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)

Neuroblastoma is a heterogeneous childhood tumour of the sympathetic nervous system, in which deletions of chromosomal region 1p and amplification of the MYCN oncogene correlate with aggressive tumour behaviour. However, the majority of neuroblastoma tumours show neither of these aberrations, indicating that other chromosomal regions may be involved in tumorigenesis. Here, we report findings of loss of heterozygosity (LOH) on chromosome 3. In our neuroblastoma material, nine of 59 (15.3%) tested tumours showed allelic loss of chromosome 3p markers. We found significant clinical and biological differences between tumours with the loss of one entire chromosome 3 vs tumours with partial loss in chromosome region 3p. All children with tumours with whole chromosome 3 loss are long-term survivors, whereas all children with tumours showing partial 3p LOH have died from tumour progression. A consensus region found to be deleted in all the tumours with 3p deletions was defined by markers D3S1286 and D3S1295, i.e. 3p25.3-p14.3, distal to the FHIT gene.
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PMID:Loss of heterozygosity of 3p markers in neuroblastoma tumours implicate a tumour-suppressor locus distal to the FHIT gene. 966 47

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

p16 regulates the G(1)-S cell cycle transition by inhibiting the cyclin D-cyclin-dependent kinase (CDK)4/CDK6-mediated phosphorylation of retinoblastoma protein (pRb). We examined the possible derangement of the p16-CDK/cyclin D-pRb pathway in 40 primary neuroblastomas including 18 samples in the unfavorable stages (C and D) and 22 in the favorable stages (A, B, and Ds) by PCR, reverse transcription-PCR, Western blot, and immunohistochemistry and correlated the results with clinical outcome. No samples harbored alterations of the p16 gene. Interestingly, the samples in the unfavorable stages exhibited expression of p16 mRNA and protein more frequently than those in the favorable stages [mRNA, 9 of 18 (50%) versus 2 of 22 (9%), P = 0.006; protein, 5 of 16 (31%) versus 0 of 18 (0%), P = 0.013]. Alterations of the downstream components of the pathway were infrequent. pRb was deregulated in the majority of samples investigated [27 of 33 (82%), 24 with hyperphosphorylated pRb and 3 with no pRb protein]. The phosphorylation status of pRb did not correlate with p16 protein expression, suggesting that the elevated p16 protein may not be functioning properly to regulate the pathway. Among patients of all stages, p16 expression was significantly associated with a lower overall survival. There was no overexpression of MDM2, and loss of p14(ARF) expression and p53 mutation were infrequent events. Taken together, these findings suggest that up-regulated p16 expression may represent a unique feature of aggressive neuroblastoma.
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PMID:p16/p14(ARF) cell cycle regulatory pathways in primary neuroblastoma: p16 expression is associated with advanced stage disease. 1170 66

Neuroblastoma exhibiting deletion of a segment of the long arm of chromosome 11 represents a genetic subtype of tumor that is distinct from those exhibiting MYCN amplification or 1p deletion. The 11q- genetic subtype is further characterized by gain of 17q and loss of distal 3p material. Gain of 11p material has also been reported in neuroblastoma with 11q loss, but at a considerably lower frequency than gain of 17q or loss of the distal 3p region. Our results, however, indicate that gain of 11p may occur more frequently in 11q- neuroblastoma than what was previously realized. Comparative genomic hybridization analyses of neuroblastoma tissue from eleven patients indicated that six of 11 tumors (55%) with loss of 11q also possessed gain of 11p. The shortest region of 11p gain was 11p11.2-->p14. G-banding and fluorescence in situ hybridization analysis performed on tumor cells from primary and metastatic sites from one patient allowed us to infer that gain of 11p arose secondarily to the abnormality that led to the loss of 11q material. Gain of an entire chromosome 7 was detected in 17 of 43 (40%) tumors, whereas gain of 7q was detected in 5 of 43 (12%) tumors. Unlike gain of 11p, gain of an entire chromosome 7 appears to be prevalent in all tumor stages and is not limited to the 11q- tumor subtype. Gain of 7q, however, is more prevalent in higher stage tumors. G-band cytogenetic analysis indicated that an unbalanced t(3;7) was responsible for the gain of 7q and loss of 3p material in one case. We discuss the possibility that gain of 7/7q, and 11p material may contribute to either tumorigenesis or progression.
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PMID:Are gains of chromosomal regions 7q and 11p important abnormalities in neuroblastoma? 1264 51

