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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inactivation of the tumor suppressor gene p53 is frequently associated with ovarian cancer. Accumulation of stabilized p53 protein is a common feature in this tumor type. Underlying mutations in the p53 core region can lead to loss of the normal conformational state or loss of residues necessary for DNA binding and transcriptional regulation. Five HPV-free ovarian cancer cell lines established in our laboratory with and without immunocytochemically detectable p53 expression were selected for the correlation of subcellular localization of aberrant p53 and the type of gene mutation. The expression level regarding staining intensity and proportion of cells accumulating p53 was characterized employing an immunoreactive score. Two cell lines with point missense mutations in the core region showed strong nuclear or nuclear plus cytoplasmic staining. One cell line with exclusive staining of the cytoplasm contained a deletion of the major nuclear localization signal. Among two cell lines without p53 accumulation, one contained a microdeletion resulting in a frame shift, the other carried the wild-type sequence. The MDM2 oncogene was not amplified and its gene product was not overexpressed. In ovarian cancer, inactivated p53 can accumulate in both major cell compartments depending on the type of the underlying mutation.
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PMID:Subcellular localization of accumulated p53 in ovarian cancer cells. 862 45

DNA-damaging agents such as ionizing radiation (IR) activate the tumor suppressor p53, and, in turn, p53 transactivates a number of downstream effector genes such as GADD45, CIP1/WAF1, and MDM2. The induction of these downstream genes following IR appears to be strictly dependent upon the presence of wild-type functional p53 known to evoke G1 arrest. In this study, we characterized 56 cell lines from 9 different tumor types with predetermined p53 genotype by measuring the induction of GADD45, CIP1/WAF1, and MDM2 relative mRNA levels after IR. A higher fraction of melanoma lines had wild-type (wt) p53 (5/8, or 63%) compared to the nonmelanoma lines (11/48, or 23%). Most wt p53 (nonmelanoma) cell lines (11/12, or 92%) showed clear induction of both GADD45 and CIP1/WAF1. On the other hand, many wt p53 melanoma lines (4/5, or 80%) showed normal induction of CIP1/WAF1, but little or no induction of GADD45. Despite this defect in GADD45 induction, we found that all wt p53 melanoma lines exhibited strong G1 arrest and increased levels of p53 protein after IR. The results demonstrated that radiation-induced G1 arrest could occur by the p53-CIP1/WAF1 pathway without appreciable induction of GADD45 in melanoma lines. Time course experiments demonstrated prolonged induced expression of CIP1/WAF1 mRNA transcripts in melanoma lines in which GADD45 induction was lacking, suggesting some sort of compensatory mechanism involving CIP1/WAF1, in cell lines with defective GADD45 induction. We could reproduce this compensatory effect in RKO colon carcinoma cells in which GADD45 expression was blocked by constitutive antisense vectors. These findings reveal that defective induction of GADD45 following IR is common in human melanoma cell lines.
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PMID:An abnormality in the p53 pathway following gamma-irradiation in many wild-type p53 human melanoma lines. 863 Oct 22

The presence of t(11;22)(q24;q12) is often considered diagnostic of Ewing sarcoma and peripheral primitive neuroectodermal tumor. We report four cases, all of which possessed this translocation as detected by reverse transcriptase polymerase chain reaction and confirmed by sequencing with or without fluorescent in situ hybridization, but none of which were Ewing sarcoma or peripheral primitive neuroectodermal tumor by histological criteria. Two were polyphenotypic tumors and two were mixed embryonal and alveolar rhabdomyosarcomas. Only one case was positive for MIC2 by immunohistochemistry and only in a rare cell. Two cases (one polyphenotypic tumor and one rhabdomyosarcoma) had double minute chromosomes with > 100 copies of the MDM2 gene. The presence of the t(11;22)(q24;ql2) translocation should probably not be considered diagnostic of Ewing sarcoma and peripheral primitive neuroectodermal tumor in the absence of supporting histological evidence. The presence of this translocation in Ewing sarcoma and peripheral primitive neuroectodermal tumor has been taken as evidence that these two tumors are related. Extending this relationship to include some polyphenotypic tumors and some rhabdomyosarcomas may not be justified unless additional evidence is gathered. Pathologists and oncologists will need to decide whether treatment regimens for tumors are better based on phenotype rather than genotype when these two profiles are seemingly in conflict.
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PMID:Is the EWS/FLI-1 fusion transcript specific for Ewing sarcoma and peripheral primitive neuroectodermal tumor? A report of four cases showing this transcript in a wider range of tumor types. 864 55

