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)

Prooxidant effect of chemotherapeutic agents is of significant interest in connection with activation of oxidative stress in cancer cells. Role of development of adaptive antioxidant response to the rise of resistance to cytotoxical effect of doxorubicin (DOX) has been studied in human erythroleukemia K562 cells. Growth of resistance to DOX caused enhancement of antioxidant enzymes (Cu, Zn-SOD, Mn-SOD, catalase) elevation of Mn-SOD activity being predominant. Additional increasing of antioxidant level was elevation of GSH maintenance and level of GST-related enzymes (glutathione peroxidase, glutathione S-transferase, glutathione reductase) in resistance K562/DOX cells. The enhancement of antioxidant system prevented activation of lipid peroxidation. Furthermore, the antioxidant growth caused decrease of level of proteintyrosine kinases, thioredoxin, thioredoxin reductase in contrary to elevation of glutaredoxin activity. Increasing of Bcl-2 and suppression of p53 levels was found to be caused by the change of redox state of K562DOX cells. The data support the suggestion that adaptive antioxidant response to prooxidant effect of DOX promotes the development of cellular drug resistance.
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PMID:[Role of the antioxidant system and redox-dependent regulation of transcription factors bcl-2 and p53 in forming resistance of human K562 erythroleukemia cells to doxorubicin]. 1178 3

We studied the alpha-radiation risks in patients who received injections of Thorotrast, an X-ray contrast medium used in Europe, Japan, and the United States from 1930 to 1955. Thorotrast was composed of thorium dioxide (ThO2) and Th-232, a naturally occurring radionuclide. Because the physical half-life of ThO2 is 14 billion years and Thorotrast is hardly eliminated from the body, tissues in which it was deposited are irradiated by alpha-radiation for the entire lifetime of the subject. The dosimetry of Thorotrast patients is very complicated, but currently its reliability is quite high compared with other irradiated populations. The major causes of the death of Thorotrast patients are liver cancer, liver cirrhosis, leukemia, and other cancers. Three histologies of liver cancer are found: cholangiocarcinoma, hepatocellular carcinoma, and angiosarcoma. Although cholangiocarcinoma is the most frequent, angiosarcoma is characteristic of alpha-radiation. Among blood neoplasms with a higher incidence of increase than the general population, erythroleukemia and myelodysplastic syndrome were remarkable. Thorotrast patients exhaled a high concentration of radon (Rn-220), a progeny of Th-232, but no excesses of lung cancer in the patients of Japan, Germany, and Denmark were reported. Mutation analyses of p53 genes and loss of heterozygosity (LOH) studies at 17p locus were performed to characterize the genetic changes in Thorotrast-induced liver tumors. Interestingly, LOH, supposedly corresponding to large deletions was not frequent; most mutations were transitions, also seen in tumors of the general population, suggesting that genetic changes of Thorotrast-induced cancers are mainly delayed mutations, and not the result of the direct effects of radiation.
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PMID:Alpha-particle carcinogenesis in Thorotrast patients: epidemiology, dosimetry, pathology, and molecular analysis. 1179 40

Cancer is a multi-step, multi-genetic event. Whether oncogenic mutations cooperate with one another to transform cells and how is not well understood. The Friend murine retroviral erythroleukemia model involves mitogenic activation of the erythropoietin receptor (EpoR) by the virus env gene (F-gp55), aberrant over-expression of the transcription factor PU.1, and inactivating mutations in p53. In this report we demonstrate that concurrent expression of F-gp55 and PU.1 in erythroid target cells, in vivo, cooperate to accelerate erythroleukemia induction. Early in the disease, prior to the detection of clonal leukemic cells, activation of the EpoR by F-gp55, but not erythropoietin, resulted in transcriptional upregulation of PU.1 through a trans regulatory mechanism. This could occur in the absence of an integrated provirus within the PU.1 gene locus. The regulation of PU.1 transcription in established erythroleukemia cell lines differed depending upon the level of PU.1 protein present. Our results suggest that the action of F-gp55 contributes to both early and late stages of Friend erythroleukemia and that persistence of F-gp55 expression may be required not only to initiate erythroleukemia but to also maintain erythroleukemia following Friend virus infection.
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PMID:Oncogene cooperativity in Friend erythroleukemia: erythropoietin receptor activation by the env gene of SFFV leads to transcriptional upregulation of PU.1, independent of SFFV proviral insertion. 1185 Aug 47

