UMLS:C0027819 - FACTA Search

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Query: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report the full genomic organization of the human gene for the corticotropin-releasing factor (CRF) receptor type 1 (CRFR1), with complete mapping of exons 1-14. The 5' flanking region (2.4 kb) of the gene encoding for human CRFR1 was isolated, sequenced, and characterized. Two major transcriptional start sites were determined at -265 and -238, relative to the ATG start site (+1). Transient expression of constructs containing sequentially deleted 5'-flanking sequences of CRFR1 fused to luciferase, revealed the minimal promoter sequence 370 bp in size, as shown by assays in neuroblastoma (SH-5YSY), teratocarcinoma (NT2), and adenocarcinoma (MCF 7) cell lines. CRF and UCN markedly increased promoter activity during transient CRFR1 expression studies. Similarly, CRF and UCN up-regulate the endogenous CRFR1 at the mRNA level in NT2 and MCF 7 cells. To dissect further the mechanisms involved, we have used primary myometrial cells transfected with the CRFR1 promoter. CRF and UCN increased the promoter activity, an effect blocked by protein kinase (PK)A and PKC inhibitors. Both CRF and UCN cause a positive feedback effect in primary cultures of human pregnant myometrial cells, by increasing mRNA expression of CRFR1. This effect appears to be dependent on activation of both PKA and PKC by CRF, whereas UCN's effect was mediated solely via PKC activation. Collectively, our data suggest that the CRFR1 gene is under the influence of both CRF and UCN, acting via distinct signaling pathways to create a positive feedback loop and regulate further the transcription of the receptor.
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PMID:Promoter analysis of human corticotropin-releasing factor (CRF) type 1 receptor and regulation by CRF and urocortin. 1514 84

Protein kinase C (PKC) isoforms have been reported to be targeted to the Golgi complex via their C1 domains. We have shown recently that the regulatory domain of PKC induces apoptosis in neuroblastoma cells and that this effect is correlated to Golgi localization via the C1b domain. This study was designed to identify specific residues in the C1 domains that mediate Golgi localization. We demonstrate that the isolated C1b domains from PKCalpha, -delta, -epsilon, -eta, and - are targeted to the Golgi complex, whereas the corresponding C1a domains localize throughout the cell. Sequence alignment showed that amino acid residues corresponding to Glu-246 and Met-267 in PKC are conserved among C1b but absent from C1a domains. Mutation of Met-267, but not of Glu-246, to glycine abolished the Golgi localization of the isolated C1b domain and the regulatory domain of PKC. The mutated PKC regulatory domain constructs lacking Golgi localization were unable to induce apoptosis, suggesting a direct correlation between Golgi localization and apoptotic activity of PKC regulatory domain. Mutation of analogous residues in the C1b domain of PKCepsilon abrogated its Golgi localization, demonstrating that this effect is not restricted to one PKC isoform. The abolished Golgi localization did not affect neurite induction by PKCepsilon. However, the PKCepsilon mutant did not relocate to the Golgi network in response to ceramide and ceramide did not suppress the neurite-inducing capacity of the protein. Thus, the specific mutations in the C1b domain influence both the localization and function of full-length PKCepsilon.
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PMID:Identification of an amino acid residue in the protein kinase C C1b domain crucial for its localization to the Golgi network. 1514 47

We have seen that protein kinase Calpha (PKCalpha) is transiently translocated to the plasma membrane by carbachol stimulation of neuroblastoma cells. This is induced by the Ca2+ increase, and PKCalpha does not respond to diacylglycerol (DAG). The unresponsiveness is dependent on structures in the catalytic domain of PKCalpha. This study was designed to investigate if and how the kinase activity and autophosphorylation are involved in regulating the translocation. PKCalpha enhanced green fluorescent protein translocation was studied in living neuroblastoma cells by confocal microscopy. Carbachol stimulation induced a transient translocation of PKCalpha to the plasma membrane and a sustained translocation of kinase-dead PKCalpha. In cells treated with the PKC inhibitor GF109203X, wild-type PKCalpha also showed a sustained translocation. The same effects were seen with PKCbetaI, PKCbetaII, and PKCdelta. Only kinase-dead and not wild-type PKCalpha translocated in response to 1,2-dioctanoylglycerol. To examine whether autophosphorylation regulates relocation to the cytosol, the autophosphorylation sites in PKCalpha were mutated to glutamate, to mimic phosphorylation, or alanine, to mimic the non-phosphorylated protein. After stimulation with carbachol, glutamate mutants behaved like wild-type PKCalpha, whereas alanine mutants behaved like kinase-dead PKCalpha. When the alanine mutants were treated with 1,2-dioctanoylglycerol, all cells showed a sustained translocation of the protein. However, neither carbachol nor GF109203X had any major effects on the level of autophosphorylation, and GF109203X potentiated the translocation of the glutamate mutants. We, therefore, hypothesize that 1) autophosphorylation of PKCalpha limits its sensitivity to DAG and 2) that kinase inhibitors augment the DAG sensitivity of PKCalpha, perhaps by destabilizing the closed conformation.
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PMID:Autophosphorylation suppresses whereas kinase inhibition augments the translocation of protein kinase Calpha in response to diacylglycerol. 1527 24

