UNIPROT:P04637 - FACTA Search

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Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ribonucleotide reductase consists of two non-identical protein subunits that are required for enzyme activity. These subunits are encoded by different genes and are not expressed coordinately as the cells pass through the cell cycle. Using specific cDNAs for the non-heme iron (NHI) and the effector-binding (EB) subunits the levels of the mRNAs for these two subunits were determined in leukemia L1210 cells during the transition from the G0/G1 phase to the S and G2/M phases of the cell cycle. Synchronized populations of L1210 cells were obtained either by ethylene glycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) treatment or by enrichment by elutriation centrifugation. The changes in the levels of the mRNAs for NHI and EB subunits were compared with the changes in the levels of the mRNAs for actin, p53, c-myc, thymidine incorporation into DNA, and DNA content by flow cytometric measurements. Synchronization of the cells by the two methods resulted in quantitative differences in the responses. The EGTA synchronized L1210 cells showed maximal increases of 9.3- and 5.7-fold in the mRNAs for the NHI and EB subunits, respectively. The peak level of the NHI mRNA was observed at 12 hr after the addition of calcium ions. The peak increase in the level of the mRNA for the EB subunit was observed between 12 and 15 hr after the addition of calcium ions. The rate of increase for the mRNA for c-myc was greater than the increase in the mRNA for the NHI subunit.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes in messenger RNA levels for the subunits of ribonucleotide reductase during the cell cycle of leukemia L1210 cells. 270 Sep 14

An oncogene product, p53, interacts with a simian virus 40-encoded T-antigen, which is an initiation protein for the viral DNA replication and also works as DNA helicase during elongation. Here we examine the interaction of p53 with cellular DNA helicase. A recombinant human wild type p53 fused with glutathione S-transferase was immobilized on glutathione-agarose as a ligand for affinity column. Hela cell extract was applied to the p53 column and the adsorbed proteins were eluted with buffers containing salt, 50% ethylene glycol, and glutathione. The ethylene glycol fraction contained a number of p53 binding proteins, and this fraction showed a DNA helicase activity measured by the displacement of DNA fragment from partially duplexed M13 DNA. The DNA helicase translocated in a 5'-to-3' direction on the single-stranded DNA using ATP as an energy source. The glutathione fraction that contained the p53 glutathione S-transferase fused protein also showed the same activity. The corresponding fractions from a control column carrying glutathione S-transferase showed only a trace amount of activity of DNA helicase. Therefore, the binding may be specific. Furthermore, an anti-p53 antibody column retained a p53-DNA helicase complex when the crude extracts of human placenta and of osteosarcoma cells were applied. These results indicate that p53 physically interacts with DNA helicase in vitro as well as in vivo.
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PMID:Anti-oncogene product p53 binds DNA helicase. 795 81

A quartz crystal microbalance DNA hybridization biosensor, based on thiol-derivatized peptide nucleic acid (PNA) probes, offers unusual in situ differentiation of single-base mismatches. A large excess of a single-base mismatch oligonucleotide has no effect on the frequency response of the target. Such remarkable distinction between perfect matches and mismatches is illustrated by the detection of a common mutation in the p53 gene. The greater specificity of the new mass-sensitive indicatorless hybridization device over those of analogous PNA-based carbon electrodes is attributed to the formation of a PNA monolayer and the use of a hydrophilic ethylene glycol linker. The improved specificity is coupled to very fast (3-5 min) hybridization in a low-ionic-strength medium.
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PMID:Mismatch-sensitive hybridization detection by peptide nucleic acids immobilized on a quartz crystal microbalance. 941 22

The binding of collagen to platelet glycoprotein VI (GPVI) leads to the subsequent activation of phospholipase Cgamma2 through a pathway that is dependent on the Fc receptor gamma (FcR gamma) chain and the tyrosine kinase p72syk. We have investigated the role of platelet Src-family kinases in this signalling pathway. The selective Src-family kinase inhibitor PP1 prevented collagen-stimulated increases in whole-cell tyrosine phosphorylation and tyrosine phosphorylation of the FcR gamma chain and p72syk. A similar set of observations was made for a collagen-related peptide (CRP), which binds to GPVI but not to the integrin alpha2beta1 (GPIa/IIa). These effects were seen at a concentration of PP1 that inhibited platelet aggregation, dense granule release and Ca2+ mobilization induced by CRP, but not aggregation and Ca2+ mobilization mediated by the G-protein-coupled receptor agonist thrombin. After stimulation by CRP or collagen, the Src-family kinases p59fyn and p53/56lyn became associated with several tyrosine-phosphorylated proteins including the FcR gamma chain. This was not true of the other platelet Src-family kinases. The association between the FcR gamma chain and p59fyn was also seen under basal conditions, and was stable only in the weak detergent Brij96 but not in Nonidet P40, suggesting a non-SH2-dependent interaction. These results provide strong evidence for the involvement of p59fyn and p53/56lyn in signalling via GPVI, with p59fyn possibly acting upstream of FcR gamma chain phosphorylation.
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PMID:Evidence for the involvement of p59fyn and p53/56lyn in collagen receptor signalling in human platelets. 993 17

