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)

We have analyzed the modulation of amyloid beta-protein precursor (APP) gene expression in human umbilical vein endothelial cells (HUVEC). The level of the APP mRNA transcripts increased as HUVEC reached confluency. In confluent culture the half-life of the APP mRNA was 4 hr. Treatment of the cells with human-recombinant interleukin 1 (IL-1), phorbol 12-myristate 13-acetate, or heparin-binding growth factor 1 enhanced the expression of APP gene in these cells, but calcium ionophore A23187 and dexamethasone did not. The protein kinase C inhibitor 1-(isoquinolinsulfonyl)-2-methylpiperazine (H7) inhibited IL-1-mediated increase of the level of APP transcripts. To map IL-1-responsive elements of the APP promoter, truncated portions of the APP promoter were fused to the human growth hormone reporter gene. The recombinant plasmids were transfected into mouse neuroblastoma cells, and the cell medium was assayed for the human growth hormone. A 180-base-pair region of the APP promoter located between position -485 and -305 upstream from the transcription start site was necessary for IL-1-mediated induction of the reporter gene. This region contains the upstream transcription factor AP-1 binding site. These results suggest that IL-1 upregulates APP gene expression in HUVEC through a pathway mediated by protein kinase C, utilizing the upstream AP-1 binding site of the APP promoter.
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PMID:Interleukin 1 regulates synthesis of amyloid beta-protein precursor mRNA in human endothelial cells. 250 93

We have examined the 5'-flanking region (944 bp) of the human choline acetyltransferase (hChAT) gene for sequences that modulate its transcriptional activity and identified a sequence 5'-TGACCCA-3' which confers c-Jun/c-Fos (AP-1) inducibility of homologous and heterologous promoters. Using transient transfections in neuroblastoma NE-1-115 and COS-1 cells, we show that ligand-activated estrogen receptor (HEGo) represses the transcriptional activation by c-Fos/c-Jun. Testing HEGo mutants in transfection assays reveals that the ligand-binding domain is crucial for this repression, whereas the N-terminal (A/B) region and the DNA-binding domain are not essential. Gel retardation assays show that the hChAT AP-1 recognition sequence binds in vitro baculovirus-produced c-Jun/c-Fos proteins. This binding is inhibited by addition of baculovirus-produced HEGo. In contrast to HEGo, ligand-activated glucocorticoid, androgen, and retinoic acid receptors (RARs) enhance the transcription activation induced by c-Jun/c-Fos. All three types of RARs--RAR alpha, beta, gamma--and RXR alpha are able to stimulate AP-1 activity on the proximal hChAT promoter. Several mechanism possibilities involving protein-protein interaction are discussed to explain the phenomena.
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PMID:Positive and negative effects of nuclear receptors on transcription activation by AP-1 of the human choline acetyltransferase proximal promoter. 774 8

In this study we have investigated DNA-protein interactions at an AP1-like motif of the neuropeptide tyrosine (NPY) promoter during in vitro differentiation of human neuroblastoma cells SH-SY5Y to mature nonproliferative sympathetic neuron-like cells. These neuroblast-like cells originate from the parental cell line SK-N-SH from which two phenotypically distinct major cell types have been subcloned: the neuroblast-like SH-SY5Y cells and the epithelial-like SH-EP cells. SH-SY5Y cells can be induced to differentiate towards mature noradrenergic ganglion-like cells by the protein kinase C activator TPA (12-O-tetradecanoyl phorbol 13-acetate). Interestingly, the effects of TPA are mimicked by the protein kinase inhibitor, staurosporine, which induces the expression of TPA target genes such as the neuronal differentiation-associated gene NPY in SH-SY5Y cells. Following activation of PKC, the effects of TPA are known to act through the transcription factor AP-1. To study transcriptional regulation during sympathetic differentiation of human neuroblastoma cells by TPA as well as by staurosporine, we focussed on protein complexes at an evolutionarily conserved AP-1 like motif located at nucleotide positions -70 to -65 within the 5'-flanking region of the NPY gene. We show that both c-Jun and c-Fos are part of the protein complexes that bind to this sequence in SH-SY5Y cells. Both staurosporine and TPA enhanced and modulated the binding of these DNA-protein complexes concomitant with the NPY mRNA expression. On the other hand, the absence of these complexes in the SH-EP subclone was associated with the absence of NPY mRNA expression and a lack of differentiation-associated morphological changes. The data suggest that Fos and Jun heterodimers are part of the protein complexes that bind to the AP-1 regulatory element of the NPY promoter in the neuroblast-like SH-SY5Y cells. These protein complexes appear to contribute to the cell specific expression of the NPY gene and seem to be required during differentiation of SH-SY5Y human neuroblastoma cells further along the sympathetic neuronal lineage induced by either TPA or staurosporine.
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PMID:Fos and Jun form cell specific protein complexes at the neuropeptide tyrosine promoter. 803 20

