Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The absolute levels of cAMP-dependent protein kinase (cAMP-dPK) subunits (R-I, R-II and C) and cGMP-dependent protein kinase (cGMP-dPK) holoenzyme were studied in neuroblastoma-glioma hybrid cells before and after dibutyryl-cAMP (Bt2cAMP) treatment which results in differentiation of these cells. The levels were determined by two different techniques utilizing antibodies which had been raised against each individual purified protein kinase subunit (or the holoenzyme in the case of the cGMP-dPK). Electrophoretic transfer of samples from SDS-polyacrylamide gels to nitrocellulose paper, followed by immunolabeling of protein kinase subunits with their respective antibodies and [125I]Protein A, demonstrated the monospecific nature of the antibodies, and a selective, several-fold increase in the R-I subunit in Bt2cAMP-treated cells, with no change in the level of R-II or C subunits. A simple enzyme-linked immunosorbent assay (ELISA) capable of measuring nanogram amounts of the various subunits confirmed the selective increase in the R-I subunit. ELISA assay results also indicated that the R-I subunits present before and after Bt2cAMP treatment are antigenically homologous. In conclusion, the specific, sensitive immunological methods described here demonstrate the capacity of neuroblastoma-glioma hybrid cells to regulate separately the levels of the two distinct subunits (R-I and C) of the Type I cAMP-dPK.
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PMID:Dibutyryl cAMP treatment of neuroblastoma-glioma hybrid cells results in selective increase in cAMP-receptor protein (R-I) as measured by monospecific antibodies. 1189 19

Preconditioning adaptation induced by transient ischemia can increase brain tolerance to oxidative stress, but the underlying neuroprotective mechanisms are not fully understood. Recently, we developed a human brain-derived cell model to investigate preconditioning mechanism in SH-SY5Y neuroblastoma cells.(1) Our results demonstrate that a non-lethal serum deprivation-stress for 2 h (preconditioning stress) enhanced the tolerance to a subsequent lethal oxidative stress (24 h serum deprivation) and also to 1-methyl-4-phenyl-pyridinium (MPP(+)).(2) Two-hour non-lethal preconditioning stress increased the expression of neuronal nitric oxide (NOS1/nNOS) mRNA, Fos, Ref-1, NOS protein, and then nitric oxide (*NO) production. As well as MnSOD expression, the *NO-cGMP-PKG pathway mediated the preconditioning-induced upregulation of antiapoptotic protein Bcl-2 and the downregulation of adaptor protein p66(shc). We also propose that cGMP-mediated preconditioning-induced adaptation against oxidative stress may be due to the synthesis of a new protein, such as thioredoxin (Trx) since the protective effect can be blocked by Trx reductase inhibitor.(3) The antioxidative potency of Trx was approximately 100 and 1,000 times greater than GSNO and GSH, respectively. These results suggest that *NO-cGMP-PKG signaling pathway plays an important role in the preconditioning-induced neuroprotection, and perhaps cardioprotection, against oxidative stress.
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PMID:Preconditioning-mediated neuroprotection: role of nitric oxide, cGMP, and new protein expression. 1207 58

Human neuroblastoma cells, SH-SY5Y, contain relatively low levels of thioredoxin (Trx); thus, they serve favorably as a model for studying oxidative stress-induced apoptosis (Andoh, T., Chock, P. B., and Chiueh, C. C. (2001) J. Biol. Chem. 277, 9655-9660). When these neurotrophic cells were subjected to nonlethal 2-h serum deprivation, their neuronal nitric oxide synthase and Trx were up-regulated, and the cells became more tolerant of oxidative stress, indicating that NO may protect cells from serum deprivation-induced apoptosis. Here, the mechanism by which NO exerts its protective effects was investigated. Our results reveal that in SH-SY5Y cells, NO inhibits apoptosis through its ability to activate guanylate cyclase, which in turn activates the cGMP-dependent protein kinase (PKG). The activated PKG is required to protect cells from lipid peroxidation and apoptosis, to inhibit caspase-9 and caspase-3 activation, and to elevate the levels of Trx peroxidase-1 and Trx, which subsequently induces the expression of Bcl-2. Furthermore, active PKG promotes the elevation of c-Jun, phosphorylated MAPK/ERK1/2, and c-Myc, consistent with the notion that PKG enhances the expression of Trx through its c-Myc-, AP-1-, and PEA3-binding motifs. Elevation of Trx and Trx peroxidase-1 and Mn(II)-superoxide dismutase would reduce H(2)O(2) and O(2)(), respectively. Thus, the cytoprotective effect of NO in SH-SY5Y cells appears to proceed via the PKG-mediated pathway, and S-nitrosylation of caspases plays a minimal role.
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PMID:Cyclic GMP-dependent protein kinase regulates the expression of thioredoxin and thioredoxin peroxidase-1 during hormesis in response to oxidative stress-induced apoptosis. 1241 92

