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)

Mice lacking expression of the p66 isoform of the ShcA adaptor protein (p66(ShcA)) are less susceptible to oxidative stress and have an extended life span. Specifically, phosphorylation of p66(ShcA) at serine 36 is critical for the cell death response elicited by oxidative damage. We sought to identify the kinase(s) responsible for this phosphorylation. Utilizing the SH-SY5Y human neuroblastoma cell model, it is demonstrated that p66(ShcA) is phosphorylated on serine/threonine residues in response to UV irradiation. Both c-Jun N-terminal kinases (JNKs) and p38 mitogen-activated protein kinases are activated by UV irradiation, and we show that both are capable of phosphorylating serine 36 of p66(ShcA) in vitro. However, treatment of cells with a multiple lineage kinase inhibitor, CEP-1347, that blocks UV-induced JNK activation, but not p38, phosphatidylinositol 3-kinase, or MEK1 inhibitors, prevented p66(ShcA) phosphorylation in SH-SY5Y cells. Consistent with this finding, transfected activated JNK1, but not the kinase-dead JNK1, leads to phosphorylation of serine 36 of p66(ShcA) in Chinese hamster ovary cells. In conclusion, JNKs are the kinases that phosphorylate serine 36 of p66(ShcA) in response to UV irradiation in SH-SY5Y cells, and blocking p66(ShcA) phosphorylation by intervening in the JNK pathway may prevent cellular damage due to light-induced oxidative stress.
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PMID:c-Jun N-terminal kinase specifically phosphorylates p66ShcA at serine 36 in response to ultraviolet irradiation. 1160 89

The compound 1-methyl-4-phenylpyridinium (MPP) is a selective inhibitor of mitochondrial complex I, and is widely used in model systems to elicit neurochemical alterations that may be associated with Parkinson's disease. In the present study treatment of human neuroblastoma SH-SY5Y cells with MPP resulted in a time- and concentration-dependent activation of the apoptosis-associated cysteine protease caspase-3, and caused morphological changes characteristic of apoptosis. To test if the activation state of the cell survival-promoting phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway affects MPP-induced caspase-3 activation, PI3K was inhibited with LY294002, or activated with insulin-like growth factor-1. MPP-induced caspase-3 activation was increased by inhibition of PI3K, and decreased by stimulation of PI3K, indicative of anti-apoptotic signaling by the PI3K/Akt pathway. To test if glycogen synthase kinase-3beta (GSK3beta), a pro-apoptotic kinase that is inhibited by Akt, is involved in regulating MPP-induced apoptosis, overexpression of GSK3beta and lithium, a selective inhibitor of GSK3beta, were used to directly alter GSK3beta activity. MPP-induced caspase-3 activity was increased by overexpression of GSK3beta. Conversely, the GSK3beta inhibitor lithium attenuated MPP-induced caspase-3 activation. To test if these regulatory interactions applied to other mitochondrial complex I inhibitors, cells were treated with rotenone. Rotenone-induced activation of caspase-3 was enhanced by inhibition of PI3K or increased GSK3beta activity, and was attenuated by inhibiting GSK3beta with lithium. Overall, these results indicate that inhibition of GSK3beta provides protection against the toxic effects of agents, such as MPP and rotenone, that impair mitochondrial function.
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PMID:Caspase-3 activation induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase kinase-3beta and attenuated by lithium. 1168 67

Motility is an important process that contributes to cancer cell spread. Growth factors are key regulators of motility in many cell types. Insulin-like growth factor I (IGF-I) causes SH-SY5Y human neuroblastoma cells to undergo dynamic morphological changes, leading to the extension of lamellipodia. IGF-I stimulated lamellipodia extension requires signaling through both phosphatidylinositol 3-kinase (PI3-K) and MAP kinase pathways. IGF-I, over a period of hours, stimulates SH-SY5Y and SHEP neuroblastoma cells to become more motile. While SH-SY5Y and SHEP cells use different insulin receptor substrate (IRS) isoforms to transduce signals from the IGF-I receptor, IGF-I has the same relative effect on the motility of both cell lines. Blocking the PI3-K and MAP kinase pathways attenuates the ability of IGF-I to increase motility. Overexpression of PTEN also attenuates IGF-I mediated motility. These results delineate some of the proximal events in the signaling mechanism utilized by IGF-I to stimulate cell motility.
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PMID:Insulin-like growth factor I stimulates motility in human neuroblastoma cells. 1170 26

