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)

Although the human c-mos proto-oncogene has been characterized for more than a decade, very little is known about its protein product and its expression in somatic cells. We generated three human c-mos-specific antisera and report here the detection of c-mos protein in a human neuroblastoma cell line, SK-N-BE2 (BE2). Both Western (immuno-) blot and immunoprecipitation analyses detected a p37 as the major form and p40 and p35 as minor forms of the c-mos protein. Using Northern blot analysis, 3.5- and 1.7-kb c-mos messages were detected. Using a highly sensitive method that combines reverse transcription and the polymerase chain reaction (RT-PCR), c-mos RNA was detected in all the human samples examined. With Western blot analysis, we further showed that c-mos proteins are expressed in cervical carcinoma-derived cell lines. This ubiquitous expression of low levels of c-mos suggests a fundamental role for the c-mos proto-oncogene.
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PMID:Detection of c-mos proto-oncogene expression in human cells. 850 88

A major goal of tumor immunotherapy is the effective eradication of established metastases associated with the induction of a T cell-mediated protective immunity. We achieved this in a poorly immunogenic murine neuroblastoma model by gene therapy with a single chain interleukin 12 (scIL-12) fusion protein that assures equal expression of its p35 and p40 subunits. Thus, NXS2 hybrid neuroblastoma cells (C1300 x dorsal root ganglion cells), which form experimental bone marrow and liver metastases in syngeneic A/J mice, were transduced with a gene encoding murine interleukin 12, monomerized by introduction of a protein linker between the p35 and p40 protein chains of this heterodimeric cytokine. We demonstrate for the first time that subcutaneous vaccination with these transduced cells induces a protective immunity, as indicated by the complete absence of liver and bone marrow metastasis after challenge with NXS2 wild-type tumor cells. Furthermore, vaccination of animals with established liver and bone marrow metastases completely eradicated liver metastases and suppressed bone marrow metastases. The local and systemic immune response against scIL-12-transduced NXS2 cells is largely dependent on CD8(+) T cells. This was demonstrated in vivo by depletion of immunocompetent A/J mice with monoclonal anti-CD4 and anti-CD8 antibodies and in vitro by specific major histocompatibility complex, class I-restricted CD8(+) T cell-mediated killing of NXS2 and their parental C1300 neuroblastoma cells. In conclusion, we demonstrate successful anti-tumor immunotherapy with an scIL-12 fusion protein that could facilitate clinical application of interleukin 12 gene therapy.
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PMID:Gene therapy with a single chain interleukin 12 fusion protein induces T cell-dependent protective immunity in a syngeneic model of murine neuroblastoma. 948 10

The cyclin-dependent kinase 5 (Cdk5) catalytic subunit is expressed in both cycling and noncycling cells and is present in many tissues. Neuronal and muscle cells contain the highest amount of this protein. The p35 protein, which is expressed solely in the brain, activates Cdk5. Cdk5 activity is involved in terminal differentiation of neurons and muscle cells. We attempted to clone cdk5 by PCR from a human fetal brain cDNA library. Surprisingly, we amplified two forms of the cdk5 gene, the wild type and a cdk5 variant that lacks the complete kinase domain VI. The variant is also found in SH-SY-5Y neuroblastoma cells but not in T-cells, HeLa cells, the thymus, and placental tissue. The protein encoded by the cdk5 variant, the Cdk5 isoform (Cdk5i), purifies with p35 when coexpressed in insect cells. The activity associated with the heterodimer Cdk5i/p35 is found to be appreciably weaker than the wild-type Cdk5/p35 kinase. Moreover, Cdk5i/p35 cannot autophosphorylate its two subunits as with Cdk5/p35. Interestingly, kinase-defective Cdk5i can abolish the activity of wild-type Cdk5 when both are coexpressed with p35 in insect cells, suggesting that Cdk5i may have a function in regulating Cdk5 activity in human cells too.
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PMID:Identification of a human cDNA encoding a kinase-defective cdk5 isoform. 987 33

We report the cloning and characterization of the human eukaryotic protein translation initiation factor EIF2C1 gene. The human EIF2C1 gene consists of 19 exons and 18 introns that span a region of almost 50 kb. It is located on the short arm of chromosome 1 in the region 1p34-p35. This genomic region is frequently lost in human cancers such as Wilms tumors, neuroblastoma, and carcinomas of the breast, liver, and colon. The human EIF2C1 gene is ubiquitously expressed at low to medium levels. Differential polyadenylation and splicing result in a complex transcriptional pattern. The cDNA sequence is 7478 bp long and contains an extremely large 3' untranslated region of 4799 bp with multiple, short repeated segments composed of mono-, tri-, or quattronucleotides interspersed throughout. The human EIF2C1 gene belongs to a multigene family in human. It is highly conserved during evolution, sharing about 90% identity with rabbit eIF2C and 70% identity with plant AGO1 at the amino acid level. These facts suggest that human EIF2C1 might play an important physiological role.
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PMID:Human eukaryotic initiation factor EIF2C1 gene: cDNA sequence, genomic organization, localization to chromosomal bands 1p34-p35, and expression. 1053 6

