Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The normal human N-ras gene has been cloned. In structure and sequence it closely resembles the human H-ras and K-ras genes. The three genes share regions of nucleotide homology and nucleotide divergence within coding sequences and have a common intron/exon structure, indicating that they have evolved from a similarly spliced ancestral gene. The N-ras gene of SK-N-SH neuroblastoma cells has transforming activity, while the normal N-ras gene does not, the result of a single nucleotide change substituting lysine for glutamine in position 61 of the N-ras gene product. From previous studies we conclude that amino acid substitutions in two distinct regions can activate the transforming potential of ras gene products.
 ...
PMID:Structure and activation of the human N-ras gene. 661 21

The oncogene of the HL-60 human promyelocytic leukemia cell line has been passed serially through NIH/3T3 mouse fibroblasts. Oncogene-specific probes prepared from the resulting tertiary transfectants by molecular cloning have been used to show that loss of the transfected oncogene from NIH/3T3 cells correlates with reversion to nontransformed morphology. Analysis of cells transfected by the oncogenes of other tumors and tumor cell lines indicates that the transforming gene of the HL-60 leukemia cell line is closely related to oncogenes of a Burkitt's lymphoma, an acute myelogenous leukemia, an adenocarcinoma of the colon, a neuroblastoma, and two sarcomas. This oncogene is distantly related to the viral oncogenes of Kirsten and Harvey sarcoma viruses. It has been termed N-ras. The active N-ras oncogene coexists with altered versions of the myc oncogene in the HL-60 and AW Ramos human tumors. This suggests a multistep mechanism involving both ras and myc genes in the creation of these tumors.
 ...
PMID:The HL-60 transforming sequence: a ras oncogene coexisting with altered myc genes in hematopoietic tumors. 668 94

Altered glycosylation of membrane glycoproteins was demonstrated in NIH 3T3 cells transformed by transfection with DNA from human neuroblastoma and bladder carcinoma cell lines. The oncogenes of these two cell lines have been identified as N-ras and c-H-ras-1, respectively. The fucose-labeled membrane glycopeptides of transfection-induced transformants had decreased binding to concanavalin A-Sepharose when compared in dual-isotope experiments to those from NIH 3T3 cells, whereas binding to lentil lectin-Sepharose and leukoagglutinating phytohemagglutinin-agarose was increased. Binding affinities to these immobilized lectins lead to the interpretation of the results as a decrease in biantennary glycopeptides with a simultaneous increase in tri- or tetraantennary glycopeptides. Sephadex G-50 profiles also indicated a size increase of the glycopeptides of the transformants. None of these changes was growth related. This altered glycosylation, representing a heretofore unreported effect of the onc genes, may be necessary for the transformed phenotype.
 ...
PMID:Change in glycosylation of membrane glycoproteins after transfection of NIH 3T3 with human tumor DNA. 674 91

We have recently demonstrated that a single local injection of the avian pathogen Newcastle disease virus (NDV; strain 73-T) causes complete regression of human neuroblastoma xenografts in athymic mice (R. M. Lorence, K. W. Reichard, B. B. Katubig, H. M. Reyes, A. Phuangsab, B. R. Mitchell, C. J. Cascino, R. J. Walter, and M. E. Peeples. J. Natl. Cancer Inst., 86: 1228-1233, 1994). In this report, we tried to determine if this in vivo antineoplastic effect of NDV extends to human sarcomas. Athymic mice with s.c. HT1080 fibrosarcoma xenografts (7-14 mm) were randomly divided into two groups and treated i.t. with a single injection of either 10(7) plaque-forming units of NDV or phosphate-buffered saline. Complete tumor regression occurred in 8 of 10 mice treated with NDV while unabated tumor growth occurred in all 9 mice treated with phosphate-buffered saline (P < 0.001). To determine if complete tumor regression was long lasting, the 8 mice were monitored for 1 year, during which time no tumor recurred. To test the antitumor effects of NDV on tumors derived from a fresh human sarcoma, a similar experiment was performed in athymic mice using TH15145 synovial sarcoma xenografts at their first and second passages. Of 9 mice with TH15145 xenografts, a single i.t. injection of NDV (10(7) plaque-forming units) caused complete regression of 3 tumors and > 80% regression in 3 more tumors. In contrast, tumors in all 5 mice treated with phosphate-buffered saline exhibited unabated growth (P < 0.03 for > 80% tumor regression). Since HT1080 fibrosarcoma cells express the N-ras oncogene, we explored the effects that transfection of this oncogene has on the sensitivity to NDV. Cultured human fibroblasts that were made tumorigenic following N-ras-transfection were found to be 1000-fold more sensitive to NDV than normal fibroblasts in a cytotoxicity assay. Oncogene expression by the HT1080 fibrosarcoma may therefore contribute to the long-lasting complete regression of this sarcoma following a single local injection of NDV.
 ...
PMID:Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy. 795 37

