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)

Effects of various differentiating agents and DNA demethylating agents on the expression of choline acetyltransferase (ChAT) and tyrosine hydroxylase (TH), marker enzymes for cholinergic and adrenergic differentiation, respectively, were examined in N-18 neuroblastoma cells. Retinoic acid (RA) and a medium conditioned over C6-glioma cells (GCM), which have been shown to enhance the ChAT activity of PC12 cells, NG108-15 cells and fetal rat brain cells, did not induce ChAT activity of N-18 cells. Treatment of the cells with the DNA demethylating agents alone also did not affect ChAT activity. But after pretreatment of the cells with the DNA demethylating agents, ChAT activity of N-18 cells was greatly increased by either RA or GCM. TH activity of N-18 cells was enhanced by forskolin, an activator of adenylate cyclase. The pretreatment of the cells with the DNA demethylating agents greatly enhanced the induction of TH activity by forskolin. Levels of ChAT and TH messenger RNA were altered in accordance with changes in ChAT and TH activities. Possible mechanisms of the actions of the demethylating agents on cholinergic and adrenergic differentiation are discussed.
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PMID:Induction of cholinergic and adrenergic differentiation in N-18 cells by differentiation agents and DNA demethylating agents. 750 29

Retinoic acid (RA) decreased growth and increased morphologic differentiation of human neuroblastoma LA-N-1 cells. These phenomena correlated with a specific enhancement of PHA-E lectin binding to a glycoprotein of MW 67 kDa (gp67). Gp67 was found susceptible to N-glycanase and displayed BSA binding by affinity chromatography analysis. The chemotherapeutic agent methotrexate (MTX) also reduced growth and induced differentiation of LA-N-1 cells. In addition, the cells responded to MTX as well as to doxorubicin by a marked increase in PHA-E binding to gp67. We conclude that reduced growth and induction of morphological differentiation of LA-N-1 cells correlates with increased binding of PHA-E to gp67.
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PMID:Retinoic acid and methotrexate specifically increase PHA-E-lectin binding to a 67-kDa glycoprotein in LA-N-1 human neuroblastoma cells. 754 81

The relationship of genes associated with contact inhibition of cell growth and the commitment for differentiation was studied in the human neuroblastoma cell line SH5Y. These cells could be induced to differentiate in vitro into neuronal-like cells upon incubation with retinoic acid, an event that was accompanied by an enhancement in levels of neuron-specific acetylcholinesterase. The kinetics of differentiation, based on morphology and acetylcholinesterase levels, showed that proliferation arrest always preceded differentiation and may be a prerequisite for differentiation. To determine if this growth arrest is mediated by the same pathway underlying contact inhibition of proliferation, the expression of a gene associated with the induction of contact inhibition, protein disulfide isomerase (PDI), was quantified by Northern blot analysis and enzymatic activity after retinoic acid treatment. Retinoic acid caused a significant elevation of PDI-mRNA within 24 hrs. after treatment with a corresponding increase in enzyme activity which immediately preceded proliferation arrest and differentiation. Bacitracin, a specific inhibitor of PDI, abrogated the ability of retinoic acid to induce differentiation. However, treatment with interferon also increased PDI activity and caused proliferation arrest and SH5Y differentiation but into a fibroblastoid cell without neurite outgrowth. These results suggest that the commitment for differentiation of SH5Y cells involves a form of proliferation arrest in which activation of PDI activity is a required and early event but one that does not determine the final differentiation pathway.
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PMID:Induction of protein disulfide isomerase during proliferation arrest and differentiation of SH5Y neuroblastoma cells. 754 84

Retinoic acid has considerable potential for the chemoprevention and chemotherapy of cancer. Neuroblastoma cells differentiate in response to retinoic acid in vitro, an observation that has led to clinical trials using either the 13-cis or all-trans isomers of retinoic acid. We review the effects of retinoic acid on neuroblastoma, and the potential involvement of nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs). 9-cis retinoic acid is a ligand for RXRs, and we review recent data on the differential effects of 9-cis and all-trans retinoic acid on neuroblastoma differentiation and proliferation in vitro, and possible mechanisms of action via hetero- and homodimers of RARs and RXRs. Although there is uncertainty whether or not 9-cis retinoic acid produces its biological effects primarily via RXR homodimers, in vitro data suggest that this isomer of retinoic acid or stable analogues may have considerable potential for the treatment of resistant, disseminated neuroblastoma.
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PMID:Gene expression and neuroblastoma cell differentiation in response to retinoic acid: differential effects of 9-cis and all-trans retinoic acid. 757 51

