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.
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.
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. [5] N-Myc is highly expressed in the fetal brain and is critical for normal brain development. [6]
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. [7] 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. [8] 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. [9]
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. [10] [11] [12] MYCN can also be activated in neuroblastoma and other cancers through somatic mutation. [13] 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. [14]
N-Myc has been shown to interact with MAX. [15] [16]
N-Myc is also stabilized by aurora A which protects it from degradation. [17] 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. [18]
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. [19]
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
Double minutes are small fragments of extrachromosomal DNA, which have been observed in a large number of human tumors including breast, lung, ovary, colon, and most notably, neuroblastoma. They are a manifestation of gene amplification as a result of chromothripsis, during the development of tumors, which give the cells selective advantages for growth and survival. This selective advantage is as a result of double minutes frequently harboring amplified oncogenes and genes involved in drug resistance. DMs, like actual chromosomes, are composed of chromatin and replicate in the nucleus of the cell during cell division. Unlike typical chromosomes, they are composed of circular fragments of DNA, up to only a few million base pairs in size, and contain no centromere or telomere. Further to this, they often lack key regulatory elements, allowing genes to be constitutively expressed. The term ecDNA may be used to refer to DMs in a more general manner.
Zinc finger protein GLI1 also known as glioma-associated oncogene is a protein that in humans is encoded by the GLI1 gene. It was originally isolated from human glioblastoma cells.
Myc is a family of regulator genes and proto-oncogenes that code for transcription factors. The Myc family consists of three related human genes: c-myc (MYC), l-myc (MYCL), and n-myc (MYCN). c-myc was the first gene to be discovered in this family, due to homology with the viral gene v-myc.
T-cell acute lymphocytic leukemia protein 1 is a protein that in humans is encoded by the TAL1 gene.
NRAS is an enzyme that in humans is encoded by the NRAS gene. It was discovered by a small team of researchers led by Robin Weiss at the Institute of Cancer Research in London. It was the third RAS gene to be discovered, and was named NRAS, for its initial identification in human neuroblastoma cells.
MAX is a gene that in humans encodes the MAX transcription factor.
DNA-binding protein inhibitor ID-3 is a protein that in humans is encoded by the ID3 gene.
PITSLRE serine/threonine-protein kinase CDC2L1 is an enzyme that in humans is encoded by the CDC2L1 gene.
60S ribosomal protein L7a is a protein that in humans is encoded by the RPL7A gene.
Rhombotin-1 is a protein that in humans is encoded by the LMO1 gene.
L-myc-1 proto-oncogene protein is a protein that in humans is encoded by the MYCL1 gene.
Probable ATP-dependent RNA helicase DDX6 is an enzyme that in humans is encoded by the DDX6 gene.
ATP-dependent RNA helicase DDX1 is an enzyme that in humans is encoded by the DDX1 gene.
MNT is a Max-binding protein that is encoded by the MNT gene
40S ribosomal protein S8 is a protein that in humans is encoded by the RPS8 gene.
Putative microRNA host gene 1 protein is a protein that in humans is encoded by the MIR17HG gene.
Pvt1 oncogene, also known as PVT1 or Plasmacytoma Variant Translocation 1 is a long non-coding RNA gene. In mice, this gene was identified as a breakpoint site in chromosome 6;15 translocations. These translocations are associated with murine plasmacytomas. The equivalent translocation in humans is t(2;8), which is associated with a rare variant of Burkitt's lymphoma. In rats, this breakpoint was shown to be a common site of proviral integration in retrovirally induced T lymphomas. Transcription of PVT1 is regulated by Myc.
T-cell acute lymphocytic leukemia 2, also known as TAL2, is a protein which in humans is encoded by the TAL2 gene.
June Biedler was an American scientist primarily known for her discovery of proteins that lead to resistance of cancer cells to chemotherapy. Her work has been crucial for an understanding of both the development of drug resistance and also for strategies to circumvent such resistance. In addition, Biedler made important contributions to an understanding of the molecular mechanisms of neuroblastoma development, particularly of the role of the N-myc oncogene in the genesis of neuroblastoma
This article incorporates text from the United States National Library of Medicine, which is in the public domain.