Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

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

The class III beta-tubulin isotype is widely used as a neuronal marker in normal and neoplastic tissues. This isotype was, however, also immunodetected in certain tumours of non-neuronal origin such as squamous cell carcinoma. Using a newly described monoclonal antibody we compared the distribution of class III beta-tubulin in normal and neoplastic tissues. The TU-20 mouse monoclonal antibody was prepared against a conserved synthetic peptide from the C-terminus of the human class III beta-tubulin isotype, and its specificity was confirmed by immunoblotting, by competitive enzyme-linked immunosorbent assay and by immunofluorescence microscopy on cultured cells. In different cell lines of various origins the antibody reacted only with neuroblastoma Neuro-2a cells and with embryonal carcinoma P19 cells stimulated to neuronal differentiation by retinoic acid. Immunohistochemistry on formaldehyde-fixed paraffin-embedded normal human tissues revealed the presence of the class III beta-tubulin isotype in cell bodies and processes of neuronal cells in the peripheral and central nervous systems. In other tissues, this beta-tubulin isotype was not immunodetected. Class III beta-tubulin was found in all cases of ganglioneuroblastoma, ganglioneuroma, medulloblastoma, neuroblastoma, sympathoblastoma and in one case of teratoma. In contrast, no reactivity was detected in tumours of non-neuronal origin, including 32 cases of squamous cell carcinoma. The results indicate a specific TU-20 epitope expression exclusively in neuronal tissues. The antibody could thus be a useful tool for the probing of class III beta-tubulin functions in neurons as well as for immunohistochemical characterisation of tumours of neuronal origin.
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PMID:Expression of class III beta-tubulin in normal and neoplastic human tissues. 954 71

We have identified a novel type II activin receptor, called type IIA-N, the expression of which was induced during the neural differentiation of murine P19 embryonal carcinoma cells (P19 cells). P19 cells differentiate into several cell types dependent on the culture conditions. The induction of type IIA-N mRNA occurred predominantly in conjunction with neural differentiation. Sequence analysis of a cDNA clone for type IIA-N indicated that type IIA-N had a 24 bp insertion in the juxtamembrane region of the type IIA activin receptor suggesting that it is an alternative splicing product of the type IIA gene. Type IIA-N was also identified in human and Xenopus, and the amino acid sequences of three species were completely conserved. The expression of type IIA-N mRNA was specifically detected in neuroblastoma cells among several activin responsive cell lines. In vivo expression of type IIA-N mRNA was detected only in the neural tissues such as brain and spinal cord in adult mouse, by RT-PCR. Furthermore, its expression in developing Xenopus embryos was restricted to the neurula and later stages. These results suggest that the expression of type IIA-N is specific to neural cells and mediates neural differentiation-specific activin signaling.
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PMID:Identification of a novel type II activin receptor, type IIA-N, induced during the neural differentiation of murine P19 embryonal carcinoma cells. 961 Mar 56

Tuberous sclerosis is an autosomal dominant disorder. Besides the development of benign growths (hamartomas) in different tissues, one hallmark of this disease is the presence of highly epileptogenic dysplastic lesions in the cerebral cortex (tubers) composed of abnormal shaped neurones. Patients often show evidence of severe mental retardation. Linkage analysis revealed two disease-determining genes on chromosome 9 and chromosome 16. The TSC2 gene on chromosome 16 encodes a 1784-amino acid putative tumour suppressor protein, tuberin, that functions as a GTPase-activating protein. Here we show that tuberin expression is upregulated upon induction of neuronal differentiation in the neuroblastoma cell lines SK-N-SH and LAN-1. This upregulation occurs at post-transcriptional level and is independent of the proliferation status. TSC2 expression is unaffected during differentiation of C2C12 myoblasts into myotubes and of F9 embryonal carcinoma cells into cells resembling parietal endoderm. Antisense inhibition of tuberin expression in SK-N-SH or LAN-1 cells inhibits neuronal differentiation, but does not affect the differentiation of F9 cells. Ectopic overexpression of TSC2 not only reverts the antisense-associated phenotype but furthermore accelerates the neuronal differentiation process. Our data show for the first time that tuberin plays a critical role in neuronal differentiation. Such role is consistent with the phenotype of tuberous sclerosis patients, who inherit one defective TSC2 allele, and frequently lose the remaining normal allele in many of the tubers/hamartomas which develop in the central nervous system of these patients.
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PMID:A role of the tuberous sclerosis gene-2 product during neuronal differentiation. 961 28

