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)

Human BCL9 gene is over-expressed in some cases of acute lymphoblastic leukemia (ALL) with t(1;14)(q21;q32). Drosophila segment polarity gene legless (lgs), encoding wingless-armadillo (WNT - beta-catenin) signaling molecule, is the homolog of human BCL9. Here, we identified and characterized human BCL9-like (BCL9L) gene as well as mouse Bcl9-like (Bcl9l) gene by using bioinformatics. Uncharacterized DLNB11 cDNA (AB094091.1) was derived from human BCL9L gene. Nucleotide sequence of mouse Bcl9l cDNA was determined in silico by assembling mouse ESTs BF464707, BQ258167, 5'-truncated BC003321 cDNA, and mouse genome clone RP24-308H8 (AC125129.5). Human BCL9L and mouse Bcl9l genes were found to consist of eight exons. Exon-intron structure was well conserved between human BCL9L and mouse Bcl9l genes. Human BCL9L (1499 aa) showed 94.0% and 34.8% total-amino-acid identity with mouse Bcl9l (1494 aa) and human BCL9, respectively. Six domains (B9H1-B9H6) were conserved among mammalian BCL9 family proteins. B9H1 and B9H2 domains, and N-terminal part of B9H3 domain were identical to HD1, HD2, and HD3 domains conserved between human BCL9 and Drosophila lgs. B9H4, B9H5 and B9H6 were novel domains. B9H4 domain was characterized by multiple Ser-Pro repeats. Human BCL9L mRNA was expressed in fetal brain, adult lung, amygdala, eye, prostate, and also in several types of tumors including pancreatic cancer, prostate cancer, head and neck tumor and embryonal tumor. BCL9L gene was located between BLR1 and UPK2 genes within the commonly deleted region of neuroblastoma at human chromosome 11q23.3. This is the first report on human BCL9L and mouse Bcl9l.
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PMID:Identification and characterization of human BCL9L gene and mouse Bcl9l gene in silico. 1296 48

Most colorectal cancers display chromosomal instability, which is characterized by gross chromosomal rearrangements, loss of heterozygosity and aneuploidy. We have previously demonstrated a link between JC virus strains Mad-1 and Delta98 and colorectal cancer. Others have also associated the virus to the induction of colon cancer and aneuploid brain tumors by producing a highly tumorigenic protein named T antigen (TAg), which binds to beta-catenin and inactivates key proteins such as p53. The aim is to demonstrate that JC virus is capable of inducing chromosomal instability in colonic cells. We used the human colon cancer cell line RKO as a model. The cell line has wild-type p53, wild-type beta-catenin and APC and is diploid. Neuroblastoma JCI cells, which are infected with the virus, VA13 fibroblasts, which are transformed by the SV40 TAg, were used as positive controls. HCT116, which has mutated beta-catenin, and SW480, which is a model of CIN, were also used as controls. The genomes of the Mad-1 and Delta98 strains were transfected into cells. As negative controls we used pUC or no plasmids. Cells were collected at 0, 7, 14, and 21 days after transfection. PCR was used for the detection of TAg and the regulatory region DNA sequences at different time frames and Southern blot of whole genomic extracts for viral DNA integration into the host genome. Immunofluorescence and Western blot were performed for TAg, viral capsid proteins, and nuclear beta-catenin expressions, whereas coimmunoprecipitation was used to detect protein interactions. Karyotype analysis and electron microscopy were performed to seek chromosomal instability and cell abnormalities, respectively. Retention of viral sequences was observed for Mad-1- and Delta98-transfected RKO cells at all time frames with PCR only, whereas Southern blot analysis showed nonintegrated sequences at T7 alone. TAg and capsid protein expressions, as well as increased p53 and nuclear beta-catenin, were observed between T0 and T7 for Mad-1 and Delta98 alone. Also, interaction between TAg and both p53 and beta-catenin was also observed between T0 and T7. Chromosomal instability, characterized by chromosomal breakage, dicentric chromosomes, and increasing ploidy, was observed at all time frames for Mad-1 and Delta98, as well as cell abnormalities. In conclusion, we demonstrate that JC virus Mad-1 and Delta98 are able to induce chromosomal instability in colonic cells with a hit and run mechanism that involves an early interaction with beta-catenin and p53.
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PMID:Induction of chromosomal instability in colonic cells by the human polyomavirus JC virus. 1461 21