Little is known as yet about the role of apoptosis in pancreatic damage. This study evaluated the effects of supraphysiologic concentrations of the cholecystokinin (CCK) analog, cerulein, which causes cell damage in vitro and acute pancreatitis in vivo, on cell proliferation and DNA fragmentation in the rat pancreatic acinar cell line AR4-2J. Cerulein inhibited the cell proliferation of AR4-2J time- and dose-dependently to approximately 60% of the control level at 10(-6) M after 72 h. DNA fragmentation, as assessed by both electrophoresis and enzyme-linked immunosorbent assay (ELISA), occurred at cerulein concentrations > or = 10(-8) M. The maximal DNA fragmentation as measured by ELISA was reached after 24 h. Cerulein at concentrations > or = 10(-9) M induced wild-type p53. Glutathione (1 mM) diminished the effects of cerulein on both cell proliferation and DNA fragmentation, whereas spermine (100 microM), which partially attenuated DNA fragmentation, did not have an effect on cell proliferation. The CCK-A-receptor antagonist loxiglumide completely abolished the effect of cerulein on DNA fragmentation. The serine-protease inhibitor FUT-175 (10 microM), the cysteine-protease inhibitor NCO-700 (5 mM), and ethylene glycol tetraacetic acid (EGTA; 500 microM) all had no effects on the changes in cell proliferation and DNA fragmentation induced by cerulein. The data suggest that supraphysiologic concentrations of cerulein rapidly induce apoptosis in AR4-2J cells and only later inhibit cell proliferation. These effects are mediated by CCK-A receptors. Cerulein-induced apoptosis may involve the induction of wild-type p53 or glutathione depletion or both.
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PMID:Supraphysiologic concentrations of cerulein induce apoptosis in the rat pancreatic acinar cell line AR4-2J. 1041 96

A novel method was developed to determine the oxidation status of proteins in cultured cells. Methoxy-polyethylene glycol-maleimide MW 2000 (MAL-PEG) was used to covalently tag p53 protein that was oxidized at cysteine residues in cultured cells. Treatment of MCF7 breast cancer cells with pyrrolidine dithiocarbamate (PDTC), a metal chelator, resulted in a minimum of 25% oxidation of p53. The oxidized p53 had an average of one cysteine residue oxidized per p53 protein molecule. The effect of PDTC treatment on downstream components of the p53 signal-transduction pathway was tested. PDTC treatment prevented actinomycin D-mediated up-regulation of two p53 effector gene products, murine double minute clone 2 oncoprotein and p21(WAF1/CIP1) (where WAF1 corresponds to wild-type p53-activated fragment 1 and CIP1 corresponds to cyclin-dependent kinase-interacting protein 1). Actinomycin D treatment led to accumulation of p53 protein in the nucleus. However, when cells were simultaneously treated with PDTC and actinomycin D, p53 accumulated in both the nucleus and the cytoplasm. The data indicate that an average of one cysteine residue per p53 protein molecule is highly sensitive to oxidation and that p53 can be efficiently oxidized by PDTC in cultured cells. PDTC-mediated oxidation of p53 correlates with altered p53 subcellular localization and reduced activation of p53 downstream effector genes. The novel method for detecting protein oxidation detailed in the present study may be used to determine the oxidation status of specific proteins in cells.
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PMID:p53 protein oxidation in cultured cells in response to pyrrolidine dithiocarbamate: a novel method for relating the amount of p53 oxidation in vivo to the regulation of p53-responsive genes. 1099 50

A single dose of Mpl ligand (Mpl-L) given immediately after lethal DNA-damaging regimens prevents the death of mice. However, the mechanism of this myeloprotection is unknown. The induction of p53-dependent apoptosis in response to DNA damage signals suggests that immediate administration of Mpl-L may inhibit p53-dependent apoptosis. This hypothesis was tested by administering a single injection of pegylated murine Megakaryocyte Growth and Development Factor (PEG-rmMGDF, a truncated recombinant Mpl-L) to p53(-/-) and wild-type mice immediately after carboplatin (80 mg/kg) and 7.5 Gy total body gamma-irradiation. PEG-rmMGDF was required to prevent the death of wild-type mice, whereas p53(-/-) mice survived with or without the exogenous cytokine. The degree of platelet depression and subsequent recovery was comparable in p53(-/-) mice to wild-type animals given PEG-rmMGDF. Hence, either Mpl-L administration or p53-deficiency protected multipotent hematopoietic progenitors and committed megakaryocyte precursors. The myelosuppressive regimen induced expression of p53 and the p53 target, p21(Cipl) in wild-type bone marrow, indicating that Mpl-L acts downstream of p53 to prevent apoptosis. Constitutive expression of the proapoptotic protein Bax, was not further increased. Bax(-/-) mice survived the lethal regimen only when given PEG-rmMGDF; however, these Bax(-/-) mice showed more rapid hematopoietic recovery than did identically-treated wild-type mice. Therefore, administration of Mpl-L immediately after myelosuppressive chemotherapy or preparatory regimens for autologous bone marrow transplantation should prevent p53-dependent apoptosis, decrease myelosuppression, and reduce the need for platelet transfusions.
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PMID:Mpl ligand prevents lethal myelosuppression by inhibiting p53-dependent apoptosis. 1156 94

