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)

Insulin-like growth factor (IGF) binding proteins (IGFBPs) modulate IGF action at cellular level through inhibition or, alternatively, potentiation, where their limited proteolysis is a contributory mechanism. Under basal conditions, neuroblastoma cells secrete IGFs (essentially IGF-II), IGFBPs (IGFBP-4 and predominantly IGFBP-2 that is partially proteolysed), and proteases, including tissue-type plasminogen (PLG) activator, whose activity is inhibited by PLG activator inhibitor-1. Neuroblastoma cells were used to investigate the influence of the plasmin system, transforming growth factor-beta retinoic acid on cell growth and the IGF system. In cells treated with 5 micrograms/ml PLG, proliferation was stimulated, an effect that was inhibited in the presence of either alpha IR-3 (which blocks the type 1 IGF receptor) or anti-IGF-II antibodies. There was a parallel increase in IGFBP-2 proteolysis, which resulted in a 5-fold loss of affinity for IGF-II. In the presence of 1 ng/ml transforming growth factor-beta, PLG-induced mitogenesis and IGFBP-2 proteolysis were reduced, and Northern blot analysis revealed increased PLG activator inhibitor-1 mRNA. Conversely, with 2 microM retinoic acid, the mitogenic effect of PLG, IGFBP-2 proteolysis, and tissue-type PLG activator mRNAs were increased. Therefore, IGF-II mediates autocrine proliferation in neuroblastoma cells under the control of IGFBPs secreted by the cells, its bioavailability being enhanced as a result of plasmin-induced IGFBP-2 proteolysis.
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PMID:Role of insulin-like growth factor binding protein-2 and its limited proteolysis in neuroblastoma cell proliferation: modulation by transforming growth factor-beta and retinoic acid. 900 3

The potent neurotrophic factor glial cell-derived neurotrophic factor (GDNF) is a distant member of the transforming growth factor-beta (TGF-beta) superfamily of proteins. We report a transcription factor that is the first nuclear protein known to be induced by GDNF, thus designated murine GDNF inducible factor (mGIF). The cDNA was cloned in the course of investigating transcription factors that bind to Sp1 consensus sequences, using the in situ filter detection method, and it was found to encode a protein having the same C2-H2 zinc finger motif as Sp1. Sequence analysis indicated that mGIF is homologous to the human TGF-beta inducible early gene (TIEG) and human early growth response gene-alpha (EGR-alpha). mGIF is widely distributed in the adult mouse with high mRNA levels in kidney, lung, brain, liver, heart, and testis. In the adult brain, mGIF is abundantly expressed in hippocampus, cerebral cortex, cerebellum, and amygdala with lower amounts in striatum, nucleus accumbens, olfactory tubercle, thalamus, and substantia nigra. During development, mGIF mRNA also has a wide distribution, including in cerebral cortex, cerebellar primordium, kidney, intestine, liver, and lung. GDNF induces the expression of mGIF rapidly and transiently both in a neuroblastoma cell line and in primary cultures of rat embryonic cortical neurons. Co-transfection of the Drosophila SL2 cells using mGIF expression plasmid and reporter constructs having Sp1 binding sites indicated that mGIF represses transcription from a TATA-containing as well as from a TATA-less promoter. These observations suggest that the zinc finger transcription factor mGIF could be important in mediating some of the biological effects of GDNF.
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PMID:Cloning and characterization of murine glial cell-derived neurotrophic factor inducible transcription factor (MGIF). 934 34

Activin, a member of the transforming growth factor-beta superfamily, regulates various physiological functions. In the present study, we investigated the effect of activin on neuronal differentiation, particularly the functional activity of voltage-dependent Ca2+ channels, in murine neuroblastoma C1300 cells. A slight K(+)-induced increase in the intracellular free Ca2+ ([Ca2+]i) was observed in C1300 cells untreated and treated with either activin A or all-trans-retinoic acid, while treatment with both agents significantly enhanced the increase. The [Ca2+]i increases potentiated by activin A and all-trans-retinoic acid were nearly abolished in the presence of 1.0 mM nickel or in the absence of extracellular Ca2+. Nifedipine (0.1 microM) and omega-conotoxin (1.0 microM), inhibitors of L- and N-type Ca2+ channels, respectively, partially inhibited these responses, however the inhibitory effects of these compounds were not additive. In addition, Bay K 8644, an activator of L-type Ca2+ channels, enhanced the K(+)-induced [Ca2+]i increase. These findings indicated that depolarization evoked the Ca2+ influx, at least in part, through L-type Ca2+ channels in C1300 cells treated with both activin A and all-trans-retinoic acid.
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PMID:Activin A and all-trans-retinoic acid cooperatively enhanced the functional activity of L-type Ca2+ channels in the neuroblastoma C1300 cell line. 942 77

