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)

Hypoxia is known to induce extravasation of lymphocytes and leukocytes during ischemic injury and increase the metastatic potential of malignant lymphoid cells. We have recently identified a new adhesion molecule, hypoxia-activated ligand-1/13 (HAL-1/13), that mediates the hypoxia-induced increases in lymphocyte and neutrophil adhesion to endothelium and hypoxia-mediated invasion of endothelial cell monolayers by tumor cells. In this report, we used expression cloning to identify this molecule as the lupus antigen and DNA-dependent protein kinase-associated nuclear protein, Ku80. The HAL-1/13-Ku80 antigen is present on the surface of leukemic and solid tumor cell lines, including T and B lymphomas, myeloid leukemias, neuroblastoma, rhabdomyosarcoma, and breast carcinoma cells. Transfection and ectopic expression of HAL-1/13-Ku80 on (murine) NIH/3T3 fibroblasts confers the ability of these normally nonadhesive cells to bind to a variety of human lymphoid cell lines. This adhesion can be specifically blocked by HAL-1/13 or Ku80-neutralizing antibodies. Loss of expression variants of these transfectants simultaneously lost their adhesive properties toward human lymphoid cells. Hypoxic exposure of tumor cell lines resulted in upregulation of HAL-1/13-Ku80 expression at the cell surface, mediated by redistribution of the antigen from the nucleus. These studies indicate that the HAL-1/13-Ku80 molecule may mediate, in part, the hypoxia-induced adhesion of lymphocytes, leukocytes, and tumor cells.
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PMID:Hypoxia-activated ligand HAL-1/13 is lupus autoantigen Ku80 and mediates lymphoid cell adhesion in vitro. 1124 7

The glioma amplified sequence 41 (GAS41) was previously isolated by microdissection mediated cDNA capture from the glioblastoma multiforme cell line TX3868 and shown to be frequently amplified in human gliomas. We determined the complete cDNA sequence of the GAS41 gene, demonstrated that the GAS41 protein is evolutionarily conserved, specifically at the N-terminus, and identified the yeast transcription factor tf2f domain within the GAS41 sequence. A human multiple-tissue Northern blot revealed ubiquitous expression of GAS41 with the highest expression in human brain. After generating polyclonal antibodies we found GAS41 protein expression in the nucleus of the TX3868 cell line by Western blot analysis and immunofluorescence microscopy. The nuclear localization was confirmed for several human tumors including gliomas of different grades of malignancy. In neuroblastoma however, GAS41 was found in the nucleoli but not in the nucleoplasm. Yeast two-hybrid screening of the TX3868 cell line identified the nuclear mitotic apparatus protein (NuMA), the KIAA1009 protein, and prefoldin subunit 1 (PFDN1) as potential interacting partners of GAS41. We generated a polyclonal antibody against the KIAA1009 protein and we demonstrated that the KIAA1009 protein is a nuclear protein, which appears to be co-localized with the GAS41 protein and NuMA.
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PMID:Expression, cellular distribution and protein binding of the glioma amplified sequence (GAS41), a highly conserved putative transcription factor. 1152 Nov 96

