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)

We examined 18 neuroblastoma cell lines and 32 primary single-copy MYCN tumor specimens to determine whether mutations of p73, a novel p53-related gene located in chromosome band 1p36.33, contribute to the genesis or progression of childhood neuroblastoma. By fluorescence in situ hybridization, 16 of the 18 cell lines, but only 3 of the 32 primary tumors, had evidence of a deleted p73 allele. Sequence analysis of the p73 coding region in the mRNAs expressed by these cell lines and tumors did not reveal inactivating mutations, suggesting that p73 is not homozygously inactivated in neuroblastoma. However, several novel splice forms of p73 mRNAs were identified, including one without exon 11 that predominated in multiple MYCN-amplified cell lines. Its encoded p73 protein differed from other splice forms in that the C-terminus was derived from an alternative reading frame. Further study of the functional properties of the protein encoded by this splice form of p73 will be needed to determine whether it contributes to the pathogenesis of childhood neuroblastoma with MYCN gene amplification.
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PMID:Lack of homozygously inactivated p73 in single-copy MYCN primary neuroblastomas and neuroblastoma cell lines. 1093 73

Alteration of the p53 tumor suppressor gene is a common, if not general, observation in human malignant tumors. p73 Is a novel member of the p53 family at chromosome 1p36.3, at which locus frequent defects are seen in many tumors including neuroblastoma. Besides structural similarities, the fact that p73 functions in the regulation of the cell cycle and apoptosis promotes the expansion of the research field concerning p53-associated tumor progression. In this paper, we review the structure and function of p73 as well as the mutational status in various human tumors. In addition, possibilities for new therapeutic applications with p73 for cancer cell control are discussed.
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PMID:p73: structure and function. 1097 55

p73 is a p53 homolog that, in vitro, inhibits cell growth and induce apoptosis. In some tumors p73 is monoallelically expressed and this raised the possibility that this gene is subjected to imprinting. Silencing of p73 in acute leukemia and in Burkitt's lymphoma occurs in association with the aberrant methylation of the first exon of the gene. We have analysed the methylation pattern of the p73 promoter and of upstream and downstream sequences in neuroblastoma. Our results demonstrate that p73 expression in this tumor is not regulated by methylation. We concluded that it is unlikely that p73 is imprinted in neuroblastoma and that the methylation-dependent silencing of this gene, thus far, is a characteristic of hematologic malignancies. Oncogene (2000) 19, 4553 - 4556.
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PMID:Methylation-independent silencing of the p73 gene in neuroblastoma. 1100 29

p73, a recently identified gene showing high homology to p53 and mapping to 1p36.33, was presented as a candidate gene for neuroblastoma. In this study the authors evaluate the levels and allelic nature of p73 expression in primary neuroblastomas using reverse transcription-polymerase chain reaction-restriction fragment length polymorphism strategies based on intragenic polymorphisms. From 32 neuroblastoma patients, 11 were heterozygous for the p73 polymorphisms analyzed. p73 expression was found to be low in the correspondent tumors and while all 6 stages 1 and 2 tumors presented biallelic expression, 4 out of the 5 stage 4 tumors showed only one active p73 allele. Analysis of blood samples from 8 healthy donors and 4 neuroblastoma patients revealed much higher levels of p73 expression, and exclusively of biallelic nature. These results are supportive of a role for p73 in the biology of neuroblastoma, particularly in some advanced tumors. Nevertheless, the G81A/C91T polymorphism, previously implicated in regulating the expression of p73, did not show any significant association with neuroblastoma development.
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PMID:P73 expression in neuroblastoma: a role in the biology of advanced tumors? 1120 39

p73 has recently been identified as a structural and functional homolog of the tumor suppressor protein p53. Overexpression of p53 activates transcription of p53 effector genes, causes growth inhibition and induced apoptosis. We describe here the effects of a tumor-derived truncated transcript of p73alpha (p73Deltaexon2) on p53 function and on cell death. This transcript, which lacks the acidic N-terminus corresponding to the transactivation domain of p53, was initially detected in a neuroblastoma cell line. Overexpression of p73Deltaexon2 partially protects lymphoblastoid cells against apoptosis induced by anti-Fas antibody or cisplatin. By cotransfecting p73Deltaexon2 with wild-type p53 in the p53 null line Saos 2, we found that this truncated transcript reduces the ability of wild-type p53 to promote apoptosis. This anti-apoptotic effect was also observed when p73Deltaexon2 was co-transfected with full-length p73 (p73alpha). This was further substantiated by suppression of p53 transactivation of the effector gene p21/Waf1 in p73Deltaexon2 transfected cells and by inhibition of expression of a reporter gene under the control of the p53 promoter. Thus, this truncated form of p73 can act as a dominant-negative agent towards transactivation by p53 and p73alpha, highlighting the potential implications of these findings for p53 signaling pathway. Furthermore, we demonstrate the existence of a p73Deltaexon2 transcript in a very significant proportion (46%) of breast cancer cell lines. However, a large spectrum of normal and malignant tissues need to be surveyed to determine whether this transdominant p73 variant occurs in a tumor-specific manner.
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PMID:Transactivation-deficient p73alpha (p73Deltaexon2) inhibits apoptosis and competes with p53. 1131 82

