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)

Activating transcription factor-3 (ATF-3) is one member of a large family of leucine zipper transcription factors which bind to promoters responsive to cAMP and phorbol ester at the related cAMP (CRE) and phorbol ester response elements. We report here that ATF-3 is coexpressed with the neuropeptide precursor proenkephalin in human neuroblastoma SK-N-MC cells. Cotransfection experiments indicate that activation of proenkephalin gene expression by ATF-3 is dependent upon both the catalytic subunit of the cAMP-dependent protein kinase and the CRE-2 element. The CRE-2 element is essential for second messenger-inducible expression and is known to bind AP-1-like transcription factors. ATF-3 expressed in bacteria or from rabbit reticulocyte lysates binds to the proenkephalin CRE-2 element as a homodimer and as a heterodimer with Jun-D, another activator of proenkephalin transcription. ATF-3 stimulates binding of Jun-D to the proenkephalin CRE-2 element and acts synergistically with Jun-D to induce proenkephalin gene expression. Sequential immunoprecipitations of ATF-3 from SK-N-MC cells expressing proenkephalin indicate that ATF-3 is complexed with Jun-D in vivo and that both proteins are highly phosphorylated. Together, our results suggest that ATF-3 may play an important role in the regulation of gene expression by cAMP-dependent intracellular signaling pathways.
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PMID:Activating transcription factor-3 stimulates 3',5'-cyclic adenosine monophosphate-dependent gene expression. 815 31

We show that expression of the p34cdc2 and cyclin A genes is induced by interleukin-2 in normal human T cells and present evidence to support the idea that these genes are deregulated in leukemic T cells. Our DNA sequencing data indicate that the promoter region of the p34cdc2 gene contains putative E2F-like binding sites which are recognized by Rb and binding sites for c-myb, Sp1, and ATF, and that the promoter region of the cyclin A gene contains binding sites for p53, Sp1, and ATF. In this study we focus on the effect of p53 and Rb on these cell cycle-regulatory genes. Cotransfection of Y79 human retinoblastoma cells with a p34cdc2 promoter-luciferase expression vector and a plasmid expressing the retinoblastoma gene (RB) indicated that RB suppresses p34cdc2 expression. Cotransfection of B104 rat neuroblastoma cells with a cyclin A promoter-luciferase expression vector and a plasmid expressing the normal or mutant p53 indicated that only the normal p53 suppresses cyclin A expression. In normal T cells, PHA stimulation reduces the amount of complexes in the p34cdc2 promoter between the E2F-like binding site and the RB gene product. These complexes were not detected in leukemic T cells. Our data support the idea that tumor suppressors modulate the expression of cell cycle-regulatory genes: RB regulates p34cdc2 expression and p53 regulates cyclin A expression.
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PMID:Effect of tumor suppressors on cell cycle-regulatory genes: RB suppresses p34cdc2 expression and normal p53 suppresses cyclin A expression. 827 2

We have examined cis-elements and trans-acting factors that regulate transcription of the human cholecystokinin (CCK) gene. Transient expression of CCK promoter deletion constructs in human SK-N-MC neuroblastoma cells depicted positive cis-elements between the positions -100 to -92, -84 to -74, and -58 to -37, 5' to the transcription initiation site. Correspondingly, DNase I protection analysis showed that transacting factors bound to elements within these regions. The sequences encompass a putative basic helix-loop-helix leucine zipper (bHLH-ZIP) element, an Sp1 element, and a combined cAMP- and TPA-responsive element (CRE/TRE) at positions -97 to -92, -39 to -34, and -80 to -73, respectively. Mobility and supershift assays demonstrated that upstream stimulatory factor (USF) and Sp1 bind to the former elements and competition experiments confirmed that CREB/ATF and AP-1 bind to the CRE/TRE element. Mutation of the bHLH-ZIP and CRE/TRE elements decreased the activity of the promoter by 65% and 42%, respectively. The activity of the promoter was increased six- and two-fold after stimulation with forskolin and TPA, respectively. Stimulation was eliminated after mutation of the CRE/TRE element. Co-transfection experiments with pRSV-c-jun, pSV-fos, and pRC-RSV-CREB constructs showed that jun, CREB, and AP-1 stimulate transcription. We conclude that USF, Sp1, and members of the CREB/ATF and AP-1 family of transcription factors are the major determinants of CCK gene transcription.
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PMID:Transcriptional regulation of the human cholecystokinin gene: composite action of upstream stimulatory factor, Sp1, and members of the CREB/ATF-AP-1 family of transcription factors. 856 97

