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)

The biological effects of exposures to high LET radiations have particular relevance to radiation protection and risk assessment. Since most cancers are of epithelial origin, it is important to obtain a better understanding of radiation-induced oncogenic transformation in this cell type. Accordingly we have initiated studies to determine whether immortalized human epidermal keratinocytes (RHEK) can be transformed with high LET radiations. Exponentially growing RHEK cells were treated with single doses (1, 10, 25, 50 and 100 cGy) of 0.85 MeV fission neutrons from the Janus reactor. Neutron exposure led to the development of morphologically altered cells and foci formation after 6 weeks at confluence. These transformed cultures grew with an increased saturation density, exhibited anchorage-independent growth and formed tumors in athymic mice. Single-strand conformational polymorphism analysis and DNA sequencing demonstrated the absence of point mutations in codons 12/13 and 61 in the Ha-ras, Ki-ras, or N-ras genes and exons 4-9 of the p53 tumor suppressor gene. These studies demonstrate that high LET radiations (fission neutrons) can transform immortalized human epithelial cells to a malignant phenotype that does not appear to involve mutations in either the cellular p53 or ras genes.
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PMID:Transformation of human epidermal keratinocytes with fission neutrons. 800 Dec 48

Thirty-six primary renal cell carcinoma samples and one metastatic lymph node DNA sample were examined for mutations of H-, K-, and N-ras and p53 genes, and genomic instability at (AC)n, (CA)n.(GT)n, and (TA)n.(GT)n repeats. No mutations were noted for H-, K-, and N-ras genes and only 2 of all the samples (5.6%) showed mutations at exon 8 of the p53 gene. Differences in unrelated microsatellites for tumor and normal DNA were detected in 9 (25.0%) of the cases examined. Somatic alterations in seven microsatellites, D3S1228, D3S643, D5S107, LPL5GT, D9S63, D17S261, and DCC, were found in 1 (2.8%), 3 (8.3%), 2 (5.7%), 5 (14.7%), 3 (8.3%), 3 (8.3%), and 3 (8.3%) cases, respectively. Five of 26 (19.2%) clear cell type and 4 of 10 (40.0%) non-clear cell type patients showed DNA instability. Two of 11 (18.2%) grade 1, 5 of 20 (25.0%) grade 2, and 2 of 5 (40.0%) grade 3 patients showed abnormal patterns. One of 2 (50.0%) stage pT1, 4 of 24 (16.7%) stage pT2, and 4 of 10 (40.0%) stage pT3 patients were shown to have microsatellite instability. In 4 of 9 alteration-positive cases (44.4%), mutations in multiple microsatellites were observed. Alterations in microsatellite instability may be more common in non-clear cell type, high-grade, and high-stage renal cell carcinoma patients.
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PMID:Genomic instability of microsatellite repeats and mutations of H-, K-, and N-ras, and p53 genes in renal cell carcinoma. 803 84

A series of changes in the genes that control hepatocyte growth, or interference with the protein products of these genes, appears to have an important role in the etiology of hepatocellular carcinoma (HCC). Mutations of the p53 tumor suppressor gene have been identified in 30-50% of HCC patients in some geographic areas. Abnormalities of the RB tumor suppressor gene have been found in 20-25% of HCCs, including 80-86% of HCCs with p53 mutations. Overexpression of transforming growth factor alpha (TGF-alpha), insulin-like growth factor II (IGF-II), and the oncogenes N-ras, c-myc, and c-fos have been found in high percentages of HCC patients. The cumulative effect of these changes may be more important than the order in which they occur. Some of these changes may explain the mechanism(s) by which the hepatitis B virus participates in the development of HCC.
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PMID:Tumor suppressor genes, growth factor genes, and oncogenes in hepatitis B virus-associated hepatocellular carcinoma. 804 25

