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)

Abeta peptides are major components of the amyloid plaques that characterize Alzheimer's disease. The enzyme activities (beta- and gamma-secretases) involved in generating Abeta from amyloid precursor protein (APP) are unidentified. It has been suggested that prolylendopeptidase (PEP), an oligopeptidase that normally cleaves after proline residues, could also cleave after the alanine at position 42 of Abeta to generate Abeta42. We investigated whether inhibition of PEP activity in human neuroblastoma cells affected Abeta levels in cell culture media. An SH-SY5Y cell line expressing SPA4CT, encoding the C-terminal 100 residues of APP and the signal sequence, was used. Only gamma-secretase activity is required for Abeta production in this cell line. The PEP inhibitor Fmoc-AlaPro-CN (10 microM) reduced PEP activity in these cells by approximately 95% in the absence of significant toxicity, but had no effect on Abeta40 or Abeta42 levels in cell culture media. We conclude that PEP is unlikely to be involved in gamma-secretase processing of APP.
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PMID:Inhibition of prolylendopeptidase does not affect gamma-secretase processing of amyloid precursor protein in a human neuroblastoma cell line. 1064 91

Single strand conformation polymorphism (SSCP) analysis of the N-ras oncogene was achieved by capillary electrophoresis with a laser-induced fluorescence detector (CE-LIF) using methylcellulose as a molecular sieving agent. The PCR-amplified N-ras oncogene, which is known to have a point mutation at codon 61 in the neuroblastoma, was investigated by CE-LIF combined with SSCP (SSCP-CE-LIF). A mixture of wild- and mutant-type single strand DNA fragments (103 bp) of the N-ras oncogene was separated by buffer solution containing 1.0% methylcellulose and 0.2 microM fluorescent dye (YO-PRO-1) at 25 degrees C. The SSCP-CE-LIF technique gave good resolution for wild- and mutant-type single strand DNA fragments with separation completed within 7 min. SSCP analysis using a CE system with a LIF detector was successfully applied to the detection of the one point mutation on the N-ras oncogene.
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PMID:Single strand conformation polymorphism analysis of ras oncogene by capillary electrophoresis with laser-induced fluorescence detector. 1086 35

A hallmark of several neurodegenerative disorders, including Alzheimer's disease and tauopathies, is the hyperphosphorylation of the microtubule-associated protein tau. Tau phosphorylation by proline-directed and non-proline-directed protein kinases has been tested using antibodies PHF1 and 12E8, respectively. The effect of the lipid peroxidation product acrolein on these modes of phosphorylation has been assayed. We have found that acrolein, a peroxidation product from arachidonic acid, increases the phosphorylation of tau at the site recognized by PHF-1 both in human neuroblastoma cells and in primary cultures of mouse embryo cortical neurons. Whereas the basal phosphorylation of tau protein at the PHF1 site seems to be largely mediated by glycogen synthase kinase-3 (which is also activated in response to Abeta peptide), the acrolein-induced tau hyperphosphorylation at the same site is also due to p38 stress-activated kinase. These results support the view that oxidative stress and subsequent formation of lipid peroxidation products may contribute to tau protein phosphorylation in Alzheimer's disease and tauopathies.
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PMID:Effect of the lipid peroxidation product acrolein on tau phosphorylation in neural cells. 1260 13

The Alzheimer's disease pathogenic peptide, beta-amyloid42 (A beta 42), induces tau protein phosphorylation. Because hyperphosphorylated tau is a consistent component of neurofibrillary tangles, a pathological hallmark of Alzheimer's disease, we investigated the signaling molecules involved in A beta 42-induced tau phosphorylation. We show that A beta 42 elicited rapid and reversible tau protein phosphorylation on three proline-directed sites (Ser-202, Thr-181, and Thr-231) in systems enriched in alpha 7 nicotinic acetylcholine receptors (alpha 7nAChR) including serum-deprived human SK-N-MC neuroblastoma cells and hippocampal synaptosomes. Although alpha 7nAChR agonists induced similar phosphorylation, pretreatment with antisense-alpha 7nAChR oligonucleotides (in cells) or alpha 7nAChR antagonists (in cells and synaptosomes) attenuated A beta-induced tau phosphorylation. Western analyses showed that the mitogen-activated kinase cascade proteins, ERKs and c-Jun N-terminal kinase (JNK-1), were concomitantly activated by A beta 42, and their respective kinase inhibitors suppressed A beta-induced tau phosphorylation. More importantly, recombinant-activated ERKs and JNK-1 could differentially phosphorylate tau protein in vitro. Thus, the alpha 7nAChR may mediate A beta-induced tau protein phosphorylation via ERKs and JNK-1.
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PMID:Alpha 7 nicotinic acetylcholine receptors mediate beta-amyloid peptide-induced tau protein phosphorylation. 1280 34

