N-myc is a DNA sequence which shares limited homology to the proto-oncogene c-myc and has been found to be amplified in both primary tissue and cell lines from neuroblastoma, a childhood tumour of neuroectodermal origin.
The N-myc gene, first detected by its homology to the second exon of the c-myc gene, is amplified and/or expressed in tumours or cell lines derived from neuroblastoma, retinoblastoma and SCLC.
To determine whether other modes of myc gene activation underlie progression of some neuroblastomas, 45 were analyzed for amplification of N-myc, c-myc and L-myc and 26 were studied for transcription of these oncogenes.
Applying this technique, we followed the metaphase location and interphase position of amplified DNA sequences corresponding to the SAMK, MYC, and MYCN genes in four cell lines derived from human tumors: two gastric carcinoma lines (KATO III and SNU-16), a neuroblastoma (NUB-7), and a neuroepithelioma (NUB-20) line.
These results, together with those obtained in human neuroblastoma, suggest that the distal part of the short arm of chromosome 1 harbors an unidentified tumor suppressor gene(s), whose inactivation may be involved in MYC family gene amplification (an example of genetic instability) in tumors of various cellular origins.
Significant promoter activity in the presence of abundant Myc protein in amplified neuroblastoma lines indicates that autoregulation is disabled in this subset of tumors.
The more complex expression pattern found for the Myc targets in neuroblastomas suggests that genes that were identified originally as targets for c-Myc regulation may be regulated by N-Myc, but other cell specific factors are also needed for transcription of the target genes.
An element in the region responsible for premature termination of transcription mediates repression of c-myc gene expression by thyroid hormone in neuroblastoma cells.
Translocation (e.g., c-myc in Burkitt's lymphoma), or amplification (e.g., N-myc in neuroblastoma) of myc genes has been causally linked to tumor formation.
As these results are of potential clinical importance, but not in agreement with our own initial observations, the putative correlation between ID2 and MYC(N) expression in neuroblastoma cell lines and tumors was reinvestigated.
Our finding that MYCN directly modulates baseline MDM2 levels suggests a mechanism contributing to the pathogenesis of neuroblastoma and other MYC-driven malignancies through inhibition of MYC-stimulated apoptosis.
Inhibition of c-myc and N-myc genes by dsRNAs in carcinoma and neuroblastoma cells was investigated. siRNA-Ex3 targeted to the third exon of c-myc gene was found to decrease the level of c-myc but not N-myc mRNA and decrease the rate or even arrest proliferation of c-myc overexpressing cell lines KB-3-1 and SK-N-MC.
Further, despite compelling evidence for MYC and RAS cooperation in vitro and in vivo to promote tumourigenesis, activation of RAS signal transduction does not constitute a preferred secondary pathway in neuroblastomas with MYCN deregulation in either human tumors or murine models.
We identified a genetic signature characterized by a subset of MYCN/MYC and E2F targets, including Skp2, encoding the F-box protein of the SCF(Skp2) E3-ligase, to be highly expressed in high-risk neuroblastomas independent of amplified MYCN.
High-risk neuroblastomas (an often lethal embryonal tumor in which MYC activation is paramount) deregulate numerous polyamine enzymes to promote the expansion of intracellular polyamine pools.
Exposures mimicking conditions of CO (2) pneumoperitoneum lead to significant overexpression of C-MYC and HMGB-1 in neuroblastoma cells with decreased apoptosis.
Using neuroblastoma as a tumor model, we established a microRNA (miRNA) signature for activated MYCN/c-MYC signaling in two independent primary neuroblastoma tumor cohorts and provide evidence that c-MYC and MYCN have overlapping functions.
It was found that Hsp90 inhibition in neuroblastoma cell lines resulted in significant growth suppression, a decrease in MYCN and MYC expression, and an increase in the expression of p53.