N-Myc Explained

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 factors and encodes a protein with a 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.^[1] N-Myc is highly expressed in the fetal brain and is critical for normal brain development.^[2]

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.^[3] 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.^[4] 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.^[5]

Clinical significance

Amplification and overexpression of N-Myc can lead to tumorigenesis. Excess N-Myc is associated with a variety of tumors, most notably neuroblastomas where patients with amplification of the N-Myc gene tend to have poor outcomes.^{[6] [7] [8]} MYCN can also be activated in neuroblastoma and other cancers through somatic mutation.^[9] 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. ^[10]

Interactions

N-Myc has been shown to interact with MAX.^{[11] [12]}

N-Myc is also stabilized by aurora A which protects it from degradation.^[13] 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.^[14]

Being independent from MYCN/MAX interaction, MYCN is also a transcriptional co-regulator of p53 in MYCN-amplified neuroblastoma. 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.^[15]

See also

• Myc

Further reading

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

Notes and References

1. Web site: Entrez Gene: MYCN v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (avian).
2. Knoepfler PS, Cheng PF, Eisenman RN . N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. . Genes Dev. . 16 . 20 . 2699–712 . 2002 . 12381668 . 10.1101/gad.1021202 . 187459.
3. Armstrong BC, Krystal GW . Isolation and characterization of complementary DNA for N-cym, a gene encoded by the DNA strand opposite to N-myc. . Cell Growth Differ. . 3 . 6 . 385–90 . 1992 . 1419902 .
4. Web site: MYCN opposite strand/antisense RNA [Homo sapiens] ]. National Center for Biotechnology Information, U.S. National Library of Medicine . Entrez Gene Database .
5. 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 . 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 . PLOS Genetics . 10 . 1 . e1003996 . 2014 . 24391509 . 10.1371/journal.pgen.1003996 . 3879166 . free .
6. Cheng JM, Hiemstra JL, Schneider SS, Naumova A, Cheung NK, Cohn SL, Diller L, Sapienza C, Brodeur GM . Preferential amplification of the paternal allele of the N-myc gene in human neuroblastomas . Nat. Genet. . 4 . 2 . 191–4 . June 1993 . 8102299 . 10.1038/ng0693-191 . 1620573 .
7. Emanuel BS, Balaban G, Boyd JP, Grossman A, Negishi M, Parmiter A, Glick MC . N-myc amplification in multiple homogeneously staining regions in two human neuroblastomas. . Proc. Natl. Acad. Sci. U.S.A. . 82 . 11 . 3736–40 . 1985 . 2582423 . 397862 . 10.1073/pnas.82.11.3736 . 1985PNAS...82.3736E . free .
8. Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM . Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. . Science . 224 . 4653 . 1121–4 . 1984 . 6719137 . 10.1126/science.6719137 . 1984Sci...224.1121B .
9. 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 . 6 . The genetic landscape of high-risk neuroblastoma . Nature Genetics . 45 . 3 . 279–84 . March 2013 . 23334666 . 3682833 . 10.1038/ng.2529 .
10. Ciaccio R, De Rosa P, Aloisi S, Viggiano M, Cimadom L, Zadran SK, Perini G, Milazzo G . Targeting Oncogenic Transcriptional Networks in Neuroblastoma: From N-Myc to Epigenetic Drugs . International Journal of Molecular Sciences . 22 . 23 . 12883 . November 2021 . 34884690 . 8657550 . 10.3390/ijms222312883 . free.
11. Blackwood EM, Eisenman RN . Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc . Science . 251 . 4998 . 1211–7 . March 1991 . 2006410 . 10.1126/science.2006410 . 1991Sci...251.1211B .
12. FitzGerald MJ, Arsura M, Bellas RE, Yang W, Wu M, Chin L, Mann KK, DePinho RA, Sonenshein GE . Differential effects of the widely expressed dMax splice variant of Max on E-box vs initiator element-mediated regulation by c-Myc . Oncogene . 18 . 15 . 2489–98 . April 1999 . 10229200 . 10.1038/sj.onc.1202611 . free .
13. Otto T, Horn S, Brockmann M, Eilers U, Schüttrumpf L, Popov N, Kenney AM, Schulte JH, Beijersbergen R, Christiansen H, Berwanger B, Eilers M . Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma . Cancer Cell . 15 . 1 . 67–78 . January 2009 . 19111882 . 10.1016/j.ccr.2008.12.005 . free .
14. 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 . Drugging MYCN through an Allosteric Transition in Aurora Kinase A. . Cancer Cell . 27 August 2014 . 25175806 . 10.1016/j.ccr.2014.07.015 . 26 . 3 . 414–27 . 4160413.
15. Gu B, Zhu WG . Surf the post-translational modification network of p53 regulation . International Journal of Biological Sciences . 8 . 5 . 672–84 . 2012 . 22606048 . 3354625 . 10.7150/ijbs.4283 .