eisenman RN . A non-AUG translational initiation in c-myc exon 1 generates an N-terminally distinct protein whose synthesis is disrupted in Burkitt's lymphomas . Cell . 52 . 2 . 185–95 . January 1988 . 3277717 . 10.1016/0092-8674(88)90507-7 . 3012009 .
• Hiyama T, Haruma K, Kitadai Y, Ito M, Masuda H, Miyamoto M, Tanaka S, Yoshihara M, Sumii K, Shimamoto F, Chayama K . c-myc gene mutation in gastric mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma . Oncol. Rep. . 8 . 2 . 289–92 . 2001 . 11182042 . 10.3892/or.8.2.289 .
• Book: Ruf IK, Rhyne PW, Yang H, Borza CM, Hutt-Fletcher LM, Cleveland JL, Sample JT . EBV Regulates c-MYC, Apoptosis, and Tumorigenicity in Burkitt's Lymphoma . Epstein-Barr Virus and Human Cancer . Curr. Top. Microbiol. Immunol. . Current Topics in Microbiology and Immunology . 258 . 153–60 . 2001 . 11443860 . 10.1007/978-3-642-56515-1_10 . 978-3-642-62568-8 .
• Hu HM, Arcinas M, Boxer LM . A Myc-associated zinc finger protein-related factor binding site is required for the deregulation of c-myc expression by the immunoglobulin heavy chain gene enhancers in Burkitt's lymphoma . J. Biol. Chem. . 277 . 12 . 9819–24 . March 2002 . 11777933 . 10.1074/jbc.M111426200 . free .
• Hilker M, Tellmann G, Buerke M, Moersig W, Oelert H, Lehr HA, Hake U . Expression of the proto-oncogene c-myc in human stenotic aortocoronary bypass grafts . Pathol. Res. Pract. . 197 . 12 . 811–6 . 2001 . 11795828 . 10.1078/0344-0338-00164 .
• Feng XH, Liang YY, Liang M, Zhai W, Lin X . Direct interaction of c-Myc with Smad2 and Smad3 to inhibit TGF-beta-mediated induction of the CDK inhibitor p15(Ink4B) . Mol. Cell . 9 . 1 . 133–43 . January 2002 . 11804592 . 10.1016/s1097-2765(01)00430-0 . free .
• Kuschak TI, Kuschak BC, Taylor CL, Wright JA, Wiener F, Mai S . c-Myc initiates illegitimate replication of the ribonucleotide reductase R2 gene . Oncogene . 21 . 6 . 909–20 . January 2002 . 11840336 . 10.1038/sj.onc.1205145 . free .
• Chettab K, Zibara K, Belaiba SR, McGregor JL . Acute hyperglycaemia induces changes in the transcription levels of 4 major genes in human endothelial cells: macroarrays-based expression analysis . Thromb. Haemost. . 87 . 1 . 141–8 . January 2002 . 11848444 . 10.1055/s-0037-1612957. 22124540 .

Notes and References

1. Web site: MYC MYC proto-oncogene, bHLH transcription factor [Homo sapiens (human) ] ]. 2020-03-02 .
2. Dang CV, McGuire M, Buckmire M, Lee WM . Involvement of the 'leucine zipper' region in the oligomerization and transforming activity of human c-myc protein . Nature . 337 . 6208 . 664–6 . February 1989 . 2645525 . 10.1038/337664a0 . 1989Natur.337..664D . 4326525 .
3. Madden SK, de Araujo AD, Gerhardt M, Fairlie DP, Mason JM . Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc . Molecular Cancer . 20 . 1 . 3 . January 2021 . 33397405 . 7780693 . 10.1186/s12943-020-01291-6 . free .
4. Dhanasekaran R, Deutzmann A, Mahauad-Fernandez WD, Hansen AS, Gouw AM, Felsher DW . The MYC oncogene - the grand orchestrator of cancer growth and immune evasion . Nature Reviews. Clinical Oncology . 19 . 1 . 23–36 . January 2022 . 34508258 . 10.1038/s41571-021-00549-2 . 9083341 .
5. Soucek L, Helmer-Citterich M, Sacco A, Jucker R, Cesareni G, Nasi S . Design and properties of a Myc derivative that efficiently homodimerizes . Oncogene . 17 . 19 . 2463–72 . November 1998 . 9824157 . 10.1038/sj.onc.1202199 . 22684888 .
6. Soucek L, Whitfield J, Martins CP, Finch AJ, Murphy DJ, Sodir NM, Karnezis AN, Swigart LB, Nasi S, Evan GI . Modelling Myc inhibition as a cancer therapy . Nature . 455 . 7213 . 679–83 . October 2008 . 18716624 . 4485609 . 10.1038/nature07260 . 2008Natur.455..679S .
7. Massó-Vallés D, Soucek L . Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc . Cells . 9 . 4 . April 2020 . 883 . 32260326 . 7226798 . 10.3390/cells9040883 . free .
8. Web site: Results revealed from phase I clinical trial of the first drug to successfully inhibit the MYC gene, which drives many common cancers . EurekAlert! . European Organisation for. Research and Treatment of Cancer . 25 October 2022 .