We investigated the effect of IGF-1 on cell death induced by peroxynitrite in human neuroblastoma SH-SY5Y cells. Exposure of the cells to 3-morpholinosydnonimine (SIN-1), a peroxynitrite donor, caused cytochrome c release from the mitochondria, caspase-3-like activation, and cell death. Pre-incubation of the cells with the caspase-3 inhibitor partially prevented SIN-1-induced cell death. Simultaneous addition of IGF-1 reduced SIN-1-induced caspase-3-like activation and cell death, whereas IGF-1 failed to reduce the release of cytochrome c. IGF-1 increased Akt phosphorylation, and Akt phosphorylation was inhibited by wortmannin, an inhibitor of phosphatidylinositol 3-kinase. In addition, wortmannin prevented IGF-1-evoked inhibition of cell death and caspase-3-like activation. In a cell-free system, addition of cytochrome c to cytosolic fraction resulted in caspase-3-like activation. The activation was reduced when the cytosolic fraction prepared from IGF-1-treated cells was used. These results suggest that IGF-1 protects peroxynitrite-induced cell death downstream of cytochrome c release through the inhibition of caspase-3-like activation.
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PMID:Insulin-like growth factor-1 protects peroxynitrite-induced cell death by preventing cytochrome c-induced caspase-3 activation. 1183 96

We investigated the effect of vanadate, a tyrosine phosphatase inhibitor, on cell death induced by peroxynitrite in human neuroblastoma SH-SY5Y cells. Vanadate prevented cell death induced by 3-morpholinosydnonimine (SIN-1), a peroxynitrite donor; whereas SIN-1-induced cell death was not prevented by neither okadaic acid, an inhibitor of serine/threonine phosphatases 1 and 2A, nor cyclosporin A, an inhibitor of serine/threonine phosphatase 2B. Vanadate did not prevent cell death induced by N-ethyl-2-(1-ethyl-hydroxy-2-nitrosohydrazino)-ethanamine, a nitric oxide donor. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-kinase), did not block the protective effect of vanadate, suggesting that the protective effect of vanadate is independent on PI3-kinase. Vanadate increased tyrosine phosphorylation of several proteins including the focal adhesion protein p130 Crk-associated substrate (p130(cas)). By the treatment with SIN-1, the endogenous association of p130(cas) and Crk was disrupted, and the association was restored by vanadate treatment. These results suggest that disruption of tyrosine phosphorylation signaling may be critical for peroxynitrite-induced cell death, and that vanadate prevents cell death at least in part through the enhancement in tyrosine phosphorylation of the proteins including p130(cas).
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PMID:Vanadate protects human neuroblastoma SH-SY5Y cells against peroxynitrite-induced cell death. 1196 12