Neuroblastoma is a pediatric malignancy of the sympathetic nervous system and is frequently characterized by genetic aberrations (including aneuploidy, chromosomal deletions, translocations, and gene amplification) that suggest inherent genomic instability. Mutations in mismatch repair (MMR) genes have been associated with genomic instability in several human cancers, such as those of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. In these cases, replication errors at microsatellite repeats lead to microsatellite instability (MSI) and mutagenesis. In neuroblastoma, we and others have detected MSI infrequently when analyzed at di- or tetranucleotide repeat polymorphic markers. More recently, however, mutations in the MMR gene GTBP/hMSH6 have been associated with a limited phenotype of instability at mononucleotide repeats only (e.g., polyadenine tracts). Furthermore, mononucleotide repeats appear to be common downstream targets of MSI-related mutagenesis and are present in the transforming growth factor-beta receptor-II gene (TGF beta RII), the BAX proapoptosis gene, and the insulin-like growth factor II receptor gene (IGFIIR) frequently in tumors arising in HNPCC kindreds. Therefore, we analyzed 46 matched normal and tumor DNAs representing all clinical stages of neuroblastoma with the use of five polymorphic mononucleotide repeat markers to assess for MSI at mononucleotide repeats. Only one tumor (2%) demonstrated mononucleotide repeat instability, and the instability was at a single locus. We conclude that MSI, including mononucleotide repeat instability, is infrequent in human neuroblastoma, and therefore defects in DNA mismatch repair are not responsible for the genomic instability seen in this neoplasm.
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PMID:Mononucleotide repeat instability is infrequent in neuroblastoma. 979 79

Previously, we demonstrated that transforming growth factor-beta (TGF-beta) pretreatment protects neuroblastoma cell lines, human hNT neurons, and primary rat embryo hippocampal neurons (REHIPs) from degeneration caused by incubation with beta-amyloid peptide (Abeta). Here we present evidence suggesting that TGF-beta interferes with an apoptotic pathway induced by Abeta. TGF-beta preteatment decreases the amount of DNA laddering seen following Abeta treatment in neuroblastoma cells, while in REHIPs, TGF-beta decreases the number of positive cells detected in situ by Klenow labelling following Abeta treatment. RT-PCR shows that in REHIPs, Abeta decreases mRNA expression of Bcl-2, as well as the ratio of Bcl-xL/Bcl-xS, with little effect on Bax expression. These changes are expected to promote apoptosis. When REHIPs are incubated with TGF-beta before addition of Abeta, the Bcl-xL/Bcl-xS ratio and Bcl-2 levels are increased compared to cells treated with Abeta alone. Again there is little effect on Bax expression. Western blotting and immunohistochemistry experiments also show that TGF-beta maintains increased levels of Bcl-2 and Bcl-xL protein in REHIPs even in the presence of Abeta. This pattern of gene expression should function to decrease apoptosis. Similarly, RT-PCR analysis of mRNA prepared from hNT cells shows that TGF-beta pretreatment before addition of Abeta maintains a higher level of Bcl-2 expression and an increased Bcl-xL/Bcl-xS ratio as compared to cells treated with Abeta alone. In neuronal cell types treated with Abeta, TGF-beta appears to regulate expression of genes in the Bcl-2 family to favor an anti-apoptotic pathway.
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PMID:Transforming growth factor-beta inhibits apoptosis induced by beta-amyloid peptide fragment 25-35 in cultured neuronal cells. 981 76

Mutations in the presenilin-1 gene are linked to the majority of early-onset familial Alzheimer's disease cases. We have previously shown that the expression of transforming growth factor-beta is altered in Alzheimer's patients, compared to controls. Here we examine presenilin- expression in human post-mitotic neurons (hNT cells), normal human astrocytes, and human brain tumor cell lines following treatment with three isoforms of transforming growth factor-beta, or glial cell line-derived neurotrophic factor, a member of the transforming growth factor-beta superfamily. As the NT2/D1 teratocarcinoma cell line is treated with retinoic acid to induce differentiation to hNT cells, presenilin-1 messenger RNA expression is dramatically increased. Furthermore, there is a 2-3-fold increase in presenilin-1 messenger RNA expression following treatment of hNT cells with growth factors and similar results are found by Western blotting and with immunohistochemical staining for presenilin-1 protein. However, treatment of normal human astrocytes with cytokines results in minimal changes in presenilin-1 messenger RNA and protein. Interestingly, the expression of presenilin-1 in human U87 MG astrocytoma and human SK-N-SH neuroblastoma cells is only increased when cells are treated with glial cell line-derived neurotrophic factor or transforming growth factor-beta3. These findings suggest that endogenous presenilin-1 gene expression in human neurons can be induced by growth factors present in normal and diseased brain tissue. Cytokines may play a major role in regulating expression of presenilin-1 which may affect its biological actions in physiological and pathological conditions.
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PMID:Differential effects of transforming growth factor-beta(s) and glial cell line-derived neurotrophic factor on gene expression of presenilin-1 in human post-mitotic neurons and astrocytes. 1047 69

