N-MYC promotes cell proliferation through a direct transactivation of neuronal leucine-rich repeat protein-1 (NLRR1) gene in neuroblastoma (original) (raw)
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Amplification and expression of the N-myc gene in neuroblastoma
European Journal of Pediatrics, 1987
Genomic configuration and expression of the N-myc gene was investigated by Southern and Northern blot analyses in 18 neuroblastomas of different clinical stages. We observed a 4-100-fold amplification of this oncogene in one of six stage III, two of four stage IV as well as one of five stage IVS tumours. Remarkably, an 80-fold N-myc amplification was demonstrated in a patient with stage IV neuroblastoma being in remission for more than 2 years; moreover, a 100-fold amplification could be detected in a stage IVS tumour from a newborn. These data are discussed in view of the recently postulated close association of N-myc amplification with rapid progression of neuroblastomas.
Proceedings of the National Academy of Sciences, 1984
Previous studies had revealed that DNA with partial similarity to the myc oncogene (N-myc) is frequently amplified in human neuroblastoma cell lines and neuroblastoma tumors. We show here for one patient that N-myc amplification is confined to the neuroblastoma tumor and is not present in normal tissue. N-myc mRNA -4.0 kilobases in size is detectable in neuroblastoma cell lines and tumors and in a retinoblastoma cell line. By contrast, appreciable amounts of this RNA were not present in a number of cell lines derived from other human tumors and in fibroblasts from a normal individual and from a neuroblastoma patient. Low levels of Nmyc RNA were found in human and murine neuroblastoma cell lines lacking amplification of this gene, up to 80-fold greater levels in all cell lines carrying amplified N-myc. In situ hybridization to sections of neuroblastoma tumors revealed high expression of N-myc predominantly in undifferentiated neuroblasts. We hypothesize that amplification and consequent elevated expression of N-myc may be related to malignant progression.
myc Gene Amplification and Expression in Primary Human Neuroblastoma
Cancer Research, 1990
Although N-myc amplification in neuroblastomas correlates with poor prognosis, not all neuroblastomas which fail to respond to therapy have N-myc amplification. To determine whether other modes of myc gene activation underlie progression of some neuroblastomas, 45 were analyzed for amplification of N-wiyc, c-myc and L-myc and 26 were studied for transcription of these oncogenes. N-myc amplification was found in 6 of 45 tumors; no tumor had amplification of c-myc or L-myc. Transcription of both N-myr and c-myc occurred in 21 of 26 neuroblastomas. No tumor without \-myc amplification had a level of \-myc expression near that of a tumor or cell line with amplification. One tumor with \-myc amplification was the only specimen with N-myc but not c-myc expres sion. Five samples had c-myc but not \-myc expression; all had histological features of ganglioneuroma. DNA index did not correlate with myc gene amplification or expression. It is concluded that N-ni.vc and c-myc are commonly expressed in primary untreated neuroblastomas, but in the absence of N-myc amplification, expression of these genes does not appear to correlate with disease progression.
Medical and Pediatric Oncology, 2000
Background. Although the association between N-myc gene amplification and poor clinical outcome in neuroblastoma is well established, the mechanism by which amplification influences prognosis is not well defined. Procedure. We used a human N-myc transgenic mouse model to investigate the role of N-myc in neuroblastoma, including its relationship to the multidrug-resistance-associated protein (MRP) gene. We developed a rapid realtime PCR method to distinguish homozygous and hemizygous N-myc mice that is comparable to Southern analysis. Results. A highly significant correlation (P < 0.0001) between Nmyc and MRP expression was demonstrated in murine tumors. Amplification of the transgene was observed in the majority of tumors, highlighting the clinical relevance of this model. However, no correlation between N-myc expression and transgene dosage or tumor latency was observed. Conclusions. The data suggest that increased N-myc dosage contributes to increased tumor incidence and decreased latency by mechanisms independent of N-myc expression. Med.