The role of the transcription factor AP-1 in regulating D2 receptor transcriptional activity was investigated in D2 receptor expressing neuroblastoma cells, NB41A3, and in non-D2 receptor expressing CHO cells. Deletion of a region containing the putative AP-1 binding site resulted in a significant reduction in the activity in CHO cells; while the activity in NB41A3 cells was increased suggesting that the AP-1 site may differentially regulate D2 gene expression in these distinct cell types. However, both cell lines were found to express significant and similar levels of the transcription factors AP-1. Analysis of phosphorylated proteins in each of the cell lines provided evidence that AP-1 is phosphorylated in NB41A3 cells, but not in CHO cells. This result suggests that differential regulation of D2 gene expression may be related to AP-1 phosphorylation.
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PMID:Differential regulation of D2 receptor gene expression by transcription factor AP-1 in cultured cells. 937 90

Lithium and sodium valproate (VPA) are effective in the treatment of bipolar disorder (BD) and may function through the regulation of signal transduction pathways and transcription factors such as c-fos and c-Jun, which in turn results to changes in gene expression. The long-term efficacy of lithium and VPA in BD suggests that the regulation of gene expression may be an important target for these drugs. Preliminary evidence suggests that c-fos levels and AP-1 binding may be regulated by lithium and VPA, but the results are inconclusive. In the present study, we report differential effects of the two most commonly prescribed mood stabilizers used to treat BD on Fos/Jun protein levels and their AP-1 binding activity in human neuroblastoma SH-SY5Y cells. At therapeutically relevant concentrations, both drugs acutely (<24 h) induced c-Fos immunoreactivity and AP-1 binding. In contrast to lithium, chronic (1 week) treatment with VPA led to continued induction of c-Fos, in addition to induction of c-Jun immunoreactivity and a 33-35 kDa band previously identified as chronic FRA. AP-1 DNA binding activity was also increased after 1 week VPA treatment. These findings suggest that both these mood stabilizers may have an effect on neuronal gene expression of target genes containing the AP-1 consensus sequence in their promoter regions after acute treatment. The present results confirm and extend previous findings on the regulation of c-fos expression and AP-1 binding after administration of mood stabilizers, and further elucidate the mechanisms through which VPA increases AP-1 DNA binding.
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PMID:Differential effects of mood stabilizers on Fos/Jun proteins and AP-1 DNA binding activity in human neuroblastoma SH-SY5Y cells. 968 95

