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)

Copper toxicity causes hepatic damage that can lead to the development of hepatocarcinoma. Similarly, copper deficiency has been reported to increase hepatocyte tumorigenesis. Thus, the objective of this work was to explore the role of copper toxicity and deficiency in the regulation of the tumor suppressor protein p53. Using Northern analysis, Western analysis, immunocytochemistry and the human hepatoma cell line Hep G2, this work showed that elevations in hepatocyte copper consistent with Wilson's disease (5.7-fold increase) induced p53 mRNA and confirmed that copper toxicity is correlated with apoptotic cell death. However, Western analysis and immunocytochemistry showed that post-transcriptional mechanisms are a significant part of the process, with p53 translocation from the cytosol into the nucleus of copper-treated cells. Treatment of Hep G2 cells with increasing concentrations of the copper chelator tetraethylenepentamine (TEPA, 0-50 micromol/L, 48 h) reduced cellular copper and increased mean p53 mRNA abundance by over fourfold with nuclear translocation of the wild-type protein. However, TEPA treatment did not result in a loss of cell viability or appear to induce apoptosis.
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PMID:Tumor suppressor protein p53 mRNA and subcellular localization are altered by changes in cellular copper in human Hep G2 cells. 1134 94

Treatment of neuroblastoma cells with the copper chelator triethylene tetramine tetrahydrochloride induced intracellular decrease of copper content paralleled by diminished activity of the enzymes Cu, Zn superoxide dismutase, and cytochrome c oxidase. This effect appears to be specific for copper-enzymes and the treatment affects neither viability nor growth capability of cells. However, molecular markers of apoptosis Bcl-2, p53, and caspase-3 were slightly affected in these cells. When copper-deficient cells were challenged with oxidative stress generated by paraquat or puromycin, they underwent a higher degree of apoptosis with respect to copper-adequate control cells. The mechanism underlying paraquat-triggered apoptosis implies dramatic activation of caspase-3 and induction of the transcription factor p53. These results demonstrate that impairment of copper balance predisposes neuronal cells to apoptosis induced by oxidative stress. Overall findings represent a contribution to the comprehension of the link between copper-imbalance and neurodegeneration, which has recently been repeatedly suggested for the most invalidating pathologies of the central nervous system.
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PMID:Increased susceptibility of copper-deficient neuroblastoma cells to oxidative stress-mediated apoptosis. 1136 9

Methamphetamine (METH)-induced alterations in the expression of p53 and bcl-2 protein were studied in the striatum of wild type, neuronal nitric oxide synthase knockout (nNOS -/-) and copper zinc superoxide dismutase overexpressed (SOD-Tg) mice. METH treatment up-regulated p53 and down-regulated bcl-2 expression in the striatum of wild type mice. No significant alterations were observed in the expression of these proteins in the nNOS -/- or SOD-Tg mice. These data suggest that METH might cause its neurotoxic effects via the production of free radicals and secondary perturbations in the expression of genes known to be involved in apoptosis and cell death machinery.
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PMID:Methamphetamine-induced alteration in striatal p53 and bcl-2 expressions in mice. 1145 7

The mechanism of metal-mediated DNA damage by carcinogenic danthron (1,8-dihydroxyanthraquinone) and anthraquinone was investigated by the DNA sequencing technique using 32P-labeled human DNA fragments obtained from the human c-Ha-ras-1 protooncogene and the p53 tumor suppressor gene. Danthron caused DNA damage particularly at guanines in the 5'-GG-3', 5'-GGGG-3', 5'-GGGGG-3' sequences (damaged bases are underlined) in the presence of Cu(II), cytochrome P450 reductase and the NADPH-generating system. The DNA damage was inhibited by catalase and bathocuproine, suggesting the involvement of H2O2 and Cu(I). The formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine increased with increasing concentration of danthron. On the other hand, carcinogenic anthraquinone induced less oxidative DNA damage than danthron. Electron spin resonance study showed that the semiquinone radical could be produced by P450 reductase plus NADPH-mediated reduction of danthron, while little signal was observed with anthraquinone. These results suggest that danthron is much more likely to be reduced by P450 reductase and generate reactive oxygen species through the redox cycle, leading to more extensive Cu(II)-mediated DNA damage than anthraquinone. In the case of anthraquinone, its hydroxylated metabolites with similar reactivity to danthron may participate in DNA damage in vivo. We conclude that oxidative DNA damage by danthron and anthraquinone seems to be relevant for the expression of their carcinogenicity.
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PMID:Sequence-specific DNA damage induced by carcinogenic danthron and anthraquinone in the presence of Cu(II), cytochrome P450 reductase and NADPH. 1169 35

