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 human fibroblast activation protein (FAP), defined by monoclonal antibody F19, is expressed in vivo in reactive stromal fibroblasts of epithelial cancers, subsets of bone and soft tissue sarcomas, and granulation tissue of healing wounds. FAP is generally absent from the stroma of benign epithelial tumors and normal adult tissues. In vitro FAP induction is observed in proliferating cultured fibroblasts and in melanocytes grown with fibroblast growth factor and phorbol ester. In the present study, we show that fibroblast and melanocyte FAP is a cell surface protein comprising noncovalently linked M(r) 95,000 (p95) and M(r) 105,000 (p105) subunits. In contrast, cultured sarcoma and melanoma cell lines express only p95 or are FAP negative. Immunoblot experiments show that p95, but not p105, carries the epitope defined by monoclonal antibody F19. Furthermore, peptide maps of purified p95 and p105 differ, suggesting that they may be distinct gene products. Loss of FAP or a change from p95/p105 to p95 expression accompanies the acquisition of growth factor independence and tumorigenicity in several in vitro test systems, including simian virus 40 transformation of normal fibroblasts, Ha-ras transformation of normal melanocytes, supertransformation of osteosarcoma cells, and enhanced N-MYC expression in variant neuroblastoma cells, whereas serum-starved normal fibroblasts continue to express p95/p105. Thus, fAP expression appears to be linked to the growth factor-dependent proliferative capacity of normal cells and is not merely a secondary event in proliferating cells; furthermore, FAP expression is inversely correlated with growth factor independence and tumorigenicity in transformed cell lines. This distribution pattern is consistent with a role for p95/p105 in mediating extrinsic, growth regulatory signals in normal cells, possibly as a heteromeric cell surface receptor. Such a physiological function may be obviated when oncogenes with cytoplasmic or nuclear sites of action are activated, reducing extrinsic growth factor dependence and permitting down-regulation of FAP in certain transformed cells.
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PMID:Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin. 839 23

The introduction of human chromosome 17 suppresses the tumourigenicity of a neuroblastoma cell line in the absence of any effects on in vitro growth and the neurofibromatosis type 1 (NF1) gene may be responsible. Here we report that 4 out of 10 human neuroblastoma lines express little or no neurofibromin and that two of these lines show evidence of NF1 mutations, providing further proof that NF1 mutations occur in tumours that are not commonly found in NF1 patients. We also show that NF1 deficient neuroblastomas show only moderately elevated ras-GTP levels, in contrast to NF1 tumour cells, indicating that neurofibromin contributes differently to the negative regulation of ras in different cell types.
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PMID:Neurofibromatosis type 1 gene mutations in neuroblastoma. 849 Jun 57

Neuroblastoma is the most common extracranial tumor in children, and cytogenetically, chromosome 1p deletions, extrachromosomal double minutes, and homogeneously staining regions (HSRs) are commonly observed in cell lines and in tumors in advanced stages. It is found that an HSR represents genomic amplification of N-myc, which plays a key role in determining the aggressiveness of neuroblastoma. However, stage IV neuroblastomas or cell lines which lack N-myc amplification are also progressive, and some of them show evidence of N-myc expression in terms of mRNA and/or N-Myc oncoprotein. It was recently shown that a small proximal locus mapped between 1p35-36.1 and 1p36.23 may function as a suppressor gene of N-myc amplification. In neuroblastoma, a pattern of diploidy is associated with rapid tumor growth and poor survival. Expression of bcl-2 proto-oncogene is strongly associated with unfavorable histology, while expressions of Ha-ras and trk-A proto-oncogenes indicate a favorable prognosis. trk-A proto-oncogene encodes a receptor for nerve growth factor. Genetic characteristics of neuroblastomas found by urinary catecholamine mass screening are also discussed.
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PMID:Genetic clinical markers of human neuroblastoma with special reference to N-myc oncogene: amplified or not amplified?--An overview. 865 15

