Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In adults, loss of heterozygosity for DNA on 17p has been shown in high-grade anaplastic astrocytomas (AAs) and glioblastomas multiforme (GMs), and mutation of the TP53 tumor suppressor gene has been reported in all grades of astrocytomas. Little is known, however, about 17p deletion and TP53 mutation in juvenile pilocytic astrocytomas (JPAs), the most common low-grade tumors seen in children. To elucidate the genetic characteristics of pediatric high-grade astrocytomas and JPAs, we performed restriction fragment length polymorphism analysis with probes derived from 17p and TP53 mutational studies in 28 tumor specimens. Telomeric chromosome arm 17p markers 144-D6 and ABR were lost in 6 (75%) of 8 informative tumors classified as high-grade (7 AAs, 1 GM) and in 2 (10%) of 20 informative JPAs. Loss of 17p probes centromeric to the TP53 gene were also detected in 3 AAs and 5 JPAs. Four of the 6 (66%) JPAs with losses of 17p DNA sequences recurred rapidly despite aggressive therapy, whereas only 5 of the other 14 (36%) recurred. Mutation of the TP53 gene was detected by polymerase chain reaction and denaturing gradient gel electrophoresis in only 1 JPA and 1 AA. These tumors were also examined for MDM2 gene amplification as an alternate inactivation mechanism for TP53 gene function: no instances of alteration were identified. These results suggest that a gene or genes in addition to TP53 on 17p may be involved in the etiology or progression of high-grade astrocytomas and aggressive JPAs in children.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Deletion of chromosome arm 17p DNA sequences in pediatric high-grade and juvenile pilocytic astrocytomas. 753 55

Sixteen methacarn-fixed and paraffin-embedded cervical squamous lesions were examined using monoclonal antibodies to p53 and MDM2 in order to compare the expression of both proteins in cervical neoplasia. Standard avidin-biotin or streptavidin-biotin immunoperoxidase techniques were employed. The results show that the overexpression of both proteins takes place in a meaningful proportion of cervical neoplastic lesions. The expression of either protein is not very frequent in CIN 1 and 2. The overexpression of either p53 (9/12) or MDM2 (4/10) proteins was recorded in the group of more advanced lesions, their level fluctuating from 10% to 60% positive cells. The results suggest the possibility of an interaction of the p53 and MDM2 proteins in some cases of cervical neoplasia.
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PMID:Overexpression of p53 and MDM2 proteins in cervical neoplasia. 758 15

In human cervical carcinomas papillomavirus DNA is frequently integrated in the cell genome. We have cloned the integration site of human papillomavirus-18 DNA in human chromosome region 12q13-15 present in the SW756 cervical carcinoma cell line. Viral DNA is broken from nucleotides 2643 to 3418 in the E1 and E2 open reading frames, resulting in a deletion of 775 bases of viral DNA. Cloning and sequence analysis of the rearranged and germline alleles shows that there is no homology between the target cellular and viral DNA, suggesting it is a nonhomologous recombination. The target cellular region is called papillomavirus associated locus 2 (PAL2). The 5'- and 3'-flanking probes derived from the hybrid viral-cellular clone detect completely different germline restriction fragments in DNA from cells with normal chromosome 12. There is no overlap between the restriction maps of the target germline clones obtained with 5'- and 3'-flanking probes. Probes from these germline clones beyond the breakpoint position do not detect any DNA rearrangement in SW756 cells DNA. These data prove that there is a deletion of cellular DNA as consequence of the integration, with an estimated minimum size of 14 kilobases. Both cellular flanking probes are outside the amplicon of this chromosome region identified in the OSA and RMS13 sarcoma cell lines, comprising SAS-CHOP-CDK4-MDM2 genes and where translocation breakpoints are located in liposarcomas. The integration at 12q13-15 might have been selected by its contribution to the tumor phenotype.
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PMID:Deletion in human chromosome region 12q13-15 by integration of human papillomavirus DNA in a cervical carcinoma cell line. 759 43

