UMLS:C0027819 - FACTA Search

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 novel candidate tumor suppressor p73, a structural and functional homolog of p53, activates various p53 responsive promoters and induces tumor cell apoptosis. Although p73 is infrequently mutated in human cancers, we have previously found two types of p73 mutation with amino acid substitution (P405R and P425L) in primary neuroblastoma and lung cancer. Here we report generations of the p73 mutants with either P405R or P425L substitution and functional analysis of these naturally occurring mutants. Indirect immunofluorescence staining revealed that nuclear accumulation of p73alpha or p73beta was not affected by these mutations. The P425L substitution reduced the ability of p73alpha to transactivate various p53 responsive promoters (p21(Waf1), Mdm2, and Bax). Moreover, this down-regulation was correlated with the reduced capability of p73alpha(P425L) to suppress cell growth in p53-deficient SAOS-2 cells. In contrast, p73beta(P425L) was as effective as wild-type p73beta in transactivation and growth inhibition. On the other hand, the P405R substitution had no significant effect on both the transcriptional activity and the growth-suppressive ability of p73alpha or p73beta. These results suggested that, at least, one of the naturally occurring p73 mutants, p73alpha(P425L), was a functionally defective mutant of p73.
...
PMID:Functional characterization of naturally occurring mutants (P405R and P425L) of p73alpha and p73beta found in neuroblastoma and lung cancer. 1142 4

Recent molecular studies have shown a relatively high rate of loss of heterozygosity (LOH) in neuroblastoma (NB) as well as other types of tumors in human chromosome band 1p36. To identify candidate tumor suppressor genes in NB, we searched for homozygous deletions in NB cell lines with PCR according to a high-density sequence tagged site (STS)-content map spanning 1p35-36. Among 25 NB cell lines examined, only one cell line, NB-1, showed no signal with 27 STSs in a 480 kb region in 1p36.2. The sequence analysis has revealed that the defective region included seven known genes (E4, KIF1B, SCYA5, PGD, Cortistatin, DFF45, and PEX14), nine expressed sequence tags (ESTs), and two microsatellite markers. These genes are related to apoptosis, an ubiquitin-proteasome pathway, a neuronal microtubule-associated motor molecule, and components of a common translocation machinery. The region between the DFF45 and KIF1B genes was defined as homozygous deletion by Southern blotting. The search in LOH regions with high-density STSs may be useful for the isolation and identification of tumor suppressor genes in other tumors as well as NBs.
...
PMID:Homozygous deletion in a neuroblastoma cell line defined by a high-density STS map spanning human chromosome band 1p36. 1143 23

We previously reported a high incidence of loss of heterozygosity (LOH) on chromosome 2q33 in neuroblastoma (NB), observed in various types of human cancers including lung cancer, head and neck cancer and follicular thyroid carcinoma. To better elucidate the role of chromosome 2q aberrations in NB, we examined common allelic imbalance (AI) regions on chromosome 2q in 82 NB patients using 10 polymorphic microsatellite markers. AI on 2q was detected in 26 (32%) of 82 NB cases. There was a distinct common AI region between the D2S115 and D2S307 markers on 2q33. The distance between these markers was about 2.0 cM. Recently, the caspase 8 and caspase 10 genes, both of which encode cystein protease, were mapped to chromosome 2q33. Since the common AI region on 2q33 includes the caspase 8 and caspase 10 genes, the alterations of these genes were examined further. Absent or reduced expression of caspase 8 and caspase 10 were found in 19 (70%) of 27 and two (7%) of 27 NB cell lines by reverse transcription-polymerase chain reaction, respectively. A missense mutation was detected at codon 96, GCT (Alanine) to GTT (Valine), of the caspase 8 gene in one of the NB cell lines lacking caspase 8 expression. Thirteen (68%) of 19 cell lines lacking caspase 8 expression displayed methylation of the CpG island of the caspase 8 gene, whereas only one (13%) of eight cell lines with caspase 8 expression showed caspase 8 methylation (P=0.031). Furthermore, there was a significant association between AI at 2q33 and loss of caspase 8 expression (P=0.026). These results indicated that there was a tumor suppressor gene in the common AI region on chromosome 2q33 involved in the pathogenesis of a subset of NB. It is possible that the caspase 8 gene is one of the candidate tumor suppressor genes for NB and inactivation of this gene plays an important role in the tumorigenesis of NB through mainly its methylation.
...
PMID:Allelic imbalance on chromosome 2q and alterations of the caspase 8 gene in neuroblastoma. 1146 26

