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)

Tenascin (TN) is an extracellular matrix glycoprotein that is expressed in a characteristic spatiotemporal pattern during development and is up-regulated in the adult during tumorigenesis, wound healing, and nerve regeneration. In previous studies, we identified a promoter within the proximal 250 bp upstream of the mouse TN gene that contains several putative regulatory elements that are conserved among vertebrate TN genes. We have identified four different DNA elements within this promoter and show that they contribute in different ways to TN gene expression in NIH 3T3 fibroblasts, C6 glioma cells, and N2A neuroblastoma cells. These elements comprise a binding site for Krox proteins, one for nuclear factor 1, an octamer motif that binds POU-homeodomain proteins, and a novel TN control element. The nuclear factor 1 and TN control element had positive effects on TN promoter activity and formed similar DNA-protein complexes with nuclear extracts from all three cell lines. The Krox element had a negative effect on TN promoter activity in N2A cells, a positive effect in C6 cells, and no effect in NIH 3T3 cells. Two DNA binding complexes, one correlated with the negative and the other with the positive activities of the Krox element, were found to contain the protein Krox24. In cotransfection experiments, the octamer motif was required for induction of TN promoter activity by the POU-homeodomain protein Brn2 in N2A cells but was inactive in C6 cells. Consistent with these findings, N2A cells transfected with Brn2 formed octamer-binding complexes containing N-Oct3, the transcriptionally active form of Brn2, whereas complexes formed in C6 cells contained only N-Oct5A and N-Oct5B. Our results provide a striking example of the diversity of regulatory mechanisms that can be called forth by combining different promoter motifs with transcriptional activators or repressors.
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PMID:Multiple promoter elements differentially regulate the expression of the mouse tenascin gene. 905 Aug 67

The proto-oncogene MYCN is often amplified in human neuroblastomas. The assumption that the amplification contributes to tumorigenesis has never been tested directly. We have created transgenic mice that overexpress MYCN in neuroectodermal cells and develop neuroblastoma. Analysis of tumors by comparative genomic hybridization revealed gains and losses of at least seven chromosomal regions, all of which are syntenic with comparable abnormalities detected in human neuroblastomas. In addition, we have shown that increases in MYCN dosage or deficiencies in either of the tumor suppressor genes NF1 or RB1 can augment tumorigenesis by the transgene. Our results provide direct evidence that MYCN can contribute to the genesis of neuroblastoma, suggest that the genetic events involved in the genesis of neuroblastoma can be tumorigenic in more than one chronological sequence, and offer a model for further study of the pathogenesis and therapy of neuroblastoma.
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PMID:Targeted expression of MYCN causes neuroblastoma in transgenic mice. 921 16

Neuroblastoma is an enigmatic tumor that has the highest rate of spontaneous regression of all human malignant neoplasms, yet has one of the poorest outcomes when occurring as disseminated disease in children. The emergence of neuroblastoma tumor biology, coupled with age and stage of diagnosis, has allowed more accurate routing of patients to risk-related therapy and refining of such therapy to minimize treatment for those with low risk for recurrent disease and searching out new treatment strategies for patients with high-risk disease. Continued assessment of tumor biologic features in all patients will provide new insights into tumorigenesis, cell differentiation, and death pathways, resulting in the potential for developing newer therapies for patients with high-risk disease.
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PMID:Biology and treatment of neuroblastoma. 928 92

We describe a gene encoding p73, a protein that shares considerable homology with the tumor suppressor p53. p73 maps to 1p36, a region frequently deleted in neuroblastoma and other tumors and thought to contain multiple tumor suppressor genes. Our analysis of neuroblastoma cell lines with 1p and p73 loss of heterozygosity failed to detect coding sequence mutations in remaining p73 alleles. However, the demonstration that p73 is monoallelically expressed supports the notion that it is a candidate gene in neuroblastoma. p73 also has the potential to activate p53 target genes and to interact with p53. We propose that the disregulation of p73 contributes to tumorigenesis and that p53-related proteins operate in a network of developmental and cell cycle controls.
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PMID:Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. 928 59

Infection with human cytomegalovirus (HCMV) is a common and generally asymptomatic affection in childhood. Its role in neuroblastoma (NB) patients has not yet been elucidated. As evidence grows that HCMV interacts with apoptotic signaling due to the interaction of HCMV gene products with cellular proteins of apoptotic pathways, we used human NB cell line UKF-NB-2 persistently infected with HCMV strain AD169 to study the effects of long-term HCMV infection on programmed cell death of neuroectodermal tumor cells. The cells designated UKF-NB-2AD169 continued to produce infectious virus in successive subcultures over a period of more than 1 year. Up to 20% of cells expressed viral genes or produced infectious virus after initiation of infection. UKF-NB-2AD169 cells were significantly less sensitive to the cytotoxic agents cisplatinum and etoposide than parental (noninfected) UKF-NB-2 cells. These effects were associated with decreased ability of UKF-NB-2AD169 cells to undergo apoptosis and continuous viral replication. UKF-NB-2AD169 cells showed increased levels of antiapoptosis Bcl-2 protein (up to 12-fold), whereas expression of p53 and c-myc was not changed. Treatment of UKF-NB-2AD169 cells with ganciclovir, abolishing virus production, reestablished sensitivity to chemotherapy, lowered Bcl-2 expression, and facilitated inducibility of apoptosis to the level of the parental cell line. The results demonstrate that persistent HCMV infection confers resistance to cytotoxic agents on neuroectodermal tumor cells and protects from apoptosis, probably due to increased levels of Bcl-2 protein. Hence, it is conceivable that HCMV infection before or during tumorigenesis may contribute in some NB patients to failure of therapy.
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PMID:Persistent human cytomegalovirus infection induces drug resistance and alteration of programmed cell death in human neuroblastoma cells. 944 19