Metastatic stage IV neuroblastoma tumors, as well as cell lines derived from them, are highly malignant and rapidly fatal. To determine whether malignant potential of these cells might be influenced by stromal tissue at sites frequently involved in metastasis, we initiated primary cultures from bone marrow of three patients (331, 337, and 91) with stage IV neuroblastoma. All three explants contained two distinct cell populations, malignant neuroblasts (Nb-type) and substrate adherent stromal-like (Str-type) cells. The cell types were separated at the first passage and studied by cytogenetic, molecular, and immunocytochemical methods. Karyotypic analyses after 3-6 passages in vitro revealed the presence of unique chromosomal abnormalities in Nb-type cells of all three lines: (1) der(1)t(1;7) (p32;q11) and der(5)t(5;17)(q35;q21) in pseudodiploid IGR-N-331 neuroblasts; (2) der(1)t(1;17)(p35;q21-22) x 2 and der(7)t(7;7)(p21;q21) in IGR-N-337 hyperdiploid neuroblasts; and (3) more than six rearranged chromosomes in two related subpopulations of hypodiploid IGR-N-91 neuroblasts. Neuroblastic cells from all three tumors amplified MYCN 25- to 50-fold (with amplified genes visible as dmin or, in one IGR-N-91 subline, as an hsr(14)[q32]) and expressed N-CAM. Str-type cells from tumors 331 and 337 had a normal diploid karyotype, did not express either N-CAM or S-100, and are probably normal bone marrow fibroblasts. By contrast, S-100 negative Str-type IGR-N-91 cells were hypodiploid and shared at least two unbalanced translocations, der(4)t(1;4)(q12;p15) and der(2)t(2;10;17)(p14;q11;q22), with neuroblastic counterparts, indicating that "stromal" cells and malignant neuroblasts had a common tumor cell origin. Thus, the Str-type cells of IGR-N-91 are examples of S-type phenotypic variants frequently described for long-term human neuroblastoma cells lines in vitro, but not previously observed in vivo.
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PMID:Phenotypic and genotypic diversity of human neuroblastoma studied in three IGR cell line models derived from bone marrow metastases. 1068 38

We describe the establishment and characterization of a new neuroblastoma (Nb) cell line, SiMa, carrying the major recurrent chromosome changes associated with poor prognosis Nb, including amplification of N-MYC by formation of double minutes (dmin), der(1)t(1;17)(p35;q12) and der(22)t(17;22)(q22;p13), and loss of chromosome 11, documented at both initiation and late passage. In contrast to these cytogenetic stigmata of poor prognosis, analysis of catecholamine synthesis by high pressure liquid chromatography (HPLC) measurement revealed an advanced degree of adrenergic differentiation with high rates of 3,4-Dihydroxyphenylalanine (DOPA), noradrenaline, homovanillic acid (HVA), and vanillylmandelic acid (VMA) production. Contrastingly advanced differentiation and poor prognostic genetic markers combine to render SiMa a unique instrument for investigating the pathology and therapy of Nb.
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PMID:SiMa, a new neuroblastoma cell line combining poor prognostic cytogenetic markers with high adrenergic differentiation. 1068 45

Neuronal differentiation involves Rac and Cdc42 GTPases. alpha-Chimaerin, a Rac/Cdc42 regulator, occurs as alpha1- and alternatively spliced Src homology 2 (SH2) domain-containing alpha2-isoforms. alpha2-chimaerin mRNA was highly expressed in the rat embryonic nervous system, especially in early postmitotic neurons. alpha1-chimaerin mRNA was undetectable before embryonic day 16.5. Adult alpha2-chimaerin mRNA was restricted to neurons within specific brain regions, with highest expression in the entorhinal cortex. alpha2-chimaerin protein localized to neuronal perikarya, dendrites, and axons. The overall pattern of alpha2-chimaerin mRNA expression resembles that of cyclin-dependent kinase regulator p35 (CDK5/p35) which participates in neuronal differentiation and with which chimaerin interacts. To determine whether alpha2-chimaerin may have a role in neuronal differentiation and the relevance of the SH2 domain, the morphological effects of both chimaerin isoforms were investigated in N1E-115 neuroblastoma cells. When plated on poly-lysine, transient alpha2-chimaerin but not alpha1-chimaerin transfectants formed neurites. Permanent alpha2-chimaerin transfectants generated neurites whether or not they were stimulated by serum starvation, and many cells were enlarged. Permanent alpha1-chimaerin transfectants displayed numerous microspikes and contained F-actin clusters, a Cdc42-phenotype, but generated few neurites. In neuroblastoma cells, alpha2-chimaerin was predominantly soluble with some being membrane-associated, whereas alpha1-chimaerin was absent from the cytosol, being membrane- and cytoskeleton-associated, paralleling their subcellular distribution in brain. Transient transfection with alpha2-chimaerin mutated in the SH2 domain (N94H) generated an alpha1-chimaerin-like phenotype, protein partitioned in the particulate fraction, and in NGF-stimulated pheochromocytoma cell line 12 (PC12) cells, neurite formation was inhibited. These results indicate a role for alpha2-chimaerin in morphological differentiation for which its SH2 domain is vital.
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PMID:alpha2-chimaerin, a Cdc42/Rac1 regulator, is selectively expressed in the rat embryonic nervous system and is involved in neuritogenesis in N1E-115 neuroblastoma cells. 1143 94

