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)

Developing animals are more sensitive than adults to acute cholinergic toxicity from anticholinesterases, including organophosphorus pesticides, when administered in a laboratory setting. It is also possible that these agents adversely affect the process of neural development itself, leading to permanent deficits in the architecture of the central and peripheral nervous systems. Recent observations indicate that organophosphorus exposure can affect DNA synthesis and cell survival in neonatal rat brain. New evidence that acetylcholinesterase may have a direct role in neuronal differentiation provides additional grounds for interest in the developmental toxicity of anticholinesterases. For example, correlative anatomic studies show that transient bursts of acetylcholinesterase expression often coincide with periods of axonal outgrowth in maturing avian, rodent, and primate brain. Some selective cholinesterase inhibitors effectively suppress neurite outgrowth in model systems like differentiating neuroblastoma cells and explanted sensory ganglia. When enzyme expression is altered by genetic engineering, acetylcholinesterase levels on the outer surface of transfected neurons correlate with ability to extend neurites. Certain of these "morphogenic" effects may depend on protein-protein interactions rather than catalytic acetylcholinesterase activity. Nonetheless, it remains possible that some pesticides interfere with important developmental functions of the cholinesterase enzyme family.
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PMID:Cholinesterases in neural development: new findings and toxicologic implications. 1022 7

Diisopropyl phosphorofluoridate (DFP) is an organophosphorus ester, and a single injection of this compound (1.7 mg/kg, s.c.) produces delayed neurotoxicity (OPIDN) in hens in 7-14 days. Clinically, the disease is marked by hindlimb ataxia followed by paralysis after some time. A characteristic feature of this neuropathy is axonal swelling in the initial stages and comparative dissolution of the accumulated material and degeneration of distal axons with disease progression. Axonal swelling consists of aggregated neurofilaments, microtubules, and proliferated smooth endoplasmic reticulum. We studied expression of neurofilament (NF) mRNAs in brain regions and spinal cord to elucidate their role in OPIDN. There was a 50-200% increase in NF transcripts in 24 hr after DFP administration. The NF-L mRNA level started falling after 1-5 days and came down to control level in susceptible brain regions (i.e. cerebellum and brainstem) and spinal cord, but not in cerebral cortex, which does not show degeneration of axons in OPIDN. Cerebral cortex exhibited elevated levels of both NF-L and NF-M transcripts in DFP-treated hens throughout the period of observation. The induction of NF messages is consistent with the previously reported effect on extension of neurites of human neuroblastoma cells in culture. The transient increase in NF messages in susceptible tissues either may be responsible for the delayed degeneration of axons in OPIDN or is the result of interruption of regulatory signal due to progressive degeneration of axons.
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PMID:Enhanced mRNA expression of neurofilament subunits in the brain and spinal cord of diisopropyl phosphorofluoridate-treated hens. 1023 Jul 68

GM1 ganglioside was previously shown to occur in the nuclear membrane, as well as the plasma membrane, of central nervous system (CNS) and peripheral nervous system (PNS) neurons undergoing morphological differentiation in culture. NG108-15 neuroblastoma cells showed the same phenomenon when induced to extend axon-like but not dendrite-like processes, although in both cases terminal differentiation was evidenced by failure of extended neurites to retract following washout of neuritogenic agent. The present study of Neuro-2a neuroblastoma cells subjected to similar treatments has revealed both similarities and differences compared to NG108-15 cells. Similar to the latter, Neuro-2a cells responded to neuraminidase and ionomycin with axon-like outgrowth together with upregulation of nuclear GM1, and to three other agents (retinoic acid, dibutyryl cyclic AMP, exogenous GM1) with dendrite-like outgrowth that was unaccompanied by nuclear GM1 increase. Although both cell types responded to low serum by extending neurites of mixed axonal-dendritic properties, Neuro-2a, in keeping with its greater tendency to extend some neurites of axonal character in low serum, showed elevated nuclear GM1 in a significant number of such differentiated cells. All three axonogenic agents induced parallel upregulation of GM1 in plasma-, nuclear-, and Golgi membranes, and these increases were stable to washout. Neurites generated in Neuro-2a cells by the three dendritogenic agents lacked stability, unlike those produced by the same agents in NG108-15 cells. This study also amplified the differences in response triggered by exogenous GM1 compared to that resulting from enzyme-mediated elevation of endogenous GM1.
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PMID:Axonogenesis in neuro-2a cells correlates with GM1 upregulation in the nuclear and plasma membranes. 1044 Sep 4