In order to clone candidate tumor suppressor genes whose loss contributes to the pathogenesis of neuroblastoma (NB), we performed polymerase chain reaction (PCR) screening using a high-density sequence tagged site-content map within a commonly deleted region (chromosome band 1p36) in 24 NB cell lines. We found a approximately 480 kb homozygously deleted region at chromosome band 1p36.2 in one of the 24 NB cell lines, NB-1, and cloned the human homologue (KIF1B-beta) of the mouseKif1B-beta gene in this region. The KIF1B-beta gene had at least 47 exons, all of which had a classic exon-intron boundary structure. Mouse Kif1B is a microtubule-based putative anterograde motor protein for the transport of mitochondria in neural cells. We performed mutational analysis of the KIF1B-beta gene in 23 cell lines using 46 sets of primers and also an allelic imbalance (AI) analysis of KIF1B-beta in 50 fresh NB samples. A missense mutation at codon 1554, GTG (Gly) to ATG (Met), silent mutations at codon 409 (ACG to ACA) and codon 1721 (ACC to ACT), and polymorphisms at codon 170, GAT (Asp) to GAA (Glu), and at codon 1087, TAT (Tyr), to TGT (Cys), were all identified, although their functional significances remain to be determined. The AI for KIF1B-beta was slightly higher (38%) than those for the other two markers (D1S244, D1S1350) (35 and 32%) within the commonly deleted region (1p36). Reverse transcriptase-PCR analysis of the KIF1B-beta gene revealed obvious expression in all NB cell lines except NB-1, although decreased expression of the KIF1B-beta gene was found in a subset of early- and advanced-stage NBs. These results suggest that the KIF1B-beta gene may not be a candidate for tumor suppressor gene of NB.
...
PMID:Genomic structure and mutational analysis of the human KIF1B gene which is homozygously deleted in neuroblastoma at chromosome 1p36.2. 1152 94

The activating transcription factor 2 (ATF-2) gene, which encodes a transcription factor involved in multiple intracellular signal transduction pathways, is located on human chromosome 2q32, which is a common region of LOH in human lung cancer. In neuroblastoma and breast cancer, a high incidence of LOH was detected on chromosome 2q. Recently we found that breast cancer is frequently developed in heterozygous mutant mice for the ATF-2 gene. Therefore, the ATF-2 gene was considered as a candidate tumor suppressor gene on 2q. To assess the role of the ATF-2 gene as a tumor suppressor in human carcinogenesis, we examined genetic alterations of the ATF-2 gene in 9 breast cancer cell lines, 10 neuroblastoma cell lines and 46 lung cancer cell lines. For this purpose, we first determined the exon-intron structure of the ATF-2 gene in the human genome. The ATF-2 gene was composed of 14 exons and 13 introns, and the ATG start codon and the TGA stop codon were present in exons 3 and 14, respectively. Genetic variants of the ATF-2 gene were detected in 5 of the 46 (10.6%) lung cancers, but not in neuroblastomas and breast cancers. Three of the five variants detected in lung cancers were genetic polymorphisms, while the remaining two, consisting of non-synonymous and synonymous substitutions, were possibly somatic mutations. The present result indicates that the ATF-2 gene is not a major tumor suppressor gene on chromosome 2q, however, it is possible that ATF-2 alterations may be involved in the development of a small subset of lung cancers.
...
PMID:Infrequent mutations of the activating transcription factor-2 gene in human lung cancer, neuroblastoma and breast cancer. 1183 64