Hypoxia encountered at high altitude, blood loss and erythroleukemia instigate stress erythropoiesis, which involves glucocorticoid-induced proliferation of erythroid progenitors (ebls). The tumour suppressor p53 stimulates hematopoietic cell maturation and antagonizes glucocorticoid receptor (GR) activity in hypoxia, suggesting that it may inhibit stress erythropoiesis. We report that mouse fetal liver ebls that lack p53 proliferate better than wild-type cells in the presence of the GR agonist dexamethasone. An important mediator of GR-induced ebl self-renewal, the c-myb gene, is induced to higher levels in p53(-/-) ebls by dexamethasone. The stress response to anemia is faster in the spleens of p53(-/-) mice, as shown by the higher levels of colony forming units erythroids and the increase in the CD34/c-kit double positive population. Our results show that p53 antagonizes GR-mediated ebl expansion and demonstrate for the first time that p53-GR cross-talk is important in a physiological process in vivo: stress erythropoiesis.
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PMID:The p53 tumour suppressor inhibits glucocorticoid-induced proliferation of erythroid progenitors. 1203 55

To examine the p53-mediated biological activities and signalling pathways, we generated stable transfectants of the p53-null IW32 murine erythroleukemia cells expressing the temperature-sensitive p53 mutant DNA, tsp53(val135). Two clones with different levels of p53 protein expression were selected for further characterization. At permissive temperature, clone 1-5 cells differentiated along the erythroid pathway, and clone 3-2 cells that produced greater levels (3.5-fold) of p53 underwent apoptosis. Apoptosis of 3-2 cells was accompanied by mitochondrial cytochrome c release and caspase activation as well as by cleavage of caspase substrates. Bax protein was induced to a similar extent in these clones by wild-type p53; expression of p21(Cip1/Waf1) and p27(Kip1) proteins was also increased. However, significantly lesser extent of induction for both CDK inhibitors was detected in the apoptotic 3-2 clone. The general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD.fmk) blocked the p53-induced apoptosis in 3-2 cells, with a concomitant elevation of p27(Kip1), suggesting that p27(Kip1) protein underwent caspase-dependent proteolysis in the apoptotic 3-2 cells. Together these results linked a pathway involving cytochrome c release, caspase activation and p27(Kip1) degradation to the p53-induced apoptosis in IW32 erythroleukemia cells.
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PMID:Modulation of caspase activation and p27(Kip1) degradation in the p53-induced apoptosis in IW32 erythroleukemia cells. 1222 Jun 22

Leukemia, a form of haematological malignancy, is a multi-stage disease and a wide range of diverse genes has been speculated to correlate with its initiation and development. Ras has been speculated to be an initiating gene for haematological malignancy, but more investigation will be needed to determine the genes associated with the progression of the disease. 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat leukemia provides a good tool for research into various stages of the disease. The entire coding regions of p53 and ras genes were examined for mutations in the present study. In this experiment, we used fluorescence-labeled polymerase chain reaction single-stranded conformation polymorphism analysis (PCR-SSCP) and direct sequencing to detect mutations of both genes on rat erythroleukemia. Fifteen out of 18 (83.3%) rat leukemias were found to have N-ras codon 61 mutation, consistent with previous results. The result of direct sequencing showed a single base substitution (CAA to CTA), resulting in an amino-acid change from Gln to Leu. No mutations were found in H-ras, K-ras or codon 12 of N-ras. The incidence of p53 gene mutation was 16.6% (3/18) in rat leukemia at late-stage. In the present study, mutation of the p53 gene was detected in three DMBA-induced leukemias as follows: a single-base substitution (CAT to CGT) at codon 177 (exon 5), resulting in an amino-acid change from Arg to Leu, a CGG to CTG/CGG changed at codon 211 (exon 6) resulting in an amino-acid change from His to Arg/His, and a GGG to TGG at codon 242 (exon 6) resulting in an amino-acid change from Gly to Trp, respectively. Thus, mutations of p53 gene do not seem to respond to the carcinogenesis of the DMBA-induced leukemia, in contrast to mutation of the N-ras oncogene, and may possibly be involved in the progress of multi-stage leukemogenesis.
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PMID:Incidence of p53 and ras gene mutations in DMBA-induced rat leukemias. 1238 83

Various cytokines have been shown to protect cells from p53-dependent apoptosis. To investigate the mechanism underlying cytokine-mediated survival, we used a Friend virus-transformed erythroleukemia cell line that expresses a temperature-sensitive p53 allele. These cells express the spleen focus-forming virus-encoded envelope glycoprotein gp55 that allows the cells to proliferate in the absence of erythropoietin (EPO). These cells respond to p53 activation at 32 degrees C by undergoing G(1) cell cycle arrest and apoptosis. In the presence of EPO, p53 activation leads only to prolonged but viable G(1) arrest. These findings indicate that EPO functions as a survival factor and that gp55/EPO receptor signaling is distinct from EPO/EPO receptor signaling. We demonstrate that p53-dependent apoptosis results in mitochondrial damage as shown by loss of mitochondrial membrane potential, increase in intracellular calcium, and release of mitochondrial cytochrome c into the cytosol. EPO prevented all of these changes including the subsequent activation of caspases. We identify an intrinsic phosphatidylinositol-3'-OH kinase/protein kinase B (PI3'K/PKB)-dependent survival pathway that is constitutively active in these cells. This survival pathway limits p53-dependent apoptosis. We propose that EPO promotes survival through a distinct pathway that is dependent on JAK2 but independent of STAT5 and PI3'K.
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PMID:The death-promoting activity of p53 can be inhibited by distinct signaling pathways. 1239 87