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.
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PMID:Functional characterization of naturally occurring mutants (P405R and P425L) of p73alpha and p73beta found in neuroblastoma and lung cancer. 1142 4

The proto-oncogene Trks encode the high-affinity receptor tyrosine kinases for neurotrophins of a nerve growth factor (NGF) family. The Trk signals spatiotemporally regulate neural development and maintenance of neural network. However, Trk was originally cloned as an oncogene fused with the tropomyosin gene in the extracellular domain. Accumulating evidence has demonstrated that the rearranged Trk oncogene is often observed in non-neuronal neoplasms such as colon and papillary thyroid cancers, while the signals through the receptors encoded by the proto-oncogene Trks regulate growth, differentiation and apoptosis of the tumors with neuronal origin such as neuroblastoma and medulloblastoma. The intracellular Trk signaling pathway is also different depending on the Trk family receptors, cell types and the grade of transformation. Furthermore, developmentally programmed cell death of neuron, which is largely regulated by neurotrophin signaling, is at least in part controlled by tumor suppressors p53 and p73 as well as their antagonist DeltaNp73. Thus, the Trks and their downstream signaling function in both ontogenesis and oncogenesis. In this short review, the dynamic role of the Trk family receptors signaling in neural development, neurogenic tumors and other cancers will be discussed.
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PMID:Trk receptor tyrosine kinases: a bridge between cancer and neural development. 1143 Oct 98

The p73 gene is a p53 homologue which induces apoptosis and inhibits cell proliferation. Although p73 maps at 1p36.3 and is frequently deleted in neuroblastoma (NB), it does not act as a classic oncosuppressor gene. In developing sympathetic neurons of mice, p73 is predominantly expressed as a truncated anti-apoptotic isoform (DeltaNp73), which antagonizes both p53 and the full-length p73 protein (TAp73). This suggests that p73 may be part of a complex tumor-control mechanism. To determine the role of DeltaNp73 in NB we analyzed the pattern of expression of this gene in vivo and evaluated the prognostic significance of its expression. Our results indicate that DeltaNp73 expression is associated with reduced apoptosis in a NB tumor tissue. Expression of this variant in NB patients significantly correlates with age at diagnosis and VMA urinary excretion. Moreover it is strongly associated with reduced survival (HR=7.93; P<0.001) and progression-free survival (HR=5.3; P<0.001) and its role in predicting a poorer outcome is independent from age, primary tumor site, stage and MYCN amplification (OS: HR=5.24, P=0.012; PFS: HR=4.36, P=0.005). In conclusion our data seem to indicate that DeltaNp73 is a crucial gene in neuroblastoma pathogenesis.
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PMID:Expression of DeltaNp73 is a molecular marker for adverse outcome in neuroblastoma patients. 1185 3

We previously reported that DAN, a founding member of the DAN family of secreted proteins, acts as an inhibitor of cell cycle progression and is closely involved in retinoic acid-induced neuroblastoma differentiation. In this study, we found that DAN as well as p73, the recently identified p53 family member, was up-regulated during osteoblast differentiation. Additionally, the expression of DAN was increased in response to cisplatin-induced cell death of neuroblastoma SH-SY5Y cells. Consistent with the previous reports, p73 was accumulated after the treatment with cisplatin. Intriguingly, we found a putative p53/p73-binding site in the 5'-upstream region of the human DAN gene. A luciferase reporter assay and an in vitro DNA-binding experiment revealed that this canonical p53/p73-binding site was a functional responsive element and was specific for p73. Our results suggest that there exists a functional association between DAN and p73 during osteoblast differentiation as well as cisplatin-induced cell death.
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PMID:p73-dependent expression of DAN during cisplatin-induced cell death and osteoblast differentiation. 1215 Sep 78

The human p73 gene is a homolog of p53, which has been localized to chromosome 1p36 in a region that is frequently deleted in neuroblastoma. Transfection of the p73 gene into neuroblastoma cells that lack detectable p73 protein has been shown to result in growth suppression and to induce neuronal differentiation. In this study, we have identified by means of restriction landmark genome scanning (RLGS) a genomic fragment that was frequently reduced in intensity in neuroblastomas. The cloned fragment contained exon 1 of p73 as well as intronic and promoter sequences. We investigated the genomic and expression status of p73 and N-myc in 34 neuroblastoma tumors and 12 neuroblastoma cell lines. Approximately a third of neuroblastomas in our series exhibited deletion of p73. Most tumors analyzed exhibited reduced expression of p73, as determined by quantitative RT-PCR, in the absence of detectable p73 gene deletion. The reduced expression of p73 correlated with overexpression of N-myc in a statistically significant manner. The N-myc gene was transfected into two neuroblastoma cell lines that lacked N-myc amplification to determine its effect on p73 RNA levels. p73 was detectable at low level by RT-PCR in untransfected SK-N-AS cells and became undetectable following N-myc transfection, whereas in SH-EP1 cells, p73 levels were substantially reduced following transfection but remained detectable. Our data suggest that the N-myc gene modulates expression of p73, allowing neuroblastoma cells to escape the growth suppressing properties of p73.
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PMID:N-myc modulates expression of p73 in neuroblastoma. 1219 2


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