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)

Incubation of purified rat brain tubulin with cholera toxin and radiolabeled [32P] or [8-3H]NAD results in the labeling of both alpha and beta subunits as revealed on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Treatment of these protein bands with snake venom phosphodiesterase resulted in quantitative release of labeled 5'-AMP, respectively labeled with the corresponding isotope. Two-dimensional separation by isoelectric focusing and SDS-PAGE of labeled and native tubulin revealed that labeling occurs at least in four different isotubulins. The isoelectric point of the labeled isotubulins was slightly lower than that of native purified tubulin. This shift in mobility is probably due to additional negative charges involved with the incorporation of ADP-ribosyl residues into the tubulin subunits. SDS-PAGE of peptides derived from [32P]ADP-ribosylated alpha and beta tubulin subunits by Staphylococcus aureus protease cleavage showed a peptide pattern identical with that of native tubulin. Microtubule-associated proteins (MAP1 and MAP2) of high molecular weight were also shown to undergo ADP-ribosylation. Incubation of permeated rat neuroblastoma cells in the presence of [32P]NAD and cholera toxin results in the labeling of only a few cell proteins of which tubulin is one of the major substrates.
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PMID:ADP-ribosylation of microtubule proteins as catalyzed by cholera toxin. 676 71

Hybridomas that secret IgG reacting specifically with the brain microtubule-associated protein MAP2 have been prepared with speen cells from BALB/c mice hyperimmunized with high molecular weight neurotubule-associated proteins. Immunofluorecence microscopy using dual fluorochrome labeling of tubulin and MAP2 antigens revealed identical patterns of interphase fiber networks in cells from explants of newborn mouse brain. The anti-MAP2 antibody did not stain primary mouse kidney cells or CHO, 3T3, HeLa, or PtK1 cell lines. Immunoprecipitation and antibody gel staining techniques failed to demonstrate any crossreacting antigen in these cells. MAP2 antigen was not seen in association with the mitotic spindle in any of the cells examined. Radioimmunoassay showed species crossreactivity of the anti-MAP2 antibody with mammalian but not avian neural cell extracts. Glial cells and some neuroblastoma cell lines did not appear to contain MAP2. However, in the B104 rat neuroblastoma cell line the MAP2 antigen appeared to be associated with the cytoskeleton concomitant with differentiation induced by dibutyryl cyclic AMP. In disagreement with most previously published reports, our data suggest that MAP2 is found only in differentiated neuronal cells and raises the possibility that MAP2 is involved in neuronal differentiation or neuron-specific processes.
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PMID:Microtubule-associated proteins: a monoclonal antibody to MAP2 binds to differentiated neurons. 700 66

In Alzheimer disease (AD) the microtubule associated protein (MAP) tau is hyperphosphorylated at several sites. In the present study, like AD tau, tau in the human neuroblastoma SH-SY5Y was found to be hyperphosphorylated, at Ser-199/202, Thr-231, Ser-396 and Ser-404. However, in contrast to AD, the tau in SY5Y cells was not hyperphosphorylated at Ser-235 and there was only one tau isoform. Quantitative analysis revealed that approximately 80% of the SY5Y-tau was phosphorylated at Ser-199/202. The phosphorylated tau was deposited in perikarya and processes of the cells whereas most of the unphosphorylated (at Ser-199/202) tau was localized in the nucleus. Tau from the cell lysates did not bind to taxol-stabilized microtubules. In contrast, MAP1b and MAP2 from cell lysates bound to stabilized microtubules in vitro and were associated to the microtubule network in situ. Phosphorylation of tau at high levels, its inactivity with microtubules and its accumulation in SY5Y cells provide for the first time a cell model of cytoskeletal changes seen in AD.
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PMID:Abnormally phosphorylated tau in SY5Y human neuroblastoma cells. 787

