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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Neuroblastoma (NB) is an unusual neuroectodermal tumor showing a high degree of spontaneous regression. NB cells can be induced to differentiate in vitro by various agents. Cell differentiation results in morphological changes characteristic of the mature neuronal phenotype, including outgrowth of neurite-like structures with several interconnections. 2. Recent experiments indicate that morphological differentiation of NB cells is associated with changes in expression of N-myc, c-myc, and c-myb oncogenes and synthesis of neurofilament proteins. However, little is known about the transcription of neurofilament genes during differentiation. 3. We have analyzed the expression of both the N-myc oncogene and mid-size neurofilament (NF) genes in the LAN-1 human NB cell line, cultured in the presence of retinoic acid (RA). Continuous treatment with RA induced morphological differentiation within 5-6 days. The transcription of N-myc was down-modulated within 24 hr of the initial exposure to RA. The mid-size NF mRNA was increased at this time. The expression of N-myc was not modified in serum-deprived LAN-1 cells, indicating that N-myc transcription is unaffected by the arrest of the cells in the G1 phase. 4. We conclude that new synthesis of mid-size NF mRNA and a decrease in N-myc transcription precede de novo formation of neurite-like processes and morphological cell differentiation of neuroblastoma cells.
Cell Mol Neurobiol 1990 Sep
PMID:Different regulation of mid-size neurofilament and N-myc mRNA expression during neuroblastoma cell differentiation induced by retinoic acid. 212 47

Since there is no nutritional requirement for the biopterin cofactor, we attempted to create a drug-induced deficiency in rats in order to study the role of tetrahydrobiopterin in regulating the biosynthesis of dopamine and serotonin. The hypothesis that dihydrofolate reductase (EC 1.5.1.3) mediates the final step in the de novo synthesis of tetrahydrobiopterin was tested by treating rats with methotrexate along with leucovorin as a protective agent; there was no reduction in total biopterin or in the fraction present as tetrahydrobiopterin in adrenal medulla, adrenal cortex, pituitary, brain, or pineal glands. Similar results were obtained with metoprine, a lipid-soluble inhibitor of dihydrofolate reductase which readily enters the central nervous system. Treatment with loading doses of phenylalanine along with methotrexate reduced the level of tetrahydrobiopterin in liver. Neuroblastoma N115 cells growing in medium supplemented with thymidine and hypoxanthine continued to form normal amounts of tetrahydrobiopterin in the presence of concentrations of methotrexate which completely inhibited dihydrofolate reductase; higher concentrations of methotrexate increased the tetrahydrobiopterin content of the cells 2-fold and the total biopterin in the medium 3-fold. Although attempts to create a drug-induced deficiency were unsuccessful, the evidence indicates that the de novo synthesis of tetrahydrobiopterin proceeds by a pathway independent of dihydrofolate reductase and that folate antagonists, such as methotrexate are unlikely to impair the hydroxylation of tyrosine and tryptophan, which is dependent upon the availability of the biopterin cofactor.
Mol Pharmacol 1983 Jul
PMID:Biosynthesis of tetrahydrobiopterin in the presence of dihydrofolate reductase inhibitors. 686 19

Neuroblastoma cells clone N-2a, differentiated by serum deprivation, were found to take up tritiated serotonin ([3H]5-HT) from the external medium by means of a saturable mechanism which follows Michaelis-Menten kinetics. The apparent Km of uptake was 1.27 microM and the Vmax 720 fmoles/min/10(6) cells. The uptake was temperature-dependent and partially sodium-dependent, and was inhibited by ouabain and by selected metabolic inhibitors (sodium azide, 2,4-dinitrophenol, and iodoacetamide). Fluoxetine and desmethylimipramine (DMI) were equally effective inhibitors of [3H]5-HT uptake (IC50 = 13.7 microM and 13.6 microM). The uptake was structurally specific, since unlabeled 5-HT was a better inhibitor of [3H]5-HT uptake than norepinephrine (NE) (IC 50 = 0.6 microM and 9.4 microM). The neurotoxins 6-hydroxydopamine and 5,6-dihydroxytryptamine were cytotoxic to differentiated N-2a cells, causing time- and concentration-dependent inhibition of [3H]thymidine incorporation into DNA, 5,7-Dihydroxytryptamine had little cytotoxic effect. Non-differentiated N-2a cells, supplemented with 5% fetal calf serum, were also found to take up [3H]5-HT by a concentration-, temperature-, and energy-dependent process. The apparent Km of uptake was 0.96 microM and the Vmax was 619 fmoles/min/10(6) cells. However, in nondifferentiated cells [3H]5-HT uptake was not sodium-dependent, not inhibited by ouabain, less effectively inhibited by fluoxetine and DMI (IC50 = 148 microM and 107 microM), and not selectively inhibited by unlabeled 5-HT as compared with NE (IC50 = 7.9 microM and 6.0 microM).
Mol Pharmacol 1982 Mar
PMID:Characterization of serotonin uptake in cultured neuroblastoma cells. Difference between differentiated and nondifferentiated cells. 709 39

