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)

Human manganese-containing superoxide dismutase (MnSOD) is a nuclear encoded mitochondrial protein that scavenges potentially toxic superoxide radicals by dismuting O2- to O2 plus H2O2. To understand the molecular mechanism governing the transcriptional regulation of the human MnSOD gene, I have isolated and sequenced a genomic clone containing the 5' flanking region of the human MnSOD gene. One major transcription start site was mapped by primer extension to a guanine residue 67 base pairs upstream from the translation start site. Eight putative Sp1 binding elements and one AP1 consensus sequence, but no TATA or CAAT box, were found in the promoter region. Furthermore, a series of chimerical/CAT reporter gene constructs were used to transfect human hepatocellular carcinoma(HepG2) human neuroblastoma and human skin fibroblast cell lines to characterize the promoter and regulatory region of the human MnSOD gene. The results show that human MnSOD gene expression is governed by one promoter and that the basic promoter is located between nucleotides -34 and +38. The results also indicate that both positive and negative elements are involved in the regulation of the cell-type specific expression of the human MnSOD gene. The functional studies indicate that the Sp1 binding sites or G+C rich regions play an important role in regulation of expression of the human MnSOD gene in vivo.
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PMID:Characterization of the 5' flanking region of the human MnSOD gene. 860 39

As an initial approach to define the regulatory elements and transcriptional factors that account for cell-restricted expression of the alpha2c-adrenergic receptor (AR) gene, we isolated and characterized the receptor gene and identified regions of the gene conferring cell-specific expression. A 4300-nucleotide (nt) fragment of the 5'-flanking region of the rat alpha2c-AR gene was isolated from a genomic library. The genomic sequence contained the uninterrupted sequence of the 5'-untranslated region of a previously isolated alpha2c-AR cDNA clone indicating the lack of introns in the 5' gene segment. RNase protection assays and/or RNA blot analysis indicated the expression of alpha2c-AR mRNA in rat brain but not in kidney or liver, which is consistent with the major expression of this gene in neuronal tissue. The 5' gene segment was used to identify sites of transcriptional initiation and promoter activity by RNase protection assays and transient transfection of reporter gene constructs. With the use of RNA probes progressively upstream of the translational start site, RNase protection assays with rat brain total RNA indicated multiple sites of transcriptional initiation within a approximately 70-nt span (-660 to -730 nt 5' to the translational start codon). The zone of transcriptional initiation was part of a larger GC-rich area of the 5' gene segment that is a characteristic of genes initiating transcripts at multiple sites. The promoter activity of this zone of transcriptional initiation and the influence of gene segments 5' to this area were addressed using chloramphenicol acetyl transferase reporter gene constructs. Transient transfection of reporter gene constructs indicated that a 96-nt gene fragment (-699/-603 relative to the translational start codon) was sufficient to direct transcription in the neuroblastoma X glioma hybrid cell line NG108-15, a cell line expressing the endogenous alpha2c-AR. Promoter activity was not observed in constructs lacking the zone of transcriptional initiation. The promoter segment was inactive when introduced into the rat glioma cell line C6B4, the rat submandibular cell line RSMT-A5, and the rat pancreatic beta cell line RIN-5AH, all of which do not express the endogenous alpha2c-AR gene. Upon incubation with nuclear extracts, a 129-nt fragment encompassing the promoter exhibited a gel mobility shift pattern that was specific for cells expressing the receptor protein and involved a nuclear protein that recognized a Sp1 oligonucleotide. These data indicate that a 96-nt gene promoter segment of the alpha2c-AR gene functions in a cell-type-specific manner.
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PMID:Analysis of the alpha2C-adrenergic receptor gene promoter and its cell-type-specific activity. 896 63

We describe the structural and functional features of the human alpha3 nicotinic receptor subunit promoter. A 0.35-kb region immediately upstream of the start codon was identified that when transfected in human neuroblastoma cells was able to drive the expression of the luciferase reporter gene with a strength comparable to that of the well-characterized simian virus 40 promoter/enhancer. This region displayed the features of a multistart-site, GC-rich, TATA-less, and CAAT-less promoter, containing many overlapping Sp1 and AP-2 putative binding sites. Further dissections of the 0.35-kb fragment revealed that its 3' region, specifying the 5' UT of the mRNA, plays a relevant positive effect in determining the strength of the promoter. This region contains putative cis-acting elements for AP-2, nuclear factor-kappaB, and the recently described multiple-start site element downstream-1. By mutation analysis, we showed that these sites are functional and when combined increase the promoter activity by 4-fold. The 0.35-kb promoter was found to be under the negative control of upstream sequences that include a modern Alu repeat. The alpha3 Alu repeat works as a composite region, containing both positive and negative elements that control the activity of the downstream promoter. Finally, we investigated the tissue-specific activity of the human alpha3 gene 5' regulatory sequences, showing that they are able to drive the expression of the reporter gene preferentially in neuronal cells.
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PMID:Structural and functional characterization of the human alpha3 nicotinic subunit gene promoter. 920 30