Neurofibromin, the gene product of the NF-1 gene is expressed in two isoforms. The m-RNA of NF-1 type II contains an insertion of 63 bases in the so called GAP-related domain, that distinguishes it from the type I transcript. By sequence homology neurofibromin is supposed to have a similar function in regulating activity of ras in intracellular signal transduction as the GTPase activating protein (GAP). Both transcripts of NF-1 are simultaneously expressed in different molar ratio in neuroblastoma tumors. 1) We examined 9 different neuroblastoma cell lines for the ratio of expression of NF-1 type I and type II. For quantification of the two transcripts we performed RT-PCR of the m-RNA of the neuroblastoma cells using primers designed to cover the GAP-related domain. We found values ranging from a more than 3-fold excess of type I transcript in the cell line Kelly to a slight excess of the type II transcript (I/II = 0.6) in the cell line IMR 5. 2) As there are indications that expression of NF-1 type II is related to the state of differentiation, we tried to shift expression of NF-1 from type I to type II by treatment of the neuroblastoma cells with retinoic acid. Treatment of Kelly cells with 5 microM retinoic acid for 24 h already lowered the excess of the type I transcript from 3-fold to an only 1.6-fold excess. An inversion of the molar ratio from an excess of the type I transcript to an excess of type II transcript would enable to investigate the different role of the two transcripts in the regulation of ras-activity and differentiation.
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PMID:Regulation of expression of two different transcripts of the NF-1 gene in neuroblastoma. 904 34

In PC12 cells, NGF and other ligands of tyrosine kinase receptors increased the activity of the Rous sarcoma virus (RSV) promoter. IGF-1 stimulated the RSV promoter in SH-SY5Y neuroblastoma cells. This promoter was also activated by oncogenic Ras and Raf in different cell types, and growth factor induction was inhibited by expression of dominant negative forms of ras and raf, showing that its effect is mediated by a Ras- and Raf-dependent mechanism. Therefore, the RSV promoter should not be used in the determination of transfection efficiency in the studies on regulation of gene expression by ligands of tyrosine kinase receptors, ras and raf.
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PMID:Growth factor ligands of tyrosine kinase receptors activate the Rous sarcoma virus promoter by a Ras- and Raf-dependent mechanism. 913 5

The neuroblastoma SK-ER3 cell line obtained by stable transfection of the human SK-N-BE cell line is proposed as a model for the study of estrogen receptor activity in cells of neural origin. In the SK-ER3 cell line the estrogen receptor, once activated, initiates a differentiation program leading to growth arrest, morphological changes, and acquisition of the dopaminergic phenotype. In the absence of estrogens, this program can be triggered by IGF-I, which can activate the unliganded estrogen receptor via the ras-pathway. It is proposed that this model system might recapitulate the events occurring in vivo during the differentiation of the nervous system and that IGF-I may play an important role in the activation of estrogen receptor at the very early stage of brain development affecting the differentiation of a number of hypothalamic and extrahypothalamic brain regions.
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PMID:SK-ER3 neuroblastoma cells as a model for the study of estrogen influence on neural cells. 937 Feb 19

Neuroblastomas show remarkable biological heterogeneity, resulting in favourable prognosis or unfavourable prognosis due to aggressive growth despite multimodal therapy. Recently, we proposed that aggressive tumours express telomerase at a high level while the favourable tumours lack or have low telomerase expression. To evaluate the correlation between telomerase activity and other biological characteristics reported as prognostic markers (MYCN gene amplification, loss of heterogeneity (LOH) in the short arm of chromosome 1, trk-A expression, Ha-ras p21 expression, and DNA ploidy), we investigated these biological features in 105 untreated neuroblastomas. In these cases, 23 showed high telomerase activity, 78 showed low activity, and telomerase activity was undetectable in 4 cases. Most tumours with genetic alterations (MYCN amplification or 1p32 LOH) showed high telomerase activity. Most tumours with low or undetectable activity were aneuploid, and showed trk-A and Ha-ras expression. Three of the four tumours with undetectable telomerase activity regressed. In 2 of the tumours with low telomerase activity, the residual tumours maturated and showed repression of telomerase activity. Thus, the level of telomerase activity correlated with other genetic alterations and/or gene expression and may be a useful prognostic indicator in neuroblastoma.
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PMID:Telomerase activity in neuroblastoma: is it a prognostic indicator of clinical behaviour? 951 27