Addiction to opiates depend on drug-induced neuroplastic changes and are underlain by alterations of gene expression. Transcription factors Ca2+/cAMP responsive element binding protein (CREB) and activator protein 1 (AP-1) may constitute a direct link between the opioid-regulated signal transduction pathways and modulation of gene expression. Acute treatment of Neuro2a MOR neuroblastoma cells with opioids stimulated CREB activity; prolonged treatment normalized it, while withdrawal from the drug again elicited an increase in phosphorylated CREB levels. Protein kinase C was responsible for the activation of transcription following acute opioid administration whereas the cAMP pathway activated similar mechanisms during withdrawal, making CREB a kind of 'a trigger' reacting to the presence or withdrawal of the opioid signal. Apart from the elevated CREB phosphorylation, CRE binding activity and expression of luciferase reporter gene regulated by CRE elements were increased after single administration and during withdrawal from the prolonged opioid treatment. Along with CREB, AP-1 binding activity and AP-1-directed transcription were stimulated after single administration and during withdrawal from the opioid. These results provide evidence that both single opioid administration and opioid withdrawal activate CREB and CRE-dependent transcriptional mechanisms via distinct intracellular signaling pathways.
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PMID:Activation of AP-1 and CRE-dependent gene expression via mu-opioid receptor. 1528 93

The membrane actions of estrogens can facilitate their genomic actions. To determine whether this facilitation bears on CNS mechanisms for estrogen-dependent behaviors, ovariectomized rats were subjected to a two-pulse treatment of estrogen directly in the hypothalamic ventromedial nucleus. Two days later, each rat was given progesterone and then tested for lordosis behavior, the induction of which requires the genomic actions of estrogen. When estrogen was given in both pulses (15 min to 2 h duration, and 5 h apart) lordosis was induced. Based on results from studies on neuroblastoma cells, we hypothesized that the membrane actions of estrogen in the first pulse would potentiate the genomic actions of estrogen in the second. This hypothesis was confirmed with the use of a membrane-impermeable estrogen. However, surprisingly, the order of the pulses could be reversed and still achieve lordosis behavior induction. Finally, activators of protein kinase A or PKC were effective substitutes for the membrane-limited pulse of estrogen. Thus, estrogen-induced membrane actions in the hypothalamus can potentiate its lordosis-inducing genomic actions on behavior and may be mediated by signaling pathways involving the activation of protein kinase A and PKC.
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PMID:The membrane actions of estrogens can potentiate their lordosis behavior-facilitating genomic actions. 1530 33

Regulation of expression and function of microtubule-associated proteins (MAPs) is critical for neurons to maintain normal cytoskeletal architecture and functions. We have shown previously that in differentiated human neuroblastoma SY5Y cells, the expression of tau, a major neuronal MAP, is dramatically increased, and tau phosphorylation is differentially regulated. In the present study, we investigated the expression, the subcellular distribution and the microtubule-binding activities of several MAPs in SY5Y cells upon differentiation. We also studied the activities of protein kinases and phosphatases that are involved in regulation of tau phosphorylation during cell differentiation. We found that the expression of MAP1b in addition to tau was upregulated upon differentiation. Tau, MAP1a, MAP1b and MAP2 had distinct immunocytochemical staining patterns in differentiated SY5Y cells, suggesting differential biological functions. The microtubule-binding activity of tau increased after cell differentiation, whereas the activities of MAP1a and MAP2 decreased. Upon differentiation, the phosphorylation of tau at Ser198/Ser199/Ser202 and Ser396/Ser404 was increased, but that at Ser262/Ser356 was decreased. These changes in tau phosphorylation were accompanied by an upregulation of activities of several protein kinases (cdk5, MAPK, PKC and CK-1) as well as protein phosphatases PP-1 and PP-2A. These results suggest that the expression, post-translational modifications and biological activities of various MAPs are differentially regulated to meet the biological needs during cell differentiation.
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PMID:Regulation of microtubule-associated proteins, protein kinases and protein phosphatases during differentiation of SY5Y cells. 1546 92

The superoxide dismutase isoenzymes (SOD) play a key role in scavenging, O*2- radicals. In contrast with previous studies, recent data have shown that human neuroblastoma cells are able to export the cytosolic Cu,Zn superoxide dismutase (SOD1), thus suggesting a paracrine role exerted by this enzyme in the nervous system. To evaluate whether SOD1 could activate intracellular signalling pathways, the functional interaction between SOD1 and human neuroblastoma SK-N-BE cells was investigated. By analyzing the surface binding of biotinylated SOD1 on SK-N-BE cells and by measuring intracellular calcium concentrations and PKC activity, we demonstrated that SOD1 specifically interacts in a dose-dependent manner with the cell surface membrane of SK-N-BE. This binding was able to activate a PLC-PKC-dependent pathway that increased intracellular calcium concentrations mainly deriving from the intracellular stores. Furthermore, we showed that this effect was independent of SOD1 dismutase activity and was totally inhibited by U73122, the PLC blocker. On the whole, these data indicate that SOD1 carries out a neuromodulatory role affecting calcium-dependent cellular functions.
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PMID:Cu,Zn superoxide dismutase increases intracellular calcium levels via a phospholipase C-protein kinase C pathway in SK-N-BE neuroblastoma cells. 1547 11

