View source for N-Myc

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Use dmy dates|date=September 2020}}
{{Infobox_gene}}
'''N-myc proto-oncogene protein''' also known as '''N-Myc''' or '''basic helix-loop-helix protein 37''' (bHLHe37), is a [[protein]] that in humans is encoded by the ''MYCN'' [[gene]].

== Function ==

The ''MYCN'' gene is a member of the MYC family of [[transcription factor]]s and encodes a protein with a basic helix-loop-helix ([[basic-helix-loop-helix|bHLH]]) domain. This protein is located in the cell nucleus and must dimerize with another bHLH protein in order to bind DNA.<ref>{{cite web | title = Entrez Gene: MYCN v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (avian)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4613 }}</ref> N-Myc is highly expressed in the fetal brain and is critical for normal brain development.<ref>{{cite journal | vauthors = Knoepfler PS, Cheng PF, Eisenman RN | title = N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. | journal = Genes Dev. | volume = 16 | issue = 20 | pages = 2699–712 | year = 2002 | pmid = 12381668 | doi = 10.1101/gad.1021202 | pmc=187459}}</ref>

The ''MYCN'' gene has an antisense RNA, N-cym or ''MYCNOS'', transcribed from the opposite strand which can be translated to form a protein product.<ref>{{cite journal | vauthors = Armstrong BC, Krystal GW | title = Isolation and characterization of complementary DNA for N-cym, a gene encoded by the DNA strand opposite to N-myc. | journal = Cell Growth Differ. | volume = 3 | issue = 6 | pages = 385–90 | year = 1992 | pmid = 1419902 }}</ref> N-Myc and ''MYCNOS'' are co-regulated both in normal development and in tumor cells, so it is possible that the two transcripts are functionally related.<ref name="url_NCBI">{{cite web | url = https://www.ncbi.nlm.nih.gov/gene/10408 | title = MYCN opposite strand/antisense RNA [Homo sapiens] | publisher = National Center for Biotechnology Information, U.S. National Library of Medicine | work = Entrez Gene Database }}</ref> It has been shown that the antisense RNA encodes for a protein, named NCYM, that has originated ''de novo'' and is specific to human and chimpanzee. This NCYM protein inhibits GSK3b and thus prevents MYCN degradation. Transgenic mice that harbor human MYCN/NCYM pair often show neuroblastomas with distant metastasis, which are atypical for normal mice. Thus NCYM represents a rare example of a de novo gene that has acquired molecular function and plays a major role in [[oncogenesis]].<ref>{{cite journal | vauthors = Suenaga Y, Islam SM, Alagu J, Kaneko Y, Kato M, Tanaka Y, Kawana H, Hossain S, Matsumoto D, Yamamoto M, Shoji W, Itami M, Shibata T, Nakamura Y, Ohira M, Haraguchi S, Takatori A, Nakagawara A | title = NCYM, a Cis-Antisense Gene of MYCN, Encodes a De Novo Evolved Protein That Inhibits GSK3β Resulting in the Stabilization of MYCN in Human Neuroblastomas | journal = PLOS Genetics | volume = 10 | issue = 1 | page = e1003996 | year = 2014 | pmid = 24391509 | doi = 10.1371/journal.pgen.1003996 | pmc=3879166 | doi-access = free }}</ref>