Neuroblastomas present a wide variety of clinical and biological behaviors, which are reflected by the heterogeneous expressions of protooncogenes related to the neuronal differentiation and amplification of the N-myc gene. High expression of trk A and Ha-ras in neuroblastomas has been shown to be associated with an excellent patient outcome. We have previously reported that neuron-specific src mRNA was increased in chemically differentiated neuroblastoma cell lines and in clinically observed neuroblastomas without N-myc amplification. In the present study, to clarify both the value of neuronal c-srcN2 expression as a prognostic indicator and the significance of the coexpression of these protooncogenes, we examined the expression of 3 alternatively spliced src, trk A and Ha-ras in neuroblastoma tissues from 60 patients by competitive RNA-polymerase chain reaction (PCR). The results indicate that protooncogene expression in neuroblastomas correlated with a favorable outcome for c-srcN2 and trk A. N-myc gene was amplified exclusively in tumors with low levels of trk A. Low expression of c-srcN2 and trk A might thus characterize different aggressive phenotypes due to different signal transduction pathways of neural differentiation in neuroblastoma. The combined analyses for c-srcN2 and trk A expression by RNA-PCR should provide information about the biological phenotype of a neuroblastoma within a short period of time after obtaining tumor material.
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PMID:Neuronal src and trk a protooncogene expression in neuroblastomas and patient prognosis. 964 42

Perillyl alcohol is a monoterpene isolated from the essential oils of lavendin, peppermint, spearmint, cherries, celery seeds, and several other plants. In animal studies it has been shown to regress pancreatic, mammary, and liver tumors, to exhibit possible application as a chemopreventative agent for colon, skin, and lung cancer, and as a chemotherapeutic agent for neuroblastoma, and prostate and colon cancer. Perillyl alcohol is active in inducing apoptosis in tumor cells without affecting normal cells and can revert tumor cells back to a differentiated state. Its mechanism of action is unclear, but it has actions on various cellular substances which control cell growth and differentiation. It has been shown to increase mannose-6-phosphate/insulin-like growth factor II receptors, increase tissue growth factor beta receptors, increase Bak, decrease ras protein prenylation, decrease ubiquinone synthesis, and induce Phase I and Phase II detoxification systems. Preliminary human trials have not demonstrated tumor regression at a four times daily dosage schedule. In addition, significant side-effects, mainly gastrointestinal, have been experienced.
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PMID:Perillyl alcohol: applications in oncology. 985 69

DAN gene was first isolated by differential screening between rat 3Y1 and v-src-transformed 3Y1 cells and showed a tumor-suppressive activity toward v-src-transformed 3Y1 cells. When DAN-transfected neuroblastoma cells were treated with a tumor promoter phorbol ester, TPA, neurite-like processes appeared within 2 h whereas no apparent change was observed in the parent and vector-transfected cells up to 8 h. This suggests some difference in TPA-receptor, protein kinase C (PKC), between DAN-transfectants and the control cells. DAN-transfected SH-SY5Y cells showed complete loss in PKCalpha and a large decrease in PKCgamma. Similar down-regulation in PKCalpha and PKCgamma was also observed in DAN-transfected Ha-ras-transformed NIH 3T3 cells. The decreased level of PKCalpha was partially recovered after treatment with a calpain inhibitor, ZLLH. A 150-kDa proteolytic product of a calpain-specific substrate, non-erythroid alpha-spectrin, was detectable in DAN-transfected SH-SY5Y cells but not in the parent or vector-transfected control cells. This suggests that DAN-transfected cells contain activated calpain which may cause down-regulation of PKC and hence induce the altered TPA response.
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PMID:Down-regulation of protein kinase C alpha and gamma and enhanced TPA-induced neurite formation in DAN-transfected neuroblastoma cells. 986 17


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