Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Medulloblastoma (MB) represents the most frequent malignant brain tumor of childhood but only a few cell lines and animal models of this primitive neuroectodermal tumor (PNET) have thus far been established. Using specific cell culture conditions, we were able to derive four human MB cell lines (MHH-MED-1-4) as well as a cell line from a spinal PNET (MHH-PNET-5). The four MB cell lines grew in suspension as floating cell aggregates or as slightly adherent cells. They consisted of undifferentiated cells that did not express markers of late neuronal or glial lineages such as neurofilaments or glial fibrillary acidic protein. They also lacked expression of major histocompatibility complex class I or II antigens on the cell surface. All four MB lines were positive for vimentin and neuron-specific enolase, whereas synaptophysin, neural cell adhesion molecule, galactocerebroside, GD2, GD3, and the A2B5 antigen were expressed inconsistently. In contrast, MHH-PNET-5 grew as adherent monolayer and expressed major histocompatibility complex class I antigen. By cytogenetic analysis, the lines were near diploid with clonal aberrations. The MB lines showed no losses of chromosome arm 17p by either cytogenetic or microsatellite analyses. The cell line MHH-MED-2 exhibited double minute chromosomes, amplification of the c-myc gene, and overexpression of c-myc mRNA and protein. N-myc, p53, and Rb protein expression were unaltered. All four continuously passaged MB cell lines and the MHH-PNET-5 line were xenotransplanted s.c. into athymic mice; three of four MB lines and the spinal PNET line gave rise to tumors. These cell lines will be useful tools for biological and preclinical studies on PNETs.
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PMID:Characterization of five new cell lines derived from human primitive neuroectodermal tumors of the central nervous system. 820 50

The primitive neuroectodermal tumor of the central nervous system is one of a number of tumors in which deletions on chromosome 17p have been identified. The tumor suppressor gene, p53, is located in the region of the deletion. To determine if the p53 gene is involved in the development of primitive neuroectodermal tumors, deoxyribonucleic acid (DNA) blot analysis, ribonucleic acid blot analysis, and p53 complementary DNA sequencing were performed on 34 primitive neuroectodermal tumors removed from children. No rearrangement in the gene was detected in 21 tumors. The p53 messenger ribonucleic acid was of the expected size in all 18 tumors for which ribonucleic acid was available. Sequencing of p53 Exons 5 through 9 revealed a mutation in the cell line DAOY and in only 1 of 14 tumors examined. A DNA rearrangement was detected in the DNA from one tumor with a probe mapping to the distal portion of 17p. Taken together, these data suggest that the p53 gene is not involved in the development of most primitive neuroectodermal tumors. In addition, a gene of interest may be present on distal 17p.
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PMID:Absence of p53 mutations in childhood central nervous system primitive neuroectodermal tumors. 839 24

Primitive neuroectodermal tumours (PNET's) or medulloblastomas are common primary brain tumours of childhood. Current treatment protocols achieve 50-60% cures. However, it has proved difficult to develop better treatment for the remaining patients because prognostic factors are not established. We have investigated the prognostic value of p53 protein expression in 87 PNET's using immunohistochemistry with DO-7 and CM-1 antibodies on biopsy paraffin sections. Eight patients (9%) had intensely reactive tumour cell nuclei, and a significantly reduced survival (P = 0.002); only one survives and this with a recurrent tumour 50 months following diagnosis. Sixty eight per cent of patients had faintly reactive tumour cell nuclei, a reduced survival up to 4 years but a long term survival not significantly different (P = 0.41) from 23% of patients with p53 negative PNET's; the 10 year survival rates were 37% and 40%, respectively. Males had a reduced survival (P = 0.04) with a 2-fold relative risk of death compared to females. Multivariate analysis showed that intense overexpression of p53 protein identifies a group of PNET patients with a 7-fold relative risk of death compared to all other cases, irrespective of sex. This marked difference suggests the involvement of p53 in the pathogenesis of PNET's which have a particularly poor response to treatment, and should help to develop new therapies for this group of patients.
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PMID:p53 protein overexpression identifies a group of central primitive neuroectodermal tumours with poor prognosis. 839 11