In order to identify Nm23-H1's structural motifs influencing its metastasis-inhibitory activity, we transfected DU 145 human prostate carcinoma cells with the expression vector encoding the Nm23-H1 protein with mutations at the following amino acids: serine-44, a phosphorylation site; proline-96, a site corresponding to the k-pn mutation that causes developmental defects in Drosophila; and serine-120, a site of mutation in human neuroblastoma and phosphorylation. Significant decrease in colonization in soft agar and invasiveness of DU 145 cells was observed in the wild type nm23-H1 transfectants, and also in the serine-44 and serine-120 to alanine mutant nm23-H1-transfected cell lines. However, the k-pn type proline-96 to serine (P96S) and neuroblastoma type serine-120 to glycine (S120G) mutations of Nm23-H1 abrogated its inhibitory activity on colonization and invasion. Meanwhile, all of the recombinant mutant Nm23-H1 proteins produced in Escherichia coli exhibited NDP kinase activity levels at the wild type protein, although the P96S and S120G mutant proteins exhibited decreased histidine protein kinase activity and autophosphorylation level, respectively. Interestingly, only two of the mutant recombinant Nm23-H1 proteins examined, P96S and S120G, exhibited reduced hexameric and increased dimeric oligomerization relative to the wild type. These correlative data suggest that the metastasis-suppressing activity of Nm23-H1 may depend on its oligomeric structure, but not on its NDP kinase activity.
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PMID:Point mutations affecting the oligomeric structure of Nm23-H1 abrogates its inhibitory activity on colonization and invasion of prostate cancer cells. 1285 52

Polycomb group proteins are implicated in embryogenesis and carcinogenesis through transcriptional regulation of target genes. ASXL1 and ASXL2 genes, encoding Polycomb group protein with ASXN and ASXM domains, are human homologs of Drosophila additional sex combs (asx) gene. Exons 2-13 of the ASXL2 gene are fused to exons 1-14 of the MYST3 gene in a case of therapy-related myelodysplastic syndrome due to t(2;8)(p23.3;p11.2). Here, we identified the ASXL3 gene, a novel human homolog of Drosophila asx, by using bioinformatics. ASXL3 gene, consisting of 12 exons, was located within human genome sequences RP11-562H1 (AC023192.8), RP11-265C19 (AC090989.8), and RP11-470B24 (AC010798.9). Complete coding sequence of human ASXL3 cDNA was determined by assembling EST BE145544, exons 4-11, and 5'-truncated KIAA1713 cDNA (AB051500.2). Partial coding sequence of mouse Asxl3 cDNA was derived from 3'-truncated C230079D11 cDNA (AK082659.1). Human ASXL3 mRNA was expressed in pancreatic islet, testis as well as in neuroblastoma, head and neck tumor. Human ASXL3 protein (2248 aa) with ASXN, ASXM and PHD domains was the third member of the human ASXL family. The region between ASXM and PHD domains was divergent among ASXL family members. Proline-rich domain was located within the divergent region of ASXL3, but not within that of ASXL1 and ASXL2. ASXL3-DTNA locus at chromosome 18q12.1 and ASXL2-DTNB locus at 2p23.3 were paralogous regions within the human genome. ASXL3 was a predicted cancer-associated gene, just like ASXL1 and ASXL2. This is the first report on identification and characterization of the ASXL3 gene.
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PMID:Identification and characterization of ASXL3 gene in silico. 1513 7