We have developed a simple and reliable procedure to screen gene mutations using DNA mismatch repair (MR) specific mut Y enzyme of Escherichia coli and thymidine DNA glycosylase from HeLa cells. The mut Y enzyme cleaves A of G/A mismatches in DNA duplex and thymidine glycosylase cleaves T at G/T mismatches. Previously, we showed the determination of G:C-->T:A mutations in the N-ras gene in two human tumor samples with mut Y G/A MR enzyme. As low as 1-2% mutant DNAs in a sample of mutant and wild-type DNA can be detected with a synthetic DNA to create G/A mispairing for the assay. In this paper, we simplify the assay, include G/T MR thymidine glycosylase from HeLa cells and evaluate the application for screening DNA point mutations of p53 and ras genes. In this method, DNA fragments amplified from normal and mutated genes by polymerase chain reaction (PCR) were mixed and annealed to create DNA mismatches for cleavage by mismatch repair enzymes. The cleaved products and the substrates were separated by gel electrophoresis and detected by autoradiography. In theory, the enzymes that cut G/A or G/T mispairs will detect the mutations of G:C-->A:T, A:T-->G:C, G:C-->T:A and T:A-->G:C. Several human tumor samples were examined for p53 or K-ras mutations with G/A and G/T mismatch repair enzymes. The reliability of mutation detection was evaluated by comparing the results with reported mutations or confirmed by DNA sequencing of the same PCR-amplified DNA fragments. Our data showed that, following mismatch repair enzyme cleavage, all mutated DNA samples yielded cleaved products with sizes as expected. In addition, our assay is able to characterize the nature of mutation by 5' end-labeling of 32P on mutant or wild-type DNA fragments. The low background, reliability and the determination of the sites of mutations as well as the types of DNA base changes indicate the advantages of the method over other techniques in testing DNA mutants.
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PMID:Detection of DNA point mutations with DNA mismatch repair enzymes. 805 47

To characterize some of the genetic events underlying the development of glioblastoma multiforme, the authors analyzed 65 astrocytic tumors (seven pilocytic astrocytomas, eight astrocytomas, 16 anaplastic astrocytomas, and 34 glioblastomas multiforme) for loss of heterozygosity for chromosome 17p, loss of heterozygosity for chromosomes 10p and 10q, amplification of the epidermal growth factor receptor (EGFR) gene, and amplification of the oncogenes N-myc, c-myc, and N-ras using Southern blot analysis. Alterations of the p53 gene (positive immunostaining for p53 protein in tumors with or without p53 gene mutations) in these 65 tumors were analyzed previously. None of the 65 tumors showed amplification or rearrangement of N-myc, c-myc, or N-ras oncogenes. The molecular analysis presented here demonstrates distinct variants of astrocytic tumors, with at least three genetic pathways leading to glioblastoma multiforme. One pathway was characterized by 43 astrocytomas with alterations in p53. Glioblastomas with p53 alterations may represent tumors that progress from lower-grade astrocytomas. This variant was more likely to show loss of chromosome 17p than tumors without p53 alterations (p < 0.04). Seventy-five percent of tumors with loss of one 17p allele demonstrated mutations in the p53 gene. Loss of chromosome 10 was associated with progression from anaplastic astrocytoma (13%) to glioblastoma (38%) (p < 0.04). Amplification of the EGFR gene was a rare (7%) but late event in tumor progression (p < 0.03). A second pathway was characterized by six astrocytomas without p53 alterations and may represent clinically de novo high-grade tumors. These tumors were more likely to show amplification of the EGFR gene (83%) than tumors with p53 alterations. Sixty percent of tumors with EGFR amplification also showed loss of chromosome 10; loss of chromosome 17p was infrequent in this variant. One or more alternative pathways were characterized by 16 astrocytomas without p53 alterations and with none of the genetic changes analyzed in this study. Glioblastomas are a heterogeneous group of tumors that may arise via multiple genetic pathways.
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PMID:Pathways leading to glioblastoma multiforme: a molecular analysis of genetic alterations in 65 astrocytic tumors. 805 51