The association of molecular characteristics with prognosis has been reported, but not their relationship with each other and their impact in the context of known clinical risk factors. In this study, data of 1249 consecutive intent-to-treat-neuroblastoma patients with more than 1 year follow-up were examined by multivariate analysis using loglinear and Cox proportional hazard regression models on a stage-related basis (stages 1-3: 600, 4S: 116, 4: 533). In a first step, risk factors were identified from 18 selected clinical variables, and risk groups defined. The second step investigated whether molecular characteristics (MYCN, LOH 1p, del 1p, CD44, N-ras, NGF-R, bcl-2, APO-1 (CD95)) contributed additional prognostic information to the model. The loglinear model demonstrated several interactions between clinical factors. By the Cox regression model, seven independent clinical risk factors were found for stages 1-3, seven for stage 4 and two for stage 4S. By subsequent introduction of all molecular variables, MYCN amplification only added significant prognostic information to the clinical factors in localised and stage 4 neuroblastoma. The models allowed the definition of risk groups for stages 1-3 patients by age (e beta = 5.09) and MYCN (e beta = 4.26), for stage 4 by MYCN (e beta = 2.78) and number of symptoms (e beta = 2.44) and for stage 4S by platelet count (e beta = 3.91) and general condition (e beta = 2.99). Molecular factors and in particular MYCN contribute significantly to risk estimation. In conjunction with clinical factors, they are powerful tools to define risk groups in neuroblastoma.
 ...
PMID:The current contribution of molecular factors to risk estimation in neuroblastoma patients. 951 60

Oncogenic Ras is responsible for malignant transformation in a variety of tumors. Farnesylation of Ras by farnesyl-protein-transferase (FPTase) is necessary for membrane localization of Ras-proteins, a prerequisite for its biological activity. Although mutations in ras genes are rare in neuroblastoma inactivation of Ras by inhibition of the FPTase is of interest in neuroblastoma. In this tumor, amplification of N-myc is frequently observed and expression of N-myc is induced via Ras signaling. Farnesyl-protein-transferase of neuroblastoma cells is inhibited by alpha-hydroxyfarnesylphosphonate. In homogenates of the cell line SK-N-AS an ID50 = 6.5 microM is estimated, in SK-N-SH the ID50 is 3.4 microM. The consequences of the inhibition of FPTase on the membrane localization was examined by immunoblots. Western blots of membrane proteins analysed with H-ras and N-ras specific antibodies revealed that H-ras protein is more sensitive to the inhibition of FPTase than N-ras protein. After culturing neuroblastoma cells for 24 hrs in the presence of 20 microM alpha-hydroxyfarnesylphosphonate H-ras protein completely dissappeared from the membrane fraction whereas N-ras protein was only affected by 50%. K-ras was not detectable on Western blots of three neuroblastoma cell lines. The experiments showed that FPTase inhibitors are effective in neuroblastoma cells but for complete inactivation of N-ras stronger conditions are required than for H-ras.
 ...
PMID:Inhibition of farnesyl-protein-transferase in neuroblastoma cells by alpha-hydroxyfarnesylphosphonate. 1065 79