MDM2 gene overexpression has been implicated in the pathogenesis of human neoplasia via inhibition of the p53 tumor-suppressor function. To investigate the potential involvement of the MDM2 oncogene in the pathogenesis of childhood rhabdomyosarcoma (RMS) we studied MDM2 abnormalities in six RMS cell lines in correlation with the p53 status. Three showed overexpression of MDM2 mRNA and protein, one with concomitant MDM2 gene amplification. All three lacked p53 mutation and expressed low levels of p53 mRNA but exhibited elevated p53 proteins. Double immunostaining revealed that the overexpressed MDM2 and p53 proteins were co-localized to the same cell nuclei. Furthermore, the two proteins were physically associated, as shown by co-immunoprecipitation and Western blot analysis. The half-life of the p53 protein was prolonged in the MDM2-expressing RMS cells. The extended half-life wildtype p53 protein and its complex formation with the elevated MDM2 suggest that the underlying mechanism for p53 protein accumulation in these cell lines is p53 stabilization by an overabundant MDM2 protein. The overexpressed MDM2 protein had a short half-life. The three remaining RMS cell lines exhibited low MDM2 mRNA and protein levels and carried p53 mutations. This study suggest that MDM2 overexpression represents an alternative mechanism for p53 inactivation in a subset of childhood RMS without p53 mutations. The results further indicate that the elevated MDM2 protein is responsible for wildtype p53 protein accumulation via stabilization.
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PMID:The MDM2 oncoprotein is overexpressed in rhabdomyosarcoma cell lines and stabilizes wild-type p53 protein. 868 37

The prognostic factors for esophageal cancer from the viewpoint of molecular biology are reviewed. Among several oncogenes and suppressor genes erbB, int2/hst1/Cyclin D1 and MDM2 gene amplifications are significant prognostic factors for esophageal cancer. The value of p53 mutation, and expression of matrix metalloproteinase (MMPs) in the prediction of patients' survival are controversial, so further research is needed. High expression of tumor proliferation-related factors (Ki67, PCNA, and AgNOR), abnormalities of adhesion molecule (E-Cadherin, alpha-Catenin), activation of autocrine mechanism of growth factor (EGFR-TGF alpha, EGF), and DNA ploidy pattern, which is thought to be the result of an accumulation of genomic abnormalities are also prognostic factors for esophageal cancer.
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PMID:[Prognostic factors for esophageal cancer--from the viewpoint of molecular biology]. 868 32

In order to study expression of MDM2 gene, antagonist of tumor suppressor gene p53 in acute leukemia, forty acute leukemia patients were tested using RT-PCT to evaluate expression level of MDM2 gene. Over-expression of MDM2 gene was found in 52.5% patients (21/40). No significant relations were found between the level of MDM2 gene expression and FAB subtypes of acute leukemia. It is suggested that the over-expression of MDM2 gene may play a role in acute leukemia.
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PMID:[Expression of MDM2 gene in acute leukemia]. 869 92