A reliable in vitro cytotoxic system is essential in neurocytotoxic and neuroprotective research. The present study examined four cytotoxic insults with the SK-N-SH human neuroblastoma cell line. These were beta-amyloid protein (Abeta), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), high density culture, and serum deprivation induced neuronal death. These insults induced significant reduction in cell numbers after 96 h culture, in a concentration dependent manner. Among all the insults, MPTP, serum deprivation, and high density culture induced apoptosis after 96 h, while Abeta presumably induced necrotic neuronal death since apoptosis was not detectable. The p38 MAP kinase inhibitor, SB203580 (1 microM), and the PKC inhibitor, chelerythrine (5 microM) successfully inhibited the loss in viability caused by Abeta and the high density culture, respectively. Other kinase inhibitors, including the non-specific protein kinase inhibitor, H7, the PKA inhibitor 14-22 Amide, the PKG inhibitor, KT5823, and the protein tyrosine kinase inhibitor, AG18 had no effect on any of the four cytotoxic models. This system allows the study of neuroprotection under conditions where the different pathways and mechanisms of the neurons can be considered within one cellular system, removing variations which may be due to different cell type studied. The present studies describe an effective model system for screening potential neuroprotective agents.
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PMID:The establishment of a reliable cytotoxic system with SK-N-SH neuroblastoma cell culture. 1258 45

We isolated and characterized cDNA clones (PKG Ialpha and PKG Ibeta) for medaka fish cGMP-dependent protein kinase (PKG) Ialpha and Ibeta, and demonstrated that both are expressed in the embryos after late gastrula stage. Whole-mount in situ hybridization using each isoform-specific probe revealed that the transcripts of the PKG Ialpha gene were present in the spinal cord and gill arch, whereas those of the PKG Ibeta gene were only weakly expressed in these organs, but highly expressed in the otic vesicles. Injection of PKG Ialpha-specific morpholino antisense oligonucleotides (Ialpha-MO) into two-cell stage medaka fish embryos caused severe abnormalities in the developing embryos, such as the development of a hammer-like head, fusion of the developing eyes, and degeneration of cells around the eyes, whereas injection of PKG Ibeta-specific morpholino antisense oligonucleotides (Ibeta-MO) caused fewer abnormalities in the embryos, even when injected at higher concentrations than Ialpha-MO. The PKG I-overexpressing embryos exhibited smaller eyes and enlargement of the forebrain, a phenotype similar to that observed in the cAMP-dependent protein kinase (PKA)-depressed embryos. In the PKG-deficient embryos, a sonic hedgehog (shh)-target gene, HNF-3beta, was expressed weakly, and this phenotype was similar to that observed in the PKA-overexpressing embryos suggesting that the cGMP/PKG signaling pathway is involved in some steps of shh signaling. We also demonstrated that Gli proteins, shh-downstream molecules, are phosphorylated by the NO/cGMP signaling pathway, probably by PKG in NG108-15 neuroblastoma cells. These results imply that PKG and PKA share common substrates and work in an opposite manner during the early embryogenesis of medaka fish.
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PMID:Expression and function of cGMP-dependent protein kinase type I during medaka fish embryogenesis. 1571 Jun 21