We have sought to determine the roles of beta-catenin and the Wnt signaling pathway in neurite outgrowth using a model cell system, the Neuro-2a neuroblastoma cell line. Activation of the Wnt signaling pathway disrupts a multiprotein complex that includes beta-catenin, Axin, and glycogen synthase kinase-3 (GSK-3), which would otherwise promote the phosphorylation and degradation of beta-catenin. Stabilized beta-catenin accumulates in the cytosol and in the nucleus; in the nucleus it binds to TCF family transcription factors, forming a bipartite transcriptional activator of Wnt target genes. These events can be mimicked by lithium (Li(+)), which inhibits GSK-3 activity. Both Li(+) and the GSK-3 inhibitor SB415286 induced neurite outgrowth of Neuro-2a cells. Li(+)-induced neurite outgrowth did not require beta-catenin-/TCF-dependent transcription, and increasing levels of beta-catenin either by transfection or using Wnt-3A was not sufficient to induce neurite outgrowth. Interestingly, Axin, which is also a substrate for GSK-3, was destabilized by Li(+) and ectopic expression of Axin inhibited Li(+)-induced neurite outgrowth. Deletion analysis of Axin indicated that this inhibition required the GSK-3 binding site, but not the beta-catenin binding site. Our results suggest that a signaling pathway involving Axin and GSK-3, but not beta-catenin, regulates Li(+)-induced neurite outgrowth in Neuro-2a cells.
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PMID:Glycogen synthase kinase-3 and Axin function in a beta-catenin-independent pathway that regulates neurite outgrowth in neuroblastoma cells. 1466 17

We investigated the effect of 10 microM clozapine on the activity of glycogen synthase kinase-3beta (GSK-3beta) and its upstream and downstream molecules in SH-SY5Y human neuroblastoma cells. Clozapine activates both Akt- and Dvl-mediated phosphorylation of GSK-3beta through phosphorylation at Ser9, and increased total cellular and intranuclear levels of beta-catenin. Pretreatment with the specific inhibitor of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, LY294002 (20 microM), prevented the phosphorylation of Akt but did not affect the phosphorylation of GSK-3beta. These results suggest that clozapine regulates the phosphorylation of GSK-3beta through Wnt signal pathways involving Dvl upstream but not through the PI3K-Akt pathway in SH-SY5Y cells.
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PMID:The effects of clozapine on the GSK-3-mediated signaling pathway. 1498 8

Phellinus linteus is a well-known Oriental medicinal fungus that has various biological activities, including immunomodulatory and anti-tumor activities, the mechanisms of which are poorly understood. In the present study, we investigated the effects of mycelium extracts of P. linteus (MEPL) on the growth of human neuroblastoma SK-N-MC cells. Upon treatment with MEPL, a concentration-dependent inhibition of cell proliferation was observed and cells developed many of the hallmark features of apoptosis, including condensation of chromatin and an increase in the sub-G1 population. The anti-proliferative and apoptotic effects of MEPL were associated with a marked induction of the Bax and cyclin-dependent kinase inhibitor p21. Western blotting and in vitro caspase-3 activity assay demonstrated that the processing/activation of caspases accompanies the generation of MEPL-mediating apoptotic cell death. In addition, the proteolytic cleavage of specific target proteins such as poly(ADP-ribose) polymerase and beta-catenin were observed. Taken together, the present results suggest that apoptotic signals evoked by MEPL in human neuroblastoma SK-N-MC cells may converge caspase-3 activation through an up-regulation of Bax rather than a down-regulation of Bcl-2.
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PMID:Induction of apoptotic cell death by mycelium extracts of Phellinus linteus in human neuroblastoma cells. 1525 70