Here we report that protein tyrosine phosphatases (PTPases), like their enzymatic counterpart the protein tyrosine kinases, can play an important role in cell differentiation. Expression of the transmembrane PTPase receptor protein tyrosine phosphatase alpha (RPTP alpha) is transiently enhanced during neuronal differentiation of embryonal carcinoma (EC) and neuroblastoma cells. Retinoic acid induces wild type P19 cells to differentiate into endoderm- and mesoderm-like cells. By contrast, retinoic acid treatment leads to neuronal differentiation of P19 cells, ectopically expressing functional RPTP alpha, as illustrated by their ability to generate action potentials. Endogenous pp60c-src kinase activity is enhanced in the RPTP alpha-transfected cells, which may be due to direct dephosphorylation of the regulatory Tyr residue at position 527 in pp60c-src by RPTP alpha. Our results demonstrate that RPTP alpha is involved in neuronal differentiation and imply a role for pp60c-src in the differentiation process.
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PMID:Receptor protein tyrosine phosphatase alpha activates pp60c-src and is involved in neuronal differentiation. 769 97

The effects of retinoic acid on components of the cAMP-dependent signalling system were examined in two related human neuroblastoma cell lines SK-N-SH-F (SHF) and SK-N-SH-N (SHN). Retinoid treatment for a week significantly increased the concentration of intracellular cAMP and the levels of activity of protein kinase A and adenylate cyclase in both cell lines. Retinoic acid treatment also caused a very marked translocation of nucleoside diphosphate kinase from the cytosol to the membrane fraction. The increases in cyclic nucleotide and protein kinase A activity were observed to occur as early as within 1 and 2 days respectively and preceded or were concurrent with the onset of observable morphological differentiation. Results also indicated that agents which elevated intracellular cAMP caused neuronal differentiation and blunted retinoic acid-induced melanocytic differentiation in SHF cells. However, increases in cAMP brought about by treatment of SHF cells with retinoic acid alone were several-fold smaller and thus insufficient to induce neuritogenesis in these cells. The results as a whole indicate that one overall effect of retinoic acid treatment is to upgrade the activity of components of the cAMP-dependent signalling system in both neuroblastoma cell lines. However, retinoic acid causes the SH-F and SH-N cell lines to differentiate along different routes which means that the upgrading responses may be related to more general aspects of differentiation rather than to specific phenotype expression.
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PMID:Effect of retinoic acid on Nm/23 nucleoside diphosphate kinase and components of cyclic adenosine monophosphate-dependent signalling in human neuroblastoma cell lines. 774 87

The effect of 2,5-hexanedione (2,5-HD) on the distribution of the neurofilamental (NF) proteins and vimentin was examined in human neuroblastoma cell line SK-N-SH with immunocytochemical methods. Retinoic acid (10 microM) induced differentiation into neuronal cells resulting in the outgrowth of processes and synthesis of NF proteins in the majority of the cells. A minority (4%) differentiated as large fibroblasts. Cells were exposed to 0-10 mM 2,5-HD for 3 days. In neuronal cells a concentration-dependent accumulation of NF proteins was detected as a spherical structure in the perikaryon. Neurofilaments in differentiated SK-N-SH cells were more susceptible to 2,5-HD than NF in undifferentiated cells, as the effects were observed at much lower 2,5-HD concentrations. In contrast, no accumulation of vimentin was detected in the fibroblastic cells.
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PMID:Sensitivity to 2,5-hexanedione of neurofilaments in neuroblastoma cell line SK-N-SH increases during differentiation. 781 83