Chromosome 9p21 is frequently deleted in many cancers. Previous reports have indicated that 9p21 LOH is an uncommon finding in neuroblastoma (NB), a tumour of childhood. We have performed an extensive analysis of 9p21 and genes located in this region (cyclin-dependent kinase inhibitor 2A - CDKN2A/p16(INK4a), CDKN2A/p14(ARF), CDKN2B/p15(INK4b), MTAP, interferon alpha and beta cluster). LOH was detected in 16.4% of 177 NB. The SRO was identified between markers D9S1751 and D9S254, at 9p21-23, a region telomeric to the CDKN2A and MTAP genes. A significantly better overall and progression-free survival was detected in stage 4 patients displaying 9p21-23 LOH. Hemizygous deletion of the region harbouring the CDKN2A and CDKN2B loci was identified in two tumours by means of fluorescent in situ hybridisation and MTAP was present by immunostaining in all but one tumour analysed. The transcriptional profile of tumours with 9p21-23 LOH was compared to that of NB displaying normal 9p21-23 status by means of oligonucleotide microarrays. Four of the 363 probe sets downregulated in tumours with 9p21-23 LOH were encoded by genes mapping to 9p22-24. The only well-characterised transcript among them was nuclear factor I-B3. Our results suggest a role for genes located telomeric of 9p21 in good risk NB.
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PMID:Comprehensive analysis of the 9p21 region in neuroblastoma suggests a role for genes mapping to 9p21-23 in the biology of favourable stage 4 tumours. 1530 92

One hallmark of Ewing's sarcoma/peripheral neuroectodermal tumors is the presence of the Ews/Fli-1 chimeric oncogene. Interestingly, infection of neuroblastoma tumor cell lines with Ews/Fli-1 switches the differentiation program of neuroblastomas to Ewing's sarcoma/peripheral neuroectodermal tumors. Here we examined the status of cytoplasmically sequestered wt-p53 in neuroblastomas after stable expression of Ews/Fli-1. Immunofluorescence revealed that in the neuroblastoma-Ews/Fli-1 infectant cell lines, p53 went from a punctate-pattern of cytoplasmic sequestration to increased nuclear localization. Western blot analysis revealed that PARC was down-regulated in one neuroblastoma cell line but not expressed in the second. Therefore, decreased PARC expression could not fully account for relieving p53 sequestration in the neuroblastoma tumor cells. Neuroblastoma-Ews/Fli-1 infectant cell lines showed marked increases in p53 protein expression without transcriptional up-regulation. Interestingly, p53 was primarily phosphorylated, without activation of its downstream target p21(WAF1). Western blot analysis revealed that whereas MDM2 gene expression does not change, p14(ARF), a negative protein regulator of MDM2, increases. These observations suggest that the downstream p53 pathway may be inactivated as a result of abnormal p53. We also found that p53 has an extended half-life in the neuroblastoma-Ews/Fli-1 infectants despite the retention of a wild-type sequence in neuroblastoma-Ews/Fli-1 infectant cell lines. We then tested the p53 response pathway and observed that the neuroblastoma parent cells responded to genotoxic stress, whereas the neuroblastoma-Ews/Fli-1 infectants did not. These results suggest that Ews/Fli-1 can directly abrogate the p53 pathway to promote tumorigenesis. These studies also provide additional insight into the relationship among the p53 pathway proteins.
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PMID:The Ews/Fli-1 fusion gene changes the status of p53 in neuroblastoma tumor cell lines. 1549 48

p53 mutations have been reported in cell lines derived from relapsed neuroblastoma tumors. We hypothesize that functional inactivation of p53 by mutation or other mechanisms is common in relapsed neuroblastoma and can contribute to chemoresistance. Our aim was to determine the frequency of p53 mutations, p14(ARF) methylation, or deletion and MDM2 amplification in 23 neuroblastoma cell lines (6 derived at diagnosis and 17 derived at relapse). One cell line was p53 mutant (BE2c) and two cell lines were deleted for p14(ARF) (LAN-6 and SHEP). Two cell lines were methylated for p14(ARF) (GIMEN and PER-108), one of which had low levels of p14(ARF) mRNA expression which increased following demethylation with 5-aza-2/deoxycytidine treatment (GIMEN), and four cell lines were confirmed to be MDM2-amplified. All these cell lines were derived from neuroblastomas at relapse. Inactivation of the p53 pathway was observed in 9 out of 17 neuroblastoma cell lines (53%) established at relapse and in none of the cell lines established from pretreatment tumors. If these data are confirmed in neuroblastoma tumors, this suggests that p53-independent therapy and reactivation of inactive p53 approaches would be useful in the management of relapsed neuroblastoma.
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PMID:Increased frequency of aberrations in the p53/MDM2/p14(ARF) pathway in neuroblastoma cell lines established at relapse. 1648 14