Members of the CREB/CREM/ATF family of transcription factors either enhance or repress transcription after binding to the cAMP response elements (CREs) of numerous genes. The rat gene for tyrosine hydroxylase (TH) bears a canonical CRE, at base pairs -38 through -45 from the transcription initiation site, that is essential for basal and cAMP-stimulated transcription (Kim, K.-S., Lee, M. K., Carroll, J., and Joh, T. H. (1993) J. Biol. Chem. 268, 15689-15695; Lazaroff, M., Patankar, S., Yoon, S. O., and Chikaraishi, D. M. (1995) J. Biol. Chem. 270, 21579-21589). The current study identifies CRE-binding proteins induced in pharmacological paradigms characterized by TH activation. PC12- and rat adrenal gland-derived nuclear proteins retarded a TH-CRE oligonucleotide in gel mobility shift assays with virtually identical patterns. These differed substantially from patterns exhibited by extracts from locus ceruleus or from neuroblastoma (SK-N-BE()C) and locus ceruleus-derived (CATH.a) cell lines. Forskolin stimulation of PC12 cells and reserpine treatment of rats increased, in nuclear extracts derived from cells and adrenal glands, respectively, the amount of a fast moving CRE/protein complex that was supershifted by an anti-CREM antibody. Subsequent Western, Northern, and polymerase chain reaction analyses indicated that a specific member of the CREM family, the inducible cAMP early repressor (ICER), was strongly induced in both systems. Cotransfection of PC12 cells with TH2400CAT plasmid and the expression vector pCMV-ICER-Ib demonstrated that ICER efficiently represses the transcriptional activity of the TH gene promoter. In addition, PKA-stimulated transcriptional activity of the promoter was effectively suppressed by ICER. These results suggest that ICER can modulate cAMP-stimulated transcription of the TH gene and provide a model accounting for rapid reversal of increased TH transcription following elevations in cAMP.
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PMID:Inducible cAMP early repressor can modulate tyrosine hydroxylase gene expression after stimulation of cAMP synthesis. 881 Mar 3

The expression of the neuropeptide galanin (GAL) is elevated in vivo upon nerve stimulation, injury, and in vitro by phorbol 12-myristate-13-acetate (PMA), suggesting that a signal pathway involving protein kinase C activation may be involved in GAL-gene activation. When plasmids containing a different length of the bovine GAL-promoter fused to luciferase were transfected into the human neuroblastoma cell line (SK-N-SH subclone SH-SY5Y), a PMA-responsive element was identified in the promoter-region -68 to -46 base pairs (bp). Co-transfection experiments with plasmids expressing cJun and cFos revealed that they could act alone, as well as synergistically with PMA to induce luciferase activity. Electrical mobility shift assays revealed that a cAMP response element (CRE)-like sequence (TGACGCGG; -59 to -52 bp) bound PMA-inducible nuclear proteins present in SH-SY5Y cells. These proteins appear to bind mainly as CRE-binding protein/activating-transcription-factor (CREB/ATF) and Jun/ATF heterodimers. In addition, an apparent PMA-inducible protein(s) not recognized by CREB/ATF and Jun antibodies bound to the CRE-like containing probe.
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PMID:Characterization of phorbolester-inducible human neuronal factors involved in trans-activation of the galanin gene. 960 91

