MYCN

MYCN
Estruturas dispoñibles
PDB	Buscar ortólogos: PDBe, RCSB
Identificadores
Nomenclatura	Outros nomes MYCN, MODED, N-myc, NMYC, ODED, bHLHe37, homólogo derivado do neuroblastoma do oncoxene v-myc da mielocitomatose viral aviaria, protooncoxene MYCN, factor de transcrición bHLH, MYCNsORF, MYCNsPEP ;
Símbolos	MYCN (HGNC: 7559) MYCN, MODED, N-myc, NMYC, ODED, bHLHe37, homólogo derivado do neuroblastoma do oncoxene v-myc da mielocitomatose viral aviaria, protooncoxene MYCN, factor de transcrición bHLH, MYCNsORF, MYCNsPEP
Identificadores; externos	OMIM: 164840 ; MGI: 97357 ; HomoloGene: 3922 ; EBI: MYCN; GeneCards: Xene MYCN; UniProt: MYCN;
Locus	Cr. 2 p24.3
Ontoloxía Xénica	Referencias: AmiGO / QuickGO
	Referencias: AmiGO / QuickGO
Padrón de expresión de ARNm
	Máis información
Ortólogos
Especies
Humano	Rato
Entrez
4613	18109
Ensembl
Véxase HS	Véxase MM
UniProt
P04198	P03966
RefSeq; (ARNm)
NM_005378	NM_008709
RefSeq; (proteína) NCBI
NP_001280157	NP_032735
Localización (UCSC)
Cr. 2:; 15.94 – 15.95 Mb	Cr. 12:; 12.99 – 15.95 Mb
PubMed (Busca)
4613 ;	18109

Para a familia de xenes véxase: Myc.

A proteína protooncoxénica N-myc tamén coñecida como N-Myc ou proteína 37 de hélice básica-bucle-hélice (bHLHe37), é unha proteína que nos humanos está codificada no xene MYCN do cromosoma 2.

Función

O xene MYCN é membro da familia Myc de factores de transcrición e codifica unha proteína cun dominio de hélice básica-bucle-hélice ou bHLH. Esta proteína está localizada no núcleo celular e debe dimerizarse con outra proteína bHLH para poder unirse ao ADN.^[1] N-Myc exprésase fortemente no cerebro fetal e é crítica para o desenvolvemento normal do cerebro.^[2]

O xene MYCN ten un ARN antisentido, N-cym ou MYCNOS, transcrito da febra oposta que se pode traducir para formar un produto proteico.^[3] N-Myc e MYCNOS son corregulados tanto no desenvolvemento normal coma en células tumorais, así que é posible que os dous transcritos estean funcionalmente relacionados.^[4] O ARN antisentido codifica unha proteína, chamada NCYM, que se orixinou de novo e é específico de humanos e chimpancés. Esta proteína inhibe GSK3b e así impide a degradación de MYCN. Os ratos transxénicos que levan o par MYCN/NCYM humano a miúdo mostran neuroblastomas con metástases distantes, que son atípicos en ratos normais. Así a NCYM representa un raro exemplo dun xene de novo que adquiriu unha función molecular e exerce un papel importante na oncoxénese.^[5]

Importancia clínica

A amplificación e sobreexpresión de N-Myc pode conducir á tumoroxénese. O exceso de N-Myc está asociado cunha variedade de tumores, principalmente neuroblastomas nos que os pacientes con amplificación do xene N-Myc adoitan ter un mal resultdo final.^[6]^[7]^[8] MYCN pode tamén activarse en neuroblastomas e outros cancros por mutacións somáticas.^[9] Perfís de H3K27ac en todo o xenoma recentes en mostras de neuroblastoma (NB) derivadas de pacientes revelaron catro subtipos epixenéticos impulsados por superamplificadores (SE, super enhancers), caracterizados polas súas redes regulatorias mestras propias e específicas. Tres deles noméanse por grupos clínicos coñecidos: neuroblastomas con MYCN amplificado, de alto risco con MYCN non amplificado e de baixo risco con MYCN non amplificado, mentres que os catro mostran características celulares que se parecen a precursores de célula de Schwann multipotentes. O xene da ciclina CCND1 era regulado por superamplificadores distintos e compartidos nos diferentes subtipos, e, o que é máis importante, algúns tumores mostraban sinais que pertencen a sinaturas epixenéticas múltiples, o que suxire que a paisaxe epixenética probablemente contribúe á heteroxeneidade intratumoral.^[10]