Mammalian homologues of the Drosophila canonical transient receptor potential (TRP) proteins have been implicated to function as plasma membrane Ca(2+) channels. This study examined the role of TRPC1 in human neuroblastoma (SH-SY5Y) cells. SH-SY5Y cells treated with an exogenous neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP(+)) significantly decreased TRPC1 protein levels. Confocal microscopy on SH-SY5Y cells treatment with MPP(+) showed decreased plasma membrane staining of TRPC1. Importantly, overexpression of TRPC1 reduced neurotoxicity induced by MPP(+). MPP(+)-induced alpha-synuclein expression was also suppressed by TRPC1 overexpression. Protection of SH-SY5Y cells against MPP(+) was significantly decreased upon the overexpression of antisense TRPC1 cDNA construct or the addition of a nonspecific transient receptor potential channel blocker lanthanum. Activation of TRPC1 by thapsigargin or carbachol decreased MPP(+) neurotoxicity, which was partially dependent on external Ca(2+). Staining of SH-SY5Y cells with an apoptotic marker (YO-PRO-1) showed that TRPC1 protects SH-SY5Y neuronal cells against apoptosis. Further, TRPC1 overexpression inhibited cytochrome c release and decreased Bax and Apaf-1 protein levels. Interpretation of the above data suggests that reduction in the cell surface expression of TRPC1 following MPP(+) treatment may be involved in dopaminergic neurodegeneration. Furthermore, TRPC1 may inhibit degenerative apoptotic signaling to provide neuroprotection against Parkinson's disease-inducing agents.
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PMID:TRPC1-mediated inhibition of 1-methyl-4-phenylpyridinium ion neurotoxicity in human SH-SY5Y neuroblastoma cells. 1554 11

Acetylcholinesterase (AChE) exists in various molecular forms, depending on alternative splicing of its transcripts and association with structural proteins. Tetramers of the 'tailed' variant (AChE(T)), which are anchored in the cell membrane of neurons by the PRiMA (Proline Rich Membrane Anchor) protein, constitute the main form of AChE in the mammalian brain. In the mouse brain, stress and anticholinesterase inhibitors have been reported to induce expression of the unspliced 'readthrough' variant (AChE(R)) mRNA which produces a monomeric form. To generalize this observation, we attempted to quantify AChE(R) and AChE(T) after organophosphate intoxication in the mouse brain and compared the observed effects with those of stress induced by swimming or immobilization; we also analyzed the effects of heat shock and AChE inhibition on neuroblastoma cells. Active AChE molecular forms were characterized by sedimentation and non-denaturing electrophoresis, and AChE transcripts were quantified by real-time PCR. We observed a moderate increase of the AChE(R) transcript in some cases, both in the mouse brain and in neuroblastoma cultures, but we did not detect any increase of the corresponding active enzyme.
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PMID:The readthrough variant of acetylcholinesterase remains very minor after heat shock, organophosphate inhibition and stress, in cell culture and in vivo. 1600 72

Alzheimer's disease (AD) is three times more prevalent in women than men, and epidemiological studies have shown that estrogen replacement in aging women forestalls the onset of AD. Hyperphosphorylation of the tau protein that forms the neurofibrillary tangles found in AD brains might be responsible for the breakdown of microtubules in affected neurons. The mechanisms by which tau protein is phosphorylated in the AD brain are not fully understood. Using a human neuroblastoma cell line (SH-SY5Y) and primary cultures of newborn male or female rat cerebral cortical neurons, we investigated the effect of 17beta-estradiol on tau protein expression and phosphorylation. We found that estradiol increased total tau and induced dephosphorylation at the proline-directed site of the molecule. Further, estradiol prevented okadaic acid-induced hyperphosphorylation of tau in both proline- and non-proline-directed sites, and antiestrogens blocked this effect. To our knowledge, this is the first report of an effect of estradiol on naturally occurring and induced tau phosphorylation. This assumes special significance because the estrogen action was found to be sexually dimorphic in rat cortical neurons and differentiation-sensitive in human neuroblastoma cells.
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PMID:Estradiol prevents neural tau hyperphosphorylation characteristic of Alzheimer's disease. 1602 64

The osmotically regulated OpuA uptake system from Bacillus subtilis is a member of the SBP-dependent subfamily of ABC-transporters. The functional complex, OpuA(A(2)B(2)C), catalyzes the osmotically controlled import of the compatible solutes glycine betaine and proline betaine. Here, we describe the purification of the isolated TMS, OpuAB. Stimulated ATPase activity of OpuAA by OpuAB demonstrated that OpuAB adopts a functional fold. An interaction between all subunits could be verified in detergent solution with the highest ATPase stimulation determined for the dimeric NBS in the re-associated complex in the presence of all transport components plus substrate.
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PMID:Functional overexpression and in vitro re-association of OpuA, an osmotically regulated ABC-transport complex from Bacillus subtilis. 1622 68


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