Late-onset Alzheimer's disease (AD) is a genetically heterogeneous neurodegenerative disorder. In addition to the apolipoprotein E (APOE) gene on chromosome 19, linkage studies suggest the existence of multiple susceptibility genes for late-onset AD. Genome-wide linkage and chromosome-12-specific linkage studies have identified a broad 50-cM pericentromeric region between 12p12 and 12q13 among non- APOE*4 carriers. Some studies have implicated the alpha2-macroglobulin (A2M) gene in 12p12 as being the chromosome 12 gene, but the results are equivocal. Because of its close proximity to the A2M gene and because it is abundantly expressed in the brain, we reasoned that the oxidized LDL-receptor 1 (OLR1) gene could be a candidate gene for AD. We screened all exons and intron-exon boundaries of the OLR1 gene for new mutations and identified three novel sequence variations in intron 4, intron 5, and the 3' untranslated region (UTR). Pair-wise comparisons between the three polymorphic sites revealed significant linkage disequilibrium ( P<0.0001). We screened more than 800 late-onset AD cases and more than 700 controls for the three OLR1 polymorphisms. All polymorphisms showed significant association with AD after stratification by APOE*4, with the strongest effect being observed for the 3'UTR polymorphism among non- APOE*4 (odds ratio 0.658; 95% confidence interval: 0.47-0.92; P=0.014) and APOE*4 (odds ratio 1.72; 95% confidence interval: 1.07-2.78; P=0.025) carriers. DNA-protein binding assay with nuclear protein extracts from neuroblastoma cells indicated that the OLR1/3'UTR polymorphism affects the binding of a transcription factor in an allele-dependent manner. Our data suggest that genetic variation in the OLR1 gene may modify the risk of AD in an APOE*4-dependent fashion.
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PMID:Investigation of oxidized LDL-receptor 1 (OLR1) as the candidate gene for Alzheimer's disease on chromosome 12. 1238 89

Nitric oxide (NO) is a signaling molecule that in excess causes cell death. Here we report a mechanism of NO-induced transcriptional up-regulation of genes encoding detoxifying enzymes and protective proteins and their role in counteracting NO-induced apoptosis of neuroblastoma cells. Promoter analysis using reporter assays identified the antioxidant response element (ARE) located in the promoter region of NAD(P)H:quinone oxidoreductase 1 (Nqo1) and other detoxifying enzyme genes as responsible for NO-mediated gene induction. The transcription factors NF-E2-related factor 2 (Nrf2) and small maf proteins were detected in NO-induced nuclear protein-ARE complexes. Nrf2 augmented NO-induced, ARE-dependent gene expression, which was blocked by dominant-negative Nrf2 (DN-Nrf2) lacking the transcriptional activation domain. Consistent with these results, Nrf2 was localized in the cytoplasm in unstimulated cells, and NO triggered its rapid nuclear accumulation. Neuroblastoma cells were stably transfected with DN-Nrf2, which repressed both the expression of protective genes and their induction by NO. These DN-Nrf2 cells exhibited reduced NQO1 enzymatic activity and were sensitized to NO-induced apoptosis. Similar results were obtained when Nrf2 expression was blocked by RNA interference. Conversely, stable cells expressing higher levels of Nrf2 protein had elevated NQO1 activity and were protected from NO. Finally, NO-mediated ARE-dependent gene induction occurred well before apoptosis as judged by caspase activation. These results together suggest that NO signals the transcriptional up-regulation of NQO1 and other detoxifying enzyme and protective genes through Nrf2 via the ARE to counteract NO-induced apoptosis of neuroblastoma cells.
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PMID:Nitric oxide-induced transcriptional up-regulation of protective genes by Nrf2 via the antioxidant response element counteracts apoptosis of neuroblastoma cells. 1498 50

Abnormalities in regulation of the beta-amyloid precursor protein (APP) gene might be a crucial factor in Alzheimer's disease (AD). Our aim is to study the role of a specific proximal APP promoter element under the apoptotic condition. Our transfection studies with APP promoter deletion constructs indicate that each cell type differently regulates promoter activity. The minimum region that was sufficient to drive basal promoter activity in neuronal PC12 and neuroblastoma SK-N-SH cells was -75/+104 and -47/+104 bp, respectively. In SK-N-SH cells, the -47/+104 construct displayed the highest promoter activity, and the -75/-46 region acted as a negative regulatory element. Results from the gel electrophoretic mobility shift assay (EMSA) indicate that the -75/-46 region binds to a distinct DNA-protein complex with nuclear protein(s) from HeLa, PC12, NIH-3T3, and neuroblastoma cells. EMSA results from HeLa cells, which were stimulated by serum starvation (SR), indicate a significant induction in the signal of the DNA-protein complex from controls. EMSA results from PC12 cells, which were subjected to hypoxia, indicate a significant reduction in the signal. Our results suggest that the -75/-46 region binds to a protein that is upregulated in serum starvation, and downregulated in hypoxia. Because serum starvation contributes to the induction of apoptosis, these results suggest a role of the 30-bp proximal APP promoter element in enhanced apoptotic neuronal cell death.
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PMID:A proximal gene promoter region for the beta-amyloid precursor protein provides a link between development, apoptosis, and Alzheimer's disease. 1503 5