PCTAIRE-1 is a CDK-related protein kinase found in terminally differentiated cells in brain and testis, and in many immortalised and transformed cell lines. Bacterially expressed PCTAIRE is completely inactive as a protein kinase, but is a very good substrate for protein kinase A (PKA), which phosphorylates a total of four sites in the N-terminus of PCTAIRE-1. Phosphorylation of one of these sites, Ser119, generates a 14-3-3 binding site, which is functional in vitro as well as in vivo. Mutation of another PKA site, Ser153, to an alanine residue generated an activated kinase in transfected mammalian cells. This activity was comparable to that of CDK5 activated by a bacterially expressed, truncated version of p35(nck), p21. Gel filtration analysis of a brain extract suggested that monomeric PCTAIRE-1 was the active species, implying that PCTAIRE-1 may not be a true CDK, in that it does not require a partner (cyclin-like) subunit for kinase activity. Finally, we found that various forms of PCTAIRE-1 transfected into neuroblastoma cell lines could either promote or inhibit neurite outgrowth, suggesting a potential role for the PCTAIRE-1 gene product in the control of neurite outgrowth.
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PMID:Regulation of the CDK-related protein kinase PCTAIRE-1 and its possible role in neurite outgrowth in Neuro-2A cells. 1215 78

Cdk5, a member of the cyclin-dependent kinase (cdk) family, is predominantly active in neurons, where its activity is tightly regulated by the binding of its neuronal activators p35 and p39. Cdk5 is implicated in regulating the proper neuronal function; a deregulation of cdk5 has been found associated with Alzheimer's disease and amyotrophic lateral sclerosis. As oxidative stress products have been seen co-localized with pathological hallmarks of neurodegenerative diseases, we studied the effect of oxidative stress on the cdk5 enzyme in human neuroblastoma IMR-32 cells. We evaluated the effects of 4-hydroxynonenal and Ascorbate plus FeSO(4) on cdk5 activity and on the expression of cdk5 and p35 proteins. We report here that oxidative stress stimulates cdk5 activity and induces an upregulation of its regulatory and catalytic subunit expression in IMR-32 vital cells, showing that the cdk5 enzyme is involved in the signaling pathway activated by oxidative stress.
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PMID:Up-regulation of cDK5/p35 by oxidative stress in human neuroblastoma IMR-32 cells. 1257 9

To better understand whether the p53-related p73 gene could induce neuronal apoptosis, we tested whether p73 induced cell killing in three neuronal cell lines and whether apoptosis could be inhibited by p35, a baculovirus-encoded protein that blocks caspase 3. Recombinant adenoviruses carrying the hemagglutinin (HA)-tagged p73beta or p35, or the green fluorescent protein gene driven by the cytomegalovirus immediate-early promoter were constructed, and used to infect human SK-N-AS and SK-N-SH neuroblastoma, and rat PC12 pheochromocytoma cells. Infection with Adp73beta virus resulted in p73beta over-expression and substantial reduction of cell viability due to apoptosis in all three neuronal cell lines as compared with the control AdGFP virus. These results indicate that p73beta over-expression in neuronal cells could induce apoptotic cell death regardless of the endogenous expression of p73. The p73 effect was partially blocked by co-expression of the wild-type p35, suggesting caspase-mediated cell killing. Insertion of a hemagglutinin (HA) tag at the N-terminus of p35 markedly reduced its ability to inhibit the p73 effect compared with the wild-type p35, while insertion of an HA tag to the C-terminus of p35 had no appreciable effect. Taken together, our results suggest that the N-terminal structure of p35 is critical for its anti-apoptotic activity on p73-induced apoptosis in neuronal cells.
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PMID:Induction of apoptosis by the p53-related p73 and partial inhibition by the baculovirus-encoded p35 in neuronal cells. 1275 1


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