View source for MYC

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{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Others|MYC (disambiguation)}}
{{Infobox_gene}}

'''MYC proto-oncogene, bHLH transcription factor''' is a [[protein]] that in humans is encoded by the MYC [[gene]]<ref name="entrez">{{cite web | title = MYC MYC proto-oncogene, bHLH transcription factor [ Homo sapiens (human) ] | url = http://www.ncbi.nlm.nih.gov/gene/4609 | access-date = 2020-03-02 }}</ref> which is a member of the ''[[Myc]]'' family of [[transcription factor]]s. The protein contains [[basic helix-loop-helix]] (bHLH) [[structural motif]].

==Function==
{{for|AUG and CUG|Start codon}}
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 (gene)|MAX]]. This complex binds to the [[E box]] DNA [[consensus sequence]] and regulates the [[Transcription (biology)|transcription]] of specific target genes. [[Gene amplification|Amplification of this gene]] is frequently observed in numerous human cancers. [[Chromosomal translocation|Translocation]]s involving this gene are associated with [[Burkitt lymphoma]] and [[multiple myeloma]] in human patients. There is evidence to show that [[Translation initiation|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 [[Basic helix–loop–helix|bHLHZip domain]] heterodimerizes with other transcription factors such as [[MXD1|MAD]], [[MAX (gene)|MAX]], and [[MNT (gene)|MNT]]. Myc/Max dimers activate gene transcription, while Mad/Max and Mnt/Max dimers inhibit the activity of Myc.<ref name="Dang_1989">{{cite journal | vauthors = Dang CV, McGuire M, Buckmire M, Lee WM | title = Involvement of the 'leucine zipper' region in the oligomerization and transforming activity of human c-myc protein | journal = Nature | volume = 337 | issue = 6208 | pages = 664–6 | date = February 1989 | pmid = 2645525 | doi = 10.1038/337664a0 | bibcode = 1989Natur.337..664D | s2cid = 4326525 }}</ref> c-MYC is over expressed in the majority of human cancers and in cancers where it is overexpressed, it drives proliferation of cancer cells.<ref name="Madden_2021">{{cite journal | vauthors = Madden SK, de Araujo AD, Gerhardt M, Fairlie DP, Mason JM | title = Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc | journal = Molecular Cancer | volume = 20 | issue = 1 | pages = 3 | date = January 2021 | pmid = 33397405 | pmc = 7780693 | doi = 10.1186/s12943-020-01291-6 | doi-access = free }}</ref><ref name="Dhanasekaran_2022">{{cite journal | vauthors = Dhanasekaran R, Deutzmann A, Mahauad-Fernandez WD, Hansen AS, Gouw AM, Felsher DW | title = The MYC oncogene - the grand orchestrator of cancer growth and immune evasion | journal = Nature Reviews. Clinical Oncology | volume = 19 | issue = 1 | pages = 23–36 | date = January 2022 | pmid = 34508258 | doi = 10.1038/s41571-021-00549-2 | pmc = 9083341 }}</ref>

A recombinant form of c-Myc called Omomyc in which four residues are mutated has been produced.<ref name="Soucek_1998">{{cite journal | vauthors = Soucek L, Helmer-Citterich M, Sacco A, Jucker R, Cesareni G, Nasi S | title = Design and properties of a Myc derivative that efficiently homodimerizes | journal = Oncogene | volume = 17 | issue = 19 | pages = 2463–72 | date = November 1998 | pmid = 9824157 | doi = 10.1038/sj.onc.1202199 | s2cid = 22684888 }}</ref> 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.<ref name="Soucek_1998" />  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.<ref name="Soucek_2008">{{cite journal | vauthors = Soucek L, Whitfield J, Martins CP, Finch AJ, Murphy DJ, Sodir NM, Karnezis AN, Swigart LB, Nasi S, Evan GI | title = Modelling Myc inhibition as a cancer therapy | journal = Nature | volume = 455 | issue = 7213 | pages = 679–83 | date = October 2008 | pmid = 18716624 | pmc = 4485609 | doi = 10.1038/nature07260 | bibcode = 2008Natur.455..679S }}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}</ref>

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.<ref name="Massó-Vallés_2020">{{cite journal | vauthors = Massó-Vallés D, Soucek L | title = Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc | journal = Cells | volume = 9 | issue = 4 | date = April 2020 | page = 883 | pmid = 32260326 | pmc = 7226798 | doi = 10.3390/cells9040883 | doi-access = free }}</ref>

