Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human neuroblastoma cells, SH-SY5Y, contain relatively low levels of thioredoxin (Trx); thus, they serve favorably as a model for studying oxidative stress-induced apoptosis (Andoh, T., Chock, P. B., and Chiueh, C. C. (2001) J. Biol. Chem. 277, 9655-9660). When these neurotrophic cells were subjected to nonlethal 2-h serum deprivation, their neuronal nitric oxide synthase and Trx were up-regulated, and the cells became more tolerant of oxidative stress, indicating that NO may protect cells from serum deprivation-induced apoptosis. Here, the mechanism by which NO exerts its protective effects was investigated. Our results reveal that in SH-SY5Y cells, NO inhibits apoptosis through its ability to activate guanylate cyclase, which in turn activates the cGMP-dependent protein kinase (PKG). The activated PKG is required to protect cells from lipid peroxidation and apoptosis, to inhibit caspase-9 and caspase-3 activation, and to elevate the levels of Trx peroxidase-1 and Trx, which subsequently induces the expression of Bcl-2. Furthermore, active PKG promotes the elevation of c-Jun, phosphorylated MAPK/ERK1/2, and c-Myc, consistent with the notion that PKG enhances the expression of Trx through its c-Myc-, AP-1-, and PEA3-binding motifs. Elevation of Trx and Trx peroxidase-1 and Mn(II)-superoxide dismutase would reduce H(2)O(2) and O(2)(), respectively. Thus, the cytoprotective effect of NO in SH-SY5Y cells appears to proceed via the PKG-mediated pathway, and S-nitrosylation of caspases plays a minimal role.
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PMID:Cyclic GMP-dependent protein kinase regulates the expression of thioredoxin and thioredoxin peroxidase-1 during hormesis in response to oxidative stress-induced apoptosis. 1241 92

Amplification of MYCN is one of the most important prognostic markers for neuroblastoma and is correlated with rapid tumor progression and poor prognosis. MYCN belongs to the Myc/Max/Mad/Mnt network of proteins that regulate proliferation, apoptosis, and differentiation. It is well established that MYCN is downregulated during induced differentiation of neuroblastoma cells carrying an amplified MYCN gene, but very little is known about other components of the network, i.e., the Max, Mad, and Mnt proteins, during this process. In this study we show that Mad and Mnt expression was only modestly regulated in differentiating SK-N-BE(2) neuroblastoma cells, while MYCN was rapidly downregulated. This downregulation was reflected in a decreased MYCN/Max DNA-binding activity while the Mnt/Max binding did not change during differentiation. In parallel experiments we also analyzed the Myc/Max/Mad expression and DNA binding capacity during induced differentiation in the MYCN single copy neuroblastoma cell line SH-SY5Y. In this cell line only modest changes in expression of the components of the MYCN/Max/Mad/Mnt network was detected, but since the cell line expresses relatively low levels of MYCN and c-Myc, these changes might be of functional significance. Cell cycle analyses of SK-N-BE(2) demonstrated an increase in the G1-phase fraction after RA-treatment. These data show that the decreased MYCN expression and MYCN DNA-binding is correlated with retarded cell cycle progression. Furthermore, when Mad1 or Mnt was overexpressed in SK-N-BE(2) cells they retained the capacity to differentiate, underscoring the notion that MYCN downregulation, and not changes in Mad/Mnt expression, is essential for neuroblastoma cell differentiation.
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PMID:Expression and DNA-binding activity of MYCN/Max and Mnt/Max during induced differentiation of human neuroblastoma cells. 1525 10

The review by D.T. Hughes examined the role of cytogenetics in cancer research in 1964. Despite the technical limitations of the day, he highlighted a number of known abnormalities which were to turn out to be crucial in our understanding of cancer genetics over the subsequent 40 years. These included the Philadelphia translocation and the Burkitt's lymphoma-associated marker chromosomes. In addition, he mentioned that a deleted chromosome had been observed in an example of retinoblastoma and double-minute chromosomes in neuroblastoma. The study of these events led to the identification of the key genes involved (BCR, ABL, C-MYC, RB1 and N-MYC) and served as models for substantial further work. We review some of the technical advances in the field of molecular cytogenetics and show how they can be applied to the events reviewed by Hughes.
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PMID:Understanding cancer at the chromosome level: 40 years of progress. 587 19

