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)

2',3'-dideoxycytidine (ddC) is a synthetic pyrimidine nucleoside analogue approved for treatment of HIV-positive patients. Previous studies indicated that ddC has the potential to cause thymic lymphoma in C57BL/6 x C3H F1 (hereafter called B6C3F1) mice. In this study, we evaluated the carcinogenic potential of ddC in two different mouse models. B6C3F1 hybrid mice carry ecotropic endogenous proviral sequences that may be activated to cause lymphoma, whereas NIH Swiss mice lack proviral sequences that can be expressed. The mice were treated with ddC by gavage at 500 and 1000 mg/kg/day for up to 6 months (human dose, 2.25 mg/day) and evaluated for toxicity, plasma levels of ddC, and pathological changes. Lymphocyte cell markers from the thymic lymphomas were assessed by immunophenotyping. Expression of p53 protein was evaluated using immunohistochemical staining. Treatment-related thymic lymphomas were present in both mouse models with a higher incidence in NIH Swiss than in B6C3F1 mice. The lymphomas were more prevalent in females than in males of both mouse models. Most mice with thymic lymphoma died during the course of the study. In addition to the thymus, lymphoma was often present in lymph nodes, spleen, and other organs. Lymphomas arose more frequently in mice that lack endogenous ecotropic retroviral sequences and thus were not due to activation of endogenous provirus. During the third month of the study, a few NIH Swiss mice that died had granulosa cell tumors of the ovary. Treatment-related but reversible thymic atrophy was observed in both mouse models. There was a very high correlation between the internal dose of ddC and the incidence of thymic lymphoma in both mouse models. Most of the lymphocytes from control thymuses and ddC-induced lymphomas were positive for Thy-1.2 (pan-T), heat stable antigen, and CD4 and CD8 markers, with no marked differences in the lymphocyte markers of the tumors between sexes or dose groups. p53 protein was detected in only 20% (23/115) of the ddC-induced lymphomas with mostly minimal expression in scattered cells. Because ddC induced lymphomas in two different mouse models, the potential carcinogenic risk should be considered in long-term treatment of HIV-positive patients, especially children and adolescent patients treated with ddC.
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PMID:Carcinogenicity of 2',3'-dideoxycytidine in mice. 884 Sep 82

This study was undertaken to assess the value of flow cytometric measurements of total p53 protein content and proliferation indices derived from in vivo halogenated pyrimidine labelling. Two series of colorectal cancer specimens were studied for which clinical outcome data were recorded. A series of 84 archival, ethanol-fixed, bromodeoxyuridine (BrdUrd) labelled colorectal tumours were analysed by flow cytometry for their total and cell cycle phase p53 protein content using the pAb1801 monoclonal antibody. A second series of 33 freshly obtained tumours was used for assay evaluation and for comparison with the archival material. In the archival series (n=84), the median p53-pAb1801 LI was 81.9% (range: 11.1-99.8%). In only three tumours could significant amounts of p53 protein not be detected. The median phase specific p53-pAb1801 LI in G0/G1 was 71.6%, in S was 95.5%, and in G2/M was 98.5%. In the series of fresh tumours (n=33), the median p53-pAb1801 labelling index (LI) was 94.6% (range: 17.9-99.9%). Only two tumours failed to express significant amounts of p53 protein. There was no significant difference in the generally high levels of p53 protein content between the fresh and archival series. Life-table analysis of the patients in the archival series failed to demonstrate a statistical difference in life expectancy in relation to Dukes' stage when tumours were stratified by the median total p53 labelling index. In this study, p53 content and proliferative indices measured by flow cytometry do not have independent predictive value over Dukes' grading in determining the outcome of colorectal cancer. Flow cytometry is confirmed as a practical tool for multi-parametric and cell cycle analysis of oncoprotein expression in human tumour biopsies.
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PMID:The flow cytometric analysis of total p53 protein content and proliferation indices in colorectal cancer, in relation to clinical outcome. 890 95

The formation of DNA photoproducts by ultraviolet (UV) light is responsible for the induction of mutations and the development of skin cancer. Cis-syn cyclobutane pyrimidine dimers (pyrimidine dimers) are the most frequent lesions produced in DNA by UV irradiation. Besides being mutagenic, pyrimidine dimers may interfere with other important DNA-dependent processes. To analyze the effects of pyrimidine dimers on the ability of DNA sequences to be recognized by trans-acting factors, we have incorporated site-specific T-T dimers into oligonucleotides containing the recognition sequences of the sequence-specific transcription factors E2F, NF-Y, AP-1, NF kappa B, and p53. In each case, presence of the photodimer strongly inhibited binding of the respective transcription factor complex. Reduction of binding varied between 11- and 60-fold. The results indicate that the most common UV-induced DNA lesion can interfere severely with binding of several important cell cycle regulatory and DNA damage responsive transcription factors. We suggest that inhibition of transcription factor binding may be a major biological effect of UV radiation since promoter regions are known to be repaired inefficiently and since UV damage can deregulate the function of a large number of different factors.
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PMID:Inhibition of transcription factor binding by ultraviolet-induced pyrimidine dimers. 896 32