Neuroblastoma (NB), a malignant childhood tumor deriving from the embryonic neural crest, is sensitive to the growth-stimulating effects of insulin-like growth factors (IGFs). Aggressive cases of this disease often acquire autocrine loops of IGF production, but the mechanisms through which the different components of the IGF axis are regulated in tumor cells remain unclear. Upon conditional expression of c-Myb in a NB cell line, we detected up-regulation of IGF1, IGF1 receptor, and insulin-like growth factor-binding protein 5 (IGFBP-5) expression. Analysis of the IGFBP-5 promoter revealed two potential Myb binding sites at position -59 to -54 (M1) and -429 to -424 (M2) from the transcription start site; both sites were bound by c-Myb and B-Myb in vitro and in vivo. Reporter assays carried out using the proximal region of the human IGFBP-5 promoter demonstrated that c-Myb and B-Myb enhanced transcription. However, site-directed mutagenesis and deletion of the Myb binding sites coupled with reporter assays revealed that M2 but not M1 was important for Myb-dependent transactivation of the IGFBP-5 promoter. The double mutant M1/M2 was still transactivated by c-Myb, suggesting the existence of Myb binding-independent mechanisms of IGFBP-5 promoter regulation. A constitutively active AKT transactivated the IGFBP-5 promoter, whereas the phosphatidylinositol 3-kinase inhibitor LY294002 suppressed it. Moreover, the kinase dead dominant negative K179M AKT mutant was able to inhibit transcription from the M2 and M1/M2 IGFBP-5 mutant promoters. Deletion analysis of the IGFBP-5 promoter revealed that the AKT-responsive region lies between nucleotides -334 and -83. Together, these data suggest that the Myb binding-independent transactivation of the IGFBP-5 promoter was due to the activation of the phosphatidylinositol 3-kinase/AKT pathway likely mediated by IGF1 receptor-dependent signals. Finally, IGFBP-5 was able to modulate proliferation of NB cells in a manner dependent on its concentration and on the presence of IGFs.
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PMID:Expression of insulin-like growth factor-binding protein 5 in neuroblastoma cells is regulated at the transcriptional level by c-Myb and B-Myb via direct and indirect mechanisms. 1197 31

Retinoic acid (RA) induces neural differentiation of SH-SY5Y neuroblastoma cells. We show that the mRNA levels of the differentiation-inhibiting basic helix-loop-helix transcription factors ID1, ID2, and ID3 are down-regulated during RA-induced differentiation of SH-SY5Y cells. The levels of ID proteins decreased in parallel to the observed transcriptional repression. The expression of other basic helix-loop-helix genes changed during RA-induced differentiation: expression of neuroblast-specific ASCL1 (HASH-1) gene was promptly reduced after RA treatment, whereas expression of differentiation-promoting genes NEUROD6 (NEX-1, HATH-2) and NEUROD1 was increased. Treatments with 12-O-tetradecanoylphorbol-13-acetate, another inducer of neuroblastoma cell differentiation, also resulted in coordinated down-regulation of ID gene expression, underscoring the role of ID genes in differentiation. Down-regulation of ID gene expression by RA involves a complex mechanism because full transcriptional repression required newly synthesized proteins and signaling by phosphatidylinositol 3-kinase (PI3K). RA treatment activates the PI3K/Akt signaling pathway, resulting in increased PI3K activity in extracts from RA-treated cells and a rapid increase in phosphorylation of Akt in Ser-473. Inhibition of PI3K by LY294002 impaired RA-induced differentiation, as assessed by morphological and biochemical criteria. We propose that RA, by activating the PI3K/Akt signaling pathway, plays an important role in the regulation of neuronal cell survival.
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PMID:Activation of the phosphatidylinositol 3-kinase/Akt signaling pathway by retinoic acid is required for neural differentiation of SH-SY5Y human neuroblastoma cells. 1200 Jul 52