Extension of dendrites and axons in neurons may compensate and rescue damaged neuronal networks in the dementia brain. Our aim is to isolate and identify constituents of coffee beans exhibiting neurite outgrowth activity. Among the extracts of raw and roasted coffee beans, a methanol fraction of the ethanol extract (1 microg/ml) of raw beans increased significantly the percentage of cells with neurites in human neuroblastoma SK-N-SH cells. Among subfractions of this methanol fraction was a basic fraction (5 microg/ml) which exhibited significant neurite outgrowth activity. Finally, trigonelline in the basic fraction was identified to be active as far neurite extension was concerned. Treatment with trigonelline (30 microM) increased the percentage of cells with neurites at 3 and 6 d after treatment. In addition, the number of neurites reacting positively to phosphorylated neurofilament-H was increased by treatment with 30 microM trigonelline for 6 d, suggesting enhancement of axonal extension. These results show that trigonelline promotes functional neurite outgrowth.
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PMID:Trigonelline-induced neurite outgrowth in human neuroblastoma SK-N-SH cells. 1044 61

We examined cytoskeleton-associated forms of NF proteins during axonal neuritogenesis in cultured dorsal root ganglion (DRG) neurons and NB2a/d1 neuroblastoma. In addition to filamentous immunoreactivity, we observed punctate NF immunoreactivity throughout perikarya and neurites. Immuno-electron microscopy revealed this punctate immunoreactivity to consist of non-membrane-bound 75 nm round/ovoid structures consisting of amorphous, fibrous material. Endogenous and microinjected NF subunits incorporated into dots prior to their accumulation within filaments. A transfected GFP-conjugated NF-M incorporated into dots and translocated at a rate consistent with slow axonal transport in real-time video analyses. Some dots converted into a filamentous form or exuded filamentous material during transport. Dots contained conventional kinesin immunoreactivity, associated with microtubules, and their transport into axons was blocked by anti-kinesin antibodies and nocodazole. These oligomeric structures apparently represent one form in which NF subunits are transported in growing axons and may utilize kinesin as a transport motor.
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PMID:Kinesin-mediated transport of neurofilament protein oligomers in growing axons. 1052 15

TGFbeta can modulate neuroblastoma (NB) cell proliferation and differentiation in vitro. In this study we used a NB cell line (LAN-5) which has been shown to partially respond to TGFbeta and to present high levels of TGFbeta receptor type I and low levels of receptor type II (TbetaRII) on the cell surface. To evaluate the role of TbetaRII in mediating TGFbeta effects, LAN-5 cells were transfected with an expression vector containing the human full-length TbetaRII cDNA or with the empty vector pcDNA3. Compared to control CLV3 cells (transfected with empty plasmid) and parental LAN-5 cells, isolated neomycin-resistant clones (CL1 and CL3) expressed higher levels of TbetaRII, had reduced cell growth rate in vitro, and were unable to form tumors in vivo. Furthermore, isolated clones modified their morphology, assuming a terminally differentiated neuronal phenotype. Immunocytochemical staining demonstrated a basal increased expression of neural-specific markers, such as axonal growth-associated protein (GAP43) and neurofilaments (NF200). TGFbeta treatment further increased the synthesis of NF200 and GAP43 in the transfected clones as revealed by Western blot analysis. These data indicate that TbetaRII overexpression potentiates the TGFbeta signal transduction pathway, reverting NB cell neoplastic phenotype with the reduction of proliferation rate and the induction of terminal maturation.
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PMID:Increased TGFbeta type II receptor expression suppresses the malignant phenotype and induces differentiation of human neuroblastoma cells. 1066 36