We investigated the effects of D1 dopamine receptor stimulation on the activation of mitogen-activated protein kinases (MAPKs) in SK-N-MC human neuroblastoma cells. We found that the D1 dopamine receptor agonist SKF38393 induced similar time- and dose-related activation of p38 MAPK and c-Jun amino-terminal kinase (JNK), whereas extracellular signal-regulated kinase activity was not affected by D1 dopamine receptor stimulation. Maximal stimulation of p38 MAPK and JNK was observed after a 15-min incubation with 100 microM SKF38393. In contrast, 10 microM quinpirole, a D2 dopamine receptor agonist, did not activate p38 MAPK or JNK. Treatment of cells with 10 muM SCH23390, a D1 dopamine receptor antagonist, significantly inhibited the activation of both kinases by SKF38393. These results indicate that activation of the p38 MAPK and JNK signaling pathways is mediated by dopamine D1 receptors in SK-N-MC neuroblastoma cells. Furthermore, dibutyryl-cAMP mimicked SKF38393-mediated stimulation of p38 MAPK and JNK. Inhibition of protein kinase A by 1 microM H-89 or 10 microM adenosine 3', 5'-cyclic monophosphothioate (Rp-isomer, triethylammonium salt) markedly attenuated the activation of p38 MAPK and JNK. Conversely, the selective protein kinase C inhibitor calphostin C did not block D1 dopamine receptor-stimulated activation of p38 MAPK and JNK. These results demonstrate, for the first time, that the Gs-coupled D1 dopamine receptor activates the p38 MAPK and JNK signaling pathways by a protein kinase A-dependent mechanism.
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PMID:D1 dopamine receptor agonists mediate activation of p38 mitogen-activated protein kinase and c-Jun amino-terminal kinase by a protein kinase A-dependent mechanism in SK-N-MC human neuroblastoma cells. 973 Sep 3

Here we compared the features of apoptosis induced by DNA-damaging agent, etoposide, and by withdrawal of the growth factors in NB 2a neuroblastoma cells. We showed that serum deprivation and etoposide induced a distinct pattern of regulation of c-Fos, c-Jun and p53 protein levels, as well as the differential changes in DNA-binding activity of AP-1 and NF-kappaB transcription factors. The late phase of apoptesis induced by serum withdrawal was associated with disintegration of nuclear DNA both into high molecular weight (HMW) and oligonucleosomal DNA fragments, whereas etoposide induced the formation of HMW-DNA fragments without internucleosomal DNA cleavage. Incubation of etoposide-treated cells without serum resulted in an additive effect on the pattern of DNA fragmentation. Differences in DNA fragmentation profiles induced by serum withdrawal and etoposide in NB 2a cells were reproducible in nonproliferating cerebellar granule cells and also in a cell free system assay after treatment of isolated normal nuclei with cytosolic extracts prepared from serum-deprived or etoposide-treated cells. Both HMW and oligonucleosomal DNA fragmentation in serum-deprived cells was inhibited by aurintricarboxylic acid and was completely abrogated by cycloheximide. In contrast, DNA fragmentation in etoposide-treated cells was insensitive to the inhibitory effect of aurintricarboxylic acid, and was not prevented by cycloheximide. Our results indicate that in NB 2a neuroblastoma cells etoposide and serum withdrawal induce a distinct mode of apoptosis which is associated with a distinct pattern of regulation of immediately early response genes in the early phase, and with recruitment of different mechanisms for DNA disintegration in the late phase of apoptosis.
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PMID:Distinct mode of apoptosis induced by genotoxic agent etoposide and serum withdrawal in neuroblastoma cells. 979 26

Previous studies in our laboratory have shown that the mood stabilizers, lithium and valproate (VPA), regulate the transcription factors, cyclic AMP responsive element binding protein (CREB), c-Fos and c-Jun, differentially in cultured human neuroblastoma SH-SY5Y cells. Here, we confirm these findings in rat brain and further study the brain-regional effects of these drugs using immunohistochemistry. We found that although chronic treatment with LiCl or VPA did not change the expression of c-Fos and c-Jun, acute treatment with either drugs increased c-Fos expression but not c-Jun expression in CA1 and CA3 regions of hippocampus. Chronic treatment with LiCl, but not VPA, decreased CREB phosphorylation in rat cerebral cortex and hippocampus. These results suggest that lithium and VPA may act on different pathways to bring about their long-term prophylactic effects on bipolar disorder (BD). The regulation of CREB phosphorylation may be relevant to lithium effect. VPA, which is also effective in BD, may be linked to other pathways.
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PMID:Lithium and valproate differentially regulate brain regional expression of phosphorylated CREB and c-Fos. 1038 42