The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) promoter 1 (LP1) is an inducible and cell type-specific promoter involved in regulating the production of an 8.3-kb primary LAT transcript during acute and latent infection of peripheral sensory neurons and during subsequent virus reactivation. A number of cis-acting regulatory elements have been identified in LP1, including two cyclic-AMP (cAMP) response element (CRE)-like sequences, designated CRE-1 and CRE-2. CRE-1 has previously been shown to confer cAMP responsiveness to LP1 and to regulate reactivation of HSV-1 from latency in vivo. A role for CRE-2 in modulating inducible activity is not yet as clear; however, it has been shown to support basal expression in neuronal cells in vitro. Electrophoretic mobility shift (EMS) analyses demonstrate that the LP1 CRE-like elements interact with distinct subsets of neuronal ATF/CREB and Jun/Fos proteins including CREB-1, CREB-2, ATF-1, and JunD. The factor-binding properties of each LP1 CRE element distinguish them from each other and from a highly related canonical CRE binding site and the TPA response element (TRE). LP1 CRE-1 shares binding characteristics of both a canonical CRE and a TRE. LP1 CRE-2 is more unusual in that it shares more features of a canonical CRE site than a TRE with two notable exceptions: it does not bind CREB-1 very well and it binds CREB-2 better than the canonical CRE. Interestingly, a substantial proportion of the C1300 neuroblastoma factors that bind to CRE-1 and CRE-2 have been shown to be immunologically related to JunD, suggesting that the AP-1 family of transcription factors may be important in regulating CRE-dependent LP1 transcriptional activity. In addition, we have demonstrated the two HSV-1 LP1 CRE sites to be unique with respect to their ability to bind neuronal AP1-related factors that are regulated by cAMP. These studies suggest that both factor binding and activation of bound factors may be involved in cAMP regulation of HSV-1 LP1 through the CRE elements, and indicate the necessity of investigating the expression and posttranslational modification of a variety of ATF/CREB and AP-1 factors during latency and reactivation.
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PMID:ATF/CREB elements in the herpes simplex virus type 1 latency-associated transcript promoter interact with members of the ATF/CREB and AP-1 transcription factor families. 984 50

Activated Transcription Factor-2 (ATF-2) is important during development of and during injury to the brain. Both Jun N-terminal Kinases (JNKs) and p38 Mitogen-Activated Protein Kinases (p38MAPKs) may phosphorylate ATF-2, but the contribution of these two pathways in cells has never been investigated. We have assayed endogenous p38MAPK activity in SK-N-MC and SH-SY5Y human neuroblastoma cells for activation of a GAL4/ATF-2 fusionprotein, by means of titrations of transfected expression plasmids and by using the p38MAPK inhibitor SB203580. It was found that basal activation of ATF-2 was independent of p38MAPK and that whereas MAPK kinase-3 (MKK3) was a weak inducer of ATF-2 activation, it was a potent activator of the stress activated transcription factor CHOP. In contrast, ATF-2 was very potently activated by the JNK pathway activator MAPK kinase kinase-1 (MEKK1). Thus, kinases downstream of MEKK1 appear relevant, but it is unlikely that p38MAPKs contribute quantitatively to activation of ATF-2 in these cells.
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PMID:Contribution of MAP kinase pathways to the activation of ATF-2 in human neuroblastoma cells. 1082 86

Recent evidence suggests that stress-activated protein kinases expressed in glial cells have very important roles during cerebral ischemia. The neuroprotective agent chlomethiazole, which is known to enhance the conductance at the GABA(A) receptor complex, is presently in clinical trials for the treatment of severe stroke. Here the authors suggested that chlormethiazole has anti-inflammatory properties because it potently and selectively inhibited p38 mitogen-activated protein (MAP) kinase in primary cortical glial cultures. The inhibition of p38 MAP kinase resulted in the attenuation of the induction of c-fos and c-jun mRNA and AP-1 DNA binding by lipopolysaccharide (LPS). In addition, chlomethiazole inhibited the activation of an AP-1-dependent luciferase reporter plasmid in SK-N-MC human neuroblastoma cells in response to glutamate. Chlomethiazole inhibited the p38 MAP kinase activity as revealed by the decrease in the LPS-induced phosphorylation of the substrates ATF-2 and hsp27, whereas the phosphorylation status of the p38 MAP kinase itself was unaffected. Interestingly, chlomethiazole exhibited an IC(50) of approximately 2 micromol/L for inhibition of c-fos mRNA expression, indicating 25 to 75 times higher potency than reported EC(50) values for enhancing GABA(A) chloride currents. The results indicated a novel mechanism of action of chlomethiazole, and provided support for a distinctive role of p38 MAP kinase in cerebral ischemia.
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PMID:Neuroprotective agent chlomethiazole attenuates c-fos, c-jun, and AP-1 activation through inhibition of p38 MAP kinase. 1090 41

