Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We have studied the effect of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), a protein kinase inhibitor, on the regulation of apoptosis in the human neuroblastoma cell line, SH-SY5Y. H-7 (20-100 microM) induced apoptosis in these cells characterized by DNA fragmentation and chromatin condensation. Immunoblot analyses were performed with specific antibody against BCL-2, BCL-XS/L, BAX, JUNB, c-JUN, ICH-1L, c-FOS, RB, CDK-2, and p53. H-7 treatment did not significantly alter the level of these proteins with the exception of p53. H-7, but not staurosporine, caused a dramatic nuclear accumulation of p53. The kinetics of nuclear accumulation of p53 correlates well with the kinetics of induction of apoptosis. The effect of H-7 was further assessed in a group of human cell lines. Only cell lines harboring the wild-type p53 gene were responsive to the stimulatory effect of H-7 on nuclear accumulation of p53. Furthermore, cell lines carrying a mutated p53 gene were resistant to the cytotoxic effect of H-7. The ability of H-7 in mediating apoptosis in the SH-SY5Y line expressing a dominant negative mutant of p53 was significantly diminished. Taken together, these data strongly suggest that a p53-dependent mechanism contributes to the cytotoxicity of H-7 in human neuroblastoma cells.
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PMID:1-(5-Isoquinolinesulfonyl)-2-methylpiperazine induces apoptosis in human neuroblastoma cells, SH-SY5Y, through a p53-dependent pathway. 902 Jan 41

Mature T cells are susceptible to activation-induced cell death in the periphery. Activation-induced cell death is thought to involve CD95/CD95 ligand interactions in vivo. Here we report that stimulated, CD45RO+ human T cell lines specific for myelin basic protein or tetanus toxoid from multiple sclerosis patients and healthy individuals resist apoptosis induced by soluble recombinant CD95 ligand in vitro. In contrast, the same CD95 ligand effectively kills Jurkat T lymphoma and human malignant glioma cells. The resistance of the T cell lines is not due to a lack of CD95 expression at the cell surface and is not overcome by coexposure to CD95 ligand and inhibitors of RNA or protein synthesis. The expression level of BCL-2 is lower in Jurkat than in Ag-specific T cells. After exposure to soluble CD95 ligand, Jurkat T cells, but not Ag-specific T cells, exhibit loss of BCL-2 and BCL-X expression whereas BAX expression is not affected. Surprisingly, Ag-specific T cells are rather sensitive to CD95 ligand expressed at the cell surface of N2A neuroblastoma cells. Accessory molecules expressed by the CD95 ligand-expressing effector cell are dispensable for apoptosis since the T cells are equally sensitive to agonistic APO-1 Ab. Further studies are required to determine whether resistance to soluble CD95 ligand-mediated apoptosis is a possible escape mechanism for T cells from peripheral deletion that may have relevance for autoimmune disorders.
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PMID:Human autoreactive and foreign antigen-specific T cells resist apoptosis induced by soluble recombinant CD95 ligand. 927 96

Neuroblastomas undergo spontaneous regression at an unusually high rate. The mechanisms are not clear, but apoptosis may be involved. A large proportion of neuroblastomas is characterized by amplification of MYCN. Using human neuroblastoma cells harbouring tetracycline controlled expression of MYCN we have analysed the role of the MycN protein and IFNgamma in cell death decision. Neither conditional expression of MYCN nor treatment with IFNgamma alone was sufficient to trigger cell death. However, when acting in concert MycN and IFNgamma efficiently triggered cell death, which was accompanied by DNA fragmentation and required caspase activity, two hallmarks of apoptosis. MycN and IFNgamma may cooperate along at least two different pathways. First, IFNgamma increased the CD95 cell surface expression while MycN enhanced the cellular susceptibility for the CD95 mediated death signal. Second, IFNgamma treatment induced expression of BAK mRNA while MycN and IFNgamma in combination increased the amount of Bax protein, another activator of apoptosis, without a concomitant increase in BAX mRNA. MycN also increased cell death in response to TRAIL and TNFalpha, suggesting that enforced MYCN expression in general increases the susceptibility of neuroblastoma cells towards a variety of death stimuli.
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PMID:MycN and IFNgamma cooperate in apoptosis of human neuroblastoma cells. 969 May 15