Hydroxyurea is a chemotherapeutic agent used for the treatment of myeloproliferative disorders (MPD) and solid tumors. The mutagenic and carcinogenic potential of hydroxyurea has not been established, although hydroxyurea has been associated with an increased risk of leukemia in MPD patients. To clarify whether hydroxyurea has potential carcinogenicity, we examined site-specific DNA damage induced by hydroxyurea using (32)P-5'-end-labeled DNA fragments obtained from the human p53 and p16 tumor suppressor genes and the c-Ha-ras-1 protooncogene. Hydroxyurea caused Cu(II)-mediated DNA damage especially at thymine and cytosine residues. NADH efficiently enhanced hydroxyurea-induced DNA damage. The DNA damage was almost entirely inhibited by catalase and bathocuproine, a Cu(I)-specific chelator, suggesting the involvement of hydrogen peroxide (H(2)O(2)) and Cu(I). Typical free hydroxyl radical scavengers did not inhibit DNA damage by hydroxyurea, but methional did. These results suggest that crypto-hydroxyl radicals such as Cu(I)-hydroperoxo complex (Cu(I)-OOH) cause DNA damage. Formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) was induced by hydroxyurea in the presence of Cu(II). An electron spin resonance spectroscopic study using N-(dithiocarboxy)sarcosine as a nitric oxide (NO)-trapping reagent demonstrated that NO was generated from hydroxyurea in the presence and absence of catalase. In addition, the generation of formamide was detected by both gas chromatography-mass spectrometry (GC-MS) and time-of-flight-mass spectrometry (TOF-MS). A high concentration of hydroxyurea induced depurination at DNA bases in an H(2)O(2)-independent manner, and endonuclease IV treatment led to chain cleavages. These results suggest that hydroxyurea could induce base oxidation as the major pathway of DNA modification and depurination as a minor pathway. Therefore, it is considered that DNA damage by hydroxyurea participates in not only anti-cancer activity, but also carcinogenesis.
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PMID:Hydroxyurea induces site-specific DNA damage via formation of hydrogen peroxide and nitric oxide. 1171 40

Carcinogenic benzo[a]pyrene (BP) is generally considered to show genotoxicity by forming DNA adducts of its metabolite, BP-7,8-diol-9,10-epoxide. We investigated oxidative DNA damage and its sequence specificity induced by BP-7,8-dione, another metabolite of BP, using (32)P-5'-end-labeled DNA. Formamidopyrimidine-DNA glycosylase treatment induced cleavage sites mainly at G residues of 5'-TG-3' sequence and at poly(C) sequences, in DNA incubated with BP-7,8-dione in the presence of NADH and Cu(II), whereas piperidine treatment induced cleavage sites at T mainly of 5'-TG-3'. BP-7,8-dione strongly damaged the G and C of the ACG sequence complementary to codon 273 of the p53 gene. Catalase and a Cu(I)-specific chelator attenuated the DNA damage, indicating the involvement of H(2)O(2) and Cu(I). BP-7,8-dione with NADH and Cu(II) also increased 8-oxo-7,8-dihydro-2'-deoxyguanosine formation. We conclude that oxidative DNA damage, especially double base lesions, may participate in the expression of carcinogenicity of BP in addition to DNA adduct formation.
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PMID:Double base lesions of DNA by a metabolite of carcinogenic benzo[a]pyrene. 1178 68