Conventional cytogenetic analysis of solid tumors is technically very demanding and requires a large number of viable cells. The technique of comparative genomic hybridization (CGH) circumvents these difficulties and has been shown to be particularly useful for identifying new gene amplifications. We have simplified the CGH technique for the detection of amplifications by utilizing a single labeling approach in which labeled tumor DNA is mixed with unlabeled normal human DNA and hybridized to normal metaphases on a slide. To examine the consistency and sensitivity of the method, initial experiments were performed using a retinoblastoma (RB) cell line and five pediatric solid tumors known to contain an amplification. The technique was easy to use and sensitive enough to detect low-level amplifications. The RB cell line showed reproducible signals at 2p24, indicative of amplified sequences, on both homologues in 95% of the metaphases (> 30) examined. Amplifications of the MYCN gene (2p24) were detected in three alveolar rhabdomyosarcomas and one medulloblastoma. CGH was then applied to six tumors in a prospective fashion, before data about specific gene amplification were available. In two, amplification of the MDM2 gene (12q13-14) was identified using CGH and later confirmed by Southern blot analysis. Four tumors negative for MDM2 and MYCN amplifications by CGH analysis were also negative by Southern blot analysis. Gene amplification as low as fourfold was detected in one tumor and the overall pattern of gene amplification detected by CGH in these tumors was not complex, involving just one amplification site for each case. Therefore, this simplified CGH technique is suitable for routine screening of pediatric solid tumors for amplifications when genetic studies are important but sample sizes are small and dividing cells are infrequent or unavailable.
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PMID:Application of a simplified comparative genomic hybridization technique to screen for gene amplification in pediatric solid tumors. 870 94

We have investigated the mutation of the TP53 gene in hepatoblastomas (HBLs) by using polymerase chain reaction-single strand conformation polymorphism and direct sequencing in 38 HBL tumor samples and in two HBL cell lines. We detected the TP53 gene mutation in an anaplastic hepatoblastoma cell line, but no aberration of the TP53 gene (exons 5-9) was found in tumor samples and in the other HBL cell line. The mutation of the cell line was a missense mutation from GAC (asparagine) to CAC (histidine) at codon 281, which was different from the G-to-T transversion of codon 249 that is frequently found in adult hepatocellular carcinomas (HCCs). In addition, we performed Southern blot analysis of the MDM2 gene, but we did not find MDM2 gene amplification in 19 cases tested. Our results suggest that, in contrast to the findings in HCCs in adults, TP53 gene aberrations are not involved in the development or progression of HBLs in children.
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PMID:Infrequent mutations of the TP53 gene and no amplification of the MDM2 gene in hepatoblastomas. 872 85

This report describes a case of rhabdomyosarcoma associated with a 2;13 translocation and multiple double minute chromosomes. The origin of the amplified DNA was identified using comparative genomic hybridization, which pinpointed a unique spot at 12q13-->q14. Band 12q13 has been shown to contain several genes that are occasionally amplified in other sarcomas. Fluorescene in situ hybridization to tumor metaphases with probes specific for this region indicated that the double minutes contained the MDM2 gene but not the CDK4 gene. MDM2 amplification was further quantified by Southern hybridization, which showed a mean value of 25 copies per haploid genome. This is the first example of MDM2 amplification in a rhabdomyosarcoma.
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PMID:MDM2 amplification in a primary alveolar rhabdomyosarcoma displaying a t(2;13)(q35;q14). 875 88

One obvious phenotype of tumor cells is the lack of terminal differentiation. We previously classified rhabdomyosarcoma cell lines as having either a recessive or a dominant nondifferentiating phenotype. To study the genetic basis of the dominant nondifferentiating phenotype, we utilized microcell fusion to transfer chromosomes from rhabdomyosarcoma cells into C2C12 myoblasts. Transfer of a derivative chromosome 14 inhibits differentiation. The derivative chromosome 14 contains a DNA amplification. MDM2 is amplified and overexpressed in these nondifferentiating hybrids and in the parental rhabdomyosarcoma. Forced expression of MDM2 inhibits MyoD-dependent transcription. Expression of antisense MDM2 restores MyoD-dependent transcriptional activity. We conclude that amplification and overexpression of MDM2 inhibit MyoD function, resulting in a dominant nondifferentiating phenotype.
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PMID:Amplification of MDM2 inhibits MyoD-mediated myogenesis. 875 63


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