Neuronal cells display different subsets of dynamic microtubules. In axons and extending neurites, this intrinsic dynamics is modulated by the microtubule-associated protein tau. Moreover, posttranslational modifications of tubulin, namely acetylation, tyrosination or glutamylation are directly involved in determining the stability of neuronal microtubules. Studies were carried out to analyze the interaction patterns of tau with subsets of microtubules in N2A neuroblastoma cells, which can differentiate in the presence of dibutyryl cAMP. Double labeling studies showed a differential pattern of tau association with microtubules containing acetylated and tyrosinated tubulin. Furthermore, studies using depolymerizing drugs revealed a selectivity in the association of tau with microtubular polymers and microfilaments, within the organization of the neuronal cytoskeleton. In order to study the association of specific tau isoforms with microtubules containing modified tubulin variants, immunoprecipitation studies were carried out. The coimmunoprecipitation data indicated a selective binding of specific tau isoforms to either modified tubulin variant. To assess the hypothesis on the roles of tau isoforms in the stabilization of microtubules containing modified tubulins, the association of those variants with tau isoforms was analyzed in overlay experiments. A preferential binding of acetylated tubulin from undifferentiated N2A cell extracts, to at least one slow-migrating tau isoform was revealed. However, acetylated tubulin from N2A cells containing long neurites displayed a preferential association with two isoforms of tau. On the other hand, tyrosinated tubulin from N2A extracts bound to the entire set of neuronal tau isoforms. These studies, along with the tau association with microtubules with different stability, indicate that tau segregates into subsets of microtubules in the axonal processes. The studies also suggest that these interactions may respond to a functional versatility of these polymers in differentiating neurons.
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PMID:Differential association of tau with subsets of microtubules containing posttranslationally-modified tubulin variants in neuroblastoma cells. 1068 5

Collapsin response mediator protein-2 (CRMP-2) is a member of the CRMP/TOAD/Ulip/DRP family of cytosolic phosphoproteins involved in neuronal differentiation and axonal guidance. CRMP-2 mediates the intracellular response to collapsin 1/semaphorin 3A, a repulsive extracellular guidance cue for axonal outgrowth. The mutation of UNC-33, a Caenorhabditis elegans homolog of CRMP-2, results in abnormality of microtubules in neurites, but the mechanism of CRMP-2 action remains to be clarified. Here, we report that overexpression of human CRMP-2 in Neuro2a cells, a mouse neuroblastoma cell line, results in blebbing of the cytoplasm. Furthermore, some cells exhibited intranuclear inclusions, which were labeled with antibodies to CRMP-2 and tubulin. CRMP-2 was found to be associated with microtubule bundles in the spindles at the metaphase and in the midbodies at the late telophase in mitotic cells. Thus, it is most likely that failure of complete disassembly of the spindle microtubules during mitosis is responsible for the formation of these intranuclear inclusions. We suggest that CRMP-2 functions by regulating the dynamics of microtubules.
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PMID:Evidence that collapsin response mediator protein-2 is involved in the dynamics of microtubules. 1077 Sep 20

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

Neurofilaments (NFs) are composed of a heteropolymer of three related subunits in mammalian neurons, where they are a major component of the cytoskeleton in large neurons and are thought to regulate axonal diameter. NFs in the lamprey, while ultrastructurally and functionally indistinguishable from mammalian NFs, are polymers of a single subunit protein, NF180. In this study, we use the simplicity of lamprey NFs and the accessibility of the lamprey central nervous system (CNS) to examine the effects of overproducing NFs in an identified giant neuron in vivo, and thus to elucidate the role of NFs in regulating neuronal size and axonal caliber in the vertebrate CNS. We show that overexpression of NF180 tagged with a variant of Green Fluorescent Protein (EYFP) in identified lamprey neurons (ABCs) and in human neuroblastoma (NB2a) cells results in the assembly of exogenous NF180 into ultrastructurally normal NFs that are tightly packed and unphosphorylated. These accumulate in the somata of NB2a cells and produce somatic swelling by 3 days post-transfection. NF180 overexpression in lamprey ABCs in vivo causes exogenous NFs to accumulate in ABC axons, somata, and dendrites, and induces a significant increase in axonal diameter without increasing axonal NF packing density. Overexpression of EYFP alone has none of these effects. We conclude that NF180 normally plays a critical role in determining axonal caliber in ABCs and may influence neuronal size in situations where NFs accumulate in the soma, such as after axonal injury.
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PMID:The single neurofilament subunit of the lamprey forms filaments and regulates axonal caliber and neuronal size in vivo. 1091 64


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