Signalling between cells in the developing vertebrate embryo is essential for normal embryonic development. In the mid 1970's, signal transduction research started at the Hubrecht Laboratory with special emphasis on analysis of the signalling mechanisms that direct cell proliferation and differentiation. The introduction of in vitro model systems contributed tremendously to the success of the signal transduction research at the Hubrecht Laboratory. Initially neuroblastoma cell lines, and later embryonal carcinoma and embryonal stem cells played an important role in identification of the molecular key players in developmental signalling. For instance, embryonal carcinoma cells were used to identify and characterise polypeptide growth factors. Growth factor signalling research was extended to analysis of growth factor receptor activation. Moreover, the second messenger systems that are linked to growth factor receptors were studied, as well as the nuclear responses to growth factor receptor activation. Finally, the role of growth factor signalling in differentiation was established using embryonal carcinoma cells. Here, we will review work that was characteristic for the growth factor receptor signalling research that was done at the Hubrecht Laboratory between 1980 and the early 1990's.
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PMID:Growth factor signalling. 1066 78

Necdin, a growth suppressor expressed predominantly in postmitotic neurons, interacts with viral oncoproteins and cellular transcription factors E2F1 and p53. In search of other cellular targets of necdin, we screened cDNA libraries from neurally differentiated murine embryonal carcinoma P19 cells and adult rat brain by the yeast two-hybrid assay. We isolated cDNAs encoding partial sequences of mouse NEFA and rat nucleobindin (CALNUC), which are Ca(2+)-binding proteins possessing similar domain structures. Necdin interacted with NEFA via a domain encompassing two EF hand motifs, which had Ca(2+) binding activity as determined by (45)Ca(2+) overlay. NEFA was widely distributed in mouse organs, whereas necdin was expressed predominantly in the brain and skeletal muscle. In mouse brain in vivo, NEFA was localized in neuronal perikarya and dendrites. By immunoelectron microscopy, NEFA was localized to the cisternae of the endoplasmic reticulum and nuclear envelope in brain neurons. NEFA-green fluorescent protein (GFP) fusion protein expressed in neuroblastoma N1E-115 cells was retained in the cytoplasm and partly secreted into the culture medium. Necdin enhanced the cytoplasmic retention of NEFA-GFP and potentiated the effect of NEFA-GFP on caffeine-evoked elevation of cytosolic Ca(2+) levels. Thus, necdin and NEFA might be involved in Ca(2+) homeostasis in neuronal cytoplasm.
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PMID:The postmitotic growth suppressor necdin interacts with a calcium-binding protein (NEFA) in neuronal cytoplasm. 1091 98

It is important to develop a system to express therapeutic genes in tumor cells with sufficient selectivity for cancer gene therapy. Midkine (MK) is a newly identified heparin-binding growth factor that is transiently expressed in the early stages of retinoic acid-induced differentiation of embryonal carcinoma cells. It has been reported that many human malignant tumors express high levels of MK mRNA or protein. However, no MK expression is detected in human or mouse liver. These interesting features of MK led us to examine the MK promoter as a candidate for tumor-specific gene expression. We thus developed new recombinant adenoviral (Ad) vectors containing either luciferase reporter gene (AdMKLuc) or herpes simplex thymidine kinase gene (AdMKTK) under the control of the human MK promoter. AdMKLuc achieved relatively high activity in Wilms' tumor (G-401) and neuroblastoma (SK-N-SH) cell lines. In addition, AdMKTK induced marked cell death in response to ganciclovir (GCV) in these same lines. Conversely, very low activity of the MK promoter was observed in mouse liver in vivo compared with the cytomegalovirus promoter. Importantly, AdMKTK + GCV did not induce liver toxicity, whereas substantial toxicity was seen with AdCMVTK + GCV treatment. On the basis of these findings, we conclude that the MK promoter is a candidate tumor-specific promoter for Wilms' tumor or neuroblastoma.
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PMID:Midkine promoter-based adenoviral vector gene delivery for pediatric solid tumors. 1096 65