N-myc oncogene expression in neuroblastoma is driven by Sp1 and Sp3
Molecular Genetics and Metabolism, 2003
Regulation of N-myc oncogene expression is an important determinant of the biological behavior of neuroblastoma. The N-myc promoter contains several potential binding sites for transcription factors of the Sp1 family. Mutation of a CT-box motif contained within a 26 bp region required for N-myc downregulation by retinoic acid decreased basal transcriptional activity and altered DNAprotein interactions of the promoter, while mutations flanking this motif did neither. On super-shift, this region was shown to recruit Sp1 and Sp3 transcription factor proteins, while a functionally significant CT-box mutation resulted in their replacement by NF-1 transcription factor. Lysates from Drosophila S2 cells expressing exogenous Sp1, Sp3, and NF-1 proteins were able to partially mimic gel shift complexes seen with neuroblastoma nuclear extract and either wild type or mutant probes. Transient transfections of S2 cells showed that both individually and together, Sp1 and Sp3 were able to trans-activate a wild type CT-box-driven luciferase reporter construct in a dose-dependent manner. Transfection of the wild type but not mutant CT-box oligonucleotide was able to decrease endogenous N-myc expression in neuroblastoma cells. Together these results suggest that the CT-box element serves a critically functional role, and in the basal state, allows for N-myc trans-activation by Sp1 and Sp3. Moreover when mutated, the CT-box may still function as a binding motif for alternate transcription factors such as NF-1 that can allow persistent N-myc expression.
A New Human Highly Tumorigenic Neuroblastoma Cell Line with Undetectable Expression of N-myc
Pediatric Research, 1990
A peculiar human cell line (GI-ME-N) derived from the metastatic bone marrow of a Zyr-old patient with stage IV neuroblastoma (NB) was extensively characterized. Cell-type-specific markers, tumorigenicity in nude mice, morphology, cytogenetics, and amplification/ expression of the N-myc gene were evaluated. All metaphases presented the typical l p deletion. Surface markers specific for NB cells, vimentin, and neurofilament proteins were all clearly detectable with immunofluorescence and/ or western blot procedures. Moreover, it was found that GI-ME-N cells did not express N-myc oncogene or HLA class 1 antigens, and were not classified as peripheral neuroectodermal tumor cells. However, extremely short latency and survival times, comparable to peripheral neuroectodermal tumor cells, were observed in nude mice grafted with GI-ME-N. In addition, no correlations were. observed in tumorigenicity of N-myc amplified (IMR32) versus unamplified (SK-N-SH GI-ME-N) human NB cell lines in nude mice. We conclude that N-myc amplification/ expression do not correlate with the aggressiveness of human NB in athymic animals, which is not always explained by the peripheral neuroectodermal tumor cell nature of the malignant cells, either. (Pediatr Res 27: 1-6, 1990) Abbreviations NB, neuroblastoma GI-ME-N, Gaslini Institute, patient initials, neuroblastoma PNET, peripheral neuroectodermal tumor BM, bone marrow s.c., subcutaneous Neuroblastoma, a neoplasm of the sympathetic nervous system, is the most common extracranial solid tumor arising in children (1, 2). In contrast to other pediatric tumors, the prognosis of NB patients has not significantly improved in the last 10 yr. With conventional chemotherapy, including local irradi-
Involvement of Myc targets in c-myc and N-myc induced human tumors
Oncogene, 1998
The myc proto-oncogenes are transcription factors that directly regulate the expression of other genes, by binding to the speci®c DNA sequence, CACGTG. Among the target genes for c-Myc regulation are ECA39, p53, ornithine decarboxylase (ODC), a-prothymosin and Cdc25A. In this study we examined the involvement of c-Myc target genes in human oncogenesis induced by c-myc or N-myc. In MCF-7 breast cancer cells, the induction of c-myc expression by estrogen was followed by the induction of all the Myc targets that we examined, indicating that those genes can serve as c-Myc targets in human oncogenesis. Moreover, in breast tumors exhibiting c-myc overexpression, several Myc targets were also overexpressed. A clear correlation between the expression of c-myc and its targets was also detected in Burkitt's lymphomas, which involve a speci®c translocation of c-myc gene, but not in other lymphoma cells. Yet, in cells derived from a neuronal origin the pattern of expression of Myc targets was more complex. In a neuroepithelioma cell line that overexpresses c-myc, only some targets were expressed. In addition in neuroblastomas, in which N-myc is ampli®ed and overexpressed, only ODC was overexpressed in all cell lines, while all other target genes were expressed in only some of the cell lines. The more complex expression pattern found for the Myc targets in neuroblastomas suggests that genes that were identi®ed originally as targets for c-Myc regulation may be regulated by N-Myc, but other cell speci®c factors are also needed for transcription of the target genes.