Biology: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] 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.[citation needed] 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
References
- ↑ "Entrez Gene: MYCN v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (avian)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4613.
- ↑ "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. doi:10.1101/gad.1021202. PMID 12381668.
- ↑ "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. PMID 1419902.
- ↑ "MYCN opposite strand/antisense RNA [Homo sapiens"]. Entrez Gene Database. National Center for Biotechnology Information, U.S. National Library of Medicine. https://www.ncbi.nlm.nih.gov/gene/10408.
- ↑ "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. doi:10.1371/journal.pgen.1003996. PMID 24391509.
- ↑ "Preferential amplification of the paternal allele of the N-myc gene in human neuroblastomas". Nat. Genet. 4 (2): 191–4. June 1993. doi:10.1038/ng0693-191. PMID 8102299.
- ↑ "N-myc amplification in multiple homogeneously staining regions in two human neuroblastomas.". Proc. Natl. Acad. Sci. U.S.A. 82 (11): 3736–40. 1985. doi:10.1073/pnas.82.11.3736. PMID 2582423. Bibcode: 1985PNAS...82.3736E.
- ↑ "Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage.". Science 224 (4653): 1121–4. 1984. doi:10.1126/science.6719137. PMID 6719137. Bibcode: 1984Sci...224.1121B.
- ↑ "The genetic landscape of high-risk neuroblastoma". Nature Genetics 45 (3): 279–84. March 2013. doi:10.1038/ng.2529. PMID 23334666. PMC 3682833. https://dash.harvard.edu/bitstream/handle/1/11877095/3682833.pdf?sequence=1.
- ↑ "Targeting Oncogenic Transcriptional Networks in Neuroblastoma: From N-Myc to Epigenetic Drugs". International Journal of Molecular Sciences 22 (23): 12883. November 2021. doi:10.3390/ijms222312883. PMID 34884690.
- ↑ "Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc". Science 251 (4998): 1211–7. March 1991. doi:10.1126/science.2006410. PMID 2006410. Bibcode: 1991Sci...251.1211B.
- ↑ "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. doi:10.1038/sj.onc.1202611. PMID 10229200.
- ↑ "Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma". Cancer Cell 15 (1): 67–78. January 2009. doi:10.1016/j.ccr.2008.12.005. PMID 19111882.
- ↑ "Drugging MYCN through an Allosteric Transition in Aurora Kinase A.". Cancer Cell 26 (3): 414–27. 27 August 2014. doi:10.1016/j.ccr.2014.07.015. PMID 25175806.
- ↑ "Surf the post-translational modification network of p53 regulation". International Journal of Biological Sciences 8 (5): 672–84. 2012. doi:10.7150/ijbs.4283. PMID 22606048.
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.
- "Specific phosphorylation of the acidic central region of the N-myc protein by casein kinase II.". Eur. J. Biochem. 209 (3): 945–50. 1992. doi:10.1111/j.1432-1033.1992.tb17367.x. PMID 1425701.
- "Dinucleotide repeat polymorphism at the human hemoglobin alpha-1 pseudo-gene (HBAP1).". Nucleic Acids Res. 20 (5): 1165. 1992. doi:10.1093/nar/20.5.1165. PMID 1549498.
- "N-myc mRNA forms an RNA-RNA duplex with endogenous antisense transcripts.". Mol. Cell. Biol. 10 (8): 4180–91. 1990. doi:10.1128/mcb.10.8.4180. PMID 1695323.
- "Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc.". Science 251 (4998): 1211–7. 1991. doi:10.1126/science.2006410. PMID 2006410. Bibcode: 1991Sci...251.1211B.
- "N-myc amplification in multiple homogeneously staining regions in two human neuroblastomas.". Proc. Natl. Acad. Sci. U.S.A. 82 (11): 3736–40. 1985. doi:10.1073/pnas.82.11.3736. PMID 2582423. Bibcode: 1985PNAS...82.3736E.
- "Sequence of a germ-line N-myc gene and amplification as a mechanism of activation.". Oncogene 2 (4): 399–402. 1988. PMID 2834684.
- "Nucleotide sequence of the human N-myc gene.". Proc. Natl. Acad. Sci. U.S.A. 83 (6): 1772–6. 1986. doi:10.1073/pnas.83.6.1772. PMID 2869488. Bibcode: 1986PNAS...83.1772S.
- "Nucleotide sequence of the 3' exon of the human N-myc gene.". Nucleic Acids Res. 13 (7): 2545–58. 1985. doi:10.1093/nar/13.7.2545. PMID 2987858.
- "Identification and characterization of the protein encoded by the human N-myc oncogene.". Science 232 (4751): 768–72. 1986. doi:10.1126/science.3008339. PMID 3008339. Bibcode: 1986Sci...232..768S.
- "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. doi:10.1093/nar/15.12.4761. PMID 3299258.
- "Alternative processing of RNA transcribed from NMYC.". Mol. Cell. Biol. 7 (12): 4266–72. 1988. doi:10.1128/mcb.7.12.4266. PMID 3437890.
- "Human N-myc is closely related in organization and nucleotide sequence to c-myc.". Nature 319 (6048): 73–7. 1986. doi:10.1038/319073a0. PMID 3510398. Bibcode: 1986Natur.319...73K.
- "Expression of N-myc and c-src during the development of fetal human brain.". Cancer Res. 47 (11): 2931–6. 1987. PMID 3552210.
- "Human proto-oncogene N-myc encodes nuclear proteins that bind DNA.". Mol. Cell. Biol. 6 (12): 4450–7. 1987. doi:10.1128/mcb.6.12.4450. PMID 3796607.
- "Gene amplification in human neuroblastomas: basic mechanisms and clinical implications.". Cancer Genet. Cytogenet. 19 (1–2): 101–11. 1986. doi:10.1016/0165-4608(86)90377-8. PMID 3940169.
- "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. doi:10.1073/pnas.80.13.4069. PMID 6575396. Bibcode: 1983PNAS...80.4069K.
- "Chromosome localization in normal human cells and neuroblastomas of a gene related to c-myc.". Nature 308 (5956): 288–91. 1984. doi:10.1038/308288a0. PMID 6700732. Bibcode: 1984Natur.308..288S.
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.
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