N-Myc
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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]
Interactions
N-Myc has been shown to interact with MAX.[10][11]
N-Myc is also stabilized by aurora A which protects it from degradation.[12] 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.[13]
See also
References
- ↑ "Entrez Gene: MYCN v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (avian)".
- ↑ Knoepfler PS, Cheng PF, Eisenman RN (2002). "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. doi:10.1101/gad.1021202. PMC 187459. PMID 12381668.
- ↑ Armstrong BC, Krystal GW (1992). "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. PMID 1419902.
- ↑ "MYCN opposite strand/antisense RNA [Homo sapiens]". Entrez Gene Database. National Center for Biotechnology Information, U.S. National Library of Medicine.
- ↑ 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 (2014). "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. doi:10.1371/journal.pgen.1003996. PMC 3879166. PMID 24391509.
- ↑ Cheng JM, Hiemstra JL, Schneider SS, Naumova A, Cheung NK, Cohn SL, Diller L, Sapienza C, Brodeur GM (June 1993). "Preferential amplification of the paternal allele of the N-myc gene in human neuroblastomas". Nat. Genet. 4 (2): 191–4. doi:10.1038/ng0693-191. PMID 8102299.
- ↑ Emanuel BS, Balaban G, Boyd JP, Grossman A, Negishi M, Parmiter A, Glick MC (1985). "N-myc amplification in multiple homogeneously staining regions in two human neuroblastomas". Proc. Natl. Acad. Sci. U.S.A. 82 (11): 3736–40. doi:10.1073/pnas.82.11.3736. PMC 397862. PMID 2582423.
- ↑ Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM (1984). "Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage". Science. 224 (4653): 1121–4. doi:10.1126/science.6719137. PMID 6719137.
- ↑ Pugh TJ, Morozova O, Attiyeh EF, Asgharzadeh S, Wei JS, Auclair D, et al. (March 2013). "The genetic landscape of high-risk neuroblastoma" (PDF). Nature Genetics. 45 (3): 279–84. doi:10.1038/ng.2529. PMC 3682833. PMID 23334666.
- ↑ Blackwood EM, Eisenman RN (March 1991). "Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc". Science. 251 (4998): 1211–7. doi:10.1126/science.2006410. PMID 2006410.
- ↑ FitzGerald MJ, Arsura M, Bellas RE, Yang W, Wu M, Chin L, Mann KK, DePinho RA, Sonenshein GE (April 1999). "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. doi:10.1038/sj.onc.1202611. PMID 10229200.
- ↑ Otto T, Horn S, Brockmann M, Eilers U, Schüttrumpf L, Popov N, Kenney AM, Schulte JH, Beijersbergen R, Christiansen H, Berwanger B, Eilers M (January 2009). "Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma". Cancer Cell. 15 (1): 67–78. doi:10.1016/j.ccr.2008.12.005. PMID 19111882.
- ↑ 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 (Aug 27, 2014). "Drugging MYCN through an Allosteric Transition in Aurora Kinase A." Cancer Cell. 26: 414–27. doi:10.1016/j.ccr.2014.07.015. PMC 4160413. PMID 25175806.
Further reading
- Lüscher B (2001). "Function and regulation of the transcription factors of the Myc/Max/Mad network". Gene. 277 (1–2): 1–14. doi:10.1016/S0378-1119(01)00697-7. PMID 11602341.
- Hagiwara T, Nakaya K, Nakamura Y, Nakajima H, Nishimura S, Taya Y (1992). "Specific phosphorylation of the acidic central region of the N-myc protein by casein kinase II". Eur. J. Biochem. 209 (3): 945–50. doi:10.1111/j.1432-1033.1992.tb17367.x. PMID 1425701.
- Fougerousse F, Meloni R, Roudaut C, Beckmann JS (1992). "Dinucleotide repeat polymorphism at the human hemoglobin alpha-1 pseudo-gene (HBAP1)". Nucleic Acids Res. 20 (5): 1165. doi:10.1093/nar/20.5.1165. PMC 312136. PMID 1549498.