The recombinantly produced Omomyc miniprotein has been developed as a drug (OMO-103) and is currently in clinical trials.<ref>{{cite web | title = Results revealed from phase I clinical trial of the first drug to successfully inhibit the MYC gene, which drives many common cancers | url = https://www.eurekalert.org/news-releases/968812 | via = EurekAlert! | work = European Organisation for. Research and Treatment of Cancer | date = 25 October 2022 }}</ref>

== References ==
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== Further reading ==
{{refbegin |30em}}
*{{cite journal |vauthors=Hann SR, King MW, Bentley DL, Anderson CW, Eisenman RN |title=A non-AUG translational initiation in c-myc exon 1 generates an N-terminally distinct protein whose synthesis is disrupted in Burkitt's lymphomas |journal=Cell |volume=52 |issue=2 |pages=185–95 |date=January 1988 |pmid=3277717 |doi=10.1016/0092-8674(88)90507-7 |s2cid=3012009 }}
*{{cite journal |vauthors=Hiyama T, Haruma K, Kitadai Y, Ito M, Masuda H, Miyamoto M, Tanaka S, Yoshihara M, Sumii K, Shimamoto F, Chayama K |title=c-myc gene mutation in gastric mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma |journal=Oncol. Rep. |volume=8 |issue=2 |pages=289–92 |date=2001 |pmid=11182042 |doi=10.3892/or.8.2.289 }}
*{{cite book |vauthors=Ruf IK, Rhyne PW, Yang H, Borza CM, Hutt-Fletcher LM, Cleveland JL, Sample JT |chapter=EBV Regulates c-MYC, Apoptosis, and Tumorigenicity in Burkitt's Lymphoma |title=Epstein-Barr Virus and Human Cancer |journal=Curr. Top. Microbiol. Immunol. |series=Current Topics in Microbiology and Immunology |volume=258 |pages=153–60 |date=2001 |pmid=11443860 |doi=10.1007/978-3-642-56515-1_10 |isbn=978-3-642-62568-8 }}
*{{cite journal |vauthors=Hu HM, Arcinas M, Boxer LM |title=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 |journal=J. Biol. Chem. |volume=277 |issue=12 |pages=9819–24 |date=March 2002 |pmid=11777933 |doi=10.1074/jbc.M111426200 |doi-access=free }}
*{{cite journal |vauthors=Hilker M, Tellmann G, Buerke M, Moersig W, Oelert H, Lehr HA, Hake U |title=Expression of the proto-oncogene c-myc in human stenotic aortocoronary bypass grafts |journal=Pathol. Res. Pract. |volume=197 |issue=12 |pages=811–6 |date=2001 |pmid=11795828 |doi=10.1078/0344-0338-00164 }}
*{{cite journal |vauthors=Feng XH, Liang YY, Liang M, Zhai W, Lin X |title=Direct interaction of c-Myc with Smad2 and Smad3 to inhibit TGF-beta-mediated induction of the CDK inhibitor p15(Ink4B) |journal=Mol. Cell |volume=9 |issue=1 |pages=133–43 |date=January 2002 |pmid=11804592 |doi=10.1016/s1097-2765(01)00430-0 |doi-access=free }}
*{{cite journal |vauthors=Kuschak TI, Kuschak BC, Taylor CL, Wright JA, Wiener F, Mai S |title=c-Myc initiates illegitimate replication of the ribonucleotide reductase R2 gene |journal=Oncogene |volume=21 |issue=6 |pages=909–20 |date=January 2002 |pmid=11840336 |doi=10.1038/sj.onc.1205145 |doi-access=free }}
*{{cite journal |vauthors=Chettab K, Zibara K, Belaiba SR, McGregor JL |title=Acute hyperglycaemia induces changes in the transcription levels of 4 major genes in human endothelial cells: macroarrays-based expression analysis |journal=Thromb. Haemost. |volume=87 |issue=1 |pages=141–8 |date=January 2002 |pmid=11848444 |doi= 10.1055/s-0037-1612957|s2cid=22124540 }}
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{{Oncogenes}}
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[[Category:Oncogenes]]
[[Category:Transcription factors]]