Delayed cardio- and neuroprotection are observed following a preconditioning procedure evoked by a brief and nontoxic oxidative stress due to deprivation of oxygen, glucose, serum, trophic factors, and/or antioxidative enzymes. Preconditioning protection can be observed in vivo and is under clinical trials for preservation of cell viability following organ transplants of liver. Previous studies indicated that ischemic preconditioning increases the expression of heat-shock proteins (HSPs) and nitric oxide synthase (NOS). Our pilot studies indicate that the treatment of neuronal NOS inhibitor (7-nitroindazole) and 6Br-cGMP blocks and mimics, respectively, preconditioning protection in human neuroblastoma SH-SY5Y cells. This minireview focuses on nitric oxide-mediated cellular adaptation and the related cGMP/PKG signaling pathway in a compensatory mechanism underlying preconditioning-induced hormesis. Both preconditioning and 6Br-cGMP increase the induction of human thioredoxin (Trx) mRNA and protein for cytoprotection, which is largely prevented by transfection of cells with Trx antisense but not sense oligonucleotides. Cytosolic Trx1 and mitochondrial Trx2 suppress free radical formation, lipid peroxidation, oxidative stress, and mitochondria-dependent apoptosis; knock out/down of either Trx1 or Trx2 is detrimental to cell survival. Other recent findings indicate that a transgenic increase of Trx in mice increases tolerance against oxidative nigral injury caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Trx1 can be translocated into nucleus and phosphoactivated CREB for a delayed induction of mitochondrial anti-apoptotic Bcl-2 and antioxidative MnSOD that is known to increase vitality and survival of cells in the brain and the heart. In conclusion, preconditioning adaptation or a brief oxidative stress induces a delayed nitric oxide-mediated compensatory mechanism for cell survival and vitality in the central nervous system and the cardiovascular system. Preconditioning-induced adaptive tolerance may be signaling through a cGMP-dependent induction of cytosolic redox protein Trx1 and subsequently mitochondrial proteins such as Bcl-2, MnSOD, and perhaps Trx2 or HSP70.
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PMID:Induction of thioredoxin and mitochondrial survival proteins mediates preconditioning-induced cardioprotection and neuroprotection. 1596 87

Polychlorinated biphenyls (PCB) are persistent environmental contaminants whose chronic exposure can affect nervous system development and function. The cellular and molecular mechanisms underlying neuronal damage are not yet clear. In the present study, we investigated whether nitric oxide (NO) could be involved in aroclor 1254 (A1254; a PCB mixture)-induced cytotoxicity in SH-SY5Y human neuroblastoma cells. Prolonged exposure (24 hr) to A1254 (10-100 microg/ml) caused a dose-dependent reduction of cell viability that was attenuated in the presence of a calcium entry blocker, gadolinum (Gd(3+)) at 10 microM, a concentration able to block voltage-sensitive calcium channels. In addition, A1254 caused an increase of cytosolic calcium that was dependent on extracellular calcium, as measured by fura-2 videomicroscopy. A1254-induced calcium rise may stimulate NO production through an activation of neuronal NOS (nNOS). Indeed, the concomitant addition of the selective nNOS inhibitor N(omega)-propyl-L-arginine (NPLA) and A1254 prevented cell injury, suggesting that NO production plays a major role in A1254-evoked cell injury. Furthermore, the exposure (14 hr) to A1254 (30 microg/ml) produced an up-regulation of the expression of beta isoform of nNOS. This up-regulation was calcium dependent and was accompanied by an enhancement of NO production as demonstrated by an increase of nitrite formation. Moreover, A1254-induced cell injury was prevented when KT 5823, a selective cGMP/PKG inhibitor, was added concomitantly to 30 microg/ml A1254. These results suggest that PCB-induced cell death in neuroblastoma cells is mediated by an activation of the cGMP/PKG pathway triggered by NO production.
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PMID:Involvement of the nitric oxide/protein kinase G pathway in polychlorinated biphenyl-induced cell death in SH-SY 5Y neuroblastoma cells. 1679 54