- Krystal GW, Armstrong BC, Battey JF (1990). "N-myc mRNA forms an RNA-RNA duplex with endogenous antisense transcripts". Mol. Cell. Biol. 10 (8): 4180–91. PMC 360949. PMID 1695323.
- Blackwood EM, Eisenman RN (1991). "Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc". Science. 251 (4998): 1211–7. doi:10.1126/science.2006410. PMID 2006410.
- Emanuel BS, Balaban G, Boyd JP, Grossman A, Negishi M, Parmiter A, Glick MC (1985). "N-myc amplification in multiple homogeneously staining regions in two human neuroblastomas". Proc. Natl. Acad. Sci. U.S.A. 82 (11): 3736–40. doi:10.1073/pnas.82.11.3736. PMC 397862. PMID 2582423.
- Ibson JM, Rabbitts PH (1988). "Sequence of a germ-line N-myc gene and amplification as a mechanism of activation". Oncogene. 2 (4): 399–402. PMID 2834684.
- Stanton LW, Schwab M, Bishop JM (1986). "Nucleotide sequence of the human N-myc gene". Proc. Natl. Acad. Sci. U.S.A. 83 (6): 1772–6. doi:10.1073/pnas.83.6.1772. PMC 323166. PMID 2869488.
- Michitsch RW, Melera PW (1985). "Nucleotide sequence of the 3' exon of the human N-myc gene". Nucleic Acids Res. 13 (7): 2545–58. doi:10.1093/nar/13.7.2545. PMC 341174. PMID 2987858.
- Slamon DJ, Boone TC, Seeger RC, Keith DE, Chazin V, Lee HC, Souza LM (1986). "Identification and characterization of the protein encoded by the human N-myc oncogene". Science. 232 (4751): 768–72. doi:10.1126/science.3008339. PMID 3008339.
- Garson JA, van den Berghe JA, Kemshead JT (1987). "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. doi:10.1093/nar/15.12.4761. PMC 305916. PMID 3299258.
- Stanton LW, Bishop JM (1988). "Alternative processing of RNA transcribed from NMYC". Mol. Cell. Biol. 7 (12): 4266–72. PMC 368108. PMID 3437890.
- Kohl NE, Legouy E, DePinho RA, Nisen PD, Smith RK, Gee CE, Alt FW (1986). "Human N-myc is closely related in organization and nucleotide sequence to c-myc". Nature. 319 (6048): 73–7. doi:10.1038/319073a0. PMID 3510398.
- Grady EF, Schwab M, Rosenau W (1987). "Expression of N-myc and c-src during the development of fetal human brain". Cancer Res. 47 (11): 2931–6. PMID 3552210.
- Ramsay G, Stanton L, Schwab M, Bishop JM (1987). "Human proto-oncogene N-myc encodes nuclear proteins that bind DNA". Mol. Cell. Biol. 6 (12): 4450–7. PMC 367228. PMID 3796607.
- Brodeur GM, Seeger RC (1986). "Gene amplification in human neuroblastomas: basic mechanisms and clinical implications". Cancer Genet. Cytogenet. 19 (1–2): 101–11. doi:10.1016/0165-4608(86)90377-8. PMID 3940169.
- Kanda N, Schreck R, Alt F, Bruns G, Baltimore D, Latt S (1983). "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. doi:10.1073/pnas.80.13.4069. PMC 394202. PMID 6575396.
- Schwab M, Varmus HE, Bishop JM, Grzeschik KH, Naylor SL, Sakaguchi AY, Brodeur G, Trent J (1984). "Chromosome localization in normal human cells and neuroblastomas of a gene related to c-myc". Nature. 308 (5956): 288–91. doi:10.1038/308288a0. PMID 6700732.
External links
- MYCN+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.