Sixty-nine round cell lesions of the sinonasal region (22 olfactory neuroblastomas [ONBs], 17 malignant lymphomas, nine Ewing's sarcomas [ES], nine rhabdomyosarcomas, three sinonasal undifferentiated carcinomas, five malignant melanomas, and four pituitary adenomas) were studied in an attempt to define the differential diagnostic capabilities of antibody to MIC2 and bcl-2 in paraffin-embedded tissue in the distinction of these lesions. In addition, antibody to p53 was applied in each case to define the incidence of p53 positivity among these various tumor types. Each of the ES cases was MIC2 positive; each of the other cases was MIC2 negative. Positivity for bcl-2 was confined to two cases, one of them a malignant lymphoma (85% of cells positive) and one an ONB (5% of cells positive). Small numbers of scattered p53-positive cells appeared in the majority of cases studied, without regard for the specific tumor type; only a single case, a malignant lymphoma, showed a majority (approximately 90%) of p53-positive cells. These results indicate that the MIC2 antibody is a useful method by which to distinguish ES from a variety of other round cell lesions that may be encountered in the sinonasal region. The practical applications of antibody to bcl-2 and p53 seem to be much more limited; by contrast, neither bcl-2 positive cells nor abundant p53 cells identified by immunohistochemical analysis seemed to be frequent findings in any of the tumor types studied. Although ONBs have been included with the peripheral primitive neuroectodermal tumors for classification purposes, these tumors diverge from the ES/primitive neuroectodermal tumor family in that they do not seem to share either the MIC2 positivity or the t(11;22) chromosomal translocation that typify the ES/primitive neuroectodermal tumor family of lesions. Although bcl-2 positivity has been associated with a light microscopic finding of an unfavorable histologic pattern in retroperitoneal neuroblastomas, it does not seem that bcl-2 positivity in ONB will select for a clinically distinctive subset of patients.
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PMID:Olfactory neuroblastoma and other round cell lesions of the sinonasal region. 878 4

The p53 tumor suppressor gene is the most commonly altered gene in human cancers. Germline mutations in p53 are the genetic alteration underlying predisposition to multiple cancers in Li-Fraumeni syndrome and Li-Fraumeni-like syndrome. We describe a patient who presented with developed adrenocortical carcinoma at age 19 months and a cerebral primitive neuroectodermal tumor at age 5 years. The patient did not have a family history of cancer. We used the enzyme mismatch cleavage (EMC) method to screen for mutations in the p53 gene and found a germline mutation in exon 7 (codon 248). Loss of heterozygosity analysis in one tumor revealed loss of the wild-type p53 allele. In our report we demonstrate the EMC method to be a rapid and sensitive method for mutation detection.
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PMID:Rapid diagnosis of germline p53 mutation using the enzyme mismatch cleavage method. 895 18

Detection of p53 protein expression and overexpression has been reported to be associated with poor prognosis in a number of human malignancies. The aim of this study was to utilize immunocytochemical antigen detection techniques to search for evidence of abnormal p53 protein accumulation in ten human childhood astrocytoma (ASTR) subtypes (five pilocytic, two pure anaplastic, one anaplastic ASTR with primitive neuroectodermal tumor elements, one ASTR containing a majority of oligodendrocytes and one glioblastoma multiforme). The immunocytochemistry was carried out on routine, formalin fixed, paraffin-wax embedded 3 to 4 microns thick ASTR tissue sections. A four step, indirect, biotin-streptavidin based method was employed with peroxidase enzyme conjugation. Surprisingly, p53 protein expression was demonstrated in all ten ASTRs. The immunoreactivity pattern was mostly heterogeneous, with cells groups of similar intensity clustered within the ASTRs. The number of cells stained and the intensity of the immunoreactivity correlated directly with the known degree of malignancy of the various subtypes of ASTRs: lowest in the pilocytic ASTR cases and highest in the glioblastoma multiforme. Low-grade human ASTRs possess an intrinsic tendency for cell dedifferentiation toward the embryonic cell immunophenotype (IP). Loss of p53 function is associated with most, if not all, human malignancies. Mutation of p53 has yet to be demonstrated in pilocytic ASTRs. The accumulation of p53 in some pilocytic ASTR cells, as demonstrated in our study, suggests that the mere dysfunction of the p53 protein may be involved in the ealry stages of ASTR progression from the grade I pilocytic subtype to the more "malignant" pure ASTR, which is characterized by p53 gene mutations. The loss of p53 provides the necessary genetic instability needed for further IP changes and further progression towards more malignant IPs, e.g. anaplastic ASTR and glioblastoma multiforme. Such facts make the use of p53 in the assessment of ASTRs indispensible. p53 levels may be used in identifying cell clones within pilocytic ASTR microenvironments, which have a clear tendency for progression toward more malignant IPs and the establishment of the alteration of the p53 gene in more advanced ASTR subtypes (grades II to IV).
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PMID:Immunohistochemical detection of p53 protein expression in various childhood astrocytoma subtypes: significance in tumor progression. 913 69

The current World Health Organization (WHO) classification groups together both infratentorial neoplasms (medulloblastomas) and their supratentorial counterparts as primitive neuroectodermal tumors (PNETs), implying a common origin. Previous analyses of medulloblastoma have shown loss of chromosome arm 17p as the most frequent genetic abnormality: the molecular genetic constitution of supratentorial PNETS has not been systematically studied. We therefore examined 8 hemispheric PNETs and 35 medulloblastomas with 17p restriction fragment length polymorphism (RFLP) and microsatellite markers. We also examined the TP53 tumor suppressor gene by a combined polymerase chain reaction-denaturing gradient gel (PCR-DGGE) technique. Our results showed that all of the 17p markers tested were preserved in all of the supratentorial PNET specimens. In contrast, loss of distal chromosome arm 17p was detected in 37% of the medulloblastomas. Analysis of the TP53 gene showed 2 mutations in the medulloblastomas and no mutations in the supratentorial tumors. These results show that the most common molecular genetic abnormality in infratentorial PNETS is absent in their supratentorial counterparts and suggests that alternative pathways and genetic events may be involved in their etiology.
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PMID:Chromosome arm 17p deletion analysis reveals molecular genetic heterogeneity in supratentorial and infratentorial primitive neuroectodermal tumors of the central nervous system. 924 14