N-Myc oncogene amplification is a frequent event in neuroblastoma and is strongly correlated with advanced disease stage and treatment failure. Similarly to c-Myc oncogenic activation, N-Myc deregulation promotes both cell proliferation and p53-dependent apoptosis by sensitizing cells to a variety of insults. Intriguingly, p53 mutations are uncommon in neuroblastomas, strongly suggesting that an alternative cooperating event circumvents this safeguard against oncogene-driven neoplasia. By performing a pangenomic cDNA microarray analysis, we demonstrate that human Twist is constantly overexpressed in N-Myc-amplified neuroblastomas. H-Twist overexpression is responsible for the inhibition of the ARF/p53 pathway involved in the Myc-dependent apoptotic response. This oncogenic cooperation of two key regulators of embryogenesis causes cell transformation and malignant outgrowth.
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PMID:Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells. 1560 66

The expression of Rbm3, a glycine-rich RNA-binding protein, is enhanced under conditions of mild hypothermia, and Rbm3 has been postulated to facilitate protein synthesis at colder temperatures. To investigate this possibility, Rbm3 was overexpressed as a c-Myc fusion protein in mouse neuroblastoma N2a cells. Cells expressing this fusion protein showed a 3-fold increase in protein synthesis at both 37 degrees C and 32 degrees C compared with control cells. Although polysome profiles of cells expressing the fusion protein and control cells were similar, several differences were noted, suggesting that Rbm3 might enhance the association of 40S and 60S ribosomal subunits at 32 degrees C. Studies to assess a direct interaction of Rbm3 with ribosomes showed that a fraction of Rbm3 was associated with 60S ribosomal subunits in an RNA-independent manner. It appeared unlikely that this association could explain the global enhancement of protein synthesis, however, because cells expressing the Rbm3 fusion protein showed no substantial increase in the size of their monosome and polysome peaks, suggesting that similar numbers of mRNAs were being translated at approximately the same rates. In contrast, a complex that sedimented between the top of the gradient and 40S subunits was less abundant in cells expressing recombinant Rbm3. Further analysis showed that the RNA component of this fraction was microRNA. We discuss the possibility that Rbm3 expression alters global protein synthesis by affecting microRNA levels and suggest that both Rbm3 and microRNAs are part of a homeostatic mechanism that regulates global levels of protein synthesis under normal and cold-stress conditions.
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PMID:Cold stress-induced protein Rbm3 binds 60S ribosomal subunits, alters microRNA levels, and enhances global protein synthesis. 1568 48

Through the inhibition of monoamine oxidase type B (MAO-B), (-)-deprenyl (selegiline) prevents the conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the toxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+) and also prevents the neurotoxicity in the dopaminergic neurons in animal models. Cumulative observations suggest that selegiline may also protect against MPP+-induced neurotoxicity, possibly through the induction of pro-survival genes. We have observed that thioredoxin (Trx) mediates the induction of mitochondrial manganese superoxide dismutase (MnSOD) and Bcl-2 during preconditioning-induced hormesis. We therefore investigated whether the redox protein Trx plays any role in the neuroprotective mechanism of selegiline against MPP+-induced cytotoxicity in human SH-SY5Y neuroblastoma cells and also in primary neuronal cultures of mouse midbrain dopaminergic neurons. After confirming that selegiline protects against MPP+-induced cytotoxicity, we observed further that selegiline, at 1 microM or less, induced Trx for protection against oxidative injury caused by MPP+. The induction of Trx was blocked by protein kinase A (PKA) inhibitor and mediated by a PKA-sensitive phospho-activation of mitogen-activated protein (MAP) kinase Erk1/2 and the transcription factor c-Myc. Selegiline-induced Trx and associated neuroprotection were concomitantly blocked by the antisense against Trx mRNA, but not the sense or antisense mutant phosphothionate oligonucleotides, not only in human SH-SY5Y cells but also in mouse primary neuronal culture of midbrain dopaminergic neurons. Furthermore, the redox cycling of Trx may mediate the protective action of selegiline because the inhibition of Trx reductase by 1-chloro-2,4-dinitrobenzene ameliorated the effect of selegiline. Trx (1 microM) consistently increased the expression of mitochondrial proteins MnSOD and Bcl-2, supporting cell survival (Andoh et al., 2002). In conclusion, without modifying MAO-B activity, selegiline augments the gene induction of Trx, leading to elevated expression of antioxidative MnSOD and antiapoptotic Bcl-2 proteins for protecting against MPP+-induced neurotoxicity.
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PMID:Role of the redox protein thioredoxin in cytoprotective mechanism evoked by (-)-deprenyl. 1609 47