Activin, a member of the transforming growth factor-beta superfamily, can regulate neuropeptide gene expression in the nervous system and in neuroblastoma cells. Among the neuropeptide genes whose expression can be regulated by activin is the gene encoding the neuropeptide vasoactive intestinal peptide (VIP). To investigate the molecular mechanisms by which activin regulates neuronal gene expression, we have examined activin's regulation of VIP gene expression in NBFL neuroblastoma cells. We report here that NBFL cells respond to activin by increasing expression of VIP mRNA. Activin regulates VIP gene transcription in NBFL cells through a 180-bp element in the VIP promoter that was previously characterized to be necessary and sufficient to mediate the induction of VIP by the neuropoietic cytokines and termed the cytokine response element (CyRE). We find that the VIP CyRE is necessary and sufficient to mediate the transcriptional response to activin. In addition, ciliary neurotrophic factor (CNTF), a neuropoietic cytokine, synergizes with activin to increase VIP mRNA expression and transcription through the VIP CyRE. Mutations in either the Stat (signal transducer and activator of transcription) or AP-1 sites within the CyRE that reduce the response to CNTF, also reduce the response to activin. However, mutating both the Stat and AP-1 sites within the wild-type CyRE, while reducing the separate responses to either activin or CNTF, eliminates the synergy between them. These data suggest that activin and CNTF, two factors that appear to signal though distinct pathways, activate VIP gene transcription through a common transcriptional element, the VIP CyRE.
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PMID:Synergy of activin and ciliary neurotrophic factor signaling pathways in the induction of vasoactive intestinal peptide gene expression. 1070 60

Brain metastases derived from abdominal neuroblastoma are an uncommon complication of this tumour; however, an increase in their occurrence has recently been reported. In the present study, we have investigated the influence of factors derived from central nervous system glial cells on the proliferation of human neuroblastoma cells (SH-SY5Y) in vitro. Co-culture experiments show that a 24-h exposure to factors released by type 1 astrocytes (A1) may induce a significant decrease in [(3)H]thymidine ([(3)H]TdR) incorporation by SH-SY5Y cells. This effect was not duplicated by fresh A1-conditioned medium (A1-CM); A1-CM became active only when it was heated or frozen. In contrast to this short-lived inhibitory effect, long-term treatment (3, 6 and 9 days) with A1-CM produced a significant and dose-dependent increase in SH-SY5Y cell number. Immunoneutralisation of A1-CM with an anti-transforming growth factor-beta antibody eliminated the inhibitory effect on [(3)H]TdR uptake in SH-SY5Y cells, but did not affect the increased number of viable cells observed after long-term treatments. In conclusion, these results showed that factor(s) released by A1 may affect the proliferation/survival of a human neuroblastoma cell line in vitro inducing: (a) a short transient negative effect on DNA synthesis and (b) an overall sustained trophic action. These results are suggestive of a possible role of glial cells in the establishment of brain metastases of neuroblastomas.
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PMID:Factors released by rat type 1 astrocytes exert different effects on the proliferation of human neuroblastoma cells (SH-SY5Y) in vitro. 1080 97

N-myc oncogene amplification is frequent in human neuroblastoma and predicts poor prognosis, but the molecular consequences have remained obscure. We report here that enhanced N-myc expression correlates with low or undetectable expression of activin A, but not other closely related members of the transforming growth factor-beta superfamily. N-myc interacts with the activin A promoter, eventually inducing down-regulation of activin A mRNA and protein. This study demonstrates for the first time N-myc-induced down-regulation of a gene implicated in signal transduction. Down-regulation of activin A could deprive neuroblastomas from a signal with growth-inhibitory activities toward the tumor and its stroma and thereby permit neuroblastoma progression.
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PMID:N-myc down-regulates activin A. 1091 51

The cytokine ciliary neurotrophic factor (CNTF) and transforming growth factor-beta (TGF-beta) both induce transcription of the vasoactive intestinal peptide (VIP) gene through a 180-base pair cytokine response element (CyRE) in the VIP promoter. While CNTF induces STAT and AP-1 proteins to bind to cognate sites in the VIP CyRE, the mechanism through which TGF-beta acts to induce VIP gene transcription is not known. Here we show that Smad3 and Smad4 proteins can bind to two distinct sites within the VIP CyRE. These sites are absolutely required for the induction of VIP CyRE transcription by TGF-beta. TGF-beta induces endogenous Smad-containing complexes to bind to these sites in human neuroblastoma cells. CNTF and TGF-beta synergize to induce VIP mRNA expression and transcription through the VIP CyRE. This synergy is dependent on the Smad, STAT, and AP-1 sites, suggesting that these two independent cytokine pathways synergize through the cooperation of pathway-specific transcription factors binding to distinct sites within the VIP CyRE.
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PMID:Transforming growth factor-beta and ciliary neurotrophic factor synergistically induce vasoactive intestinal peptide gene expression through the cooperation of Smad, STAT, and AP-1 sites. 1125 31


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