Neuroblastoma, a malignancy of early childhood arises in the embryonal neural crest. Neuroblastoma cells are in a state of arrested differentiation; however, they can be induced to differentiate in vitro by retinoic acid. As a first step toward understanding the molecular mechanisms of neuroblastoma differentiation we analyzed the expression pattern of the developmentally important Homeobox genes in cells treated with retinoic acid. The strategy employed involved rapid screening of a cDNA library prepared from retinoic acid treated human LA-N-5 neuroblastoma cells for Homeobox genes by the polymerase chain reaction. Multiple Homeobox genes were amplified from recombinant phage DNA using degenerate primers directed against the conserved homeobox. To date 6 Homeobox genes (HoxC6, HoxC8, HoxD1, HoxD4, HoxD8, and HoxD9) have been identified in the cDNA library prepared from LA-N-5 cells treated with retinoic acid. HoxD1 and HoxC8 are being reported for the first time to be expressed in neuroblastoma cells. Preliminary studies indicate that there is an induction of Homeobox gene expression in differentiating LA-N-5 neuroblastoma cells.
Biochem Mol Biol Int 1993 Jul
PMID:Hox gene expression in differentiating human neuroblastoma cells. 810 20

Neuroblastoma X glioma hybrid NG108-15 cells were transfected to express stably either the wild-type human beta2-adrenoceptor or a constitutively active mutant (CAM) version of this receptor. Basal adenylyl cyclase activity in cells expressing the CAM beta2-adrenoceptor correlated well with the level of expression of the receptor and was substantially greater than that in cells expressing the wild-type beta2-adrenoceptor. The CAM beta2-adrenoceptor displayed higher affinity for the agonist isoprenaline than the wild-type receptor but not for the antagonist alprenolol or the inverse agonist betaxolol. Pretreatment of cells harboring the CAM beta2-adrenoceptor with betaxolol resulted in a large (4-7-fold within 24 hr) up-regulation in levels of this receptor. This was not observed after exposure of the CAM beta2-adrenoceptor-expressing cells to alprenolol, and a much smaller effect of betaxolol was produced in cells expressing the wild-type receptor. Betaxolol-mediated up-regulation of the CAM beta2-adrenoceptor was both time and concentration dependent. However, this up-regulation did not result in a substantial alteration in the cellular distribution profile of the receptor. Half-maximal up-regulation of the CAM beta2-adrenoceptor required concentrations of betaxolol similar to those needed to cause half-maximal inhibition of basal adenylyl cyclase activity, indicating the receptor up-regulation is associated with the inverse agonist properties of this compound. Despite the large up-regulation of CAM beta2-adrenoceptor levels, treatment with betaxolol did not significantly alter levels of the G protein that couples to this receptor (G(Salpha)). After sustained treatment with betaxolol, Northern analyses did not demonstrate up-regulation of either CAM beta2-adrenoceptor or G(Salpha) mRNA, and up-regulation of the receptor was prevented by cotreatment of the cells with cycloheximide. These data indicate that the up-regulation of the receptor by betaxolol is likely to reflect an increase in translational efficiency of existing mRNA and/or stabilization of the receptor polypeptide from proteolytic degradation and indicate that such effects can be produced by inverse agonists but not by neutral antagonists.
Mol Pharmacol 1996 Dec
PMID:Inverse agonist-induced up-regulation of the human beta2-adrenoceptor in transfected neuroblastoma X glioma hybrid cells. 896 68

Neuroblastoma is one of the most frequent tumors in infancy. We analyzed 26 neuroblastomas, two ganglioneuromas, and a neuroblastoma metastasis for mutations and homozygous deletions of the p16 (or MTS1 or CDKN2) gene by means of the polymerase chain reaction (PCR) in combination with the single-strand conformation polymorphism (SSCP) technique and by multiplex PCR analysis. We detected mobility shifts in the SSCP gels in seven cases in the 3 half of exon 2 (named exon 2C) of the p16 gene. By PCR amplification of this particular region and SacII restriction enzyme digestion, we confirmed that those cases had a known polymorphism at codon 140 of the p16 gene. Neither mutations nor homozygous deletions were detected. Our results confirm those of Beltinger et al. (Cancer Res 55:2053-2055, 1995), which showed no p16 mutations or homozygous deletions in 18 primary neuroblastomas and nine tumor-derived cell lines. We conclude that the common pattern of p16 inactivation by homozygous deletion or mutation does not seem to be relevant to the development of neuroblastomas.
Mol Carcinog 1997 Mar
PMID:Mutational analysis of the p16 gene in human neuroblastomas. 911 82