The epithelia from the crypts of the intestine are exquisitely sensitive to metabolic perturbation and undergo cell death with the classical morphology of apoptosis. Administration of 40 mg/kg 5-fluorouracil (5-FU) to BDF-1 p53+/+ mice resulted in an increase in p53 protein at cell positions in the crypts that were also those subjected to an apoptotic cell death. In p53-/- mice apoptosis was almost completely absent, even after 24 hr. 5-FU is a pyrimidine antimetabolite cytotoxin with multiple mechanisms of action, including inhibition of thymidylate synthase (TS), which gives rise to DNA damage, and incorporation into RNA. The inhibition of TS can be increased by coadministration of folinic acid and can be abrogated by administration of thymidine. The incorporation of 5-FU into RNA is inhibited by administration of uridine. p53-Dependent cell death induced by 5-FU was only inhibited by administration of uridine. Uridine had no effect on the apoptosis initiated by 1 Gy of gamma-radiation. Although thymidine abrogated apoptosis induced by the pure TS inhibitor Tomudex, it had no effect on 5-FU-induced apoptosis, and coadministration of folinic acid did not increase apoptosis. The data show that 5-FU-induced cell death of intestinal epithelial cells is p53-dependent and suggests that changes in RNA metabolism initiate events culminating in the expression of p53.
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PMID:Inhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: evidence for the involvement of RNA perturbation. 905 Aug 58

DNA amplification is a readily measurable indicator for genome destabilization. Contrary to normal senescing cells, those of most immortal or transformed cell lines are karyotypically unstable and permissive for amplification. Permissivity for amplification can be generated by gene products of several DNA tumor viruses whereby their interaction with the tumorsuppressor protein p53 is important. p53 is the major protein involved in check point control of DNA damage. Polyomavirus large T antigen is also involved in immortalization and transformation of cells but it does not interact with p53. We, therefore, examined whether this protein could still make the non-permissive cell line REF52 permissive for gene amplification. To this end REF52 cell lines were constructed which conditionally expressed the wild type polyomavirus large T antigen or a mutant form unable to bind the retinoblastoma protein. Using the inhibitor of de novo pyrimidine biosynthesis, phosphonoacetyl-L-aspartate (PALA), as selective agent we found that PALA resistant cells arise with a frequency of about 5 x 10(-5) and that the interaction of polyomavirus large T protein with the retinoblastoma protein or another related pocket protein is important for this to occur. PALA resistant cells have an increased number of chromosomes and dicentric chromosomes which are considered as starting point for DNA structures characteristic for amplified DNA. Such structures were indeed found with the help of fluorescence in situ hybridization. PALA resistant cells appear normal with respect to p53. Our data indicate that PALA induces a G1 block which can be partially overcome by polyomavirus large T protein by its interaction with E2F-pocket protein complexes providing further evidence that these complexes are downstream targets of p53.
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PMID:Polyomavirus large T antigen-dependent DNA amplification. 905 Sep 98

Nucleotide excision repair (NER) is a fundamental process required for maintaining the integrity of the genome in cells exposed to environmental DNA damage. Humans defective in NER suffer from the hereditary cancer-prone disease xeroderma pigmentosum. In order to model this disease in mice a mutation in the mouse XPC gene was generated and used to replace a wild-type XPC allele in mouse embryonic stem cells by homologous recombination. These cells were used to derive XPC mutant mice. Fibroblasts from mutant embryos were more sensitive to the cytotoxic effects of ultraviolet light than wild-type and heterozygous cells. Repair synthesis of DNA following irradiation with ultraviolet light was reduced in these cells, indicating a defect in NER. Additionally, XPC mutant embryo fibroblasts were specifically defective in the removal of pyrimidine (6-4) pyrimidone photoproducts from the non-transcribed strand of the transcriptionally active p53 gene. Mice defective in the XPC gene appear to be an excellent model for studying the role of NER and its interaction with other proteins in the molecular pathogenesis of cancer in mammals following exposure to environmental carcinogens.
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PMID:Characterization of defective nucleotide excision repair in XPC mutant mice. 906 11

The theory of somatic mutagenesis predicts that the frequency pattern of induced selectable mutations along a gene is the product of the probability patterns of the several sequential steps of mutagenesis, e.g., damage, repair, polymerase misreading, and selection. Together, the variance of these component steps is propagated to generate a mutagen's induced mutational spectrum along a gene. The step with the greatest component of variance will drive most of the variability of the mutation frequency along a gene. This most variable step, for UV-induced mutations, is the cyclobutyl pyrimidine dimer repair rate. The repair rate of cyclopyrimidine dimers is quite variable from nucleotide position to nucleotide position and we show that this variation along the p53 gene drives the C-->T transition frequency of non-melanocytic skin tumors. On showing that the kinetics of cyclopyrimidine dimer repair at any one nucleotide position are first order, we use this kinetic and the somatic mutation theory to derive Leq, the adduct frequency along a gene as presented to a DNA polymerase after a cell population reaches damage-repair equilibrium from a chronic dose of mutagen. Leq is the product of the first two sequential steps of mutagenesis, damage and repair, and the frequency of this product is experimentally mapped using ligation-mediated PCR. The concept of Leq is applied to mutagenesis theory, chronic dose genetic toxicology, genome evolution, and the practical problems of molecular epidemiology.
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PMID:Somatic mutation theory, DNA repair rates, and the molecular epidemiology of p53 mutations. 910 Aug 56

