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)

Insulin-like growth factor-I (IGF-I) induces neuronal differentiation in vitro. In the present study, we examined the signaling pathway underlying IGF-I-mediated neurite outgrowth. In SH-SY5Y human neuroblastoma cells, treatment with IGF-I induced concentration- and time-dependent tyrosine phosphorylation of the type I IGF receptor (IGF-IR) and extracellular signal-regulated protein kinases (ERK) 1 and 2. These effects of IGF-I were blocked by a neutralizing antibody against IGF-IR. Whereas IGF-IR phosphorylation was observed within 1 min, maximal phosphorylation of ERKs was not reached for 30 min. Both IGF-IR and ERK phosphorylation were maintained for at least 24 h. Also, the concentration dependence of IGF-I-stimulated IGF-IR and ERK tyrosine phosphorylation paralleled that of IGF-I-mediated neurite outgrowth. We further examined the role of mitogen-activated protein kinase activation in IGF-I-stimulated neuronal differentiation using the mitogen-activated protein kinase/ERK kinase inhibitor PD98059. Whereas PD98059 had no effect on IGF-IR phosphorylation, PD98059 reduced IGF-I-mediated ERK tyrosine phosphorylation and ERK phosphorylation of the substrate Elk-1. PD98059 also produced a parallel reduction of IGF-I-stimulated neurite outgrowth. Finally, consistent with its ability to block neuronal differentiation, PD98059 inhibited IGF-I-dependent changes of GAP-43 and c-myc gene expression. Together these results suggest that activation of ERKs is essential for IGF-I-stimulated neuronal differentiation.
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PMID:Insulin-like growth factor-I-mediated neurite outgrowth in vitro requires mitogen-activated protein kinase activation. 926 Nov 37

Point mutations, deletions, and recombinations of the RET proto-oncogene are associated with several inherited human diseases of neural crest-derived cells: Hirschsprung's disease, familial medullary thyroid carcinoma, and the multiple endocrine neoplasia (MEN) syndromes, types 2A and 2B. RET expression is restricted to normal and malignant cells of neural crest origin, such as human neuroblastoma cells. To better understand the role of the activated RET oncogene in neural crest cells, we transfected two adherent human neuroblastoma tumor cell lines with oncogenic MEN2 mutant RET cDNAs. Transfectant clones from both cell lines overexpressing MEN2B RET demonstrated a marked increase in the cell fraction growing in suspension. Both control and MEN2B cells formed tumors at the site of injection in all cases. However, mice injected with MEN2B cells developed lung metastases at a much higher frequency than control mice. Only RET protein derived from MEN2A transfectant cells had increased autokinase activity, whereas MEN2B transfectant cells demonstrated selective activation of the mitogen-activated protein kinase, Jun kinase-1 (Jnk1). These results indicate a biochemical signaling pathway that may link oncogenic RET with the metastatic process.
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PMID:Expression of multiple endocrine neoplasia 2B RET in neuroblastoma cells alters cell adhesion in vitro, enhances metastatic behavior in vivo, and activates Jun kinase. 939 66

Studies by comparative genomic hybridization (CGH) have defined a chromosomal site at 17q22-q24 that is often overrepresented in breast cancer, neuroblastoma, and several other tumor types. Due to the limited resolution and dynamic range of CGH, it remain unclear whether this gain reflects high-level amplification of small subregion(s) or low-level gain of most of the distal 17q. We used 32 physically mapped 17q probes to construct more accurate copy number profiles for 14 breast cancer cell lines by interphase fluorescence in situ hybridization (FISH). Six cell lines (43%) showed an increased copy number of the 17q-22q24 region by CGH, and seven (50%) by FISH. FISH copy number profiles had a substantially higher dynamic range than did CGH profiles. FISH revealed two independent, highly amplified regions (A and B) at 17q23, separated by about 5 Mb of non-amplified DNA. These regions were distinctly telomeric from the ERBB2 gene locus. However, region A was often co-amplified with ERBB2, whereas B was amplified in cell lines that showed no ERBB2 amplification. We conclude that distal 17q gains recently discovered in breast cancer by CGH are due to high-level amplifications of two different regions at 17q23. This chromosomal region has previously been reported to undergo allelic loss and therefore was thought to harbor a tumor suppressor gene. The present FISH data provide support for the presence, and a starting point for the positional isolation, of 17q23 genes whose upregulation by amplification may play a role in the progression of breast cancer and many other tumor types.
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PMID:Increased copy number at 17q22-q24 by CGH in breast cancer is due to high-level amplification of two separate regions. 940 53

The RET proto-oncogene encodes a receptor tyrosine kinase expressed during neural crest development. RET expression is enhanced in vitro by several differentiating agents, including retinoic acid (RA), which up-regulates RET expression in neuroblastoma cell lines. In the present work we sequenced and analysed a 5 kbp genomic fragment 5' to RET. Three deletion fragments of this region were tested for their RA inducibility in transient transfection assays and failed to support the hypothesis of a direct transcriptional activation. Finally, our functional analysis of a candidate RA response element present in the RET promoter provides new hints for the understanding of the interaction between nuclear receptors and their specific recognition sites.
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PMID:Sequence and characterisation of the RET proto-oncogene 5' flanking region: analysis of retinoic acid responsiveness at the transcriptional level. 942 23