Interaccións

N-Myc presenta interaccións con MAX.^[11]^[12]

N-Myc é tamén estabilizado pola quinase aurora A que o protexe da degradación.^[13] Están desenvolvéndose fármacos que teñen como diana esta interacción e están deseñados para cambiar a conformación de aurora A. O cambio conformacional en aurora A causa a liberación de N-Myc, a cal é despois degradada de maneira dependente da ubiquitina.^[14]

MYCN é independente da interacción MYCN/MAX e tamén un corregulador transcricional de p53 no neuroblastoma con MYCN amplificado.^{[Cómpre referencia]} MYCN altera a transcrición de xenes diana de p53 que regulan as repostas de apoptose e reparación de danos no ADN no ciclo celular. Esta interacción MYCN-p53 realízase pola unión exclusiva de MYCN aos dominios C-terminais da p53 tetramérica. Como unha modificación postranscricional, a unión de MYCN aos dominios C-terminais da p53 tetramérica afecta a selectividade do promotor de p53 e interfire na unión doutros cofactores nesta rexión.^[15]

Notas

↑ "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. PMC 187459. PMID 12381668. doi:10.1101/gad.1021202.
↑ 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. PMC 3879166. PMID 24391509. doi:10.1371/journal.pgen.1003996.
↑ 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. PMID 8102299. doi:10.1038/ng0693-191.
↑ 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. Bibcode:1985PNAS...82.3736E. PMC 397862. PMID 2582423. doi:10.1073/pnas.82.11.3736.
↑ 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. Bibcode:1984Sci...224.1121B. PMID 6719137. doi:10.1126/science.6719137.
↑ Pugh TJ, Morozova O, Attiyeh EF, Asgharzadeh S, Wei JS, Auclair D, et al. (marzo de 2013). "The genetic landscape of high-risk neuroblastoma" (PDF). Nature Genetics 45 (3): 279–84. PMC 3682833. PMID 23334666. doi:10.1038/ng.2529.
↑ Ciaccio R, De Rosa P, Aloisi S, Viggiano M, Cimadom L, Zadran SK, Perini G, Milazzo G (novembro de 2021). "Targeting Oncogenic Transcriptional Networks in Neuroblastoma: From N-Myc to Epigenetic Drugs". International Journal of Molecular Sciences 22 (23): 12883. PMC 8657550. PMID 34884690. doi:10.3390/ijms222312883.
↑ Blackwood EM, Eisenman RN (marzo de 1991). "Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc". Science 251 (4998): 1211–7. Bibcode:1991Sci...251.1211B. PMID 2006410. doi:10.1126/science.2006410.
↑ FitzGerald MJ, Arsura M, Bellas RE, Yang W, Wu M, Chin L, Mann KK, DePinho RA, Sonenshein GE (abril de 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. PMID 10229200. doi:10.1038/sj.onc.1202611.
↑ Otto T, Horn S, Brockmann M, Eilers U, Schüttrumpf L, Popov N, Kenney AM, Schulte JH, Beijersbergen R, Christiansen H, Berwanger B, Eilers M (xaneiro de 2009). "Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma". Cancer Cell 15 (1): 67–78. PMID 19111882. doi:10.1016/j.ccr.2008.12.005.
↑ 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 (27 de agosto de 2014). "Drugging MYCN through an Allosteric Transition in Aurora Kinase A.". Cancer Cell 26 (3): 414–27. PMC 4160413. PMID 25175806. doi:10.1016/j.ccr.2014.07.015.
↑ Gu B, Zhu WG (2012). "Surf the post-translational modification network of p53 regulation". International Journal of Biological Sciences 8 (5): 672–84. PMC 3354625. PMID 22606048. doi:10.7150/ijbs.4283.