The thyroid hormone triiodothyronine (T3) has a profound effect on growth, differentiation, and metabolism in higher organisms. Here we demonstrate that T3 inhibits ras-induced proliferation in neuroblastoma cells and blocks induction of cyclin D1 expression by the oncogene. The hormone, at physiological concentrations, strongly antagonizes the transcriptional response mediated by the Ras/mitogen-activated protein kinase/ribosomal-S6 subunit kinase (Rsk) signaling pathway in cells expressing thyroid hormone receptors (TRs). T3 blocks the response to the oncogenic forms of the three ras isoforms (H-, K-, and N-ras) and both TRalpha and TRbeta can mediate this action. The main target for induction of cyclin D1 transcription by oncogenic ras in neuroblastoma cells is a cyclic AMP response element (CRE) located in proximal promoter sequences, and T3 represses the transcriptional activity of b-Zip transcription factors such as CREB (CRE-binding protein) or ATF-2 (activation transcription factor 2) that are direct targets of Rsk2 and bind to this sequence. The hormone also blocks fibroblast transformation by oncogenic ras when TR is expressed. Furthermore, TRs act as suppressors of tumor formation by the oncogene in vivo in nude mice. The TRbeta isoform has stronger antitransforming properties than the alpha isoform and can inhibit tumorigenesis even in hypothyroid mice. These results show the existence of a previously unrecognized transcriptional cross talk between the TRs and the ras oncogene which influences relevant processes such as cell proliferation, transformation, or tumorigenesis.
 ...
PMID:The thyroid hormone receptor is a suppressor of ras-mediated transcription, proliferation, and transformation. 1531 61

Single point mutations of ras oncogenes are found in many tumors and contribute to the pathogenesis of the cancer. The product of the ras gene, p21 protein, was found expressed in several neuroblastoma tissues. However, the role of ras gene in this tumor has yet to be clarified. To contribute to the understanding of the ras activation, 79 fresh biopsies of neuroblastoma were studied to investigate the possibility that ras would be activated by point mutation. Analysis of H-ras and N-ras was performed by means of PCR and SSO, while K-ras mutations were detected by multiplex-ASPCR. None of the neuroblastomas examined showed H- or K-ras activation, while N-ras mutations were demonstrated in only three patients (3,7%). N-myc oncogene is amplified in a substantial number of patients with neuroblastoma. N-myc amplification was studied by Southern blot technique. N-myc amplification was demonstrated in 13.2% of patients less than 1 year of age at diagnosis and 23% of older children. Two of the patients (one stage I and one stage IVs) with N-ras mutation and without N-myc amplification had a good outcome, while the third (stage IVs) with N-myc amplification had a poor prognosis. These results suggest that ras activation is a rare event in both amplified and non-amplified neuroblastoma tumors and that N-ras activation was not involved in the clinical outcome of these patients. Moreover, our data suggest that p21 expression is induced by a post-transcriptional activation.
 ...
PMID:Rare frequencey of point mutations for codon 12, 13 and 61 of ras gene in italian neuroblastoma. 2157 96

Ras genes were first identified in the 1960s as transforming oncogenes that caused tumors in rats infected with Harvey and Kirsten sarcoma viruses (Ha-ras and Ki-ras oncogenes, accordingly). Subsequently, transforming ras genes were found in human cancer cells. Further investigations of neuroblastoma cells resulted in the finding of the third ras gene in the human, which was called N-ras. Ras gene products play an important role in the processes of cellular proliferation and differentiation and are controlled by receptor tyrosine kinases. Using drosophila as a model object allowed us to perform a successful genetic analysis while studying the functions of ras genes. Three polytene chromosome bands were detected in D. melanogaster with the help of the v-Ha ras sampling. According to Bridges' map, all three bands (Dras1, Dras2, Dras3) were mapped to regions 85D, 64B, and 62B of chromosome 3. Among them, only Drasl has a common origin with ras genes of mammals. Although there are numerous investigations of the role played by ras genes in the de- velopment of insects, this problem is still not fully understood. The importance of ras gene variations in the course of the evolutionary process has been insufficiently studied as well. Currently, Ras target proteins are actively identified, their signal pathways, as well as effects of influencing these pathways in the drosophila tissues, are studied in the cells of yeast and mammals. The main functions of Ras protein is in the signaling pathways controlling mutations during drosophila's morphogenesis and the connections of ras gene with phenotypic symptoms of tumors.
 ...
PMID:[Universal intracellular transducer RAS and its role in the development of Drosophila]. 2543 2


<< Previous 1 2