Neuroblastoma has several clinical and molecular genetic parallels with the other paediatric embryonal tumours, such as retinoblastoma, including a hereditary form of the disease. We hypothesised that neuroblastoma susceptibility is due to germline mutations in a tumour suppressor gene and that this predisposition gene may be involved in sporadic neuroblastoma tumorigenesis as well. We therefore aimed to localise the familial neuroblastoma predisposition gene by linkage analysis in neuroblastoma kindreds. Eighteen families segregating for neuroblastoma were ascertained for candidate locus linkage analysis. Although many of the 49 affected individuals in these families were diagnosed as infants with multifocal primary tumours, there was marked clinical heterogeneity. We originally hypothesised that familial neuroblastoma predisposition would map to the telomeric portion of chromosome band 1p36, a genomic region likely to contain a sporadic neuroblastoma suppressor gene. However, neuroblastoma predisposition did not map to any of eight polymorphic markers spanning 1p36.2-.3 in three large kindreds. In addition, there was strong evidence against linkage to two Hirschsprung disease susceptibility genes (RET and EDNRB), a condition that can cosegregate with neuroblastoma as in one of the kindreds tested here. We conclude that the neuroblastoma susceptibility gene is distinct from the 1p36 neuroblastoma suppressor and two of the currently identified Hirschsprung disease susceptibility genes.
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PMID:Molecular genetic analysis of familial neuroblastoma. 951 25

Choline acetyltransferase and vesicular acetylcholine-transporter genes are adjacent and coregulated. They define a cholinergic locus that can be turned on under the control of several factors, including the neurotrophins and the cytokines. Hirschprung's disease, or congenital megacolon, is characterized by agenesis of intramural cholinergic ganglia in the colorectal region. It results from mutations of the RET (GDNF-activated) and the endothelin-receptor genes, causing a disregulation in the cholinergic locus. Using cultured cells, it was shown that the cholinergic locus and the proteins involved in acetylcholine (ACh) release can be expressed separately ACh release could be demonstrated by means of biochemical and electrophysiological assays even in noncholinergic cells following preloading with the transmitter. Some noncholinergic or even nonneuronal cell types were found to be capable of releasing ACh quanta. In contrast, other cells were incompetent for ACh release. Among them, neuroblastoma N18TG-2 cells were rendered release-competent by transfection with the mediatophore gene. Mediatophore is an ACh-translocating protein that has been purified from plasma membranes of Torpedo nerve terminal; it confers a specificity for ACh to the release process. The mediatophores are activated by Ca2+; but with a slower time course, they can be desensitized by Ca2+. A strictly regulated calcium microdomain controls the synchronized release of ACh quanta at the active zone. In addition to ACh and ATP, synaptic vesicles have an ATP-dependent Ca2+ uptake system; they transiently accumulate Ca2+ after a brief period of stimulation. Those vesicles that are docked close to Ca2+ channels are therefore in the best position to control the profile and dynamics of the Ca2+ microdomains. Thus, vesicles and their whole set of associated proteins (SNAREs and others) are essential for the regulation of the release mechanism in which the mediatophore seems to play a key role.
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PMID:Acetylcholine release and the cholinergic genomic locus. 955 99

We previously isolated and characterized cDNA clones of DRT (EPHB2), encoding a receptor protein-tyrosine kinase of the EPH family. Northern blot analysis showed that EPHB2 transcripts are expressed in three sizes of approximately 4, 5, and 11 kb, suggesting that these transcripts are generated by alternative splicing and/or alternative use of polyadenylation sites. To explore this possibility, we isolated additional EPHB2 cDNA clones, including clone 5K-1, by re-screening the human fetal brain cDNA library. Nucleotide sequence analysis of clone 5K-1 revealed that it represents a variant transcript of EPHB2 (EPHB2v). Relative to the EPHB2 cDNA sequence previously reported, clone 5K-1 has two coding region deletions of 3 and 93 nucleotides. Nucleotide sequence analyses of EPHB2 genomic DNA fragments corresponding to these deletions suggest that the EPHB2v transcript is generated by alternative splicing. The 3' end of clone 5K-1 contains a polyadenosine stretch preceded by a potential polyadenylation signal, which is not used to generate the EPHB2 transcript. Taken together, these data indicate that EPHB2v is generated by both alternative splicing and alternative use of polyadenylation sites. The EPHB2v protein lacks one arginine residue that resides immediately following the EPHB2 transmembrane domain. In contrast, as a result of the frame shift caused by the 93 nucleotide deletion, the C-terminus of the EPHB2v protein is longer by 70 amino acids than that of EPHB2. We also show that the human neuroblastoma cell line SY5Y and NTera-2N neurons express high levels of EPHB2 and lower levels of EPHB2v. These structural variations found between the EPHB2 and EPHB2v proteins may reflect functional heterogeneity of EPHB2.
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PMID:A variant transcript encoding an isoform of the human protein tyrosine kinase EPHB2 is generated by alternative splicing and alternative use of polyadenylation signals. 969 46

