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)

Elevated intracellular Ca(2+) triggers numerous signaling pathways including protein kinases such as the calmodulin-dependent kinases (CaMKs) and the extracellular signal-regulated kinases (ERKs). In the present study we examined Ca(2+)-dependent "cross-talk" between these two protein kinase families. Using a combination of pharmacological inhibitors and dominant-negative kinases (dnKinase), we identified a requirement for CaMKK acting through CaMKI in the stimulation of ERKs upon depolarization of the neuroblastoma cell line, NG108. Depolarization stimulated prolonged ERK and JNK activation that was blocked by the CaMKK inhibitor, STO-609; this inhibition of ERK activation by STO-609 was rescued by expression of a STO-609-insensitive mutant of CaMKK. However, activation of ERK by epidermal growth factor or carbachol were not suppressed by inhibition of CaMKK, indicating specificity for this "cross-talk." To identify the downstream target of CaMKK that mediated ERK activation upon depolarization, dnKinases were expressed. The dnCaMKI completely suppressed ERK2 activation whereas dnAKT/PKB or nuclear-targeted dnCaMKIV, other substrates for CaMKK, were not inhibitory. ERK activation upon depolarization or transfection with constitutively active (ca) CaMKI was blocked by dnRas. Additionally, depolarization of NG108 cells promoted neurite outgrowth, and this effect was blocked by inhibition of either CaMKK (STO-609) or ERK (UO126). Co-transfection with caCaMKK plus caCaMKI also stimulated neurite outgrowth that was blocked by inhibition of ERK (UO126). These data are the first to suggest that ERK activation and neurite outgrowth in response to depolarization are mediated by CaMKK activation of CaMKI.
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PMID:Calcium activation of ERK mediated by calmodulin kinase I. 1515 Feb 58

Although corticotropin-releasing hormone (CRH) plays a pivotal role in the regulation of the hypothalamo-pituitary-adrenal axis, the mechanism of CRH gene expression in the neuronal cell is not completely understood. In this study, we examined the transcriptional regulation of human CRH gene 5'-promoter, using a human BE(2)C neuroblastoma cell line expressing intrinsic CRH. In particular, we focused on the involvement of calmodulin kinases (CaMKs), which are known to play an important role in excitation-induced gene expression through the rise in intracellular calcium in the central nervous system. RT-PCR analysis confirmed the expression of CaMK as well as CRH mRNA in BE(2)C cells. When we introduced approximately 1.1 kb of the 5'-promoter region of the human CRH fused with luciferase reporter gene into the cells, a substantial transcriptional activity was observed, and this was further increased by the activation of the cAMP/PKA pathway. We then examined the effect of activation of CaMKs by introducing the expression vectors of each kinase, revealing a potent stimulatory effect of CaMKIV, but no effect of CaMKII. Depolarization of the cells caused an increase in CRH promoter activity, which was completely abolished by the treatment with the CaMK antagonist K252a. Interestingly, KCREB, a dominant negative form of CREB, antagonized the effect of the CaMKIV-mediated effect. Altogether, we conclude that not only the cAMP/PKA but also the calcium/CaMKIV signaling pathway is involved in the regulation of CRH gene expression. Furthermore, CREB is thought to be involved in CaMK- as well as cAMP/PKA-mediated CRH gene expression. Since the CRH gene is expressed in the neuronal cells of the hypothalamus, the calcium/CaMKIV signaling pathway may play an important role in the excitation-mediated regulation of CRH synthesis.
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PMID:Calcium/calmodulin kinase IV pathway is involved in the transcriptional regulation of the corticotropin-releasing hormone gene promoter in neuronal cells. 1559 Oct 24

Opioid receptors are involved in regulating neuronal survival. Here we demonstrate that activation of the mu-opioid receptor in human neuroblastoma SH-SY5Y cells led to the phosphorylations of IkappaB kinase (IKK) and p65, denoting the stimulation of the nuclear factor-kappaB (NFkappaB) transcription factor. This response was mediated through pertussis toxin-sensitive G proteins. The mu-opioid-induced IKK phosphorylation required extracellular signal-regulated protein kinase, phosphatidylinositol 3-kinase and c-Src. Moreover, c-Jun N-terminal kinase and calmodulin-dependent kinase II also participated in the IKK activation, despite the lack of involvement of phospholipase Cbeta and protein kinase C. These data suggest that the mu-opioid receptor is capable of simulating NFkappaB signaling via the phosphorylation of IKK and p65 in human neuroblastoma SH-SY5Y cells.
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PMID:Mu-opioid receptor-mediated phosphorylation of IkappaB kinase in human neuroblastoma SH-SY5Y cells. 1608 28