Microtubules and their associated proteins play a prominent role in many physiological and morphological aspects of brain function. Abnormal deposition of the microtubule-associated proteins (MAPs), MAP2 and tau, is a prominent aspect of Alzheimer's disease. MAP2 and tau are heat-stable phosphoproteins subject to high rates of phosphorylation/dephosphorylation. The phosphorylation state of these proteins modulates their affinity for tubulin and thereby affects the structure of the neuronal cytoskeleton. The dinoflagellate toxin okadaic acid is a potent and specific inhibitor of protein phosphatases 1 and 2A. In cultured rat cortical neurons and a human neuroblastoma cell line (MSN), okadaic acid induces increased phosphorylation of MAP2 and tau concomitant with early changes in the neuronal cytoskeleton and ultimately leads to cell death. These results suggest that the diminished rate of MAP2 and tau dephosphorylation affects the stability of the neuronal cytoskeleton. The effect of okadaic acid was not restricted to neurons. Astrocytes stained with antibodies to glial fibrillary acidic protein (GFAP) showed increased GFAP staining and changes in astrocyte morphology from a flat shape to a stellate appearance with long processes.
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PMID:Okadaic acid induces early changes in microtubule-associated protein 2 and tau phosphorylation prior to neurodegeneration in cultured cortical neurons. 833 48

The effect of ganglioside GM1 on components of the neuronal cytoskeleton was studied in Neuro-2a neuroblastoma cells using immunofluorescent, immunogold-labeled, and Western-blot analysis. Exposure of cells to GM1 for 24 h resulted in an increased microtubular network and level of tubulin, a redistribution of MAP2 immunoreactivity from perikarya to distal neuritic processes, and an increased MAP2 gold label in the subplasmalemmal cytoplasm, neuritic spines, and growth cones. A similar change in the distribution of actin-positive fluorescent immunoreactivity was observed. In contrast to the redistribution of MAP2, immunolocalization of MAP5 and tau did not change following 24 h GM1 exposure. Our results suggest that gangliosides enhance neuritogenesis by selectively altering the distribution of MAP2 from perikaryon to neuritic spines. Furthermore, the enhanced presence of MAP2 in regions known to be rich in microfilaments following GM1 treatment suggests that an interaction of MAP2 with microfilaments may be necessary for early neurite formation.
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PMID:The ganglioside GM1 enhances microtubule networks and changes the morphology of Neuro-2a cells in vitro by altering the distribution of MAP2. 863 55

Alzheimer disease (AD) has polyetiology. Independent of the etiology the disease is characterized histopathologically by the intraneuronal accumulation of paired helical filaments (PHF), forming neurofibrillary tangles, neuropil threads and dystrophic neurites surrounding the extracellular deposits of beta-amyloid in plaques, the second major lesion. The clincal expression of AD correlates with the presence of neurofibrillary degeneration; beta-amyloid alone does not produce the disease clinically. Thus arresting neurofibrillary degeneration offers a promising key target for therapeutic intervention of AD. The major protein subunit of PHF is the microtubule-associated protein tau. Tau in AD brain, especially PHF, is abnormally hyperphosphorylated and glycosylated. With maturation, the tangles are increasingly ubiquitinated. Levels of tau and conjugated ubiquitin are elevated both in AD brain and CSF. The AD abnormally phosphorylated tau (AD P-tau) does not promote microtubule assembly, but on dephosphorylation its microtubule promoting activity is restored to approximately that of the normal tau. The AD P-tau competes with tubulin in binding to normal tau, MAP1 and MAP2 and inhibits their microtubule assembly promoting activities. Furthermore, the AD P-tau sequesters normal MAPs from microtubules. The association of AD P-tau with normal tau but not with MAP1 or MAP2 results in the formation of tangles of 3.3 +/- 0.5 mm filaments. Deglycosylation of Alzheimer neurofibrillary tangles with endoglycosidase F/N-glycosidase F untwists the PHF resulting in tangles of thin filaments similar to those formed by association between the AD P-tau and normal tau. Dephosphorylation or deglycosylation plus dephosphorylation but not deglycosylation alone restores the microtubule assembly promoting activity of tau. In vitro AD P-tau can be dephosphorylated by protein phosphatases PP-2B, PP-2A and PP-1 but not PP-2C and all the three tau phosphatases are present in brain neurons. Tau phosphatase activity is decreased by approximately 30% in AD brain. Inhibition of PP-2A and PP-1 activities in SY5Y neuroblastoma by 10 nM okadaic acid causes breakdown of microtubules and the degeneration of these cells. It is suggested (I) that a defect(s) in the protein phosphorylation/dephosphorylation system(s) leads to a hyperphosphorylation of tau, (ii) that this altered tau causes disassembly of microtubules and consequently a retrograde neuronal degeneration; (iii) a pharmacological approach to AD is to enhance the tau phosphatase activity; and (iv) that CSF tau and conjugated ubiquitin levels are promising markers of AD brain pathology.
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PMID:Mechanisms of neurofibrillary degeneration and the formation of neurofibrillary tangles. 970 Jun 55