In this study, we report that the human p14(ARF) associates in vivo with the N-Myc and inhibits N-Myc mediated transcriptional activation. We have determined that the region (aa 140-300) encompassing the N-Myc BoxIII is required for efficient interaction in vivo. Furthermore, we demonstrate that in the SK-N-BE neuroblastoma cell line p14(ARF) over-expression delocalized N-Myc from the nucleoplasm into nucleoli and that N-Myc regions required for interaction with p14(ARF) are also important for nucleoli co-localization. Finally, we determine that the N-terminal region of the p14(ARF) protein is involved in binding to c-Myc and N-Myc proteins.
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PMID:p14ARF interacts with N-Myc and inhibits its transcriptional activity. 1728 33

The MYC family oncogenes cause transformation and tumor progression by corrupting multiple cellular pathways, altering cell cycle progression, apoptosis, and genomic instability. Several recent studies show that MYCC (c-Myc) expression alters DNA repair mechanisms, cell cycle checkpoints, and karyotypic stability, and this is likely partially due to alterations in centrosome replication control. In neuroblastoma cell lines, MYCN (N-Myc) expression induces centrosome amplification in response to ionizing radiation. Centrosomes are cytoplasmic domains that critically regulate cytokinesis, and aberrations in their number or structure are linked to mitotic defects and karyotypic instability. Whereas centrosome replication is linked to p53 and Rb/E2F-mediated cell cycle progression, the mechanisms downstream of MYCN that generate centrosome amplification are incompletely characterized. We hypothesized that MDM2, a direct transcriptional target of MYCN with central inhibitory effects on p53, plays a role in MYC-mediated genomic instability by altering p53 responses to DNA damage, facilitating centrosome amplification. Herein we show that MYCN mediates centrosome amplification in a p53-dependent manner. Accordingly, inhibition of the p53-MDM2 interaction with Nutlin 3A (which activates p53) completely ablates the MYCN-dependent contribution to centrosome amplification after ionizing radiation. We further show that modulating MDM2 expression levels by overexpression or RNA interference-mediated posttranscriptional inhibition dramatically affects centrosome amplification in MYCN-induced cells, indicating that MDM2 is a necessary and sufficient mediator of MYCN-mediated centrosome amplification. Finally, we show a significant correlation between centrosome amplification and MYCN amplification in primary neuroblastoma tumors. These data support the hypothesis that elevated MDM2 levels contribute to MYCN-induced genomic instability through altered regulation of centrosome replication in neuroblastoma.
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PMID:MYCN-directed centrosome amplification requires MDM2-mediated suppression of p53 activity in neuroblastoma cells. 1736 62

The human PVT-1 gene is located on chromosome 8 telomeric to the c-Myc gene and it is frequently involved in the translocations occurring in variant Burkitt's lymphomas and murine plasmacytomas. It has been proposed that PVT-1 regulates c-Myc gene transcription over a long distance. To get new insights into the functional relationships between the two genes, we have investigated PVT-1 and c-Myc expression in normal human tissues and in transformed cells. Our findings indicate that PVT-1 expression is restricted to a relative low number of normal tissues compared to the wide distribution of c-Myc mRNA, whereas the gene is highly expressed in many transformed cell types including neuroblastoma cells that do not express c-Myc. Reporter gene assays were used to dissect the PVT-1 promoter and to identify the region responsible for the elevated expression observed in transformed cells. This region contains two putative binding sites for Myc proteins. The results of transfection experiments in RAT1-MycER cells and chromatin immunoprecipitation (ChIP) assays in proliferating and differentiated neuroblastoma cells indicate that PVT-1 is a downstream target of Myc proteins.
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PMID:The PVT-1 oncogene is a Myc protein target that is overexpressed in transformed cells. 1750 67

The c-Myc and MYCN oncogenes strongly induce cell proliferation. Although a limited series of cell cycle genes were found to be induced by the myc transcription factors, it is still unclear how they mediate the proliferative phenotype. We therefore analysed a neuroblastoma cell line with inducible MYCN expression. We found that all members of the minichromosome maintenance complex (MCM2-7) and MCM8 and MCM10 were up-regulated by MYCN. Expression profiling of 110 neuroblastoma tumours revealed that these genes strongly correlated with MYCN expression in vivo. Extensive chromatin immunoprecipitation experiments were performed to investigate whether the MCM genes were primary MYCN targets. MYCN was bound to the proximal promoters of the MCM2 to -8 genes. These data suggest that MYCN stimulates the expression of not only MCM7, which is a well defined MYCN target gene, but also of the complete minichromosome maintenance complex.
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PMID:Direct regulation of the minichromosome maintenance complex by MYCN in neuroblastoma. 1782 80


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