Dishevelled (Dvl) is a cytoplasmic protein involved in the Wnt-Frizzled signaling cascade, which has also been shown to interact with the cytoskeleton in part through inhibition of glycogen synthase kinase 3beta (GSK3beta). Using mouse neuroblastoma 2A (N2A) cells as a model system, we have found that overexpression of Dvl promotes the outgrowth of neurite-like processes, and leads to the induction of a striking, bipolar morphologic phenotype during neuronal differentiation. In contrast, suppression of Dvl expression using isoform-specific siRNAs led to an inhibition of neurite outgrowth in these cells. In order to further elucidate the mechanism(s) responsible for this effect, we overexpressed several mutant forms of Dvl in the N2A cells, including deletions in each of the three major functional subdomains of the protein (DeltaDIX, DeltaPDZ, DeltaDEP) and point mutations in the two well-defined interaction motifs within the DIX domain (the actin-binding and vesicle-association elements; K58A and K68A/E69A, respectively). These experiments revealed that the DIX domain (and its vesicle-binding subregion) was essential for Dvl's effect on neurite extension and morphogenesis in N2A cells. In contrast, direct overexpression of a degradation-resistant form of beta-catenin (S37A), or a dominant negative GSK3beta mutant (K85R), had no effect on neurite outgrowth or morphology in neuronally differentiating N2A cells; exposure of cells to a pharmacologic inhibitor of GSK3beta (lithium) also had no effect. Taken together, these results suggest that Dvl induces cytoskeletal and morphologic rearrangements in neuronal differentiating N2A cells through a mechanism that cannot be attributed exclusively to modulation of GSK3beta or beta-catenin activity, but which does depend upon a DIX-domain/vesicle-association-dependent signaling pathway.
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PMID:Dishevelled promotes neurite outgrowth in neuronal differentiating neuroblastoma 2A cells, via a DIX-domain dependent pathway. 1554 27

In addition to neuronal vacuolation and astrocytic hypertrophy, dendritic atrophy is a prominent feature of prion disease. Because increased Notch-1 expression and cleavage releasing its intracellular domain (NICD) inhibit both dendrite growth and maturation, we measured their levels in brains from mice inoculated with Rocky Mountain Laboratory (RML) prions. The level of NICD was elevated in the neocortex, whereas the level of beta-catenin, which stimulates dendritic growth, was unchanged. During the incubation period, levels of the disease-causing prion protein isoform, PrPSc, and NICD increased concomitantly in the neocortex. Additionally, increased levels of Notch-1 mRNA and translocation of NICD to the nucleus correlated well with regressive dendritic changes. In scrapie-infected neuroblastoma (ScN2a) cells, the level of NICD was elevated compared with uninfected control (N2a) cells. Long neurofilament protein-containing processes extended from the surface of N2a cells, whereas ScN2a cells had substantially shorter processes. Transfection of ScN2a cells with a Notch-1 small interfering RNA decreased Notch-1 mRNA levels, diminished NICD concentrations, and rescued the long process phenotype. These results suggest that PrPSc in neurons and in ScN2a cells activates Notch-1 cleavage, resulting in atrophy of dendrites in the CNS and shrinkage of processes on the surface of cultured cells. Whether diminishing Notch-1 activation in vivo can prevent or even reverse neurodegeneration in prion disease remains to be established.
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PMID:Notch-1 activation and dendritic atrophy in prion disease. 1564 Mar 54