p21ras is a membrane-associated guanine nucleotide-binding protein with intrinsic GTPase activity. Like other guanine nucleotide-binding proteins p21ras is active when GTP bound and inactive when GDP bound. Phosphorylation of p21ras is regulated by the GTPase activity of type I GAP120 and NF1-GRD. In this study we have identified type I GAP120 and two NF1-GRD mRNAs in three neuroblastoma cell lines, IMR-32, SK-N-SH and SK-N-MC. NF1-GRD mRNA was expressed in all cell lines at a similar level but type I GAP120 mRNA was more abundant in the IMR-32 cell line. Retinoic acid induced differentiation of all three cell lines, this effect was most marked in the SK-N-SH line. This differentiation was accompanied by an increase in both type I GAP120 and NF1-GRD mRNAs. Retinoic acid induced differentiation had no effect on the ratio of type I to type II NF1-GRD mRNA. In seven patient tumour samples examined type I GAP120 and NF1-GRD were coexpressed, type I GAP120 at a higher level than NF1-GRD in all tumour stages. Type I was the predominant NF1-GRD mRNA. The expression of type I GAP120 was similar in all tumour stages but the total level of NF1-GRD was higher in stage 2 and 3 tumours than in stage 4 tumours. In summary, these results suggest increased type I GAP120 and NF1-GRD mRNA are associated with differentiation in neuroblastoma cells.
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PMID:Changing expression of GTPase activating proteins with differentiation in neuroblastoma. 785 16

RC3 encodes a thyroid hormone-dependent, calmodulin-binding, protein kinase C substrate (neurogranin, p17) present in the dendritic spines of discrete neuronal populations in the forebrain. Its physiological role could be related to synaptic plasticity, memory, and other processes. In the present work we have isolated and sequenced 2.4 kbp of genomic DNA upstream from the origin of transcription and determined its nucleotide sequence. The major features of the RC3 promoter are the absence of TATA and CAAT boxes and the presence of an Initiator sequence surrounding the cap site. By sequence analysis we identified several cis-acting regulatory elements, among them response elements for retinoic acid and steroid (glucocorticoids/progesterone) hormone receptors. An oligonucleotide containing the retinoic acid responsive element bound to retinoic acid receptors specifically in vitro and conferred retinoic acid regulation to a heterologous promoter after transfection in COS-7 cells. Retinoic acid and dexamethasone, respectively, increased activity of the RC3 promoter in neuroblastoma cells when a deletion construct containing the retinoic acid and the glucocorticoid responsive elements was cotransfected with retinoic acid receptor or glucocorticoid receptor expression vectors. When added together all-trans retinoic acid and dexamethasone had additive effects. Despite the fact that RC3 expression in vivo is thyroid hormone-dependent, no evidence for the presence of a thyroid hormone responsive element was found within the 2.4 kbp flanking region analyzed and thyroid hormone did not increase reporter activity after cotransfection of suitable constructs with thyroid hormone receptor expression vectors. Our results suggest that the expression of RC3 in vivo could be subject to complex physiological signals, including retinoids and steroid hormones in addition to thyroid hormones.
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PMID:Characterization of the promoter region and flanking sequences of the neuron-specific gene RC3 (neurogranin). 789 4

Retinoic acid (RA) nuclear receptors (RARs) are thought to mediate the cellular and molecular effects of RA on a wide variety of tissues. In most cell types, RAR alpha expression remains relatively constant following exposure to RA, while that of RAR beta is rapidly induced. In this study, we show that in human neuroblastoma, a cell type exceptionally sensitive to RA-induced differentiation, RAR alpha as well as RAR beta is markedly up-regulated by RA treatment. This effect was consistent in all 5 neuroblastoma cell lines tested and was reflected in a 2- to 5-fold increase in receptor mRNA levels as assessed by Northern-blot analysis. Using LA-N-5 human neuroblastoma cells, we found that receptor up-regulation occurred in a time- and dose-dependent fashion with increases in both RAR alpha and beta mRNA detectable 1-2 hr after the addition of RA. These inductions were not abrogated by cycloheximide, indicating that protein synthesis was not required for the RA responses. Nuclear run-off experiments combined with Northern-blot analysis of RAR alpha stability directly demonstrated that the up-regulation of RAR alpha mRNA levels reflected an increased rate of transcription without changes in message half-life. These findings, showing direct activation by RA of RAR alpha gene transcription in human neuroblastoma cells, suggest differences in the overall regulation of this receptor from that found in most other RA-inducible tissue.
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PMID:Retinoic acid up-regulates nuclear retinoic acid receptor-alpha expression in human neuroblastoma cells. 811 74


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