Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cholinergic neurons are unique among cells since they alone utilize choline not only as a component of major membrane phospholipids, such as phosphatidylcholine (Ptd-Cho), but also as a precursor of their neurotransmitter acetylcholine (AcCho). It has been hypothesized that choline-phospholipids might serve as a storage pool of choline for AcCho synthesis. The selective vulnerability of cholinergic neurons in certain neurodegenerative diseases (e.g., Alzheimer disease, motor neuron disorders) might result from the abnormally accelerated liberation of choline (to be used as precursor of AcCho) from membrane phospholipids, resulting in altered membrane composition and function and compromised neuronal viability. However, the proposed metabolic link between membrane turnover and AcCho synthesis has been difficult to demonstrate because of the heterogeneity of the preparations used. Here we used a population of purely cholinergic cells (human neuroblastoma, LA-N-2), incubated in the presence of [methyl-3H]methionine to selectively label PtdCho synthesized by methylation of phosphatidylethanolamine, the only pathway of de novo choline synthesis. PtdCho, purified by thin-layer chromatography, contained 90% of the label incorporated into lipids, demonstrating that LA-N-2 cells contained phosphatidylethanolamine N-methyltransferase. Three peaks of radioactive material that cochromatographed with authentic Ac-Cho, choline, and phosphocholine were observed when the water-soluble metabolites of the [3H]PtdCho were purified by high-performance liquid chromatography. Their identities were ascertained by subjecting them to enzymatic modifications with acetylcholinesterase, choline oxidase, and alkaline phosphatase, respectively. The results demonstrate that AcCho can be synthesized from choline derived from the degradation of endogenous PtdCho formed de novo by methylation of phosphatidylethanolamine.
 ...
PMID:Synthesis of acetylcholine from choline derived from phosphatidylcholine in a human neuronal cell line. 347 63

The axonal microtubule-associated protein, tau, is thought to play an important role in axonal growth and in the establishment of neuronal polarity. In adult human brain there are six alternatively spliced tau isoforms, which have different microtubule binding affinities in vitro. The tubulin-tau interaction is further modified by phosphorylation of tau and, compared to adult brain tau, both foetal brain tau and paired helical filament (PHF) tau, characteristic of Alzheimer's disease, are hyperphosphorylated. In vivo both the expression of tau isoforms and their phosphorylation states are developmentally regulated. In order to establish the correlation between the expression of tau isoforms and their pattern of phosphorylation, we have characterised these two features in several in vitro models of neuronal differentiation, including the human neuroblastoma cell lines, SK-N-SH, SH-SY5Y and IMR32 cells, rat PC12 cells and primary rat cortical neurones. Sensitive RT-PCR analysis revealed a different complement of tau isoforms in the different cell lines and neuritogenesis was associated mainly with an increase in the overall tau protein level with no apparent phosphorylation changes. A switch in tau isoform expression occurred only at the terminal stages of neuronal development, when it may be important in reinforcing the previously established axonal cytoarchitecture.
 ...
PMID:Tau isoform expression and phosphorylation state during differentiation of cultured neuronal cells. 749 9

To investigate the regulation of posttranslational modifications of tau that might be pertinent to the production of the paired helical filament (PHF) of Alzheimer's disease, we incubated human neuroblastoma cells with the protein phosphatase inhibitor okadaic acid. This treatment results in increased immunoreactivity of tau with the monoclonal antibodies Alz-50, PHF-1, T3P, and NP8, a reduction in Tau-1 immunoreactivity, and an elevation in apparent molecular weight of tau. Moreover, our data demonstrate that accumulation of phosphates in tau leads to a decrease in the turnover rate of tau in the neuroblastoma cells. It is suggested that similar build-up of hyperphosphorylated tau in the neuronal perikarya may represent an early event in PHF formation. The present system facilitates the investigation of regulatory mechanisms governing the occurrence of PHF epitopes, their effects on neuronal cell metabolism, and possible pharmacological intervention.
 ...
PMID:Increased production of paired helical filament epitopes in a cell culture system reduces the turnover of tau. 750 14

Circulating autoantibody to a 48-kD nuclear protein in neurons and astrocytes of the human and bovine cerebrum were present in the serum of a demented patient with an autoimmune disorder. Other human visceral organs, dorsal root ganglion cells, neuroblastoma and glioblastoma cell lines, and rat cerebrum did not react with the patient's serum. No sera from age-matched controls, including those with Alzheimer's disease, reacted with the 48-kD protein. Only the mature neurons and astrocytes of humans and some mammals express the 48-kD protein. This antibody may be responsible for the patient's demented condition.
 ...
PMID:Circulating autoantibody to mature neurons and astrocytes of humans and some mammals present in a demented patient with autoimmune disorder. 750 94