In eukaryotic cells IQGAP1 binds to and alters the function of several proteins, including actin, E-cadherin, beta-catenin, Cdc42, and Rac1. Yeast IQGAP1 homologues have an important role in cytoskeletal organization, suggesting that modulation of the cytoskeleton is a fundamental role of IQGAP1. Phosphorylation is a common mechanism by which cells regulate protein function. Here we demonstrate that endogenous IQGAP1 is highly phosphorylated in MCF-7 human breast epithelial cells. Moreover, incubation of cells with phorbol 12-myristate 13-acetate (PMA) stimulated phosphate incorporation into IQGAP1. By using mass spectrometry, Ser-1443 was identified as the major site phosphorylated on IQGAP1 in intact cells treated with PMA. Ser-1441 was also phosphorylated but to a lesser extent. In vitro analysis with purified proteins documented that IQGAP1 is a substrate for protein kinase Cepsilon, which catalyzes phosphorylation on Ser-1443. Consistent with these findings, inhibition of cellular protein kinase C via bisindolymaleimide abrogated Ser-1443 phosphorylation in response to PMA. To elucidate the biological sequelae of phosphorylation, Ser-1441 and Ser-1443 were converted either to alanine, to create a nonphosphorylatable construct, or to glutamic acid and aspartic acid, respectively, to generate a phosphomimetic IQGAP1. Although overexpression of wild type IQGAP1 promoted neurite outgrowth in N1E-115 neuroblastoma cells, the nonphosphorylatable IQGAP1 S1441A/S1443A had no effect. In contrast, the S1441E/S1443D mutation markedly enhanced the ability of IQGAP1 to induce neurite outgrowth. Our data disclose that IQGAP1 is phosphorylated at multiple sites in intact cells and that phosphorylation of IQGAP1 will alter its ability to regulate the cytoskeleton of neuronal cells.
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PMID:IQGAP1 promotes neurite outgrowth in a phosphorylation-dependent manner. 1569 13

Changes in plasma membrane electrical potential evoke signals that regulate the expressions of various genes in the nervous system. However, the role of glycogen synthase kinase 3beta (GSK-3beta) in this process has not been elucidated. Thus, this study was performed to examine whether membrane depolarization can regulate the phosphorylation of GSK-3beta and to identify the molecular mechanisms involved in this regulation. The depolarization by treating with 100 mm KCl for 5 min resulted in the undulating phosphorylation of GSK-3beta at Ser-9 in SH-SY5Y human neuroblastoma cells, in H19 -7/IGF-IR rat embryonic hippocampal cells, and in PC12 rat pheochromocytoma cells, but not in A172 human glioblastoma cells. Cellular beta-catenin contents showed a temporal pattern similar to that of the Ser-9 phosphorylation of GSK-3beta. Treatment with wortmannin or calphostin C or the expression of dominant negative Akt inhibited phosphorylation of GSK-3beta at Ser-9 following the KCl-induced depolarization of SH-SY5Y cells. Moreover, pretreatment with okadaic acid or cyclosporin A blocked the dephosphorylation of GSK-3beta at Ser-9 at 0, 15, and 30 min after KCl-induced depolarization, and the activity of protein phosphatases (PP) 2A and 2B increased at these times. Treatment with nifedipine or calcium-free medium inhibited GSK-3beta dephosphorylation following membrane depolarization, and the amounts of co-immunoprecipitated GSK-3beta and PP2A changed in parallel with GSK-3beta dephosphorylation. Our study demonstrated that KCl-induced depolarization caused undulating GSK-3beta phosphorylation/dephosphorylation, which was regulated for the most part by phosphatidylinositol 3-kinase and Akt (phosphorylation) and PP2A and PP2B (dephosphorylation), respectively.
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PMID:Membrane depolarization induces the undulating phosphorylation/dephosphorylation of glycogen synthase kinase 3beta, and this dephosphorylation involves protein phosphatases 2A and 2B in SH-SY5Y human neuroblastoma cells. 1579 72

Neuroblastoma (NB), an embryonal malignancy, poses a major challenge in pediatric oncology for the treatment of disseminated forms. Here, we report the decrease of Wnt-5a gene expression in high-risk NB (HR-NB) as well as in cultured metastatic neuroblasts. Wnt-5a is a member of the Wnt signaling pathway which is mainly associated with patterning decisions in the embryonic nervous system. Moreover, Wnt-5a has been involved in metastatic melanoma progression and invasive ductal breast cancer via adhesion and migration alterations. As retinoic acid (RA) plays a major role in the neural crest induction and differentiation, we showed that RA reverses the aberrant negative regulation of Wnt-5a in metastatic neuroblasts. While beta-catenin expression remained unchanged, PKC-theta, a protein kinase C isoform, was evidenced to increase and parallel Wnt-5a level. For the first time, the involvement of Wnt-5a through the Wnt/calcium signaling is highlighted in the pathogenesis of a pediatric embryonal malignancy, NB.
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PMID:Wnt-5a gene expression in malignant human neuroblasts. 1592 44


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