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)

Synapsin Ia and synapsin Ib are abundant synaptic vesicle proteins that are derived by differential splicing from a single gene. To identify control elements directing the neuronal expression of synapsins Ia/b, we functionally analyzed the promoter region of the human synapsin I gene. A hybrid gene was constructed containing 2 kilobases of 5' flanking sequence from the synapsin I gene fused to the bacterial gene chloramphenicol acetyltransferase and transfected into 12 different neuronal and nonneuronal cell lines. In general, expression of the chimeric reporter gene showed excellent correlation with endogenous expression of synapsin I in different neuronal cell lines, whereas transcription was low in all nonneuronal cell lines examined. The addition of the simian virus 40 enhancer promoted non-tissue-specific expression. Deletion mutagenesis of the synapsin I promoter revealed the presence of positive and negative sequence elements. A basal (constitutive) promoter that directs reporter gene expression in neuronal and nonneuronal cell lines was mapped to the region -115 to +47. The promoter region from -422 to -22 contains positive elements that upon fusion with the herpes simplex virus thymidine kinase promoter potentiate its transcription in PC12 and neuroblastoma cells but not in Chinese hamster ovary cells.
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PMID:Characterization of tissue-specific transcription by the human synapsin I gene promoter. 184 57

The 5'-terminal region of the rat gene for the neuron-specific phosphoprotein, synapsin I, was isolated and sequenced. It comprises 1472 nucleotides (nt) of 5'-flanking sequence, 507 nt of the first exon, and 242 nt of the first intron. A single transcription start site was mapped by primer extension and S1 nuclease analysis. A sequence of 340 nt upstream from the transcription start site and the first exon are G+C-rich and enriched in CpG dinucleotides, resembling a CpG island. The 5'-flanking sequence lacks TATA and CAAT consensus elements but contains a consensus motif for the cAMP-responsive element. Furthermore, we notice two potential consensus motifs which are also found in corresponding positions in the genes for the nerve growth factor receptor and the 68-kDa neurofilament protein. The 5'-terminal region of the human synapsin I gene was also cloned and sequenced. A high degree of sequence conservation between rat and human is found in the upstream 340 nt that coincides precisely with the G+C-rich domain and includes the consensus elements, and throughout the first exon including the untranslated sequence. Sequence conservation is also observed further upstream and at the beginning of the first intron. In a transient chloramphenicol acetyltransferase expression assay, 5'-flanking sequences of the rat synapsin I gene function as strong promoters in neuroblastoma cells, but not in fibroblastoid cells. 225 nt of 5'-flanking sequence and 105 nt of 5'-untranslated sequence are sufficient for cell-type specific transcription in this assay.
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PMID:The 5'-flanking region of the synapsin I gene. A G+C-rich, TATA- and CAAT-less, phylogenetically conserved sequence with cell type-specific promoter function. 211 19

Synapsin I is implicated in the modulation of neurotransmitter release and in synaptogenesis and is regulated by phosphorylation. The rat and human synapsin I genes both carry CRE and TRE consensus sequences in their promoter regions. This suggested that protein kinase-mediated signal pathways might also regulate synapsin I activity at the level of gene expression and thus contribute, on a slower time scale, to synaptic plasticity. We have therefore investigated, in neuroblastoma cell lines, the effects of agents that activate protein kinases on synapsin I gene expression. Unexpectedly, treatment with forskolin/IBMX was not found to enhance synapsin I mRNA levels. Rather, it causes a decrease to approximately 50% within 1 day although several CRE-dependent control genes are strongly induced. The calcium ionophore, A23187, lowers synapsin I mRNA to approximately 75%, and the phorbol ester, TPA, is without effect. Transient expression of a CAT fusion gene under the control of the synapsin I promoter region is also inhibited by forskolin/IBMX, as well as by protein kinase A (PKA) overexpression, suggesting that the decrease of synapsin I mRNA in response to forskolin/IBMX is due to the inhibition of transcription. Mutation of the CRE consensus does not affect the response to PKA, but it reduces the constitutive activity of synapsin I promoter constructs down to 30-50%. Nuclease footprinting experiments demonstrate sequence-specific binding proteins from brain, liver and NS20Y cell nuclear extracts to the CRE consensus sequence of the rat synapsin I promoter.
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PMID:The CRE consensus sequence in the synapsin I gene promoter region confers constitutive activation but no regulation by cAMP in neuroblastoma cells. 771 Oct 68