Retinoic acid (RA), the biologically active derivative of vitamin A, induces a variety of embryonal carcinoma and neuroblastoma cell lines to differentiate into neurons. The molecular events underlying this process are reviewed with a view to determining whether these data can lead to a better understanding of the normal process of neuronal differentiation during development. Several transcription factors, intracellular signaling molecules, cytoplasmic proteins, and extracellular molecules are shown to be necessary and sufficient for RA-induced differentiation. The evidence that RA is an endogenous component of the developing central nervous system (CNS) is then reviewed, data which include high-pressure liquid chromotography (HPLC) measurements, reporter systems and the distribution of the enzymes that synthesize RA. The latter is particularly relevant to whether RA signals in a paracrine fashion on adjacent tissues or whether it acts in an autocrine manner on cells that synthesize it. It seems that a paracrine system may operate to begin early patterning events within the developing CNS from adjacent somites and later within the CNS itself to induce subsets of neurons. The distribution of retinoid-binding proteins, retinoid receptors, and RA-synthesizing enzymes is described as well as the effects of knockouts of these genes. Finally, the effects of a deficiency and an excess of RA on the developing CNS are described from the point of view of patterning the CNS, where it seems that the hindbrain is the most susceptible part of the CNS to altered levels of RA or RA receptors and also from the point of view of neuronal differentiation where, as in the case of embryonal carcinoma (EC) cells, RA promotes neuronal differentiation. The crucial roles played by certain genes, particularly the Hox genes in RA-induced patterning processes, are also emphasized.
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PMID:Role and distribution of retinoic acid during CNS development. 1158 Jan 99

The vesicular GABA transporter (VGAT) loads GABA from neuronal cytoplasm into synaptic vesicles and is selectively expressed in inhibitory neurons that contain GABA and/or glycine. To elucidate the molecular mechanisms of mouse VGAT (mVGAT) gene expression, we have isolated and characterized the mVGAT gene. The mVGAT gene was found to be 4.7 kilobases in size and to contain three exons and two introns by comparison of the cloned genomic DNA with the cDNA (termed mVGATa) sequence reported by Sagne et al. [FEBS Lett. 417 (1997) 177]. Analysis of transcripts and genomic DNA revealed an alternatively spliced mVGAT isoform (termed mVGATb) that retains intron 2 of mVGATa as an exon. This alternative transcript specifies 514 amino acid residues identical to VGATa followed by a unique C-terminal sequence of 11 amino acids encoded by intron 2. Fluorescent in situ hybridization studies showed that the mVGAT gene is localized on chromosome 2. One major transcription start site of the mVGAT gene is an A residue 209 bp upstream from the translational initiation site, as shown using the 5'-RACE method. RT-PCR analysis revealed that the mVGAT gene was expressed at a high level in retinoic acid-treated P19 embryonal carcinoma cells, at a very low level in non-treated P19 cells, and not detectably expressed in Neuro-2a neuroblastoma cells. Sequence analysis of the 5'-flanking region revealed a number of putative regulatory elements including Sp1, Egr-1 and Pitx binding sites. In transient transfection assays, 2 kilobases of the mVGAT 5'-flanking region generated similar levels of luciferase reporter activity in three kinds of cultured cells. Deletion analysis and gel mobility shift assays demonstrated that the region -161 to +155 contained the basal promoter activity of the mVGAT gene and that an activating region from -49 to -27 bound an Sp1-like protein. These results suggest a possible mechanism for regulation of the expression of the mVGAT gene.
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PMID:Mouse vesicular GABA transporter gene: genomic organization, transcriptional regulation and chromosomal localization. 1257 41

Ceruloplasmin (CP) is a copper-dependent ferroxidase. It regulates iron metabolism and is involved in inflammation, angiogenesis, and protection against oxidative stress. CP also modulates K(+) channel activity in neuroblastoma cells and affects cardiodynamics of isolated hearts. Considering the presence of CP in the nervous system and the importance of iron ions and K(+) channels in neuronal activity, we postulated a role of CP in neuronal development. This hypothesis was tested using the P19 mouse embryonal carcinoma cell line, a model of neuronal differentiation. Addition of CP to the culture medium of newly differentiated P19 neurons induced cell aggregation within 24 h. This effect was concentration-dependent half-maximal at 50 nM, and not associated with necrosis, apoptosis or changes in secretory function. Deglycosylated CP was aggregative but not denatured CP, copper salts, His(2)Cu complex, or other copper enzymes or serum proteins. CP-induced aggregation was less pronounced with aging neurons and seemed not to involve K(+) channels. Immunocytofluorescence analysis demonstrated that digoxigenin-labeled CP bound to P19 neurons and the proportion of responding neurons decreased with aging. The interaction of digoxigenin-labeled CP with neurons was half-maximal at 120 nM by enzyme-linked immunosorbent assay and displaced by unlabeled CP. Our data indicate a specific aggregative action of CP on young neurons in vitro, possibly involving CP receptors. A potential developmental role of CP in nervous system organization is thus demonstrated.
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PMID:The blue copper ceruloplasmin induces aggregation of newly differentiated neurons: a potential modulator of nervous system organization. 1294 1


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