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

We recently cloned cDNAs encoding three subtypes of human alpha1-adrenergic receptors (alpha1ARs), alpha1a, alpha1b, and alpha1d (Schwinn, D. A., Johnston, G. L., Page, S. O., Mosley, M. J., Wilson, K. H., Worman, N. P., Campbell, S., Fidock, M. D., Furness, L. M., Parry-Smith, D. J., Peter, B., and Bailey, D. S. (1995) J. Pharmacol. Exp. Ther. 272, 134-142) and demonstrated predominance of alpha1aARs in many human tissues (Price, D. T., Lefkowitz, R. J., Caron, M. G., Berkowitz, D., and Schwinn, D. A. (1994) Mol. Pharmacol. 45, 171-175). Several lines of evidence indicate that alpha1aARs are important in clinical diseases such as myocardial hypertrophy and benign prostatic hyperplasia. Therefore, we initiated studies to understand mechanisms underlying regulation of alpha1aAR gene transcription. A genomic clone containing 6.2 kb of 5'-untranslated region of the human alpha1aAR gene was recently isolated. Ribonuclease protection and primer extension assays indicate that alpha1aAR gene transcription occurs at multiple initiation sites with the major site located 696 base pairs upstream of the ATG, where a classic initiator sequence is located. Transfection of luciferase reporter constructs containing varying amounts of 5'-untranslated region into human SK-N-MC neuroblastoma cells indicate that a region extending 125 base pairs upstream from the main transcription initiation site contains full alpha1aAR promoter activity. Furthermore, distinct activator and suppressor elements lie 2-3 and 3-5 kilobase pairs upstream, respectively. Although the alpha1aAR promoter contains neither TATA or CAAT elements, gel shift mobility assays targeting three GC boxes immediately upstream of the main transcription initiation site confirm binding of Sp1. Activity of the alpha1aAR promoter is cell-specific, demonstrating highest activity in cells endogenously expressing alpha1aARs. The human alpha1aAR gene also contains several cis regulatory elements, including several insulin and cAMP response elements. Consistent with these observations, we provide the first evidence that treatment of SK-N-MC cells with insulin and cAMP elevating agents leads to an increase in alpha1aAR expression. In conclusion, these data represent the first characterization of the alpha1aAR gene; our findings should facilitate further studies designed to understand mechanisms regulating alpha1AR subtype-specific expression in healthy and diseased human tissue.
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PMID:Transcriptional regulation of the human alpha1a-adrenergic receptor gene. Characterization Of the 5'-regulatory and promoter region. 935 75

The mouse gene encoding ST8Sia IV/PST, one of two polysialic acid synthases, was isolated and characterized. The mST8Sia IV/PST gene was found to comprise over 60 kilobases and to be composed of five exons. Primer extension analysis revealed that transcription started from 333 nucleotides upstream of the translational initiation site. Transfection with nested deletion mutants of the 5'-flanking region fused to the luciferase reporter gene revealed that the promoter activity of the -107/+145 region was correlated with the gene expression of mST8Sia IV/PST in embryonal carcinoma P19 and neuroblastoma F11 cells. This proximal promoter region lacks an apparent TATA box but has putative binding sites for transcription factors Sp1 and NF-Y (CCAAT binding protein) at nucleotide positions -66/-57 and -47/-37, respectively. Individual deletions and mutations of the inverted Sp1 binding site or inverted NF-Y binding site caused significant reduction of the promoter activity, indicating that each binding site was involved in essential transcription control. Mobility shift assaying also revealed that Sp1 and NF-Y in a nuclear extract of P19 cells bind to the promoter region of the mST8Sia IV/PST gene. Deletion of the region from -60 to -40, which contains parts of both the Sp1 and NF-Y binding sites, completely abolished the promoter activity, suggesting that both Sp1 and NF-Y are synergetically involved in transcription regulation of the mST8Sia IV/PST gene in P19 and F11 cells. Although the overall structures of the two polysialic acid synthase genes (ST8Sia II/STX and IV/PST) are very similar, there is no extensive sequence homology between the 5'-flanking regions of the ST8Sia II/STX and IV/PST genes, suggesting that these two genes are expressed under different regulatory systems.
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PMID:Genomic structure and promoter activity of the mouse polysialic acid synthase (mST8Sia IV/PST) gene. 951 73