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expanding CAG repeat coding for polyglutamine in the huntingtin protein. Recent data have suggested the possibility that an N-terminal fragment of huntingtin may aggregate in neurons of patients with HD, both in the cytoplasm, forming dystrophic neurites, and in the nucleus, forming intranuclear neuronal inclusion bodies. An animal model of HD using the short N-terminal fragment of huntingtin has also been found to have intranuclear inclusions and this same fragment can aggregate in vitro . We have now developed a cell culture model demonstrating that N-terminal fragments of huntingtin with expanded glutamine repeats aggregate both in the cytoplasm and in the nucleus. Neuroblastoma cells transiently transfected with full-length huntingtin constructs with either a normal or expanded repeat had diffuse cytoplasmic localization of the protein. In contrast, cells transfected with truncated N-terminal fragments showed aggregation only if the glutamine repeat was expanded. The aggregates were often ubiquitinated. The shorter truncated product appeared to form more aggregates in the nucleus. Cells transfected with the expanded repeat construct but not the normal repeat construct showed enhanced toxicity to the apoptosis-inducing agent staurosporine. These data indicate that N-terminal truncated fragments of huntingtin with expanded glutamine repeats can aggregate in cells in culture and that this aggregation can be toxic to cells. This model will be useful for future experiments to test mechanisms of aggregation and toxicity and potentially for testing experimental therapeutic interventions.
Hum Mol Genet 1998 May
PMID:Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture. 953 81

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.
Mol Cell Probes 1998 Aug
PMID:Absence of MEN2A- or 2B-type RET mutations in primary neuroblastoma tumour tissue. 972 1

Neuroblastoma is a tumor that is derived from the neural crest. Recent studies demonstrated that several human neuroblastoma cell lines exhibit at least three morphologic types: neuroblastic (N)-type, substrate-adhesive (S)-type and intermediate (I)-type cells. However, the origin of the S-type cells has not been clearly identified. In this study, the expressions of smooth muscle-specific proteins (desmin, alpha-smooth muscle actin, basic calponin and the smooth muscle myosin heavy-chain isoforms of SM1 and SM2) in three parent and four cloned neuroblastoma cell lines, composed of S-type cells, were examined by indirect immunofluorescence, Western blot and/or by reverse transcription-polymerase chain reaction (RT-PCR). Desmin was found in two of the seven cell lines, and alpha-smooth muscle actin and basic calponin were detected in all of seven of the cell lines. In three parent cell lines and one cloned cell line composed of N-type cells, none of three smooth muscle-specific proteins were detected. In smooth muscle myosin heavy-chain isoforms, SM1 was detected in two parent cell lines composed of S-type cells (MP-N-MS and KP-N-YS) by immunofluorescence, Western blot and/or by RT-PCR, whereas the SM2 isoform was detected in one parent cell line (MP-N-MS) by RT-PCR. These findings indicate that S-type cells have either the immature or mature smooth muscle cell phenotype, and neural crest cells very likely have the ability of to differentiate into smooth muscle cells in the human system.
Diagn Mol Pathol 2000 Dec
PMID:Neuroblastoma cell lines showing smooth muscle cell phenotypes. 1112 46

Deletion of the short arm of chromosome 1 is frequently observed in neuroblastoma (NB). We performed loss of heterozygosity (LOH) analysis of 120 well characterized NB to better define specific regions of 1p loss and any association with clinical and biological prognostic features (DNA index, MYCN, age, and stage). All categories of disease were represented including 7 ganglioneuromas, 8 stage 4S, 33 local-regional (stages 1, 2, and 3), and 72 stage 4 NB according to the International Neuroblastoma Staging System. Patients were consistently treated with stage-appropriate protocols at a single institution. Sixteen highly informative, polymorphic loci mapping to chromosome 1 were evaluated using a sensitive, semi-automated, fluorescent detection system. Chromosome arm 1p deletions were detected in all categories of tumor except ganglioneuroma. Frequent LOH was detected at two separate regions of 1p and distinct patterns of losses were associated with individual clinical/biological categories. Clinically aggressive stage 4 tumors were predominantly diploid with extensive LOH frequently detected in the region of 1ptel to 1p35 (55%) and at 1p22 (56%). The shortest region of overlap for LOH at 1p36 was between D1S548 and D1S1592 and for 1p22 was between D1S1618 and D1S2766. Local-regional tumors were mostly hyperdiploid with short regions of loss primarily involving terminal regions of 1p36 (42%). Most spontaneously regressing stage 4S tumors (7/8) were hyperdiploid without loss of 1p36 or 1p22. These findings suggest that genes located on at least two separate regions of chromosome arm 1p play a significant role in the biology of NB and that distinct patterns of 1p LOH occur in individual clinical/biological categories.
J Mol Diagn 2000 Feb
PMID:Clinical categories of neuroblastoma are associated with different patterns of loss of heterozygosity on chromosome arm 1p. 1127


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