The neurodegenerative pathology observed in Alzheimer's Disease (AD) has been partially attributed to the neurotoxic effects of the amyloid beta-peptide (A beta P), although the mechanisms underlying this neurotoxicity are unknown. Since A beta P is capable of forming cation channels in lipid bilayers, it is possible that the neurotoxic effects on neurons may be mediated by a cation flux. We have used patch-clamp recording techniques to study the effects of A beta P on cation currents in differentiated mouse N1E-115 neuroblastoma cells. In whole-cell recordings, incubation of cells with A beta P for 24 h significantly increased the median peak inward current from -201.8 pA to -352.0 pA, and shifted the voltage at peak current (Vpeak) and that of current activation (Vact) towards more positive potentials. For untreated cells, median Vpeak was 1.7 mV and Vact was -28.9 mV, vs. 10.5 mV and -24.7 mV in A beta P-treated cells. Incubation with the reverse sequence A beta P(40-1) or A beta P(25-35) did not produce significant changes in the amplitude or kinetic behavior of the inward current. At the single channel level, A beta P added to the pipette increased the open probability of cation-conducting ion channels. As determined by cell viability counts, both A beta P(1-40) and the A beta P(25-35) fragment had neurotoxic effects; within 24 h, addition of A beta P reduced the number of viable cells by more than 50%. It is suggested that the neurotoxic effects of A beta P may be mediated by its ability to form cation channels de novo and/or alter the activity of cation channels already present in the cell membrane.
 ...
PMID:Amyloid beta-peptide (A beta P) potentiates a nimodipine-sensitive L-type barium conductance in N1E-115 neuroblastoma cells. 751 31

Galanin (GAL) is a biologically active neuropeptide that has been suggested to play a role in stress-induced inhibition of insulin secretion, in dementia of the Alzheimer's type, and in the regulation of growth hormone secretion. We report here the isolation of a bovine genomic clone containing more than 5-kb 5'-flanking sequences. Partial sequence analysis of the genomic clone revealed an atypical TATA-box in the promoter (ATAAATA) and several consensus sequences that typically bind transcription factors, including those that bind NF kappa B, Sp1, and AP-2. Primer extension and RNase protection analyses revealed that transcription is initiated at two sites, 28 and 31 bp, respectively, downstream from the TATA-box. To locate functionally active regulatory elements on the GAL gene, we first identified a neural crest-derived human neuroblastoma cell line, SK-N-SH subclone SH-SY5Y, that expressed easily detectable levels of endogenous GAL mRNA. We then constructed plasmids containing various lengths of bovine GAL 5'-flanking sequences and the first exon fused to a reporter plasmid encoding luciferase. Transfection of these plasmids into the SH-SY5Y cells and analysis by transient expression indicated that 131 bp of 5' gene sequence was sufficient to obtain maximal basal expression. Further, expression was suppressed 16-fold when 5 kb were included, suggesting the presence of a distal repressor element(s). In another set of experiments, we found that GAL mRNA levels could be induced more than 10-fold by 20-hr treatment with phorbol 12-myristate 13-acetate (PMA). In cells transfected with the same plasmids, luciferase activity was also induced by PMA, but the degree of induction did not significantly differ among the deletion constructions (varying from six- to eight-fold), suggesting that elements conferring PMA induction and/or RNA stabilization may be located within 131 bp of the transcriptional start site, in the first exon, or on gene sequences not studied here.
 ...
PMID:Primary sequence and functional analysis of the bovine galanin gene promoter in human neuroblastoma cells. 752 Jul 3

beta/A4 peptides are known to induce neurodegeneration in cultures of rat brain cells and rat neural cell lines (Yankner et al: Science 250:279-282, 1990; Behl et al: Biochem Biophys Res Commun 186:944-950, 1992). The current data show that these peptides induce similar neurodegeneration in SH-SY5Y neuroblastoma cells, extending characterization of beta/A4 toxicity to a human nerve cell line. Human SH-SY5Y cells respond to aggregated beta/A4 with changes in cell shape, membrane blebbing, antigenic modification, loss of attachment to the substrate, and cell death. beta/A4 peptides require aggregation for maximum toxic effects, as cellular degeneration is evoked by aggregated beta/A4 1-42 and 4-41 cysteine but not by monomeric beta/A4 1-40. Aged (pre-aggregated) beta/A4 1-40 also evoked neurodegeneration. Antigenic changes comprise upregulation of Alzheimer's-type tau epitopes, recognized by the PHF-1 and Alz-50 monoclonals. These particular changes in tau support the connectivity between this in vitro model and mechanisms leading to neurodegeneration in Alzheimer's disease. A significant feature of the SH-SY5Y response is that cells must be differentiated before they become sensitive to the degeneration evoked by beta/A4. Signaling pathways leading to beta/A4-evoked neurodegeneration thus are under experimental control, becoming complete only when proliferating cells withdraw from the cell cycle and develop a postmitotic phenotype.
 ...
PMID:Beta/A4-evoked degeneration of differentiated SH-SY5Y human neuroblastoma cells. 753 43