The cellular protein MDM2 can bind to the tumor suppressor gene product p53 and abrogate its transcriptional activity. In addition, p53 can regulate expression of the mdm2 gene. We and others have previously shown that p53 is present at high levels in adenovirus-transformed cells which express the larger E1B protein. In view of these observations the expression of MDM2 in a panel of adenovirus transformed human cell lines has been examined. Two major species (98K and 80K) were detected, together with a number of minor species of higher and lower molecular weight. While there was little variation in levels of 98K protein between cell lines, appreciable differences in the expression of the 80K component were apparent. There was no correlation between MDM2 and p53 expression in any of the adenovirus transformants, nor with the viral proteins expressed. The pattern and level of MDM2 detected was similar to that seen in human tumor cell lines and in human fetal tissue. Northern blot analysis suggested that MDM2 expression was regulated at the transcriptional level. Stable interactions were observed between p53 and MDM2 in the adenovirus-transformed cell lines and in Ad5 E1 HEK 293 cells a ternary complex of p53, MDM2, and the Ad5 E1B 58K protein was demonstrated. In view of the lack of correlation between the level of p53 and MDM2 in adenovirus E1-transformed cells, the capacity of p53 to cause transcriptional activation was assessed using transfected CAT constructs linked to p53 responsive elements. p53 transcriptional activity was similar in all of the cell lines examined and did not correlate with protein expression. It is concluded, on the basis of all of these data, that the high concentrations of p53 found in adenovirus transformants are not transcriptionally active and have no influence on MDM2 expression. However, when expression of p53 was increased following infection with mutant adenoviruses, which do not express the larger E1B proteins, there was an appreciable increase in p53 transcriptional activity and in the levels of all of the MDM2 components.
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PMID:The high levels of p53 present in adenovirus early region 1-transformed human cells do not cause up-regulation of MDM2 expression. 761 70

Loss of function of the tumor-suppressor protein p53 is, in general, either caused by mutation, inducing a conformational change, or by binding to inactivating cellular (e.g. MDM2) or viral (e.g. SV40 large T) proteins. In adenovirus type 12 (Ad12)-transformed cells, p53 is stabilized without detectable binding to the Ad12 E1B/54 kDa protein and still present in a wild-type conformation but contains a mutant-like activity in cellular transformation. In this study we examined whether the changed characteristics of p53 in Ad12-transformed cells are correlated with changes in phosphorylation or complex formation of the protein. By making tryptic phosphopeptide maps we found a significant increase in the phosphorylation of the N-terminus of p53. Furthermore, expression of E1A was found to be essential for the altered phosphorylation, while expression of only Ad12 E1B/54 kDa is sufficient to increase the protein half-life. Additionally, we observed p53 to be present in increased molecular weight complexes in Ad12-transformed cells. We conclude that both the phosphorylation and oligomerization of p53 is changed as a result of Ad12 transformation.
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PMID:Altered phosphorylation and oligomerization of p53 in adenovirus type 12-transformed cells. 762 31

To investigate the relevance of the C-terminal domains of the human p53 tumor suppressor gene to its growth suppressive and transcriptional regulatory properties deletion mutants were generated which eliminated 30 (p53 delta 363), 60 (p53 delta 333) and 87 (p53 delta 306) amino acids from the C-terminus of the p53 protein. p53 delta 363 has lost the highly basic tail of the protein (residues 360-386). p53 delta 333 and p53 delta 306 lack the oligomerization domain (residues 320-360); p53 delta 306 has also lost the major nuclear localization signal of p53 (NLSI, residues 316-325). These mutants were assayed for transactivation from two p53 consensus binding sites and for transcriptional repression of two promoter systems in Calu6 lung cancer cells (p53 null). Moreover, their ability to inhibit cell growth in tumor cell lines with a defined p53 status was analysed. Deletion of the oligomerization domain correlated with significant loss of: (a) transactivation from a genomic sequence; (b) transcriptional repression; (c) the ability to inhibit colony formation. An intact NLSI was not a prerequisite for transactivation. p53 delta 363 behaved similarly to wt p53 in all the assays. We established an inducible expression system for p53 delta 363 in a human fibrosarcoma cell line known to be growth-suppressed by wt p53. The induction of p53 delta 363 expression also inhibited cell proliferation albeit to a lesser extent than wt p53. However, p53 delta 363 could upregulate WAF1/CIP1, GADD45 and MDM2 genes. Thus, the basis tail of p53 appears not to be required for the biological functions of the protein assayed.
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PMID:The basic carboxy-terminal domain of human p53 is dispensable for both transcriptional regulation and inhibition of tumor cell growth. 762 48