In this study, we report that the human p14(ARF) associates in vivo with the N-Myc and inhibits N-Myc mediated transcriptional activation. We have determined that the region (aa 140-300) encompassing the N-Myc BoxIII is required for efficient interaction in vivo. Furthermore, we demonstrate that in the SK-N-BE neuroblastoma cell line p14(ARF) over-expression delocalized N-Myc from the nucleoplasm into nucleoli and that N-Myc regions required for interaction with p14(ARF) are also important for nucleoli co-localization. Finally, we determine that the N-terminal region of the p14(ARF) protein is involved in binding to c-Myc and N-Myc proteins.
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PMID:p14ARF interacts with N-Myc and inhibits its transcriptional activity. 1728 33

The INK4A locus encodes two tumor suppressor genes, p16(INK4A) and p14(ARF), transcribed using alternative exons 1alpha or 1beta spliced onto the same exons 2 and 3. Both p16(INK4A) and p14(ARF) are capable of inhibiting the cell-cycle progression, albeit in different manner; p16(INK4A) is phosphorylation of retinoblastoma (pRB) dependent while p14(ARF) is p53-dependent. In this study, we report the discovery of a novel variant of p16(INK4A), termed p16gamma, in a primary T-cell acute lymphoblastic leukemia (T-ALL) patient sample and a neuroblastoma cell line, which was expressed at both the transcriptional and translational levels. Cloning and sequencing of the p16gamma cDNA revealed that p16gamma was identical to p16(INK4A), except that it contained an in-frame insertion of 197 bp between exons 2 and 3. p16gamma expression was detected in the majority of p16(INK4A)-expressing primary T-ALL and B-ALL patient samples and other p16(INK4A)-expressing tumor samples, but was only barely detectable in some normal mononuclear cells and other non-tumor samples. Structural analysis by nuclear magnetic resonance and circular dichroism confirmed that p16gamma, like p16(INK4A), is also an ankyrin-repeat protein. Functional analysis of p16gamma revealed that p16gamma protein interacted with cyclin D-dependent kinase4 and inhibited its kinase activity. Using a luciferase reporter assay, the transfection of p16gamma repressed the E2F response, the downstream target of pRB, with an efficacy equivalent to that of p16(INK4A). Moreover p16gamma, like p16(INK4A), induced cell-cycle arrest at G(0)/G(1), and inhibited cell growth in colony formation assay.
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PMID:Human p16gamma, a novel transcriptional variant of p16(INK4A), coexpresses with p16(INK4A) in cancer cells and inhibits cell-cycle progression. 1748 64

Ras proteins are small guanosine triphosphatases involved in the regulation of important cellular functions such as proliferation, differentiation, and apoptosis. Understanding the intracellular trafficking of Ras proteins is crucial to identify novel Ras signaling platforms. In this study, we report that epidermal growth factor triggers Kirsten Ras (KRas) translocation onto endosomal membranes (independently of calmodulin and protein kinase C phosphorylation) through a clathrin-dependent pathway. From early endosomes, KRas but not Harvey Ras or neuroblastoma Ras is sorted and transported to late endosomes (LEs) and lysosomes. Using yellow fluorescent protein-Raf1 and the Raichu-KRas probe, we identified for the first time in vivo-active KRas on Rab7 LEs, eliciting a signal output through Raf1. On these LEs, we also identified the p14-MP1 scaffolding complex and activated extracellular signal-regulated kinase 1/2. Abrogation of lysosomal function leads to a sustained late endosomal mitogen-activated protein kinase signal output. Altogether, this study reveals novel aspects about KRas intracellular trafficking and signaling, shedding new light on the mechanisms controlling Ras regulation in the cell.
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PMID:A clathrin-dependent pathway leads to KRas signaling on late endosomes en route to lysosomes. 1928 94


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