We have reported previously that genipin, a natural iridoid compound, induces neuritogenesis through a nitric oxide (NO)-cyclic GMP (cGMP)-cGMP-dependent protein kinase (PKG) signaling pathway in PC12h cells and that neuronal NO synthase (nNOS) is one of the target molecules of genipin in vitro. Recently, it has been suggested that the neurotrophic effects of NO are due to its direct activation of receptor-tyrosine kinase, especially TrkA. In this study, we investigated whether mouse neuroblastoma Neuro2a cells, which express nNOS but not TrkA, respond to genipin with neurite outgrowth through the mechanism observed in PC12h cells, to assess the involvement of TrkA in the mechanism. Neuro2a cells expressed all three types of NO synthase (NOS), and nNOS was detectable as the main component in Western blot analysis. Genipin significantly induced neurite outgrowth and activation of NADPH-diaphorase, which were significantly blocked by a non-selective NOS inhibitor. Both a soluble guanylate cyclase inhibitor and a PKG inhibitor also inhibited the genipin-induced neuritogenesis. Genipin induced sustained phosphorylation of mitogen-activated protein kinase (MAPK). In fact, the genipin-induced neurite outgrowth was completely inhibited by a specific MAPK kinase inhibitor. Moreover, a NOS inhibitor abolished MAPK phosphorylation as well as neurite outgrowth in genipin-treated cells. These results suggest that genipin induces neurite outgrowth through an NO-cGMP-PKG signaling pathway followed by MAPK phosphorylation without TrkA activation in Neuro2a cells and that PKG downstream to NOSs, which may be mainly nNOS, is very important for the signaling molecule to induce neuritogenesis by genipin.
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PMID:Genipin exhibits neurotrophic effects through a common signaling pathway in nitric oxide synthase-expressing cells. 1817 84

Adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels couple cellular metabolic status to membrane electrical activity. In this study, we performed patch-clamp recordings to investigate how cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) regulates the function of K(ATP) channels, using both transfected human SH-SY5Y neuroblastoma cells and embryonic kidney (HEK) 293 cells. In intact SH-SY5Y cells, the single-channel currents of Kir6.2/sulfonylurea receptor (SUR) 1 channels, a neuronal-type K(ATP) isoform, were enhanced by zaprinast, a cGMP-specific phosphodiesterase inhibitor; this enhancement was abolished by inhibition of PKG, suggesting a stimulatory role of cGMP/PKG signaling in regulating the function of neuronal K(ATP) channels. Similar effects of cGMP accumulation were confirmed in intact HEK293 cells expressing Kir6.2/SUR1 channels. In contrast, direct application of purified PKG suppressed rather than activated Kir6.2/SUR1 channels in excised, inside-out patches, while tetrameric Kir6.2LRKR368/369/370/371AAAA channels expressed without the SUR subunit were not modulated by zaprinast or purified PKG. Lastly, reconstitution of the soluble guanylyl cyclase/cGMP/PKG signaling pathway by generation of nitric oxide led to Kir6.2/SUR1 channel activation in both cell types. Taken together, here, we report novel findings that PKG exerts dual functional regulation of neuronal K(ATP) channels in a SUR subunit-dependent manner, which may provide new means of therapeutic intervention for manipulating neuronal excitability and/or survival.
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PMID:Dual regulation of the ATP-sensitive potassium channel by activation of cGMP-dependent protein kinase. 1823 7

Aging populations with neurodegenerative disorders will gradually become a greater problem for society. Serum deprivation-induced cell death is recognized as one of the standard models for the study of neurotoxicity. Increasing evidence indicates that cGMP/PKG pathway may play a rescue role in serum deprivation-induced toxicity. The aim of this study was to investigate protective effects of KMUP-1, an enhancer of cGMP/PKG signaling on serum deprivation-induced neurotoxicity in SH-SY5Y neuroblastoma cells. Under normal serum condition, KMUP-1 enhanced protein expression of nNOS, PKG and sGCalpha1, increased intracellular cyclic GMP level, and attenuated PDE5 expression. KMUP-1 also increased expression of BDNF and Bcl-2, but it did not affect Bax expression. The phosphorylation of Akt and CREB induced by KMUP-1 was inhibited by tyrosine kinase (TrK) inhibitor K252a and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, respectively. Under serum deprivation condition, flow cytometric analysis using Annexin V showed KMUP-1 increased cell viability, but lacked protective effects in the presence of nitric oxide synthase inhibitor l-NAME, PKG inhibitor Rp-8-pCPT-cGMPS or LY294002. KMUP-1 not only enhanced expression of nNOS, sGCalpha1, PKG, p-CREB, p-Akt and Bcl-2, but also attenuated Bax expression in serum deprivation-treated cultures. In conclusion, cGMP/PKG, PI3K/Akt/CREB and Bcl-2/Bax signals play critical roles in the neuroprotective effects of KMUP-1 on serum deprivation-induced toxicity.
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PMID:KMUP-1 attenuates serum deprivation-induced neurotoxicity in SH-SY5Y cells: roles of PKG, PI3K/Akt and Bcl-2/Bax pathways. 1996 17


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