GTP cyclohydrolase I (GTPCH) gene expression was investigated in the human monoamine-containing neuroblastoma cell line SK-N-BE(2)M17. Northern blot analysis revealed a single GTPCH mRNA transcript that was confirmed by RNase protection assay to encode for Type 1 GTPCH; no alternatively spliced forms of GTPCH mRNA were detected with this assay. Incubation with 8Br-cAMP, but not nerve growth factor or leukemia inhibitory factor, produced a rapid increase in GTPCH mRNA and protein levels; protein levels remained elevated during the entire treatment period while mRNA content declined rapidly between 10 and 24 h. Treatment with 8Br-cAMP did not significantly modify the stability of GTPCH mRNA but did increase GTPCH transcription as determined by transient transfection assays of a luciferase reporter construct containing 1171 bp of human GTPCH 5'-flanking sequence. Cis-acting elements required for maximal basal and cAMP-dependent transcription were localized by deletion analysis to the 146 bp proximal promoter. DNase I footprint analysis of the proximal promoter using SK-N-BE(2)M17 nuclear extracts identified two protein binding domains: one an upstream Sp1-like site and the other a combined CRE-Sp1-CCAAT-box element. EMSA and supershift assays demonstrated that the combined CRE-Sp1-CCAAT-box element recruits ATF-2 and NF-Y but not Sp1-4 or Egr-1-3. NF-Y binding was confirmed using pure recombinant human NF-Y protein. Transcription of the human GTPCH gene in human SK-N-BE(2)M17 cells is thus enhanced by cAMP acting through regulatory elements located in the proximal promoter and may involve the transcription factors NF-Y and ATF-2.
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PMID:Characterization of GTP cyclohydrolase I gene expression in the human neuroblastoma SKN-BE(2)M17: enhanced transcription in response to cAMP is conferred by the proximal promoter. 1170 61

The activating transcription factor 2 (ATF-2) gene, which encodes a transcription factor involved in multiple intracellular signal transduction pathways, is located on human chromosome 2q32, which is a common region of LOH in human lung cancer. In neuroblastoma and breast cancer, a high incidence of LOH was detected on chromosome 2q. Recently we found that breast cancer is frequently developed in heterozygous mutant mice for the ATF-2 gene. Therefore, the ATF-2 gene was considered as a candidate tumor suppressor gene on 2q. To assess the role of the ATF-2 gene as a tumor suppressor in human carcinogenesis, we examined genetic alterations of the ATF-2 gene in 9 breast cancer cell lines, 10 neuroblastoma cell lines and 46 lung cancer cell lines. For this purpose, we first determined the exon-intron structure of the ATF-2 gene in the human genome. The ATF-2 gene was composed of 14 exons and 13 introns, and the ATG start codon and the TGA stop codon were present in exons 3 and 14, respectively. Genetic variants of the ATF-2 gene were detected in 5 of the 46 (10.6%) lung cancers, but not in neuroblastomas and breast cancers. Three of the five variants detected in lung cancers were genetic polymorphisms, while the remaining two, consisting of non-synonymous and synonymous substitutions, were possibly somatic mutations. The present result indicates that the ATF-2 gene is not a major tumor suppressor gene on chromosome 2q, however, it is possible that ATF-2 alterations may be involved in the development of a small subset of lung cancers.
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PMID:Infrequent mutations of the activating transcription factor-2 gene in human lung cancer, neuroblastoma and breast cancer. 1183 64


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