Nuclear Ca2+/calmodulin-dependent protein kinase phosphatase (CaMKP-N) is an enzyme that dephosphorylates and concomitantly downregulates multifunctional Ca2+/calmodulin-dependent protein kinases (CaMKs) in vitro. However, the functional roles of this enzyme in vivo are not well understood. To investigate the biological significance of CaMKP-N during zebrafish embryogenesis, we cloned and characterized zebrafish CaMKP-N (zCaMKP-N). Based on the nucleotide sequences in the zebrafish whole genome shotgun database, we isolated a cDNA clone for zCaMKP-N, which encoded a protein of 633 amino acid residues. Transiently expressed full-length zCaMKP-N in mouse neuroblastoma, Neuro2a cells, was found to be localized in the nucleus. In contrast, the C-terminal truncated mutant lacking RKKRRLDVLPLRR (residues 575-587) had cytoplasmic staining, suggesting that the nuclear localization signal of zCaMKP-N exists in the C-terminal region. Ionomycin treatment of CaMKIV-transfected Neuro2a cells resulted in a marked increase in the phosphorylated form of CaMKIV. However, cotransfection with zCaMKP-N significantly decreased phospho-CaMKIV in ionomycin-stimulated cells. Whole mount in situ hybridization analysis of zebrafish embryos showed that zCaMKP-N is exclusively expressed in the head and neural tube regions. Gene knockdown of zCaMKP-N using morpholino-based antisense oligonucleotides induced significant morphological abnormalities in zebrafish embryos. A number of apoptotic cells were observed in brain and spinal cord of the abnormal embryos. These results suggest that zCaMKP-N plays a crucial role in the early development of zebrafish.
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PMID:Knockdown of nuclear Ca2+/calmodulin-dependent protein kinase phosphatase causes developmental abnormalities in zebrafish. 1716 23

Post-translational modification of cellular proteins by beta-o-linked N-acetylglucosamine (o-GlcNAc) moieties plays a significant role in signal transduction by modulating protein stability, protein-protein interactions, transactivation processes, and the enzyme activities of target proteins. Though various classes of proteins are known to be regulated by o-GlcNAc modification (o-GlcNAcylation), the mechanism that regulates o-linked GlcNAc transferase (OGT) activity remains unknown. Here, we report that potassium chloride-induced depolarization provokes the activation of OGT and subsequent o-GlcNAcylation of proteins in neuroblastoma NG-108-15 cells. Moreover, such an induction of protein o-GlcNAcylation was abolished by treating cells with either a voltage-gated calcium channel inhibitor or a calcium/calmodulin-dependent protein kinase (CaMK) inhibitor. In addition, CaMKIV was found to specifically phosphorylate and activate OGT in vivo and in vitro, which implies that CaMKIV is required for depolarization-induced activation of OGT. Furthermore, we found that OGT is involved in depolarization-induced and CaMKIV-dependent activation of activator protein-1 (AP-1) and subsequent tissue inhibitor of metalloproteinase-1 (Timp-1) gene expression. Taken together, our findings suggest that CaMKIV activated OGT, and OGT has an essential role on the process of CaMKIV-dependent AP-1 activation under depolarization in neuronal cells.
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PMID:o-GlcNAc transferase is activated by CaMKIV-dependent phosphorylation under potassium chloride-induced depolarization in NG-108-15 cells. 1802 44