Neuroblastoma is a pediatric malignancy of the sympathetic nervous system and is frequently characterized by genetic aberrations (including aneuploidy, chromosomal deletions, translocations, and gene amplification) that suggest inherent genomic instability. Mutations in mismatch repair (MMR) genes have been associated with genomic instability in several human cancers, such as those of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. In these cases, replication errors at microsatellite repeats lead to microsatellite instability (MSI) and mutagenesis. In neuroblastoma, we and others have detected MSI infrequently when analyzed at di- or tetranucleotide repeat polymorphic markers. More recently, however, mutations in the MMR gene GTBP/hMSH6 have been associated with a limited phenotype of instability at mononucleotide repeats only (e.g., polyadenine tracts). Furthermore, mononucleotide repeats appear to be common downstream targets of MSI-related mutagenesis and are present in the transforming growth factor-beta receptor-II gene (TGF beta RII), the BAX proapoptosis gene, and the insulin-like growth factor II receptor gene (IGFIIR) frequently in tumors arising in HNPCC kindreds. Therefore, we analyzed 46 matched normal and tumor DNAs representing all clinical stages of neuroblastoma with the use of five polymorphic mononucleotide repeat markers to assess for MSI at mononucleotide repeats. Only one tumor (2%) demonstrated mononucleotide repeat instability, and the instability was at a single locus. We conclude that MSI, including mononucleotide repeat instability, is infrequent in human neuroblastoma, and therefore defects in DNA mismatch repair are not responsible for the genomic instability seen in this neoplasm.
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PMID:Mononucleotide repeat instability is infrequent in neuroblastoma. 979 79

RE repeats encoded (RERE) was identified recently as a protein with high homology to the atrophin-1 protein, which appears to be causal in the hereditary neurodegenerative disorder termed dentatorubral-pallidoluysian atrophy (DRPLA) caused by an abnormal glutamine expansion. We have independently identified RERE in a search for genes localized to the translocation breakpoint region at chromosome 1p36.2 in the neuroblastoma cell line NGP. Here we show that neuroblastoma tumor cell lines display reduced abundance of RERE transcripts. Furthermore, we detected RERE protein mainly in the nucleus, where it colocalizes with the promyelocytic leukemia protein in promyelocytic leukemia oncogenic domains (PODs). Overexpression of RERE recruits a fraction of the proapoptotic protein BAX to PODS: This observation correlates with RERE-induced apoptosis, which occurs in a caspase-dependent manner. These results identify RERE as a novel component of PODs and suggest an important role of RERE in the control of cell survival.
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PMID:Human RERE is localized to nuclear promyelocytic leukemia oncogenic domains and enhances apoptosis. 1133 Dec 49

Polo-like kinase 1 (Plk1) has an important role in the regulation of M phase of the cell cycle. In addition to its cell cycle-regulatory function, Plk1 has a potential role in tumorigenesis. Here we found for the first time that Plk1 physically binds to the tumor suppressor p53 in mammalian cultured cells, and inhibits its transactivation activity as well as its pro-apoptotic function. During the cisplatin-induced apoptosis in human neuroblastoma SH-SY5Y cells, the expression level of Plk1 was significantly decreased both at mRNA and protein levels, whereas cisplatin treatment caused a remarkable stabilization of p53. Systematic immunoprecipitation analyses using a series of deletion mutants of p53 revealed that a sequence-specific DNA-binding region of p53 is required and sufficient for the physical interaction with Plk1. The ectopically overexpressed Plk1 was co-localized with the endogenous p53 in mammalian cell nucleus, as shown by confocal laser microscopy. Expression of exogenous Plk1 and p53 in p53-deficient lung carcinoma H1299 cells greatly decreased the p53-mediated transcription from the p53-responsive p21(WAF1), MDM2, and BAX promoters, whereas the kinase-deficient mutant form of Plk1 failed to reduce the transcriptional activity of p53. Consistent with the luciferase reporter analysis, Plk1 had an ability to block the p53-dependent induction of the endogenous p21(WAF1). In addition, Plk1 inhibited the pro-apoptotic function of p53 in H1299 cells. Intriguingly, Plk1-mediated repression of p53 was attenuated with ATM. Thus, our present findings strongly suggest that p53 is a critical target of Plk1, and its function is abrogated through the physical interaction with Plk1.
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PMID:Polo-like kinase 1 (Plk1) inhibits p53 function by physical interaction and phosphorylation. 1502 21

Cellular stress leads to DNA damage and activation of the intrinsic apoptotic pathway in which translocation of mitochondrial cytochrome c to the cytosol plays a critical role. Previous studies have suggested alternative mechanisms responsible for this process. We examined initiation mechanisms of the intrinsic apoptotic pathway using human neuroblastoma and breast cancer cells. Results indicated that translocation of cytochrome c does not require prior activation of caspases but rather depends on activation of specific BCL-2 family members, depending upon the type of death signal. Thus, DNA damage-induced apoptosis requires new protein synthesis, accumulation of p53 tumor suppressor protein, and p53-dependent induction of BOK and NOXA genes, while a role for BAX in this pathway is not essential. In contrast, apoptosis induced by staurosporine does not require protein synthesis but is characterized by translocation of BAX. Based on these findings, we propose a model of the intrinsic apoptotic cascade induced by DNA damage where proapoptotic BOK substitutes for a function of BAX.
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PMID:BOK and NOXA are essential mediators of p53-dependent apoptosis. 1510 63