Mutation spectra of the p53 gene from human skin carcinomas have been connected to solar UV radiation. For comparison we have characterized the mutation spectrum of the p53 gene in a very large sample of squamous cell carcinomas from hairless mice induced with UV of wavelength 280-320 nm (UV-B), which have substantiated the mutagenic effects of UV-B radiation in vivo. Tumors from hairless mice, random bred SKH:HR1 as well as inbred SKH:HRA strains, which are analyzed for mutations in the conserved domains of the p53 protein present a very specific mutation spectrum. The observed mutation frequency after chronic UV-B radiation in the p53 gene ranged from 54% (SKH-HRA) to 73% (SKH-HR1) among the 160 tumors analyzed. Over 95% of the mutations were found at dipyrimidine sites located in the non-transcribed strand, the majority were C-->T transitions and 5% were CC-->TT tandem double mutations. Four distinct UV-B mutation hot spots have been identified for the first time: two major ones at codons 267 (33%) and 272 (19%) and two minor ones at codons 146 (10%) and 173 (4%). The codon 267 hot spot consists of a CpG preceded by a pyrimidine, which confirms in vivo an important role for this UV-B mutable site in UV-B-induced skin tumors that is not found in other types of mouse tumors. Comparison with mutation spectra from human skin carcinomas fully validates the merits of the hairless mouse model for studying the molecular mechanisms of skin carcinogenesis. For example, the murine hot spot at codon 272 does have a full equivalent in human skin carcinomas. In contrast, the human equivalent of the murine codon 267 lacks the dipyrimidine site and therefore fails to be a pronounced hot spot in human skin carcinomas; however, this site is one of the major hot spots in human internal cancers (evidently not induced by UV radiation but probably by deamination of the 5 methyl cytosine).
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PMID:The role of UV-B light in skin carcinogenesis through the analysis of p53 mutations in squamous cell carcinomas of hairless mice. 916 73

In tissue culture conditions, exogeneous active transforming growth factor-beta1 (TGF-beta1) enhances the lethal effect of DNA-damaging agents (UV-C, gamma rays, cisplatin, methotrexate and 5-fluorouracil) toward human A549 cells and mink Mv1Lu cells, as detected by the loss of their capacity to give rise to colonies; both these cell lines harbor a wild-type p53, as determined by immunoprecipitation. Contrastingly, the sole effect of the cytokine used alone is to inhibit reversibly the multiplication of the same cells without further impairing, once withdrawn from their environment, their capacity to divide and give rise to colonies. The lethal synergy between TGF-beta1 and UV-C was studied on mink and human cell lines, and the biomodulation by TGF-beta1 of cell killing by cisplatin, gamma rays, 5-fluorouracil or methotrexate was tested only on human cells. As investigated with UV-C-irradiated human A549 cells, TGF-beta1 appears to enhance apoptosis rather than to disturb the repair of DNA photolesions (mainly pyrimidine dimers) by the nucleotidic excision repair pathway according to results of nucleosomal ladder and comet tests. Our data raise the possibility that, in vivo, TGF-beta1 might affect the curative and/or undesirable secondary side effects of cancer therapy.
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PMID:Transforming growth factor-beta1 enhances the lethal effects of DNA-damaging agents in a human lung-cancer cell line. 921 46

A conventional and a computer search of the literature yielded 627 sequenced point mutations in the ras and p53 genes in 575 patients with leukaemia and myelodysplasia (MDS) out of a total of 4214 investigated. ras Mutations predominated in myeloid leukaemia and were more common in the disease in relapse than at presentation. There was no clinical, or haematological difference or difference in survival between ras positive and ras negative patients with acute myeloid leukaemia (AML) in adults or children, but ras mutations carried a poorer prognosis in childhood acute lymphocytic leukaemia and an increased risk of leukaemia in MDS. p53 mutations predominated in lymphoid leukaemia and were several fold more frequent in leukaemia in relapse than in the de novo disease, were associated with loss of the normal p53 allele (monosomy 17) in > 50% of cases and carried a poor prognosis in AML, MDS and chronic lymphatic leukaemia and a 3.8-fold increase risk of death in T cell acute lymphocytic leukaemia. There were 163 transitions for every 100 transversions, the expected number being ca 50. Consideration of the molecular mechanisms by which nitrous acid produces transitions allows transitions resulting from the deamination of cytosine to be distinguished from those resulting from the deamination of adenine. The former constitute 84.67% and the latter 15.33% of the 372 transitions present. Again purine-->pyrimidine and pyrimidine-->purine transversions form 80.35 and 19.65%, respectively, of the 228 transversions present. The possible bearing of this highly non-random distribution on the aetiology of point mutations in leukaemia and myelodysplasia is discussed.
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PMID:The non-random distribution of point mutations in leukaemia and myelodysplasia--a possible pointer to their aetiology. 927 67


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