Human SH-SY5Y neuroblastoma cells have been used to investigate mechanisms involved in CREB phosphorylation after activation of two endogenously expressed Gq/11-protein-coupled receptors, the M3 muscarinic acetylcholine (mACh) and B2 bradykinin receptors. Stimulation with either methacholine or bradykinin resulted in maximal increases in CREB phosphorylation within 1 min, with either a rapid subsequent decrease (bradykinin) to basal levels, or a sustained response (methacholine). Inhibitor studies were performed to assess the involvement of a number of potential kinases in signalling to CREB phosphorylation. Removal of extracellular Ca2+, inhibition of Ca2+/calmodulin-dependent protein kinase II and down-regulation of protein kinase C (PKC) resulted in reduced CREB phosphorylation after both M3 mACh and B2 bradykinin receptor activation. In contrast, inhibition of MEK1/2 by U0126 resulted in significantly reduced CREB phosphorylation levels after B2 bradykinin, but not M3 mACh receptor activation. In addition, we demonstrate that maintained phosphorylation of CREB is necessary for CRE-dependent gene transcription as the M3 mACh, but not the B2 bradykinin receptor activates both a recombinant CRE-dependent reporter gene, and the endogenous c-Fos gene. These data highlight the involvement of multiple, overlapping signalling pathways linking these endogenous Gq/11-coupled metabotropic receptors to CREB and emphasize the importance of the duration of signalling pathway activation in converting a CREB phosphorylation event into a significant change in transcriptional activity.
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PMID:Regulation of cyclic AMP response-element binding-protein (CREB) by Gq/11-protein-coupled receptors in human SH-SY5Y neuroblastoma cells. 1803 9

The neurotrophic actions of pituitary adenylate cyclase-activating polypeptide (PACAP)-38 and leukemia inhibitory factor (LIF) were investigated in human neuroblastoma SH-SY5Y cells. Effects on differentiation were assessed through monitoring morphological changes and Western blot analysis of the expression of neuronal marker proteins. In contrast to PACAP-38, which induced a 5.5-fold increase in the number of neurite-bearing cells, LIF had no significant effect on cell morphology compared to control cells over the 4-day time course. Cells co-treated with PACAP-38+LIF showed a similar increase in neurite-bearing cells compared to those treated with PACAP-38 alone. Cell morphology was similar for PACAP-38-treated and PACAP-38+LIF-co-treated cells, with the formation of bipolar neuron-like cells with long thin neurites, topped by growth cone-like structures and varicosities. SH-SY5Y cells express tyrosine hydroxylase (TH) but only low levels of the neuronal marker proteins: Bcl-2, GAP-43 and choline acetyltransferase (ChAT). Treatment of cells with PACAP-38 induced the expression of Bcl-2, GAP-43, and ChAT but did not appear to alter the expression of TH. LIF failed to induce the expression of GAP-43 and had little effect on the expression of TH, but did induce the expression of Bcl-2 and upregulated the expression of ChAT. Co-treatment with LIF had no effect on PACAP-38-induced expression of Bcl-2, GAP-43, and ChAT. Cells differentiated for 4 days with PACAP-38 or treated with LIF also displayed increased resistance to hypoxic conditions and to treatment with H2O2 and TNFalpha. The increased resistance to hypoxic conditions for PACAP-differentiated cells was blocked by the p38 MAP kinase inhibitor, SB203580, but not by the MEK1 inhibitor, PD98059. Additionally, cell proliferation assays show that LIF, but not PACAP-38, stimulates proliferation of SH-SY5Y cells, and this observed increase by LIF is not attenuated by co-treatment with PACAP. Further investigation of the intracellular signaling pathways mediating the neurotrophic effects of PACAP on SH-SY5Y cells indicate that neither phospholipase C activation nor Ca2+/calmodulin-dependent kinase II (CAMKII) are involved.
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PMID:Neurotrophic actions of PACAP-38 and LIF on human neuroblastoma SH-SY5Y cells. 1850 35