Alz-50, a monoclonal antibody originally prepared using Alzheimer brain homogenates, reacts with PHF-tau and normal tau on immunoblots, and stains specific neuronal populations in sections from Alzheimer's disease brain. Although the Alz-50 epitope has been mapped to amino acids 2-10 present in all human tau isoforms, minimal Alz-50 immunoreactivity is present in tissue from control brain, suggesting Alz-50 binding may be dependent on tau conformational differences. The absence of conclusive results concerning Alz-50 binding presents the possibility of Alz-50 immunoreactivity with proteins other than tau. The present study demonstrates Alz-50 cross-reactivity with denatured bovine serum albumin (BSA) and human serum albumin (HSA). Using LA-N-5 neuroblastoma cells, BSA from serum-containing media was present in cell homogenates and was found to be Alz-50-reactive on immunoblots. In fact, Alz-50 (0.1 microgram/ml) recognized as little as 78 ng of BSA and 312 ng of HSA. Since Alz-50 does not recognize native BSA, blocking of immunoblots with 3% BSA did not alter Alz-50 reactivity with tau from LA-N-5 cells. On SDS-polyacrylamide gels, HSA (approximately 69 kDa) migrates very closely to the pattern of A68 (PHF-tau) from Alzheimer brain homogenates. Hence, the presence of BSA or other albumins in cell or brain homogenates may be an important concern when using the Alz-50 antibody.
 ...
PMID:Monoclonal antibody Alz-50 reacts with bovine and human serum albumin. 753 57

We have characterized somatostatinergic phenotype markers of the human neuroblastoma, LA-N-2. A single mRNA-transcript (approximately 850bp) and two cellular somatostatin immunoreactivity forms, a high molecular weight form (M(r) 15,000) and a fragment corresponding to somatostatin-28 was found, while the somatostatin-14 peptide was absent. Saturation binding experiments demonstrated a single class of high-affinity somatostatin receptors with Kd and Bmax of 0.27 +/- 0.03 nM and 45 +/- 1 fmol/mg protein. Partial G-protein uncoupling (30%) was demonstrated, using GTP gamma S, with an affinity of 9.7 nM. The LA-N-2 cell line, previously shown to be cholinergic, may serve as a simplified system to elucidate heterologous neurotransmittor interactions. Such studies are of interest since dysfunctions of the cholinergic basal forebrain neurons and somatostatin immunoreactive interneurons have been consistently observed in Alzheimer's disease.
 ...
PMID:Somatostatinergic phenotype markers in the human neuroblastoma cell-line LA-N-2. 755 50

Neurofibrillary tangles in Alzheimer's disease brain consist mainly of abnormally phosphorylated tau proteins organised in paired helical filaments. Induction of tau phosphorylation in living neurons by hyperstimulation is monitored by specific monoclonal antibodies, such as AT-8 and PHF-1. By quantitative immunocytochemistry, we show that aberrant phosphorylation at the Ser199/Ser202 epitope (AT-8) and at the Ser 396 epitope (PHF-1) are moderately induced, proportionally to the degree of kinase stimulation. Whereas AT8 expression is prominent after 48 h, cell death becomes significant at 72 h and is related to the degree of stimulation and the expression level of aberrant tau phosphorylation. Time-lapse videomicroscopy of individual neuroblastoma cells suggest that hyperstimulation leads to a form of morphological over-differentiation. Immediately before cell death, some cells tend to display some features of mitosis. The data suggest a strong correlation between the expression of specific PHF-epitopes and subsequent cell death. The extended time scale of toxicity in this model may be appropriate to study in more detail the steps leading to aberrant phosphorylation associated neurotoxicity.
 ...
PMID:Neuronal kinase stimulation leads to aberrant tau phosphorylation and neurotoxicity. 756 53


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>