== Clinical significance ==
Amplification and overexpression of N-Myc can lead to tumorigenesis. Excess N-Myc is associated with a variety of tumors, most notably [[neuroblastoma]]s where patients with amplification of the N-Myc gene tend to have poor outcomes.<ref name="pmid8102299">{{cite journal | vauthors = Cheng JM, Hiemstra JL, Schneider SS, Naumova A, Cheung NK, Cohn SL, Diller L, Sapienza C, Brodeur GM | title = Preferential amplification of the paternal allele of the N-myc gene in human neuroblastomas | journal = Nat. Genet. | volume = 4 | issue = 2 | pages = 191–4 | date = June 1993 | pmid = 8102299 | doi = 10.1038/ng0693-191 | s2cid = 1620573 }}</ref><ref>{{cite journal | vauthors = Emanuel BS, Balaban G, Boyd JP, Grossman A, Negishi M, Parmiter A, Glick MC | title = N-myc amplification in multiple homogeneously staining regions in two human neuroblastomas. | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 82 | issue = 11 | pages = 3736–40 | year = 1985 | pmid = 2582423 | pmc = 397862 | doi = 10.1073/pnas.82.11.3736 | bibcode = 1985PNAS...82.3736E | doi-access = free }}</ref><ref>{{cite journal | vauthors = Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM | title = Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. | journal = Science | volume = 224 | issue = 4653 | pages = 1121–4 | year = 1984 | pmid = 6719137 | doi = 10.1126/science.6719137 | bibcode = 1984Sci...224.1121B }}</ref> MYCN can also be activated in neuroblastoma and other cancers through somatic mutation.<ref>{{cite journal | vauthors = Pugh TJ, Morozova O, Attiyeh EF, Asgharzadeh S, Wei JS, Auclair D, Carter SL, Cibulskis K, Hanna M, Kiezun A, Kim J, Lawrence MS, Lichenstein L, McKenna A, Pedamallu CS, Ramos AH, Shefler E, Sivachenko A, Sougnez C, Stewart C, Ally A, Birol I, Chiu R, Corbett RD, Hirst M, Jackman SD, Kamoh B, Khodabakshi AH, Krzywinski M, Lo A, Moore RA, Mungall KL, Qian J, Tam A, Thiessen N, Zhao Y, Cole KA, Diamond M, Diskin SJ, Mosse YP, Wood AC, Ji L, Sposto R, Badgett T, London WB, Moyer Y, Gastier-Foster JM, Smith MA, Guidry Auvil JM, Gerhard DS, Hogarty MD, Jones SJ, Lander ES, Gabriel SB, Getz G, Seeger RC, Khan J, Marra MA, Meyerson M, Maris JM | display-authors = 6 | title = The genetic landscape of high-risk neuroblastoma | journal = Nature Genetics | volume = 45 | issue = 3 | pages = 279–84 | date = March 2013 | pmid = 23334666 | pmc = 3682833 | doi = 10.1038/ng.2529 | url = https://dash.harvard.edu/bitstream/handle/1/11877095/3682833.pdf?sequence=1 }}</ref> Intriguingly, recent genome-wide H3K27ac profiling in patient-derived NB samples revealed four distinct SE-driven epigenetic subtypes, characterized by their own and specific master regulatory networks. Three of them are named after the known clinical groups: MYCN-amplified, MYCN non-amplified high-risk, and MYCN non-amplified low-risk NBs, while the fourth displays cellular features which resemble multipotent Schwann cell precursors. Interestingly, the cyclin gene CCND1 was regulated through distinct and shared SEs in the different subtypes, and, more importantly, some tumors showed signals belonging to multiple epigenetic signatures, suggesting that the epigenetic landscape is likely to contribute to intratumoral heterogeneity. <ref> {{cite journal | vauthors = Ciaccio R, De Rosa P, Aloisi S, Viggiano M, Cimadom L, Zadran SK, Perini G, Milazzo G | display-authors = | title = Targeting Oncogenic Transcriptional Networks in Neuroblastoma: From N-Myc to Epigenetic Drugs | journal = International Journal of Molecular Sciences | volume = 22 | issue = 23 | pages = 12883 | date = November 2021 | pmid = 34884690 | pmc = 8657550 | doi = 10.3390/ijms222312883 | doi-access = free}}</ref>

== Interactions ==
N-Myc has been shown to [[Protein-protein interaction|interact]] with [[MAX (gene)|MAX]].<ref name="pmid2006410">{{cite journal | vauthors = Blackwood EM, Eisenman RN | title = Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc | journal = Science | volume = 251 | issue = 4998 | pages = 1211–7 | date = March 1991 | pmid = 2006410 | doi = 10.1126/science.2006410 | bibcode = 1991Sci...251.1211B }}</ref><ref name="pmid10229200">{{cite journal | vauthors = FitzGerald MJ, Arsura M, Bellas RE, Yang W, Wu M, Chin L, Mann KK, DePinho RA, Sonenshein GE | title = Differential effects of the widely expressed dMax splice variant of Max on E-box vs initiator element-mediated regulation by c-Myc | journal = Oncogene | volume = 18 | issue = 15 | pages = 2489–98 | date = April 1999 | pmid = 10229200 | doi = 10.1038/sj.onc.1202611 | doi-access = free }}</ref>