To understand the domain structure responsible for different enzymatic properties, we constructed chimera cDNAs of the alpha and beta isoforms of Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase II). The chimera DNAs were expressed in neuroblastoma cells, and the affinity for calmodulin and the subcellular localization of chimera enzymes were investigated. Here, we found that the region in immediately N-terminal of the calmodulin-binding site (exons 10 and 11), including the autophosphorylation site, mainly affected the affinity of each isoform for calmodulin and that the N-terminal region (exons 1 and 2), including the ATP-binding site, modified the affinity for calmodulin of each isoform. It was confirmed that the association of beta CaM kinase II with the particulate fraction was determined by beta-specific insertion, and also found that the association with the particulate fraction was modified by exons 1 and 2 of each isoform. Kinases without beta-specific insertion and chimera kinases consisting of exons 1 and 2 of beta and other regions of alpha appeared reduced in the transport of kinases to neurite. These results indicated that the structure of exons 10 and 11 and exons 1 and 2 modified the properties of CaM kinase II holoenzyme.
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PMID:Domain structure responsible for the different properties between alpha and beta Ca2+/calmodulin-dependent protein kinase II analyzed by their chimera enzymes. 1870 25

Huntington's disease (HD) is a neurodegenerative disease caused by mutant huntingtin protein containing an expanded polyglutamine tract, which may cause abnormal protein-protein interactions such as increased association with calmodulin (CaM). We previously demonstrated in HEK293 cells that a peptide containing amino acids 76-121 of CaM (CaM-peptide) interrupted the interaction between CaM and mutant huntingtin, reduced mutant huntingtin-induced cytotoxicity and reduced transglutaminase (TG)-modified mutant huntingtin. We now report that adeno-associated virus (AAV)-mediated expression of CaM-peptide in differentiated neuroblastoma SH-SY5Y cells, stably expressing an N-terminal fragment of huntingtin containing 148 glutamine repeats, significantly decreases the amount of TG-modified huntingtin and attenuates cytotoxicity. Importantly, the effect of the CaM-peptide shows selectivity, such that total TG activity is not significantly altered by expression of CaM-peptide nor is the activity of another CaM-dependent enzyme, CaM kinase II. In vitro, recombinant exon 1 of huntingtin with 44 glutamines (htt-exon1-44Q) binds to CaM-agarose; the addition of 10 microM of CaM-peptide significantly decreases the interaction of htt-exon1-44Q and CaM but not the binding between CaM and calcineurin, another CaM-binding protein. These data support the hypothesis that CaM regulates TG-catalyzed modifications of mutant huntingtin and that specific and selective disruption of the CaM-huntingtin interaction is potentially a new target for therapeutic intervention in HD.
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PMID:Neuroprotective effects of calmodulin peptide 76-121aa: disruption of calmodulin binding to mutant huntingtin. 1933 77

ATP, via purinergic P2X receptors, acts as a neurotransmitter and modulator in both the central and peripheral nervous systems, and is also involved in many biological processes, including cell proliferation, differentiation and apoptosis. Previously, we have reported that P2X7 receptor inhibition promotes axonal growth and branching in cultured hippocampal neurons. In this article, we demonstrate that the P2X7 receptor negatively regulates neurite formation in mouse Neuro-2a neuroblastoma cells through a Ca2+/calmodulin-dependent kinase II-related mechanism. Using both molecular and immunocytochemical techniques, we characterized the presence of endogenous P2X1, P2X3, P2X4 and P2X7 subunits in these cells. Of these, the P2X7 receptor was the only functional receptor, as its activation induced intracellular calcium increments similar to those observed in primary neuronal cultures, exhibiting pharmacological properties characteristic of homomeric P2X7 receptors. Patch-clamp experiments were also conducted to fully demonstrate that ionotropic P2X7 receptors mediate nonselective cation currents in this cell line. Pharmacological inhibition of the P2X7 receptor and its knockdown by small hairpin RNA interference resulted in increased neuritogenesis in cells cultured in low serum-containing medium, whereas P2X7 overexpression significantly reduced the formation of neurites. Interestingly, P2X7 receptor inhibition also modified the phosphorylation state of focal adhesion kinase, Akt and glycogen synthase kinase 3, protein kinases that participate in the Ca2+/calmodulin-dependent kinase II signalling cascade and that have been related to neuronal differentiation and axonal growth. Taken together, our results provide the first mechanistic insight into P2X7 receptor-triggered signalling pathways that regulate neurite formation in neuroblastoma cells.
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PMID:Ca2+/calmodulin-dependent kinase II signalling cascade mediates P2X7 receptor-dependent inhibition of neuritogenesis in neuroblastoma cells. 1968 70


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