The expression of members of the Jun family of transcription factors was examined by immunohistochemistry, Western blotting, in situ hybridization and Northern blotting in the developing and adult rat brain following colchicine administration. Apoptotic cells, as revealed by their typical morphology and positive staining with the method of in situ end-labeling of nuclear DNA fragmentation, were restricted to granule cells of the dentate gyrus and olfactory bulb, and a few cells in the upper layers of the entorhinal cortex in adult rats, whereas widespread apoptosis occurred in developing rats after colchicine administration. No modifications in the expression of Jun D and Jun B, except for a generalized and moderate Jun B expression in glial cells, were observed in colchicine-treated rats. Generalized and strong c-jun mRNA induction and c-Jun/AP-1 (Ab-1) protein expression was observed in the cerebral neocortex, entorhinal and piriform cortices, CAI and CA3 areas of the hippocampus and granule cell layer of the dentate gyrus in adult treated rats, thus indicating a generalized c-Jun response to colchicine administration. In contrast, c-Jun/AP-1 (N) and c-Jun/AP-1 (Ab-2) immunoreactivity was restricted to apoptotic cells in colchicine-treated adult and developing brains. Western blots of hippocampal homogenates and total brain homogenates in adult and developing rats, respectively, demonstrated a band of 39 kDa for the c-Jun/AP-1 (Ab-1) antibody in control animals, the intensity of which increased in colchicine-treated rats. However, a band of 37 kDa, the intensity of which also increased following colchicine administration, was observed for the c-Jun/AP- (N) and c-Jun/AP- (Ab-2) antibodies. Selective c-Jun/AP-1 (N) and c-Jun/AP-1 (Ab-2) expression was also observed in apoptotic cells of the SH-SY5Y neuroblastoma line after the addition of colchicine to the culture medium. Taken together, the present in vivo and in vitro results indicate a generalized c-Jun response to colchicine in sensitive cells, whereas the antibodies c-Jun/AP- (N) and c-Jun/AP-1 (Ab-2) recognize vulnerable cells dying via apoptosis.
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PMID:Localization and expression of Jun-like immunoreactivity in apoptotic neurons induced by colchicine administration in vivo and in vitro depends on the antisera used. 1044 50

Vasoactive intestinal peptide (VIP) gene expression is highly restricted throughout the neuroaxis and regulated by extracellular factors that activate tyrosine- or serine/threonine-directed protein kinase pathways. Cytokine, cyclic AMP, and tissue-specific response elements on the VIP gene have been characterized. Those mediating responsiveness to protein kinase C have not. The endogenous VIP gene and a 5.2-kilobase pair (kb) VIP-luciferase reporter gene, are up-regulated by phorbol 12-myristate 13-acetate (PMA) in SK-N-SH neuroblastoma cells. PMA stimulation was abolished by deletion of sequences at -1.37 to -1.28 or -1.28 to -0.904 kb, but not by removal of the single phorbol ester response element (TRE; TGACTCA) located at -2.25 kb. Mutation of sites at -1.32 or -1.20 that mediate neurotrophin responsiveness of the VIP gene (Symes, A., Lewis, S., Corpus, L., Rajan, P., Hyman, S. E., and Fink, J. S. (1994) Mol. Endocrinol. 8, 1750-1763) each reduced PMA induction in SK-N-SH cells by >50%, and double mutation abolished it. The two mutations also reduced basal VIP reporter gene transcription in SH-EP neuroblastoma cells expressing VIP constitutively. Both cis-active elements bound pre-existing AP-1 proteins in SH-EP- or PMA-stimulated SK-N-SH cell nuclear extracts. The AP-1 complex at both sites contained a Fos-related protein with c-Jun in SH-EP cells and c-Fos with a Jun-related protein in SK-N-SH cells. Recruitment of combinatorially distinct AP-1 complexes to these elements may underlie cell type-specific regulation of the VIP gene.
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PMID:Two separate cis-active elements of the vasoactive intestinal peptide gene mediate constitutive and inducible transcription by binding different sets of AP-1 proteins. 1046 93


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