Protein sulfhydryl groups can undergo reversible oxidation reactions in response to reactive oxygen and reactive nitrogen species. Sensitive detection of sulfhydryl group oxidation in specific proteins is required to further our understanding of protein redox changes in biological systems. In general, to detect reversible oxidation reactions the oxidized sulfur atom is reduced to a sulfhydryl group followed by a reaction with a quantifiable agent. Our aim was to develop a sensitive method to detect reversibly oxidized protein sulfhydryl groups in a Western blot format. Conjugation of methoxypolyethylene glycol-maleimide (MAL-PEG) to protein sulfhydryl groups was optimized. Once MAL-PEG forms a covalent bond with the protein, the MAL-PEG-protein conjugate can be detected as a band shift by western analysis. The efficiency of MAL-PEG conjugation to protein was determined with creatine kinase. MAL-PEG conjugated to approximately 100% of the available sulfhydryl groups on creatine kinase within 30 min. Band shift detection sensitivity was measured using the redox-regulated protein p53. MAL-PEG conjugation coupled to western analysis detected a minimum of 0.23 pmol of oxidized p53. The MAL-PEG conjugation method described in this communication can be used to assess the reversible sulfhydryl oxidation status of proteins for which antibodies suitable for western analysis are available.
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PMID:Development of a sensitive assay to detect reversibly oxidized protein cysteine sulfhydryl groups. 1181 84

A sterically stabilized immunolipoplex (TsPLP), containing an antitransferrin receptor single-chain antibody fragment (TfRscFv)-PEG molecule, has been developed to specifically and efficiently deliver a therapeutic gene to tumor cells. A postcoating preparation strategy was employed in which a DNA/lipid complex (lipoplex) was formed first and then sequentially conjugated with PEG and TfRscFv. The complex prepared by this method was shown to be superior in ability to deliver genes to tumor cells than when prepared by a common precoating strategy, in which DNA is mixed with TfRscFv-PEG conjugated liposome. Using prostate cancer cell line DU145, a comparison was made between the in vitro and in vivo gene delivery efficiencies of four complexes, Lipoplex (LP), PEG-Lipoplex (PLP), TfRscFv-PEG-Lipoplex (TsPLP) and our standard TfRscFv-Lipoplex (TsLP). In vitro, the order of transfection efficiency was TsLP>LP approximately TsPLP>PLP. However, in vivo the order of transfection efficiency, after systemic administration via the tail vein, was TsPLP>TsLP>LP or PLP with TsPLP-mediated exogenous gene expression in tumor being two-fold higher than when mediated by TsLP. This suggests that the in vitro transfection efficiency of TsPLP was not indicative of its in vivo efficiency. In addition, it was found that the level of exogenous gene expression in the tumor mediated by TsPLP was higher than that mediated by TsLP and did not decrease over the time. More importantly, high exogenous gene expression in tumor, but low expression in liver, was observed after an i.v. delivery of TsPLP carrying either the GFP reporter gene or the p53 gene, indicating that tumor preferential targeting was maintained by this complex in the presence of PEG. These findings show that incorporation of PEG into our targeted lipoplex results in a more efficient delivery of the complex to the tumor cells, possibly by inhibiting the first pass clearance observed with non-PEG containing liposomes. Therefore, these data demonstrate that TsPLP is a improvement over our previously established tumor targeted gene delivery complex for systemic gene therapy of cancer.
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PMID:A sterically stabilized immunolipoplex for systemic administration of a therapeutic gene. 1522 29

Experimental hyperoxaluria and calcium oxalate (CaOx) crystals are associated with renal epithelial injury and cell death. A recent study has demonstrated an oxalate-induced increase in cellular apoptosis in vitro, and speculates that this phenomenon may contribute to stone formation. We investigated the incidence of apoptotic cells and the expression of apoptosis related genes in the kidneys of stone-forming rats. Male Wistar rats were administrated ethylene glycol in drinking water and force fed with 1alpha-OH-D3. Apoptosis was detected as a ladder of fragmented DNA in agarose gels of electrophoresed genomic DNA. Apoptotic cells were localized by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method. The expression of apoptosis-related genes was analyzed by both reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. While no labeling was detected in the controls or on the first day of administration by the TUNEL method, labeling began to be detected in the renal tubular epithelium of the outer medulla at day 3, and the number of labeled cells increased progressively during the observation period. A ladder of DNA fragments was demonstrated in the kidneys of rats after 2 weeks. Immunohistochemical studies revealed the expression of Fas ligand (Fas L), Bax and interleukin-1 beta converting enzyme (ICE) in the renal tubular epithelium of the descending limb of loop of Henle and the distal convoluted tubules. mRNA of the ICE, c-myc, p53 and Fas L genes was also upregulated in the kidneys of the stone-forming rats.
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PMID:Apoptosis and its related genes in renal epithelial cells of the stone-forming rat. 1523 56

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