Patients with Fanconi anemia (FA) have an extraordinary predisposition to acute myelogenous leukemia (AML). The genetic mechanisms underlying the neoplastic transformation of FA hematopoietic cells are unknown. In this study, we have investigated the molecular features of hematopoiesis in the course of FA at different stages of the disease, including aplastic anemia, myelodysplastic syndrome (MDS), and AML. The analysis focused on defining the clonality status of FA hematopoiesis as well as the putative involvement of N-ras, a dominantly acting oncogene, and p53, a tumor suppressor gene, which are known to play a role in human hematopoietic tumors. Clonality of hematopoiesis was assessed by testing X-chromosome inactivation at the DXS255 locus, which displays different methylation patterns according to the activation status of the corresponding X homolog. Five out of seven FA cases analysed for clonality displayed monoclonal hematopoiesis, including one case at the aplastic anemia stage, three cases with MDS and one with AML. Mutations of the N-ras and p53 genes were studied by a combination of single strand conformation polymorphism (SSCP) analysis and direct sequencing of the PCR product in the bone marrow and/or peripheral blood of 18 FA patients (seven with aplastic anemia, seven with MDS, four with AML). Only normal N-ras and p53 sequences were detected in all cases analyzed. These results suggest that monoclonal hematopoiesis is a frequent finding in the course of FA and may precede the onset of neoplasia in some cases. The genetic mechanisms underlying FA-associated leukemogenesis appear to be independent of N-ras and p53 mutations, which are relatively frequent events in myeloid tumors associated with other hematologic disorders.
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PMID:Clonality studies and N-ras and p53 mutation analysis of hematopoietic cells in Fanconi anemia. 805 73

Although pituitary tumors arise as benign monoclonal neoplasms, genetic alterations have not readily been identified in these adenomas. We studied restriction fragment abnormalities involving the GH gene locus, and mutations in the p53 and H-, K- and N-ras genes in 22 human GH cell adenomas. Twenty two nonsecretory adenomas were also examined for p53 and ras gene mutations. Seven prolactinoma DNA samples were tested for deletions in the multiple endocrine neoplasia-1 (MEN-1) locus, as well as for rearrangements in the hst gene, a member of the fibroblast growth factor family. Pituitary adenoma tissue and lymphocytes were obtained from patients at the time of transsphenoidal surgery. In DNA from GH-cell adenomas, identical GH restriction patterns were detected in both pituitary and lymphocyte DNA in all patients and in one patient with a mixed GH-TSH cell adenoma. Using polymerase chain reaction (PCR)-single stranded conformation polymorphism analysis, no mutations were detected in exons 5, 6, 7, and 8 of the p53 gene in GH cell adenomas nor in 22 nonsecretory adenomas. Codons 12/13 and 61 of H-ras, K-ras, and N-ras genes were also intact in GH cell adenomas and in nonsecretory adenomas. Site-specific probes for chromosome 11q13 including PYGM, D11S146, and INT2 were used in 7 sporadic PRL-secreting adenomas to detect deletions of the MEN-1 locus on chromosome 11. One patient was identified with a loss of 11p, and the remaining 6 patients did not demonstrate loss of heterozygosity in the pituitary 11q13 locus, compared to lymphocyte DNA. None of these patients, demonstrated hst gene rearrangements which also maps to this locus. These results show that p53 and ras gene mutations are not common events in the pathogenesis of acromegaly and nonsecretory tumors. Although hst gene rearrangements and deletions of 11q13 are not associated with sporadic PRL-cell adenoma formation, a single patient was detected with a partial loss of chromosome 11, including the putative MEN-1 site.
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PMID:Molecular screening of pituitary adenomas for gene mutations and rearrangements. 810 Aug 31