Important roles have been suggested for caspase-8, caspase-9 and Apaf-1 in controlling tumor development and their sensitivity to chemotherapeutic agents. Methylation and deletion of Apaf-1 and CASP8 results in the loss of their expression in melanoma and neuroblastoma, respectively, while CASP9 localization to 1p36.1 suggests it is a good candidate tumor suppressor. The status of CASP9 and Apaf-1 expression in numerous neuroblastoma cell lines with/without amplified MYCN and chromosome 1p36 loss-of-heterozygosity (LOH) was therefore examined to test the hypothesis that one or both of these genes are tumor suppressors in neuroblastoma. Although CASP9 is included in the region encompassing 1p36 LOH in all neuroblastoma cell lines examined, the remaining CASP9 allele(s) express a functional caspase-9 enzyme. Apaf-1 is also expressed in all neuroblastoma tumor cell lines examined. Thus, the CASP9 or Apaf-1 genes do not appear to function as tumor suppressors in MYCN amplified neuroblastomas. However, approximately 20% of the neuroblastoma cell lines with methylated CASP8 alleles are also highly resistant to staurosporine (STS)- and radiation-induced cell death, presumably because cytochrome c is not released from mitochondria. This suggests that a second, smaller sub-group of MYCN amplified neuroblastoma tumors exists with defect(s) in apoptotic signaling components upstream of caspase-9 and Apaf-1. Since no consistent differences in Bcl-2, Bcl-x(L) or Bax expression were seen in the STS- and radiation-resistant neuroblastomas, it suggests that a unique mitochondrial signaling factor(s) is responsible for the defect in cytochrome c release in this sub-group of tumors.
...
PMID:Caspase-9 and Apaf-1 are expressed and functionally active in human neuroblastoma tumor cell lines with 1p36 LOH and amplified MYCN. 1189 17

Neuroblastoma (Nb) is a malignancy of the sympathetic nervous system which affects children in their first decade. It is the most common extra-cranial solid tumor in children with an incidence of approximately 1 in 8-10 000 live births annually and accounts for approximately 10% of all children's cancers. Ganglioneuroblastoma is a relatively benign form of Nb and consists of a mixture of fibrils, mature and maturing ganglion cells, as well as undifferentiated neuroblasts. During routine cytogenetic analysis of patients with different manifestations of neuroblastoma we have identified one patient with ganglioneuroblastoma that carries an apparently balanced t(1:13)(q21:q12) reciprocal translocation. Positional cloning of the translocation breakpoint on chromosome 13 resulted in the mapping of the breakpoint between coding exon 2 and exon 3 of WAVE3, a member of WASP gene family. Although the breakpoint region on chromosome 1 was localized to within 2 kb of genomic sequence, no gene was found to be interrupted on this chromosome. The WAVE3 transcript is mainly expressed in the nervous system and, like all the members of the WASP gene family, WAVE3 is a key element in actin polymerization and cytoskeleton organization. WAVE3, therefore, is important for cell differentiation and motility and its expression is lost in a number of low grade and stage 4S tumors. From analysis of its expression pattern and function, WAVE3 is a candidate tumor suppressor gene, at least in some forms of neuroblastoma.
...
PMID:WAVE3, an actin-polymerization gene, is truncated and inactivated as a result of a constitutional t(1;13)(q21;q12) chromosome translocation in a patient with ganglioneuroblastoma. 1218

p73 is a candidate tumor suppressor and imprinted gene that shares significant homology with the p53 gene. It is located on 1p36, a region frequently deleted in neuroblastoma and other tumors. To investigate the pattern of inactivation of this gene in human lymphomas, we studied 59 tumors to identify abnormal methylation in exon 1 and loss of heterozygosity (LOH) at this locus. p73 was methylated in 13/50 (26%) B cell lymphomas. There was no evidence of p73 methylation in the 9 T cell lymphomas analyzed. Burkitt's lymphomas showed the highest proportion of methylated cases (36%), although this alteration also affected other aggressive lymphomas such as diffuse large cell and some marginal zone lymphomas. LOH at the p73 locus was detected in 4/34 (11%) B and 1/9 (11%) T cell lymphomas. The p73 expression analysis showed absence or low level of p73 product in methylated lymphomas, whereas p73 was always detected in unmethylated tumors. We found monoallelic expression in normal peripheral blood samples, consistent with imprinting. None of the tumors showed LOH and methylation of the remaining allele simultaneously, suggesting that alteration of the expressed allele could lead to the total inactivation of the gene. Our results show that deletion or methylation of the p73 gene could be important mechanisms in suppressing p73 expression in B cell non-Hodgkin's lymphomas.
...
PMID:Frequent inactivation of the p73 gene by abnormal methylation or LOH in non-Hodgkin's lymphomas. 1235 28

