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N-Myc

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N-Myc

V-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog
Identifiers
Symbols  ; MODED; N-myc; NMYC; ODED; bHLHe37
External IDs GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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.

Contents

  • Function 1
  • Clinical significance 2
  • Interactions 3
  • See also 4
  • References 5
  • Further reading 6
  • External links 7

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 proteins are functionally related.[4] It has been shown that NCYM antisense RNA encodes for a protein 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]

Interactions

N-Myc has been shown to interact with MAX.[9][10]

N-Myc is also stabilized by aurora A which protects it from degradation.[11] 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.[12]

See also

References

  1. ^ "Entrez Gene: MYCN v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (avian)". 
  2. ^ 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.  
  3. ^ 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.  
  4. ^ "MYCN opposite strand/antisense RNA [Homo sapiens]". Entrez Gene Database. National Center for Biotechnology Information, U.S. National Library of Medicine. 
  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 (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.  
  6. ^ 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.  
  7. ^ 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.  
  8. ^ 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.  
  9. ^ 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.  
  10. ^ 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.  
  11. ^ 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.  
  12. ^ 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.  

Further reading

  • Lüscher B (2001). "Function and regulation of the transcription factors of the Myc/Max/Mad network.". Gene 277 (1-2): 1–14.  
  • 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.  
  • 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.  
  • 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.  
  • 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.  
  • 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.  
  • 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.  
  • 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.  
  • Michitsch RW, Melera PW (1985). "Nucleotide sequence of the 3' exon of the human N-myc gene.". Nucleic Acids Res. 13 (7): 2545–58.  
  • 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.  
  • 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.  
  • Stanton LW, Bishop JM (1988). "Alternative processing of RNA transcribed from NMYC.". Mol. Cell. Biol. 7 (12): 4266–72.  
  • 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.".  
  • 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.  
  • 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.  
  • Brodeur GM, Seeger RC (1986). "Gene amplification in human neuroblastomas: basic mechanisms and clinical implications.". Cancer Genet. Cytogenet. 19 (1-2): 101–11.  
  • 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.  
  • 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.  

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