Expression of cellular oncogenes in 3 lymphoid cell lines, BTL-PC3 (BoCD2-, BoCD4-, BoCD8-, BoWC1+), BLS1 (BoCD2+, BoCD4-, BoCD8-, BoWC1+) and BLT2 (BoCD2-, BoCD4-, BoCD8-, BoWC1-), which have been established from calf, skin, and thymic types of lymphosarcomas, respectively, were analyzed by DNA-RNA (northern blot) hybridization. To determine specific expression of oncogenes involved in malignant transformation of the lymphoid cells, cellular RNA was isolated from bovine tumor cell lines, BTL-PC3, BLS1, and BLT2, and from Madin Darby bovine kidney cells used as a control for bovine cell lines. The RNA was hybridized against 5 viral oncogene probes (v-jun, v-myc, v-erbB, v-erbA and v-fes), 6 human cellular oncogene probes (N-ras, c-Blym-1 c-erbB-2, c-fos, c-myb and c-abl), human p53 tumor suppressor gene, and bovine LDH-A gene probes. Line BTL-PC3 expressed 2.4-kilobase (kb) c-myc and 4.0- and 3.6-kb c-myb transcripts, and line BLT2 expressed a 3.8-kb c-myb transcript, but line BLS1 expressed no message for the oncogenes tested. Specific transcripts of p53 were found in BTL-PC3 and BLT2 lines, but not in BLS1. Madin Darby bovine kidney cell line expressed multiple cellular oncogenes, c-jun, c-myc, and c-fos, and p53 genes. Southern blot hybridization did not reveal abnormal DNA rearrangements associated with the expressed oncogenes (c-myc and c-myb) in the 3 bovine tumor lines. (ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Specific expression of cellular oncogenes c-myc and c-myb in T-cell lines established from three types of bovine lymphosarcomas. 811 30

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant of the heterocyclic amines, a group of potent carcinogens contained in cooked meat and fish. Female F344 rats fed a diet containing 100 or 400 ppm PhIP developed mammary carcinomas within 104 or 52 wk, respectively, at the rate of 47% for each group; these carcinomas were examined for mutations in three members of the ras gene family and in the p53 gene. Single-strand conformation polymorphism (SSCP) analysis and direct sequencing demonstrated a G-->A transition at the second position of Ha-ras codon 12, with the resultant substitution of glutamic acid for glycine, in two of 10 carcinomas induced by 100 ppm PhIP and in one of seven induced by the 400 ppm dose. No mutations in Ki-ras or N-ras were detected. cDNA polymerase chain reaction-SSCP analysis and direct sequencing demonstrated a G-->T transversion at the third position of p53 codon 130, with the resultant substitution of asparagine for lysine, in one of the 10 carcinomas induced by 100 ppm of PhIP for which freshly frozen samples were available. PhIP-induced rat mammary carcinogenesis can be regarded as a unique system in that rat mammary carcinomas are negative for ras and p53 mutations.
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PMID:Infrequent mutation of Ha-ras and p53 in rat mammary carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. 818 28

The frequency of simultaneously detecting N-ras and p53 gene mutations was studied in leukaemia cells of patients with acute myeloid leukaemia (AML) or with myelodysplastic syndrome (MDS). Using in vitro DNA amplification followed by oligonucleotide hybridization analysis, 45 AML and six MDS patients were screened for activating mutations in codons 12, 13 and 61 of N-ras. Ten of them (eight AML and two MDS) were found positive. These 10 patients and 10 others without activating N-ras mutation were further analysed by direct sequencing of the amplified exons for p53 mutations and for atypical N-ras mutations. Beside the activating mutations in the N-ras gene, no additional transforming or nontransforming mutations could be detected in the N-ras. However, exon 7 of p53 was mutated in two AML patients without activating N-ras mutation. These data show that p53 mutations occurred with half the frequency of N-ras mutations in AML and that no positive correlation could be found between the onset of mutations in N-ras and p53 genes.
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PMID:Occurrence of point mutations in p53 gene is not increased in patients with acute myeloid leukaemia carrying an activating N-ras mutation. 821 95


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