Despite significant advances in understanding the genetic background in Hirschsprung's disease (HD), the majority of cases are believed to be multigenic and multifactorial. Conditions associated with an increased risk of HD suggest some common inherited factor and include Down's syndrome, Waardenburg syndrome (WS), dominant sensorineural deafness, neurofibromatosis, neuroblastoma, phaechromocytoma, the MEN type 2B syndrome, and other abnormalities. The reported incidence of Down's syndrome in HD is approximately 2%, but the range varies from 2% to 15%. WS, on the other hand, is one of a number of uncommon human conditions in which pigmentary disturbances are associated with sensorineural deafness. HD mutations have been mapped to a number of genes, i.e., RET proto-oncogene, at 10q11.2; the recessive EDNRB gene, located at 13q22; its ligand endothelin 3 (EDN3); and the glial cell line-derived neurotrophic factor (GDNF) in humans. Mutations of known genes appear to account for only a relatively small number of HD cases (20% in the case of RET). GDNF may modulate the disease phenotype by interacting with other susceptibility loci (e.g., RET). The genetic aspects of HD occurring in association with trisomy 21 and WS are reviewed. Clinical presentation, diagnosis, treatment and long-term outcome in this patient group are evaluated. Additional data are presented on 12 children with Down's syndrome out of 408 surgically treated HD patients. The role of associated anomalies is evaluated, and an increased susceptibility to severe enterocolitis associated with a high mortality rate is reported. Surgical correction can be achieved, but patients may require some form of ongoing help to facilitate acceptable bowel function. The decision as to the nature and timing of the surgical correction must be individualized.
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PMID:Hirschsprung's disease: genetic and functional associations of Down's and Waardenburg syndromes. 971 53

Specific germline mutations in the RET proto-oncogene predispose to the familial cancer syndromes: multiple endocrine neoplasia (MEN) types 2A and 2B, and familial medullary thyroid carcinoma. Expression of the RET receptor tyrosine kinase is tightly restricted to tumours of neural crest origin, such as neuroblastoma, and neuroblastoma has been observed in RET transgenic mice. Neuroblastoma tumour cell lines transfected with the MEN2A RET gene exhibit spontaneous neuritic differentiation, whereas MEN2B-type RET transfectants demonstrate altered cell adhesion and enhanced metastatic potential. In this study, the authors examined genomic DNA from 26 primary neuroblastoma tumours for MEN2A and MEN2B RET mutations, using restriction enzyme digestion of polymerase chain reaction products as an alternative to direct sequencing. Examination of RET exons 10 (codons 611, 618, 620), 11 (codons 632, 633, 634) and 16 (codon 918) in all 26 tumours revealed no RET mutations. Taken together these data suggest that abnormalities of the RET signalling pathway, rather than oncogenic, MEN2-type RET activation by mutation, may play a role in neuroblastoma tumorigenesis.
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PMID:Absence of MEN2A- or 2B-type RET mutations in primary neuroblastoma tumour tissue. 972 1

Norepinephrine (NE) transporters (NETs) found in the neuronal plasma membrane mediate the removal of NE from the extracellular space, limiting the activation of adrenoceptors at noradrenergic synapses. Our previous studies with the noradrenergic neuroblastoma SK-N-SH have revealed a muscarinic receptor-triggered regulation of NET surface density and transport capacity, mediated in part by protein kinase C activation. Low abundance of NET proteins in this native cell model, however, preclude direct confirmation of altered trafficking of NET proteins. In our study, we monitored the activity and surface distribution of human NET proteins in transient and stably-transfected cell lines after application of kinase activators and inhibitors. Using hNET stably transfected HEK-293 and LLC-PK1 cells, as well as transiently transfected COS-7 cells, we demonstrate that PKC-activating phorbol esters, beta-PMA or beta-PDBu selectively diminish l-NE transport capacity (Vmax) with little change in NE Km. Effects of phorbol esters are rapid, stereospecific and blocked by protein kinase C inhibitors, staurosporine and bisindolylmaleimide I. As in SK-N-SH cells, beta-PMA induces a reduction in intact cell [3H]nisoxetine binding sites with no change in nisoxetine Kd or total membrane NET density. Cell-surface biotinylation and confocal immunofluorescence techniques confirm that protein kinase C-dependent reductions in NE transport capacity and whole-cell antagonist binding density are accompanied by reductions in cell-surface human NET protein expression. Together these findings argue for kinase-modulated protein trafficking as a potential route for acute regulation of antidepressant-sensitive NE clearance.
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PMID:Acute regulation of norepinephrine transport: II. PKC-modulated surface expression of human norepinephrine transporter proteins. 980 5


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