The amyloid beta-protein (Abeta) deposited in brains of Alzheimer's disease (AD) patients is proteolytically derived from a large Abeta precursor protein (APP). APP gene expression patterns in the AD brain region indicate that abnormalities of gene regulation may be important in AD pathology. To understand the contribution of different cell types to APP gene expression, we studied it at four levels: promoter activity (by reporter gene assay of transfected cells), DNA-nuclear protein interaction (by electrophoretic mobility shift assay), RNA message and protein (by northern and western blotting, respectively). APP mRNA and protein expression levels were greater in neuroblastoma and PC12 cells than in glial or cervix epithelial cells. Relative activity among 12 different promoter regions and within single regions varied according to cell type/cell line. An upstream regulatory region containing a GATA-1 site is necessary for activity in PC12 and glial cells but not in neuroblastoma cells. DNA-protein interactions were examined in three distal and one proximal promoter elements in nuclear extracts belonging to neuronal and non-neuronal cells. The proximal promoter region is important for cell line-specific APP gene expression. Characterization of the APP regulatory region's interaction with cell type-specific nuclear factor(s) is important to understand tissue-specific expression of APP seen in AD subjects.
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PMID:Mechanism of promoter activity of the beta-amyloid precursor protein gene in different cell lines: identification of a specific 30 bp fragment in the proximal promoter region. 1534 27

p73, the homologue of p53, is a nuclear protein whose ectopic expression, in p53+/+ and p53-/- cells, recapitulates the most well-characterized p53 effects, such as growth arrest, apoptosis and differentiation. Unlike p53, which is mutated in half of human cancers, p73 is rarely mutated. However, altered expression of the p73 gene has been reported in neuroblastoma, lung cancer, prostate cancer and renal cell carcinoma. To investigate the potential involvement of p73 in acute myeloid leukemias (AMLs), we analyzed 71 samples from AML patients for the expression pattern of N-terminal transactivation-p73alpha (TA-p73alpha), its spliced isoforms and N-terminal-deleted-p73 transcripts (DeltaN-p73). We detected p73 gene expression in AML irrespective of FAB (French-American-British) subtypes. Notably, the analysis of DeltaN-p73 expression, which has been reported to inactivate both p53 and p73 antitumor effects, revealed a rather peculiar pattern. In fact, DeltaN-p73 transcript and protein were detectable in 27/28 (96.4%) cases of M0, M1, M2, M4, M5 and M6 AML and in 13/41 (31.7%) cases of PML-RARalpha-positive M3 AML (P<0.01). Thus, the distinct gene expression profile of p73 further supports the notion that acute promyelocytic leukemia is a biologically different subset of AML.
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PMID:Analysis of p73 expression pattern in acute myeloid leukemias: lack of DeltaN-p73 expression is a frequent feature of acute promyelocytic leukemia. 1538 38