The p21 protein inhibits the activity of cyclin-Cdk complexes and suppresses cell cycle progression. Wild type p53 can induce p21, but mutated p53 cannot. Previous studies have demonstrated that mutation of p53 is absent in neuroblastoma (NB). These reports prompted us to examine whether p53 induced p21 in NB. We examined the expression of p21 and p53 mRNA in eight NB, two Ewing's sarcoma (ES) and two primitive neuroectodermal tumor (PNET) cell lines by Northern blot analysis, and sequenced p53 cDNA of these cells. Although p53 mRNA was detected in all analyzed cell lines by Northern blot analysis, p21 mRNA was detected in six NB but not in two NB, two ES and two PNET cell lines. We detected the point mutation of p53 at codon 273 (CGT to TGT) in one NB and two ES cell lines. The non-transforming substitution at codon 72 (CCC to CGC) was detected in all analyzed cell lines. One PNET cell line had a large deletion of p53 cDNA. These results showed that p21 mRNA was usually expressed in NB but not in ES and PNET. This may suggest that the down stream of the p53 signal transduction pathway in NB is different from that of the closely related tumors of ES and PNET.
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PMID:p21 (WAF1/Cip1/Sdi1/Pic1) mRNA is expressed in neuroblastoma cell lines but not in Ewing's sarcoma and primitive neuroectodermal tumor cell lines. 936 58

Cytogenetic and molecular analysis of soft tissue tumours has yielded a wealth of new information over the past 10-15 years. Many soft tissue neoplasms show specific karyotypic aberrations which have proved to be diagnostically valuable, and have also assisted in the understanding of pathogenetic mechanisms and rationalisation of classification systems (e.g. lipomatous tumours and Ewing's sarcoma/PNET). In certain clinical subsets, especially round cell sarcomas and fatty neoplasms, determination of karyotype (whether by conventional analysis, FISH or RT-PCR) has proved often to be useful in the diagnostic setting. Additionally the recognition of clonal abnormalities in both benign neoplasms as well as lesions formerly thought to be non-neoplastic (e.g. inflammatory "pseudotumour") has prompted reassessment of biologic concepts with regard to growth control. Inherited molecular genetic defects which predispose to soft tissue neoplasia (e.g. NF-1, Li-Fraumeni syndrome) have been characterised, leading to a greater understanding of tumour suppressor genes. Mesenchymal differentiation genes, the modes of action of which may help to expunge concepts of histogenesis, are being characterised. It is becoming clear that there exist growth control genes (such as the HMGI family) which, irrespective of differentiation, play an important role in a wide range of different mesenchymal tumours. Additionally it is evident that different histologic types of sarcoma (e.g. variants of liposarcoma) show quite different abnormalities of cell cycle control (notably at the G1-S checkpoint) and it seems increasingly likely that certain genetic aberrations, identifiable either at the chromosomal or individual gene level, may prove to be of prognostic relevance in sarcomas and may also open novel therapeutic avenues. While the validity of all molecular genetic data depends totally on skilled histological diagnosis and grading, there has never been a better time for close collaboration between pathologists and basic scientists in the study of soft tissue neoplasia.
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PMID:Soft tissue tumours: the impact of cytogenetics and molecular genetics. 947 86

Cytogenetic and molecular analyses of primitive neuroectodermal tumors (PNETs) of the central nervous system (CNS) have demonstrated material losses of 17p, the region that contains the TP53 gene, as the most frequent abnormality. Mutations in the TP53 gene are, however, very rare in these tumors. These findings strongly suggest that another, as yet unidentified, gene on 17p may be involved. We performed a search for loss of heterozygosity (LOH) on 17p by microsatellite markers on 26 childhood CNS tumors as well as TP53 gene mutations (exons 5-8) by single-strand conformational polymorphism analysis on 41 pediatric brain tumor samples of distinct histologic types. LOH was detected in 10 cases: 7 PNET, 2 astrocytomas, and 1 glioblastoma multiforme. In 4 of the PNETs the losses were limited to more distal markers. On the other hand, TP53 mutations were detected in 6 of 41 samples studied. Our results not only confirm the low penetrance of the TP53 gene on pediatric CNS tumors, but also provide further evidence of a putative tumor suppressor gene distal to TP53, between markers (D17S938, D17S926) and 17pter, specifically taking part in the development of PNET.
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PMID:Pediatric brain tumors: loss of heterozygosity at 17p and TP53 gene mutations. 954 59


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