Aluminum maltolate (Al-malt) causes neurodegeneration following in vivo exposure, and apoptosis plays a prominent role. The objective of this study was to define the form of cell death induced by Al-malt and to establish an in vitro model system amenable to mechanistic investigations of Al-malt-induced cell death. Neuro-2a cells, a murine neuroblastoma cell line, were treated with Al-malt for 24 h, following which mode of cell death and alterations in apoptosis-related gene expression were studied. Al-malt concentration-dependently increased cell death. The mode of cell death was a combination of apoptosis and necrosis. Treatment with Al-malt resulted in caspase 3 activation and the externalization of phosphatidyl serine, both indicative of apoptosis. In addition, nuclear condensation and fragmentation were evident. Interestingly, pretreatment with cycloheximide (CHX), a potent protein synthesis inhibitor markedly reduced Al-malt-induced apoptosis, indicating that altered gene expression was critical for this form of cell death. Pretreatment with CHX had no effect on necrosis induced by Al-malt. Analysis of gene expression showed that p53 mRNA was increased following treatment with Al-malt. This increase was accompanied by a marked inhibition of Bcl2 expression and an increase in BAX expression, a pattern of gene expression suggestive of a pro-apoptotic shift. Results show for the first time that p53 is induced by Al in neuron-like cells and suggest that the p53-dependent intrinsic pathway may be responsible for Al-induced apoptosis. Future studies investigating the role of p53 in Al neurotoxicity both in vivo and in vitro are warranted.
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PMID:Aluminum-maltolate induces apoptosis and necrosis in neuro-2a cells: potential role for p53 signaling. 1553 49

The p73 gene codes for various different protein isoforms. They include proteins expressed under the control of the P1 promoter that contain a transactivation domain and are similar in function to p53 (TAp73 isoforms), as well as proteins regulated by the P2 promoter that lack this domain and function as dominant negative inhibitors of TAp73 and p53 (DeltaNp73 isoforms). Whereas TAp73 functions as a tumor suppressor with pro-apoptotic function, DeltaNp73 is likely to prevent the induction of apoptosis in tumor cells and to participate in oncogenesis. Here we used a loss-of-function strategy to assess the role of DeltaNp73 in SH-SY5Y neuroblastoma cells. An antisense oligonucleotide designed to target DeltaNp73 mRNA, but not TAp73, was used to effectively downregulate this transcript. DeltaNp73 downregulation was accompanied by increased levels of the pro-apoptotic BH3 family member PUMA at the mRNA and protein level, and by conformational activation of BAX which translocated to mitochondria. These DeltaNp73 antisense-mediated alterations led to the induction of apoptosis as detected by decreased cell viability, augmented DNA fragmentation and increased caspase-3 activity in cell lysates. Our results demonstrate the cytoprotective role of DeltaNp73 in neuroblastoma and suggest its use as a target for molecular intervention therapy.
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PMID:DeltaNp73 antisense activates PUMA and induces apoptosis in neuroblastoma cells. 1580 72

Salsolinol, an endogenous neurotoxin, may be involved in the pathogenesis of Parkinson's disease. In this study, we sought to determine whether salsolinol-induced cytotoxicity in SH-SY5Y human neuroblastoma cells, a cloned cell line which expresses dopaminergic activity, could be prevented by overexpressing a Ca(2+) channel, transient receptor potential (TRPC1) protein. Exposure of SH-SY5Y cells to 500 microM salsolinol for 12 h resulted in a significant decrease in thapsigargin or carbachol-mediated Ca(2+) influx. Consistent with these results, SH-SY5Y cells treated with salsolinol showed approximately 60% reduction in TRPC1 protein levels. Confocal microscopy also showed that SH-SY5Y cells treated with salsolinol had a significant decrease in the plasma membrane staining of the TRPC1 protein. Interestingly, overexpression of TRPC1 increases TRPC1 protein levels and also protected SH-SY5Y neuroblastoma cells against salsolinol-mediated cytotoxicity as determined by 3,[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. The protective effect of TRPC1 was blocked by the addition of TRPC1 blockers lanthanum, or 2APB. Activation of TRPC1 protein by either thapsigargin or carbachol further protected SH-SY5Y cells from salsolinol treatments. Staining of SH-SY5Y cells with an apoptotic marker (YO-PRO-1) showed that TRPC1 protein protects against apoptosis. Furthermore, TRPC1 overexpression also inhibited cytochrome c release and decreased BAX protein levels required for apoptosis. Taken together, these findings suggest that the reduction in cell surface TRPC1 protein expression in response to salsolinol may be a contributory factor in cellular toxicity of the dopaminergic neurons. Furthermore, overexpression of TRPC1 could inhibit apoptotic complex thereby increasing neuronal cell survivability in Parkinson's disease.
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PMID:TRPC1 protects human SH-SY5Y cells against salsolinol-induced cytotoxicity by inhibiting apoptosis. 1676 19


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