Véxase tamén

Bibliografía

Lüscher B (2001). "Function and regulation of the transcription factors of the Myc/Max/Mad network.". Gene 277 (1–2): 1–14. PMID 11602341. doi:10.1016/S0378-1119(01)00697-7.
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. PMID 1425701. doi:10.1111/j.1432-1033.1992.tb17367.x.
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. PMC 312136. PMID 1549498. doi:10.1093/nar/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. PMC 360949. PMID 1695323. doi:10.1128/mcb.10.8.4180.
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. Bibcode:1991Sci...251.1211B. PMID 2006410. doi:10.1126/science.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. Bibcode:1985PNAS...82.3736E. PMC 397862. PMID 2582423. doi:10.1073/pnas.82.11.3736.
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. Bibcode:1986PNAS...83.1772S. PMC 323166. PMID 2869488. doi:10.1073/pnas.83.6.1772.
Michitsch RW, Melera PW (1985). "Nucleotide sequence of the 3' exon of the human N-myc gene.". Nucleic Acids Res. 13 (7): 2545–58. PMC 341174. PMID 2987858. doi:10.1093/nar/13.7.2545.
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. Bibcode:1986Sci...232..768S. PMID 3008339. doi:10.1126/science.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. PMC 305916. PMID 3299258. doi:10.1093/nar/15.12.4761.
Stanton LW, Bishop JM (1988). "Alternative processing of RNA transcribed from NMYC.". Mol. Cell. Biol. 7 (12): 4266–72. PMC 368108. PMID 3437890. doi:10.1128/mcb.7.12.4266.
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. Bibcode:1986Natur.319...73K. PMID 3510398. doi:10.1038/319073a0.
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. doi:10.1128/mcb.6.12.4450.
Brodeur GM, Seeger RC (1986). "Gene amplification in human neuroblastomas: basic mechanisms and clinical implications.". Cancer Genet. Cytogenet. 19 (1–2): 101–11. PMID 3940169. doi:10.1016/0165-4608(86)90377-8.
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. Bibcode:1983PNAS...80.4069K. PMC 394202. PMID 6575396. doi:10.1073/pnas.80.13.4069.
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. Bibcode:1984Natur.308..288S. PMID 6700732. doi:10.1038/308288a0.

Ligazóns externas

MYCN protein, human Medical Subject Headings (MeSH) na Biblioteca Nacional de Medicina dos EUA.

Este artigo incorpora textos da Biblioteca Nacional de Medicina dos Estados Unidos, que están en dominio público.

[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. PMC 187459. PMID 12381668. doi:10.1101/gad.1021202.

[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. PMID 1419902.

[url_NCBI-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. PMC 3879166. PMID 24391509. doi:10.1371/journal.pgen.1003996.

[pmid8102299-6] 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. PMID 8102299. doi:10.1038/ng0693-191.

[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. Bibcode:1985PNAS...82.3736E. PMC 397862. PMID 2582423. doi:10.1073/pnas.82.11.3736.

[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. Bibcode:1984Sci...224.1121B. PMID 6719137. doi:10.1126/science.6719137.

[9] Pugh TJ, Morozova O, Attiyeh EF, Asgharzadeh S, Wei JS, Auclair D, et al. (marzo de 2013). "The genetic landscape of high-risk neuroblastoma" (PDF). Nature Genetics 45 (3): 279–84. PMC 3682833. PMID 23334666. doi:10.1038/ng.2529.

[10] Ciaccio R, De Rosa P, Aloisi S, Viggiano M, Cimadom L, Zadran SK, Perini G, Milazzo G (novembro de 2021). "Targeting Oncogenic Transcriptional Networks in Neuroblastoma: From N-Myc to Epigenetic Drugs". International Journal of Molecular Sciences 22 (23): 12883. PMC 8657550. PMID 34884690. doi:10.3390/ijms222312883.

[pmid2006410-11] Blackwood EM, Eisenman RN (marzo de 1991). "Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc". Science 251 (4998): 1211–7. Bibcode:1991Sci...251.1211B. PMID 2006410. doi:10.1126/science.2006410.

[pmid10229200-12] FitzGerald MJ, Arsura M, Bellas RE, Yang W, Wu M, Chin L, Mann KK, DePinho RA, Sonenshein GE (abril de 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. PMID 10229200. doi:10.1038/sj.onc.1202611.

[pmid19111882-13] Otto T, Horn S, Brockmann M, Eilers U, Schüttrumpf L, Popov N, Kenney AM, Schulte JH, Beijersbergen R, Christiansen H, Berwanger B, Eilers M (xaneiro de 2009). "Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma". Cancer Cell 15 (1): 67–78. PMID 19111882. doi:10.1016/j.ccr.2008.12.005.

[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 (27 de agosto de 2014). "Drugging MYCN through an Allosteric Transition in Aurora Kinase A.". Cancer Cell 26 (3): 414–27. PMC 4160413. PMID 25175806. doi:10.1016/j.ccr.2014.07.015.

[15] Gu B, Zhu WG (2012). "Surf the post-translational modification network of p53 regulation". International Journal of Biological Sciences 8 (5): 672–84. PMC 3354625. PMID 22606048. doi:10.7150/ijbs.4283.

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