The tumor suppressor and transcription factor p53 is a key modulator of cellular stress responses, and activation of p53 can trigger apoptosis in many cell types, including neurons. We found that this nuclear protein was significantly phosphorylated when human neuroblastoma SH-SY5Y cells were exposed to in vitro oxidized polyunsaturated fatty acids. To identify an oxidized lipid that induces p53 phosphorylation, we conducted a screening of lipid peroxidation products in human neuroblastoma SH-SY5Y cells and identified 4-oxo-2-nonenal (ONE), a recently identified aldehyde originating from the peroxidation of omega6 polyunsaturated fatty acids, as a potential inducer of the p53 phosphorylation. We also found that ONE induced the phosphorylation of ataxia telangiectasia-mutated, which plays an essential role in transmitting DNA damage signals by the phosphorylation of p53. In addition, exposure of the cells to ONE resulted in an accumulation of ubiquitinated proteins and in a significant inhibition of proteasome activities, suggesting that ONE acted on the ubiquitin-proteasome pathway, a regulatory mechanism of p53 turnover. In addition, the observation that the ONE-induced p53 response was associated with the induction of apoptosis suggested that ONE activated the p53-dependent apoptosis mechanism via activation of the p53 signaling pathway and down-regulation of the p53 turnover. Finally, we observed that the ONE-2'-deoxyguanosine adduct, 7-(2-oxo-heptyl)-substituted 1,N(2)-etheno-2'-deoxyguanosine, was accumulated in the spinal cord motor neurons of patients with sporadic amyotrophic lateral sclerosis. These data may suggest the potential critical role for ONE in the induction of a neuronal apoptosis program during oxidative processes.
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PMID:Identification of a lipid peroxidation product as a potential trigger of the p53 pathway. 1625 Nov 87

Innate immunity is critical for sensing and defending against microbial infections in multicellular organisms. In plants, disease resistance genes (R genes) play central roles in recognizing pathogens and initiating downstream defense cascades. Arabidopsis SNC1 encodes a TIR-NBS-LRR-type R protein with a similar structure to nucleotide binding oligomerization domain (Nod) proteins in animals. A point mutation in the region between the NBS and LRR of SNC1 results in constitutive activation of defense responses in the snc1 mutant. Here, we report the identification and characterization of mos2-1, a mutant suppressing the constitutive defense responses in snc1. Analysis of mos2 single mutants indicated that it is not only required for resistance specified by multiple R genes, but also for basal resistance. Map-based cloning of MOS2 revealed that it encodes a novel nuclear protein that contains one G-patch and two KOW domains and has homologs across the animal kingdom. The presence of both G-patch and KOW domains in the MOS2 protein suggests that it probably functions as an RNA binding protein critical for plant innate immunity. Our discovery on the biological functions of MOS2 will shed light on functions of the MOS2 homologs in animals, where they may also play important roles in innate immunity.
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PMID:MOS2, a protein containing G-patch and KOW motifs, is essential for innate immunity in Arabidopsis thaliana. 1627 71

Here we report a method for efficient transfection of in vitro-transcribed mRNA into two different types of human adherent cells, the neuroblastoma cell line SK-N-AS, and the transformed kidney cell line HEK293. By using newly trypsinized adherent cells in suspension and Lipofectaminetrade mark 2000, we detected a transfection efficiency of 80-90% in both cell lines and a cell viability of 90% in SK-N-AS and 60% in HEK293, 24 h after transfection when using cytoplasmic enhanced green fluorescent protein (EGFP)-mRNA. We have evaluated the different effects of the generally used EGFP that mainly localizes to the cytoplasm and nuclear EGFP, where the nuclear EGFP are more toxic to the cells than the cytoplasmic EGFP. In order to develop a null experiment, we constructed a short non-functional mRNA including a nuclear localization signal and evaluated the concentrations at which mRNA encoding nuclear proteins can be added without a general toxicity, depending on the fact that the proteins are localized to the nucleus. For both SK-N-AS and HEK293 cells, a concentration of up to 100 ng mRNA in 10(5) cells, encoding a nuclear protein with no other function, did not affect the cells. For evaluation of the method, we screened four different human mRNAs, PDG, DFFA, CORT and PEX14, for their ability to affect cell proliferation in these cells. PEX14 was the only gene that significantly (p=0.03) reduced cell proliferation for both cell types, DFFA significantly (p=0.04) reduced cell proliferation in SK-N-AS but not in HEK293 cells. PGD and CORT did not have any effect on cell proliferation. We have developed an easy method for efficient delivery of in vitro-transcribed mRNA into the adherent cell lines, SK-N-AS and HEK293. This method is useful for a quick screening of how different genes affect cell proliferation.
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PMID:Method for efficient transfection of in vitro-transcribed mRNA into SK-N-AS and HEK293 cells: difference in the toxicity of nuclear EGFP compared to cytoplasmic EGFP. 1668 9


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