In our laboratory, we are interested in hyperosmolarity-induced apoptosis in neuronal cells. We have shown that high concentrations of glucose or mannitol induce apoptotic cell death in dorsal root ganglia in culture and in SH-SY5Y and SH-EP human neuroblastoma cells. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that has a critical role for transmitting integrin-mediated-signals. In this study, we report that hyperosmolar treatment mediates FAK dephosphorylation and cleavage, which is prevented by insulin-like growth factor I (IGF-I) treatment. Mannitol treatment of SH-EP cells transfected with vector (SH-EP/pSFFV) results in concentration- and time-dependent dephosphorylation and degradation of FAK. Dephosphorylation and degradation of FAK are tightly correlated with apoptotic morphological changes, including the disruption of actin stress fibers, the loss of focal adhesion sites, membrane blebbing, and cell detachment. Treatment of SH-EP/pSFFV cells with IGF-I or transfection of IGF-I receptor prevents these changes. Treatment of cells with pharmacologic inhibitors of the mitogen-activated protein kinase or phosphatidylinositol 3-kinase pathways does not affect mannitol-induced FAK dephosphorylation and degradation. However, phosphatidylinositol 3-kinase is necessary for IGF-I-mediated protection against FAK alteration. Mannitol treatment also results in the degradation of Akt. Mannitol induces the activation of caspases-3 and -9 in a time course similar to the dephosphorylation and degradation of FAK. Treatment of the cells with ZVAD, a general caspase inhibitor, blocks the mannitol-induced FAK and Akt degradation as well as cell detachment and apoptosis. These results suggest that one of the pathways of mannitol-mediated apoptosis is through the degradation of FAK and Akt and that IGF-I protects the cells from apoptosis by blocking the activation of caspases, which may be responsible for the loss of FAK and Akt.
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PMID:Insulin-like growth factor I prevents mannitol-induced degradation of focal adhesion kinase and Akt. 1201 Oct 46

Glycogen synthase kinase-3beta (GSK-3beta) is a central component in many critical intracellular signaling mechanisms. These include the phosphatidylinositol 3-kinase/Akt cell survival pathway, which inhibits GSK-3beta activity. GSK-3beta itself inhibits the activation of several transcription factors, which are important cell survival factors, such as heat shock factor 1. These factors likely contribute to the recent revelation that GSK-3beta is a pro-apoptotic enzyme. Recently, lithium has been identified as a selective and direct inhibitor of GSK-3beta. Based on these findings, we have proposed that part of the neuroprotectant properties of lithium is due to its ability to inhibit GSK-3beta, and thus block the facilitation of apoptosis produced by GSK-3beta. Since several anticonvulsants recently have been shown to be effective mood stabilizers, we examined if these agents are capable of protecting cells from GSK-3beta-facilitated apoptosis. In addition to lithium, both valproic acid and lamotrigine, but not carbamazepine, provided protection from GSK-3beta-facilitated apoptosis in human neuroblastoma SH-SY5Y cells. These results demonstrate that several drugs therapeutic for bipolar disorder can provide neuroprotection by inhibiting the pro-apoptotic effects of GSK-3beta, providing new evidence that dysregulation of GSK-3beta may contribute to the pathophysiology of bipolar disorder.
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PMID:Glycogen synthase kinase-3beta, mood stabilizers, and neuroprotection. 1207 11

Brain-derived neurotrophic factor (BDNF) is a major neurotrophin in the brain and abnormal regulation of BDNF may contribute to the pathophysiology of mood disorders. In the present study, we examined if alterations in the activity of glycogen synthase kinase-3-beta (GSK3beta) or treatment with mood stabilizers modulated BDNF-mediated signal transduction pathways in differentiated human neuroblastoma SH-SY5Y cells. BDNF increased the phosphorylation of the forkhead transcription factor FKHRL1 through activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, and the phosphorylation of the cyclic AMP response element binding protein (CREB) through activation of extracellular signal-regulated kinase1/2 (ERK1/2). BDNF also increased serine(9) -phosphorylation of GSK3beta, which inhibits GSK3beta activity. Overexpression of GSK3beta did not affect BDNF-induced phosphorylation of Akt, ERK1/2, or FKHRL1, but abolished CREB phosphorylation induced by BDNF. This inhibition of BDNF-induced CREB phosphorylation in GSK3beta-overexpressing SH-SY5Y cells was blocked by treatment with lithium. In contrast to lithium, sodium valproate and lamotrigine did not affect BDNF-mediated signaling, whereas carbamazepine induced a rapid and prolonged phosphorylation of ERK1/2 and CREB in the absence or the presence of BDNF. Therefore, increased GSK3beta selectively attenuates BDNF-induced CREB phosphorylation, and lithium and carbamazepine can facilitate activation of CREB.
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PMID:BDNF-mediated signal transduction is modulated by GSK3beta and mood stabilizing agents. 1209 67


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