Prosaposin is the precursor of four low molecular weight sphingolipid-activating proteins (SAPs) or saposins. These four proteins function as intracellular activators of several lysosomal enzymes involved in the degradation of glycosphingolipids, and prosaposin itself has neurite outgrowth effects. Expression of prosaposin is regulated in a temporal and spatial manner with expression in specific brain neurons and visceral cell types. Here a major regulatory fragment was characterized within 310 bp 5' to the transcription start site. Using electrophoretic mobility shift assay (EMSA) and DNA footprinting, members of the Sp family (Sp1, Sp3, and Sp4), the orphan nuclear receptor (RORalpha), and an unknown transcription factor (U; TGGGGGAG) were shown to bind to this region. To evaluate the role of such transcription factor binding sites for this locus, a series of mutant constructs was generated within this region, and their function was evaluated in cultured NS20Y neuroblastoma cells. A 3' Sp1 site, a 5' Sp1/U cluster and the RORalpha binding sites were functional. The data are consistent with a model in which the factors that bind to the Sp1/U cluster and RORE site interact negatively to diminish promoter activity to a background level that is determined primarily by the 3' Sp1 site. These interactions depend on the tissue-specific repertoire of transcription factors leading to differential expression of this locus.
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PMID:Role of Sp proteins and RORalpha in transcription regulation of murine prosaposin. 958 64

The neuronal promoter of human aromatic l-amino acid decarboxylase gene has been analysed to elucidate the mechanisms of neuron type-specific expression. The (-560/+92) promoter segment was sufficient to direct luciferase expression at a higher level in SK-N-BE neuroblastoma cells, than in CHP126 neuroepithelia, HepG2 hepatoma or SK-Hep1 epithelioma cells. Deletions experiments showed that this segment contained a neuronal-specific (element T1) and a SK-N-BE-specific (element N1) cis-activating sequences. Element T1 (-72/-36) bound Sp1 and NF-Y proteins, and unidentified neuronal-specific factors. Element N1 (-102/-72) bound cell-specific factors, identified as HNF-3, N-Oct-3/Brn-2 and N-Oct-2. HNF-3 proteins recognized the sequence TCAGTAAATA that matches the consensus motif. Oct-1, N-Oct-2 and N-Oct-3 bound the AAATAATGC sequence that overlaps the HNF-3 binding site. In addition, we show that the HNF-3 binding sites from aldolase C and HNF-3beta gene promoters also bind N-Oct-2 and N-Oct-3 proteins. These data suggest a functional interplay of winged helix/forkhead and POU-domain transcription factors on a variety of neuronal gene promoters.
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PMID:Winged helix hepatocyte nuclear factor 3 and POU-domain protein brn-2/N-oct-3 bind overlapping sites on the neuronal promoter of human aromatic L-amino acid decarboxylase gene. 960 35

Sequences from -420 to -70 from the ICPO transcriptional start site of herpes simplex virus type 1 are dispensable for reactivation from latency. A putative cAMP-response element (CRE) outside of this region was non-functional in both murine neuroblastoma (NB41A3) and rat pheochromocytoma (PC12) cells. Also, poor binding of cAMP-response element binding protein (CREB) was observed. Sequences from -95 to -37 are important for constitutive activity in NB41A3, PC12 and baby hamster kidney (BHK) cells. The TATA box and Sp1 site were also shown to be major contributors to constitutive activity. Finally, high constitutive activity of a deleted construct (-420 to -1) in NB41A3 and BHK cells suggests transcription initiates upstream of -420 in the absence of VP16. The implications of these observations regarding ICPO expression during the virus life-cycle are discussed.
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PMID:Analysis of the basal and inducible activities of the ICPO promoter of herpes simplex virus type 1. 974 16

Prosaposin is a multifunctional protein that encodes four glycoproteins, named saposins A, B, C and D. They participate in the catabolism of glycosphingolipids in lysosomes. When secreted, intact prosaposin may function as a neuritogenic factor. Human and mouse prosaposin displayed similar temporal and spatial regulation of expression. To gain insight into the transcriptional regulation of this locus, the 5' region was characterized from the human prosaposin gene. The putative human promoter was shown to be TATA-less, i.e. it belonged to the TATA-less housekeeping gene family. The transcription initiation sites were localized to -23, -27, -31 and -83bp 5' to ATG, compared to -87 and -94bp in the mouse. In SK-N-SH neuroblastoma cells, positive regulatory elements were detected -343 to -813bp upstream of ATG. A negative regulatory region existed between -813 and -2500bp using SK-N-SH, H441 and NS20Y cells. EMSA and DNA-footprint analysis showed that Sp1 and Sp3 are involved in human prosaposin gene regulation. Compared to the mouse promoter, the human promoter is missing a Sp1 cluster within a 310-bp upstream segment, and has AP-1, Oct-1 and two RORalpha sites that are protected from DNaseI by selected nuclear extracts.
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PMID:Isolation and characterization of the human prosaposin promoter. 975

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