It has recently been reported that mismatch repair enzymes, which are one type of DNA repair enzymes, are the causative genes for a major group of hereditary non-polyposis colon cancers (HNPCC). Abnormalities in the mismatch repair system can be monitored by observing instability at the microsatellite loci (MSI) in cancer cells. MSI has been reported not only in tumors associated with hereditary non-polyposis colorectal cancer but also in sporadic forms of various tumors. No correlation between pediatric malignant tumors and the mismatch repair system has yet been reported. In the present study, we examined the frequency of MSI in 21 neuroblastomas, which are the most common solid tumors in childhood, using a high resolution fluorescent microsatellite analysis. MSI on five microsatellite loci was detected in none of the 21 samples. Other mechanisms independent of mismatch repair deficiency may thus play a role in both tumorigenesis and the development of neuroblastoma.
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PMID:A microsatellite instability analysis in neuroblastoma based on a high resolution fluorescent microsatellite analysis. 950 Jan 92

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

Deletions and translocations resulting in loss of distal 1p-material are known to occur frequently in advanced neuroblastomas. Fluorescence in situ hybridisation (FISH) showed that 17q was most frequently involved in chromosome 1p translocations. A review of the literature shows that 10 of 27 cell lines carry 1;17 translocations. Similar translocations were also observed in primary tumours. Together with the occurrence of a constitutional 1;17 translocation in a neuroblastoma patient, these observations suggest a particular role for these chromosome re-arrangements in the development of neuroblastoma. Apart from the loss of distal 1p-material, these translocations invariably lead to extra copies of 17q. This also suggested a possible role for genes on 17q in neuroblastoma tumorigenesis. Further support for this hypothesis comes from the observation that in those cell lines without 1;17 translocations, other chromosome 17q translocations were present. These too lead to extra chromosome 17q material. Molecular analysis of 1;17 translocation breakpoints revealed breakpoint heterogeneity both on 1p and 17q, which suggests the involvement of more than 2 single genes on 1p and 17q. The localisation of the different 1p-breakpoints occurring in 1;17 translocations in neuroblastoma are discussed with respect to the recently identified candidate tumor suppressor regions and genes on 1p. In this study, we focused on the molecular analysis of the 17q breakpoints in 1;17 translocations. Detailed physical mapping of the constitutional 17q breakpoint allowed for the construction of a YAC contig covering the breakpoint. Furthermore, a refined position was determined for a number of 17q breakpoints of 1;17 translocations found in neuroblastoma cell lines. The most distal 17q breakpoint was identified in cell line UHG-NP and mapped telomeric to cosmid cCI17-1049 (17q21). This suggests that genes involved in a dosage-dependent manner in the development of neuroblastoma map in the distal segment 17q22-qter. Future studies aim at the molecular cloning of 1;17 translocation breakpoints and at deciphering the mechanisms leading to 1;17 translocations and possibly to the identification of neuroblastoma genes at or in the vicinity of these breakpoints.
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PMID:Analysis of 1;17 translocation breakpoints in neuroblastoma: implications for mapping of neuroblastoma genes. 951 36

A family of p34Cdc2 related protein kinases, the PITSLRE kinases, is generated by alternative splicing and promoter utilization from three duplicated and tandemly linked genes on human chromosome 1p36.3, which is frequently deleted during the late stages of tumorigenesis. PITSLRE mRNA, protein, and enzyme activity are induced during Fas receptor- and glucocorticoid-mediated apoptosis of human T cells. Several PITSLRE isoforms are specific targets of proteolysis during apoptosis, generating an enzymatically active 50 kDa isoform. Inhibition of this protease activity blocks PITSLRE processing and enzyme activation, as well as apoptosis. Thus, PITSLRE kinases may be integral downstream components of apoptotic signal transduction pathway(s). Furthermore, PITSLRE genes, and their products, are physically altered in human neuroblastoma tumors, suggesting that they may be tumor suppressors.
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PMID:The PITSLRE protein kinase family. 955 75

Neuroblastoma demonstrates various clinical behaviors, ranging from spontaneous regression to rapid progression regardless of the therapy used. To study the possibility that progression occurs in neuroblastoma through the accumulation of genetic aberrations, we analyzed the clonal constitution of the primary tumor and metastatic tumor samples from a stage-4 patient. Using cytofluorometry and FISH analyses, intratumor clonal heterogeneity was revealed. In the initial primary tumor sample, the nuclear DNA content indicated the coexistence of diploid and aneuploid clones, and the copy number of chromosome 1 varied from two to six. The chromosome 1 aneusomy population was composed of MYCN-amplified and 1p-deleted clones, whereas, in the chromosome 1 disomy population, coexistence of MYCN-amplified and non-amplified clones as well as 1p-deleted and 1p-intact clones was revealed. In the primary tumor after chemotherapy, the DNA-diploid component had become predominant, although the coexistence of MYCN-amplified and non-amplified clones could still be demonstrated in poorly- and well-differentiated tumor regions, respectively. This contrasted with the findings in the metastatic tumors, in which either diploid or aneuploid clone with MYCN amplification and 1p deletion dominated completely in each metastatic site. The findings suggest that the aneuploid clones had evolved from a diploid clone with MYCN amplification and a 1p deletion which, in turn, may have evolved from a diploid clone with neither MYCN nor 1p abnormality. This illustrates how various stages of multiple-step tumorigenesis may provide clues to a better understanding of the clinical heterogeneity of neuroblastoma.
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PMID:Human neuroblastoma demonstrating clonal evolution in vivo. 959 33


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