Synapsin I is a phosphoprotein localized to the cytoplasmic surface of synaptic vesicles and is one of the best characterized neuron-specific proteins. Synaptophysin is an integral membrane glycoprotein, also located on presynaptic vesicles, which has been shown to be a useful immunohistochemical marker for neuroendocrine/neuronal differentiation in tumor diagnosis. The sensitivity and specificity of immunohistochemical staining for these two proteins in formalin-fixed, paraffin-embedded tissues was studied in a series of 67 neuroectodermal, neuroendocrine, and non-neural tumors. Intense immunoreactivity for both synapsin I and synaptophysin was observed in tumors containing well-differentiated neurons (gangliocytoma, ganglioglioma, neurocytoma). In these tumors, immunostaining was primarily concentrated along the outer surface of the cell membrane of the neuronal cells. Primitive neuroectodermal tumors (PNETs) (cerebral PNET, medulloblastoma, neuroblastoma) and most neuroendocrine tumors generally showed less intense and more variable immunoreactivity for these proteins. In most cases, immunostaining for synapsin I was sharper and often more intense than for synaptophysin. Some PNETs and neuroendocrine tumors that were immunoreactive for synapsin I did not stain for synaptophysin. We conclude that synapsin I is a reliable, sensitive immunohistochemical marker for neuronal/neuroendocrine differentiation in human neoplasms and may offer some advantages over synaptophysin when applied to formalin-fixed, paraffin-embedded tissues, particularly in the evaluation of primitive neuroectodermal tumors and neuroendocrine tumors.
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PMID:Immunohistochemistry of synapsin I and synaptophysin in human nervous system and neuroendocrine tumors. Applications in diagnostic neuro-oncology. 828 27

Non-neuronal cells and undifferentiated neuronal progenitors express the neuron-restrictive silencer factor (NRSF), a silencer protein which represses neuronal gene transcription in these cell types. Neuroblastoma, a childhood tumor of neuroectodermal origin, shares some biological properties with neuronal progenitor cells and can acquire neuronal phenotypes in response to a variety of agents, including cyclic AMP and staurosporine. We report here that NRSF mRNA content was markedly decreased in a human neuroblastoma cell line following differentiation induced by staurosporine plus cyclic AMP, with a concomitant increase in mRNA levels of synapsin I, whose expression is restricted to neuronal cell types. Our novel finding suggests that NRSF expression is related to an undifferentiated state and regarded as a biochemical marker of neuronal differentiation in neuroblastoma cells.
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PMID:Decrease in neuron-restrictive silencer factor (NRSF) mRNA levels during differentiation of cultured neuroblastoma cells. 883 Aug 54

We examined the phenotypic changes of neuroblastoma cells chronically treated with cAMP and nanomolar concentrations of staurosporine. These agents, given together, produced cells with a neuronal morphology and a delayed increase (approximately 10 days) in synapsin I mRNA levels. Dopamine-beta hydroxylase mRNA was upregulated within 24 h. We provide evidence that low-dose staurosporine acts cooperatively with cyclic AMP in the acquisition of mature neuronal phenotypes.
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PMID:Long-term regulation of synapsin I gene expression and neuronal morphology by cyclic AMP and low-dose staurosporine. 884 26