KIF1a is a member of the kinesin superfamily proteins that are microtubule-dependent molecular motors involved in important intracellular functions such as organelle transport and cell division. We previously determined the structure of the human KIF1Bbeta gene, which was found to be a homologue of the murine Kif1bbeta, and demonstrated that the human KIF1Bbeta is a causative gene of Charcot-Marie-Tooth disease type 2A although we did not prove that it is a tumor suppressor gene of neuroblastoma. Here, we identified another isoform of the human KIF1B gene, KIF1Balpha. The KIF1Balpha and KIF1Bbeta are alternative splicing products of the KIF1B gene located on 1p36.2. The KIF1Balpha is distinct from KIF1Bbeta in the C-terminal cargo-binding domain; however, they have the same N-terminal motor domain. We found that the transcript of approximately 7.8 kb of KIF1Balpha was expressed in several tissues, especially in skeletal muscle, by Northern blot analysis. To determine whether this gene is one of the candidate tumor suppressor genes for neuroblastoma (NB) or other pediatric solid tumors, we performed mutational screening of KIF1Balpha in 25 NB, 9 rhabdomyosarcoma, 12 Ewing sarcoma and 24 other pediatric solid tumor cell lines. Using RT-PCR single-strand conformation polymorphism analysis and direct sequencing we detected a missense mutation (M807I) in 1 NB cell line (SK-N-SH), 3 silent mutations in 2 NB cell lines and 1 primitive neuroectodermal tumor cell line, respectively. RT-PCR analysis revealed that KIF1Balpha was obviously expressed in almost all of the tumor cell lines examined except NB-1. Furthermore, real-time quantitative RT-PCR showed that there was no significant difference in KIF1Balpha expression between 14 early-stage (stage I and II) and 14 advanced-stage (stage III and IV) NB fresh tumor specimens. These results suggest that KIF1Ba in addition to KIF1Bbeta may not be a candidate tumor suppressor gene for NB.
...
PMID:Genomic structure and mutational analysis of the human KIF1Balpha gene located at 1p36.2 in neuroblastoma. 1288 11

Several tumor suppressor genes are located within human chromosome 11q23 region. We have cloned and characterized MFRP and RNF26 genes at 11q23.3. We also identified and characterized KIAA1735/MTHDIX gene at 11q23.1 and CLDN24 gene at 11q23.2 by using bioinformatics. Here, a novel human gene corresponding to a 5'-truncated FLJ20535 cDNA was identified. FLJ20535 corresponded to nucleotide position 55-2255 of FLJ13859, and nucleotide position 52-2169 of FLJ13859 was the coding region. Because of tetratricopeptide repeat (TPR) and armadillo repeat (ARM) domains within its gene product, the novel human gene was designated TPARM. Mouse E330017O07Rik cDNA was derived from mouse Tparm gene. Human TPARM (705 aa) and mouse Tparm (704 aa), showing 75.4% total-amino-acid identity, consist of TPR domain and three ARM domains. TPR domain of TPARM was most homologous to that of SMAP1, while ARM1-ARM3 domains of TPARM were most homologous to ARM7-ARM9 domains of CTNNB1 (also known as beta-catenin). TPARM might be implicated in the WNT-beta-catenin signaling pathway. TPARM mRNA was expressed in testis, prostate, lung, germinal center B-cells, and also in neuroblastoma, teratocarcinoma, colon cancer, and gastric cancer. Human TPARM gene was found to consist of 22 exons. TPARM gene, located between NCAM1 and DRD2 genes, was mapped to human chromosome 11q23.2. TPARM as well as NCAM1 and DRD2 were predicted to be candidate tumor suppressor genes within the commonly deleted region of malignant melanoma on 11q23.1-q23.2 (between microsatellite markers D11S1347 and D11S4122).
...
PMID:Identification and characterization of TPARM gene in silico. 1296 6

<< Previous 1 2 3 4 Next >>