Tumor cells can acquire aggressive phenotypes secondary to the loss of expression of the wild-type p53 (WTp53) protein or by the gain of function for selected mutant p53 (MTp53) proteins. However, it is unclear as to whether the development of aggressive phenotypes is inter-related. Herein we report the radiosensitivity, chemosensitivity, and in vivo growth characteristics of isogenic p53(-/-) MEF ras-transformants that variably express an MTp53 protein. Initial experiments revealed significant clonal heterogeneity with respect to cellular sensitivity to DNA-damaging agents (i.e. ionizing radiation, ultraviolet radiation, cis-platinum, and methotrexate) within subclones of a pre-existing p53(-/-) MEF cell population. Moreover, this differential sensitivity was also observed within subclones of p53(-/-) MEF cells transformed with an activated ras allele, suggesting that secondary genetic events and clonal selection, but not cellular transformation per se, may drive the resistance patterns for certain null-p53 tumors. In contrast, uniform resistance was observed following the additional transfection of an MTp53 allele (MTp53pro193) into p53(-/-) MEF transformants and p53(-/-) DP-16 Friend erythroleukemia cells, consistent with a gain of MTp53 function for this allele. Relative tumor growth rate and experimental metastatic ability was not enhanced by MTp53pro193 expression. Our results support the concept that gain of MTp53pro193 function leads to the selection of dominant clones, which may exhibit cellular resistance following cancer therapy.
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PMID:Resistance to DNA-damaging agents is discordant from experimental metastatic capacity in MEF ras-transformants-expressing gain of function MTp53. 1277 47

Retroviruses lacking oncogenes have been known to induce various types of cancer when inoculated into animals. Among these, Friend virus, discovered by Charlotte Friend in 1957, is capable of inducing erythroleukemias when injected into susceptible strains of mice. Since its discovery, this murine model of leukemogenesis has been extensively used to study the multistage nature of cancer. In the past two decades, several oncogenes and tumour suppressor genes, which play critical roles in the induction and progression of Friend erythroleukemia, have been identified. Retroviral insertional activation of Fli-1 and Spi-1/PU.1, as well as loss of tumour suppressor genes such as p53 or p45 NFE2 have been shown to be critical for the induction and progression of Friend virus-induced erythroleukemias. The majority of these genetic changes have also been implicated in various types of human neoplastic transformations. In this review we will discuss the genetic changes associated with Friend Disease, the temporal order during induction and progression of disease, and the function of these genes in both normal erythroid development as well as malignant transformation.
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PMID:Friend virus-induced erythroleukemias: a unique and well-defined mouse model for the development of leukemia. 1289 91

We studied the role of p53 gene in the biophysics and biology in murine erythroleukemia cell line (MEL), with the goal of understanding the influence of this tumor suppressor gene on the deformability and metastasis of tumor cells. Experiments were performed on MEL and p53-transfected MEL (MEL-M with mutant p53 gene and MEL-W with wild-type p53 gene). The cell growth curves indicated that the over-expression of wild-type p53 gene significantly suppressed the growth of MEL, with G(0)-G(1) arrest and apoptosis shown by flow cytometric assays. Confocal laser scanning microscopy revealed that the MEL-W had a more compact organization of the F-Actin cytoskeleton than MEL and MEL-M. Fluorescence polarization measurement indicated a higher membrane fluidity of MEL-W than the other two groups. Fourier transform infrared spectroscopy (FT-IR) showed changes in the composition and/or structure of membrane lipids in MEL-W, with decreases in secondary structures of proteins such as alpha-helix, turns and bends and random coil, in comparison to MEL and MEL-M. The osmotic fragility curves indicated that MEL-W was more fragile and micropipette experiments showed that they had increased elasticity and reduced deformability in comparison to MEL and MEL-M. The adhesion assay with the use of the flow chamber revealed a lower adhesion rate of MEL-W to endothelial cells at high shear stress. The present study on the molecular biology with biophysics of MEL cells contributes to our knowledge on the tumor suppressor gene p53.
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PMID:Wild type p53 gene causes reorganization of cytoskeleton and, therefore, the impaired deformability and difficult migration of murine erythroleukemia cells. 1290 27


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