Amplification of the genes MDM2, SAS, and CDK4, all located on the long arm of chromosome 12, has recently been demonstrated in human soft tissue tumors. To determine the extent of the amplification unit, we examined 16 soft tissue tumor samples, including pleomorphic liposarcoma, malignant fibrous histiocytoma (MFH), and atypical lipoma, by Southern blot analysis using 13 chromosome 12 probes. All tumors had previously been shown to have 3- to 20-fold amplification of MDM2. In five samples, all MFH, only MDM2 was amplified, whereas in the remaining 11 samples, two to five additional genes were amplified. The amplicon included markers both proximal and distal to MDM2, but was in all but one atypical lipoma confined to the chromosome region 12q13-15. Discontinuous amplicons were found in two of the tumors. This study indicates that MDM2, or possibly an as-yet-unidentified gene in its proximity, is the target gene of the 12q13-15 amplification in soft tissue tumors.
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PMID:Characterization of the 12q13-15 amplicon in soft tissue tumors. 765 1

Amplification of the MYCN gene is a well documented genetic alteration of aggressively growing human neuroblastomas. Through cytogenetic studies we have identified neuroblastoma cell lines which, in addition to amplified MYCN, carry amplified DNA not harbouring MYCN. In situ hybridization of biotinylated total genomic DNA to metaphase chromosomes of normal human lymphocytes by reverse genomic hybridization revealed the amplified DNA to be derived from chromosome 12 band q13-14. Subsequent filter analyses showed a 20- to 40-fold amplification of the MDM2 gene, located at 12q13-14, both in three cell lines and in an original tumor, in addition to amplified MYCN. As the apparent consequence of amplification abundant MDM2 protein was present, a part of which was complexed with p53.
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PMID:Non-syntenic amplification of MDM2 and MYCN in human neuroblastoma. 770 Jun 32

Induction of apoptosis in tumor cells is an important mechanism of chemotherapy-induced cell death. The tumor-suppressor gene p53 is required for the efficient activation of apoptosis following chemotherapy. However, the molecular mechanism regulating p53-associated apoptosis remains controversial. In this study, we show that the expression of both wild-type p53 and MDM2 (murine double minute 2) proteins was induced when cis-diamminedichloroplatinum (cisplatin) caused apoptosis in human glioblastoma U87-MG cells, which expressed neither wild-type p53 nor MDM2 protein prior to treatment. Overexpression of MDM2 in U87-MG cells transfected with human mdm2 expression vector conferred the resistance of tumor cell to cisplatin-induced apoptosis. In contrast, the treatment with mdm2 antisense oligonucleotide targeted against mdm2 mRNA increased the susceptibility of tumor cells to apoptosis. Changes in expression level of MDM2 protein, however, did not affect the expression of wild-type p53 protein. These findings suggest that MDM2 protein may act as a negative regulator of cisplatin-induced apoptosis, and moreover, may play an important role in the development of resistance to cisplatin in human tumors.
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PMID:MDM2 protein confers the resistance of a human glioblastoma cell line to cisplatin-induced apoptosis. 776 Nov

Our knowledge of the molecular biology of sarcomas has progressed considerably over the past year, with major emphasis on the role of p53 and MDM2 gene mutations. Further studies on drug resistance mechanisms and the role of MDR1 expression in sarcomas have been reported. The investigations using different imaging techniques as ways of predicting tumor necrosis more accurately than our current response measurements after therapy have led to promising results. The many clinical phase II studies with new drugs led to the identification of taxotere as a new active agent against soft tissue sarcomas. Similar impressive results, such as those obtained with isolated limb perfusion in melanoma, have been reported in limb sarcomas with an identical regimen. The activity of ifosfamide in pretreated patients, administered at an increased dose, is suggestive of dose dependency. The improved results in phase II studies of dose-intensive chemotherapy with the support of colony-stimulating factors are encouraging and these regimens are now being investigated in the adjuvant setting.
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PMID:Diagnosis and treatment of soft tissue sarcomas in adults. 780 38


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