Disseminated forms of neuroblastoma (NB), a tumor derived from neuroectodermal tissue, pose a major therapeutic challenge for pediatric oncology. By performing a comparative cDNA array analysis of metastatic neuroblasts versus primary xenograft from the human IGR-N-91 NB model, we were able to identify a set of downregulated developmental genes in metastatic neuroblasts. One of these genes was Wnt-5a, a member of the Wnt signaling pathway, known to be involved in the development of neural crest cells. Since we also found a significant decrease in Wnt-5a mRNA in unfavorable versus favorable categories in 37 primary NB tumors (P<0.007), we wondered whether retinoic acid (RA), which has a role in neural crest induction and differentiation, might reverse the aberrant negative regulation of Wnt-5a in metastatic malignant neuroblasts. Following treatment with 10 muM RA for 6 days, the MYCN-amplified IGR-N-91 cell lines underwent neuronal differentiation as assessed by reduced MYCN gene expression and neuritic extension. In these conditions, data showed an upregulation of Wnt-5a and PKC-theta; isoform expressions. Our study highlights, for the first time, the involvement of Wnt-5a, which has a role in embryonic and morphogenetic processes, in the response of malignant neuroblasts to RA. In conclusion, we demonstrated that RA, which is used in the treatment of high-risk NB patients with recurrent/residual disease in the bone marrow, is able to upregulate Wnt-5a gene expression.
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PMID:Low expression of Wnt-5a gene is associated with high-risk neuroblastoma. 1559 17

Sodium butyrate (NaBt), a histone deacetylase inhibitor, can cause apoptosis in a number of cancer cells. However, the mechanism of this action is poorly understood. Increased intracellular [Ca(2+)] level has been suggested as a likely mechanism, but there is little corroborating data. In this report we provide evidence that NaBt-treated MSN neuroblastoma cells undergo massive apoptosis in the presence of serum and regardless of external or internal [Ca(2+)] levels. Presented data suggest that apoptotic effect of NaBt is both time- and dose-dependent (LD50 1 mM); and that, presence of serum or cAMP, a second messenger molecule that modulates the apoptotic program in a wide variety of cells could not circumvent the apoptotic effect of NaBt. Our findings suggest that NaBt-induced apoptosis in MSN neuroblastoma cells occurs via a pathway that is independent of Ca(2+) flux, intracellular [Ca(2+)] or cAMP levels. Further, we also present data that exclude a role for PKC or histones acetylation.
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PMID:Sodium butyrate induces apoptosis in MSN neuroblastoma cells in a calcium independent pathway. 1566 47

Hypothalamic proTRH mRNA levels are rapidly increased (at 1 h) in vivo by cold exposure or suckling, and in vitro by 8Br-cAMP or glucocorticoids. The aim of this work was to study whether these effects occurred at the transcriptional level. Hypothalamic cells transfected with rat TRH promoter (-776/+85) linked to the luciferase reporter showed increased transcription by protein kinase (PK) A and PKC activators, or by dexamethasone (dex), but co-incubation with dex and 8Br-cAMP decreased their stimulatory effect (as observed for proTRH mRNA levels). These effects were also observed in NIH-3T3-transfected cells supporting a characteristic of TRH promoter and not of hypothalamic cells. Transcriptional regulation by 8Br-cAMP was mimicked by noradrenaline which increased proTRH mRNA levels, but not in the presence of dex. PKA inhibition by H89 avoided 8Br-cAMP or noradrenaline stimulation. TRH promoter sequences, cAMP response element (CRE)-like (-101/-94 and -59/-52) and glucocorticoid response element (GRE) half-site (-210/-205), were analyzed by electrophoretic mobility shift assays with nuclear extracts from hypothalamic or neuroblastoma cultures. PKA stimulation increased binding to CRE (-101/-94) but not to CRE (-59/-52); dex or 12-O-tetradecanoylphorbol-13-acetate (TPA) increased binding to GRE, a composite site flanked by a perfect and an imperfect activator protein (AP-1) site in the complementary strand. Interference was observed in the binding of CRE or GRE with nuclear extracts from cells co-incubated for 3 h with 8Br-cAMP and dex; from cells incubated for 1 h, only the binding to GRE showed interference. Rapid cross-talk of glucocorticoids with PKA signaling pathways regulating TRH transcription constitutes another example of neuroendocrine integration.
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PMID:Dexamethasone represses cAMP rapid upregulation of TRH gene transcription: identification of a composite glucocorticoid response element and a cAMP response element in TRH promoter. 1569 87

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