N-Myc is also stabilized by [[aurora A]] which protects it from degradation.<ref name="pmid19111882">{{cite journal | vauthors = Otto T, Horn S, Brockmann M, Eilers U, Schüttrumpf L, Popov N, Kenney AM, Schulte JH, Beijersbergen R, Christiansen H, Berwanger B, Eilers M | title = Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma | journal = Cancer Cell | volume = 15 | issue = 1 | pages = 67–78 | date = January 2009 | pmid = 19111882 | doi = 10.1016/j.ccr.2008.12.005 | doi-access = free }}</ref> Drugs that target this interaction are under development, and are designed to change the conformation of [[aurora A]]. Conformational change in [[Aurora A]] leads to release of N-Myc, which is then degraded in a [[ubiquitin]]-dependent manner.<ref>{{cite journal | vauthors = Gustafson WC, Meyerowitz JG, Nekritz EA, Chen J, Benes C, Charron E, Simonds EF, Seeger R, Matthay KK, Hertz NT, Eilers M, Shokat KM, Weiss WA | title = Drugging MYCN through an Allosteric Transition in Aurora Kinase A. | journal = Cancer Cell | date = 27 August 2014 | pmid = 25175806 | doi=10.1016/j.ccr.2014.07.015 | volume=26 | issue = 3 | pages=414–27 | pmc=4160413}}</ref>

Being independent from MYCN/MAX interaction, MYCN is also a transcriptional co-regulator of p53 in MYCN-amplified neuroblastoma.{{cn|date=November 2020}} MYCN alters transcription of p53 target genes which regulate apoptosis responses and DNA damage repair in cell cycle. This MYCN-p53 interaction is through exclusive binding of MYCN to C-terminal domains of tetrameric p53. As a post-translational modification, MYCN binding to C-terminal domains of tetrameric p53 impacts p53 promoter selectivity and interferes other cofactors binding to this region.<ref>{{cite journal | vauthors = Gu B, Zhu WG | title = Surf the post-translational modification network of p53 regulation | journal = International Journal of Biological Sciences | volume = 8 | issue = 5 | pages = 672–84 | date = 2012 | pmid = 22606048 | pmc = 3354625 | doi = 10.7150/ijbs.4283 }}</ref>