Extension of dendrites and axons in neurons may compensate for and repair damaged neuronal circuits in the dementia brain. Our aim in the present study was to explore drugs activating neurite outgrowth and regenerating the neuronal network. We found that the methanol extract of Ashwagandha (roots of Withania somnifera; 5 microg/ml) significantly increased the percentage of cells with neurites in human neuroblastoma SK-N-SH cells. The effect of the extract was dose- and time-dependent mRNA levels of the dendritic markers MAP2 and PSD-95 by RT-PCR were found to be markedly increased by treatment with the extract, whereas those of the axonal marker Tau were not. Immunocytochemistry demonstrated the specific expression of MAP2 in neurites extended by the extract. These results suggest that the methanol extract of Ashwagandha promotes the formation of dendrites.
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PMID:Dendrite extension by methanol extract of Ashwagandha (roots of Withania somnifera) in SK-N-SH cells. 1088 56

Accumulating evidence suggests that Rho family GTPases play critical roles in the organization of the nervous system. We previously identified a guanine nucleotide exchange factor of Rac1, STEF (SIF and Tiam 1-like exchange factor), which can induce ruffling membrane in KB cells and is predominantly expressed in the brain during development. Here, we characterize the molecular nature of STEF and its involvement in neurite growth. Deletion analyses revealed distinct roles for individual domains: PHnTSS for membrane association, DH for enzymatic activity, and PHc for promoting catalytic activity. Ectopic expression of STEF in N1E-115 neuroblastoma cells induced neurite-like processes containing F-actin, betaIII tubulin, MAP2, and GAP43 in a Rac1-dependent manner even under the serum-containing neurite-inhibiting conditions. We further found that a PHnTSS STEF fragment specifically inhibited the function of both STEF and Tiam1, a closely related Rac1 guanine nucleotide exchange factor. Suppression of endogenous STEF and Tiam1 activities in N1E-115 cells by ectopically expressed PHnTSS STEF resulted in inhibition of neurite outgrowth in serum-starved conditions, which usually induce neurite formation. Furthermore, these inhibitory effects were rescued by exogenously expressed STEF or Tiam1, suggesting that STEF and Tiam1 are involved in neurite formation through the activation of Rac1 and successive cytoskeletal reorganization of neuronal cells during development.
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PMID:Characterization of STEF, a guanine nucleotide exchange factor for Rac1, required for neurite growth. 1170 41

We previously reported that the methanol extract of Ashwagandha (roots of Dunal) induced dendrite extension in a human neuroblastoma cell line. In this study, we found that six of the 18 compounds isolated from the methanol extract enhanced neurite outgrowth in human neuroblastoma SH-SY5Y cells. Double immunostaining was performed in rat cortical neurons using antibodies to phosphorylated NF-H as an axonal marker, and to MAP2 as a dendritic marker. In withanolide A-treated cells, the length of NF-H-positive processes was significantly increased compared with vehicle-treated cells, whereas, the length of MAP2-positive processes was increased by withanosides IV and VI. These results suggest that axons are predominantly extended by withanolide A, and dendrites by withanosides IV and VI.
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PMID:Axon- or dendrite-predominant outgrowth induced by constituents from Ashwagandha. 1239 10

Tau is a microtubule-associated protein (MAP) whose transcript undergoes complex regulated splicing in the mammalian nervous system. Our previous work with exon 6 established that tau shows a unique expression pattern and splicing regulation profile, and that it utilizes alternative splice sites in several human tissues. The mRNAs from these splicing events, if translated, would result in truncated tau variants that lack the microtubule-binding domain. In this study, we demonstrate that at least one of these tau variants is present as a stable protein in several tissues. The novel isoform shows a localization distinct from that of canonical tau in SH-SY5Y neuroblastoma cells which stably overexpress it. In both normal and Alzheimer's hippocampus, the novel isoform is found in dentate gyrus granular cells and CA1/CA3 pyramidal cells. However, it does not co-localize with canonical tau but, rather, partly co-localizes with MAP2.
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PMID:Novel isoforms of tau that lack the microtubule-binding domain. 1522 91


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