N18TG2 neuroblastoma clone is defective for biosynthetic neurotransmitter enzymes; its inability to establish functional synapses is overcome in the neuroblastoma x glioma 108CC15, where acetylcholine synthesis is also activated. These observations suggest a possible relation between the ability to produce acetylcholine and the capability to advance in the differentiation program and achieve a fully differentiated state. Here, we report the characterization of several clones after transfection of N18TG2 cells with a construct containing a cDNA for rat choline acetyltransferase (ChAT). The ability of these clones to synthesize acetylcholine is demonstrated by HPLC determination on cellular extracts. In the transfected clones, northern blot analysis shows increased expression of mRNAs for a specific neuronal protein associated with synaptic vesicles, synapsin I. Fiber outgrowth of transfected clones is also evaluated to establish whether there is any relation between ChAT levels and morphological differentiation. This analysis shows that the transfected clone 1/2, not expressing ChAT activity, displays a very immature morphology, and its ability to extend fibers also remains rather poor in the presence of "differentiation" agents such as retinoic acid. In contrast, clones 2/4, 3/1, and 3/2, exhibiting high ChAT levels, display higher fiber outgrowth compared with clone 1/2 in both the absence and the presence of differentiating agents.
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PMID:Cellular acetylcholine content and neuronal differentiation. 932 65

We investigated the effect of rabies virus infection on the actin cytoskeleton using various techniques. Confocal microscopic examination of rabies virus-infected neuroblastoma cells at late stages of infection revealed a dramatic decrease in F-actin staining. The results of a fluorimetric assay with pyrenylated actin indicated that purified rabies virus nucleocapsid has no direct action on the kinetics of actin polymerization and only a weak effect on the final extent of polymerization. Video-microscopy experiments with purified components showed that rabies virus nucleocapsid inhibits the actin-bundling effect induced by dephospho-synapsin I, a neuron-specific protein which is known to exert a control on the actin-based cytoskeleton. Thus, the observed decrease in F-actin staining in infected cells might be ascribed to an indirect action of rabies nucleocapsid on the effects of actin-binding proteins such as synapsin I.
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PMID:Alteration of the actin-based cytoskeleton by rabies virus. 936 69

Early events in rabies virus entry into cultured IMR-32 human neuroblastoma cells were investigated. After adsorption of rabies virus to the cell surface in the cold and warming to 37 degrees C in the presence of tracers for early endosomes, rabies virus and tracers were localized by immunofluorescence microscopy. After 5 min, rabies virus colocalized with Lucifer Yellow, Texas Red-dextran, rhodamine-wheat germ agglutinin, and transferrin receptor in puncta in the cell body, neurites, and nerve terminals. Rabies virus did not colocalize with lysosomal glycoprotein. An acidotropic probe revealed that some of the virus-containing puncta were acidified. Rabies virus also colocalized with synapsin I, a synaptic vesicle marker, in swellings along processes, indicating some virus enters nerve terminals. Electron microscopy revealed the presence of rabies virus within irregular membrane compartments located near the cell surface in the cell body and neurites. The membrane of the virus particle was often continuous with that of the vacuole. It is concluded that rabies virus enters IMR-32 neuroblastoma cells by adsorptive endocytosis and that, shortly after entry, rabies virus is located within and fuses with acidic endosomes.
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PMID:Rabies virus entry into endosomes in IMR-32 human neuroblastoma cells. 974 68

The zinc finger protein RE-1-silencing transcription factor (REST)1 is a transcriptional repressor that represses neuronal genes in nonneuronal tissues. Transfection experiments of neuroblastoma cells using a REST expression vector revealed that synapsin I promoter activity is controlled by REST. The biological activity of REST was further investigated using a battery of model promoters containing strong promoters/enhancers and REST binding sites. REST functioned as a transcriptional repressor when REST binding motifs derived from the genes encoding synapsin I, SCG10, alpha1-glycine receptor, the beta2-subunit of the neuronal nicotinic acetylcholine receptor, and the m4-subunit of the muscarinic acetylcholine receptor were present in the promoter region. No differences in the biological activity of these REST binding motifs tested were detected. Moreover, we found that REST functioned very effectively as a transcriptional repressor at a distance. Thus, REST represents a general transcriptional repressor that blocks transcription regardless of the location or orientation of its binding site relative to the enhancer and promoter. This biological activity could also be attributed to isolated domains of REST. Both repressor domains identified at the N and C termini of REST were transferable to a heterologous DNA binding domain and functioned from proximal and distal positions, similar to the REST protein.
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PMID:Biological activity and modular structure of RE-1-silencing transcription factor (REST), a repressor of neuronal genes. 975 36


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