== See also ==
*[[Myc]]
{{Clear}}

== References ==
{{reflist}}

== Further reading ==
{{refbegin|32em}}
*{{cite journal | author = Lüscher B | title = Function and regulation of the transcription factors of the Myc/Max/Mad network. | journal = Gene | volume = 277 | issue = 1–2 | pages = 1–14 | year = 2001 | pmid = 11602341 | doi = 10.1016/S0378-1119(01)00697-7 }}
*{{cite journal | vauthors = Hagiwara T, Nakaya K, Nakamura Y, Nakajima H, Nishimura S, Taya Y | title = Specific phosphorylation of the acidic central region of the N-myc protein by casein kinase II. | journal = Eur. J. Biochem. | volume = 209 | issue = 3 | pages = 945–50 | year = 1992 | pmid = 1425701 | doi = 10.1111/j.1432-1033.1992.tb17367.x | doi-access = free }}
*{{cite journal | vauthors = Fougerousse F, Meloni R, Roudaut C, Beckmann JS | title = Dinucleotide repeat polymorphism at the human hemoglobin alpha-1 pseudo-gene (HBAP1). | journal = Nucleic Acids Res. | volume = 20 | issue = 5 | pages = 1165 | year = 1992 | pmid = 1549498 | pmc = 312136 | doi = 10.1093/nar/20.5.1165 }}
*{{cite journal | vauthors = Krystal GW, Armstrong BC, Battey JF | title = N-myc mRNA forms an RNA-RNA duplex with endogenous antisense transcripts. | journal = Mol. Cell. Biol. | volume = 10 | issue = 8 | pages = 4180–91 | year = 1990 | pmid = 1695323 | pmc = 360949 | doi =  10.1128/mcb.10.8.4180}}
*{{cite journal | vauthors = Blackwood EM, Eisenman RN | title = Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. | journal = Science | volume = 251 | issue = 4998 | pages = 1211–7 | year = 1991 | pmid = 2006410 | doi = 10.1126/science.2006410 | bibcode = 1991Sci...251.1211B }}
*{{cite journal | vauthors = Emanuel BS, Balaban G, Boyd JP, Grossman A, Negishi M, Parmiter A, Glick MC | title = N-myc amplification in multiple homogeneously staining regions in two human neuroblastomas. | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 82 | issue = 11 | pages = 3736–40 | year = 1985 | pmid = 2582423 | pmc = 397862 | doi = 10.1073/pnas.82.11.3736 | bibcode = 1985PNAS...82.3736E | doi-access = free }}
*{{cite journal | vauthors = Ibson JM, Rabbitts PH | title = Sequence of a germ-line N-myc gene and amplification as a mechanism of activation. | journal = Oncogene | volume = 2 | issue = 4 | pages = 399–402 | year = 1988 | pmid = 2834684 }}
*{{cite journal | vauthors = Stanton LW, Schwab M, Bishop JM | title = Nucleotide sequence of the human N-myc gene. | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 83 | issue = 6 | pages = 1772–6 | year = 1986 | pmid = 2869488 | pmc = 323166 | doi = 10.1073/pnas.83.6.1772 | bibcode = 1986PNAS...83.1772S | doi-access = free }}
*{{cite journal | vauthors = Michitsch RW, Melera PW | title = Nucleotide sequence of the 3' exon of the human N-myc gene. | journal = Nucleic Acids Res. | volume = 13 | issue = 7 | pages = 2545–58 | year = 1985 | pmid = 2987858 | pmc = 341174 | doi = 10.1093/nar/13.7.2545 }}
*{{cite journal | vauthors = Slamon DJ, Boone TC, Seeger RC, Keith DE, Chazin V, Lee HC, Souza LM | title = Identification and characterization of the protein encoded by the human N-myc oncogene. | journal = Science | volume = 232 | issue = 4751 | pages = 768–72 | year = 1986 | pmid = 3008339 | doi = 10.1126/science.3008339 | bibcode = 1986Sci...232..768S }}
*{{cite journal | vauthors = Garson JA, van den Berghe JA, Kemshead JT | title = Novel non-isotopic in situ hybridization technique detects small (1 Kb) unique sequences in routinely G-banded human chromosomes: fine mapping of N-myc and beta-NGF genes. | journal = Nucleic Acids Res. | volume = 15 | issue = 12 | pages = 4761–70 | year = 1987 | pmid = 3299258 | pmc = 305916 | doi = 10.1093/nar/15.12.4761 }}
*{{cite journal | vauthors = Stanton LW, Bishop JM | title = Alternative processing of RNA transcribed from NMYC. | journal = Mol. Cell. Biol. | volume = 7 | issue = 12 | pages = 4266–72 | year = 1988 | pmid = 3437890 | pmc = 368108 | doi =  10.1128/mcb.7.12.4266}}
*{{cite journal | vauthors = Kohl NE, Legouy E, DePinho RA, Nisen PD, Smith RK, Gee CE, Alt FW | title = Human N-myc is closely related in organization and nucleotide sequence to c-myc. | journal = [[Nature (journal)|Nature]] | volume = 319 | issue = 6048 | pages = 73–7 | year = 1986 | pmid = 3510398 | doi = 10.1038/319073a0 | bibcode = 1986Natur.319...73K | s2cid = 4344361 }}
*{{cite journal | vauthors = Grady EF, Schwab M, Rosenau W | title = Expression of N-myc and c-src during the development of fetal human brain. | journal = Cancer Res. | volume = 47 | issue = 11 | pages = 2931–6 | year = 1987 | pmid = 3552210 }}
*{{cite journal | vauthors = Ramsay G, Stanton L, Schwab M, Bishop JM | title = Human proto-oncogene N-myc encodes nuclear proteins that bind DNA. | journal = Mol. Cell. Biol. | volume = 6 | issue = 12 | pages = 4450–7 | year = 1987 | pmid = 3796607 | pmc = 367228 | doi =  10.1128/mcb.6.12.4450}}
*{{cite journal | vauthors = Brodeur GM, Seeger RC | title = Gene amplification in human neuroblastomas: basic mechanisms and clinical implications. | journal = Cancer Genet. Cytogenet. | volume = 19 | issue = 1–2 | pages = 101–11 | year = 1986 | pmid = 3940169 | doi = 10.1016/0165-4608(86)90377-8 }}
*{{cite journal | vauthors = Kanda N, Schreck R, Alt F, Bruns G, Baltimore D, Latt S | title = Isolation of amplified DNA sequences from IMR-32 human neuroblastoma cells: facilitation by fluorescence-activated flow sorting of metaphase chromosomes. | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 80 | issue = 13 | pages = 4069–73 | year = 1983 | pmid = 6575396 | pmc = 394202 | doi = 10.1073/pnas.80.13.4069 | bibcode = 1983PNAS...80.4069K | doi-access = free }}
*{{cite journal | vauthors = Schwab M, Varmus HE, Bishop JM, Grzeschik KH, Naylor SL, Sakaguchi AY, Brodeur G, Trent J | title = Chromosome localization in normal human cells and neuroblastomas of a gene related to c-myc. | journal = Nature | volume = 308 | issue = 5956 | pages = 288–91 | year = 1984 | pmid = 6700732 | doi = 10.1038/308288a0 | bibcode = 1984Natur.308..288S | s2cid = 4333762 }}
{{refend}}

== External links ==
* {{MeshName|MYCN+protein,+human}}

{{NLM content}}
{{Transcription factors|g1}}

[[Category:Transcription factors]]
[[Category:Human proteins]]