The p53 tumour-suppressor protein is a transcription factor that activates the expression of genes involved in cell cycle arrest, apoptosis and DNA repair. The p53 protein is vulnerable to oxidation at cysteine thiol groups. The metal-chelating dithiocarbamates, pyrrolidine dithiocarbamate (PDTC), diethyldithiocarbamate, ethylene(bis)dithiocarbamate and H(2)O(2) were tested for their oxidative effects on p53 in cultured human breast cancer cells. Only PDTC oxidized p53, although all oxidants tested increased the p53 level. Inductively coupled plasma MS analysis indicated that the addition of 60 microM PDTC increased the cellular copper concentration by 4-fold, which was the highest level of copper accumulated amongst all the oxidants tested. Bathocuproinedisulphonic acid, a membrane-impermeable Cu(I) chelator inhibited the PDTC-mediated copper accumulation. Bathocuproinedisulphonic acid as well as the hydroxyl radical scavenger d-mannitol inhibited the PDTC-dependent increase in p53 protein and oxidation. Our results show that a low level of copper accumulation in the range of 25-40 microg/g of cellular protein increases the steady-state levels of p53. At copper accumulation levels higher than 60 microg/g of cellular protein, p53 is oxidized. These results suggest that p53 is vulnerable to free radical-mediated oxidation at cysteine residues.
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PMID:Copper uptake is required for pyrrolidine dithiocarbamate-mediated oxidation and protein level increase of p53 in cells. 1196 41

Metal ions are essential components of biological systems; nevertheless, even essential elements may have toxic or carcinogenic properties. Thus, besides As(III) and Cd(II), also Ni(II) and Co(II) have been shown previously to disturb different types of DNA repair systems at low, non-cytotoxic concentrations. Since some metals exert high affinities for SH groups, we investigated whether zinc finger structures in DNA-binding motifs of DNA repair proteins are potential targets for toxic metal ions. The bacterial formamidopyrimidine-DNA glycosylase (Fpg protein) involved in base excision repair was inhibited by Cd(II), Cu(II) and Hg(II) with increasing efficiencies, whereas Co(II), As(III), Pb(II) and Ni(II) had no effect. Furthermore, Cd(II) still disturbed enzyme function when bound to metallothionein. Strong inhibition was also observed in the presence of phenylselenyl chloride, followed by selenocystine, while selenomethionine was not inhibitory. Regarding the mammalian XPA protein involved in the recognition of DNA lesions during nucleotide excision repair, its DNA-binding capacity was diminished by Cd(II), Cu(II), Ni(II) and Co(II), while Hg(II), Pb(II) and As(III) were ineffective. Finally, the H(2)O(2)-induced activation of the poly(ADP-ribose)polymerase (PARP) involved in DNA strand break detection and apoptosis was greatly reduced by Cd(II), Co(II), Ni(II) and As(III). Similarly, the disruption of correct p53 folding and DNA binding by Cd(II), Ni(II) and Co(II) has been shown by other authors. Therefore, zinc-dependent proteins involved in DNA repair and cell-cycle control may represent sensitive targets for some toxic metals such as Cd(II), Ni(II), Co(II) and Cu(II), as well as for some selenium compounds. Relevant mechanisms of inhibition appear to be the displacement of zinc by other transition metals as well as redox reactions leading to thiol/disulfide interchange.
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PMID:Interference by toxic metal ions with zinc-dependent proteins involved in maintaining genomic stability. 1206 81

High concentrations of the trace metal zinc (Zn) have previously been shown to provide transient protection of cells from apoptotic death. The molecular mechanisms responsible for this protection are not known. Thus, this work explored the ability of Zn to protect human neurons in culture (NT2-N) from Cu-mediated death and tested the hypotheses that the tumor-suppressor protein p53 plays a role in Cu-induced neuronal death and is part of the mechanism of Zn protection. Copper toxicity (100 microM) resulted in significant apoptotic neuronal death by 12 h. Addition of 100 microM Zn to Cu-treated cells increased neuronal death. However, the addition of 700 microM Zn to Cu-treated cells resulted in neuronal viability that was not different from untreated controls through 24 h. p53 mRNA abundance, while increased by the addition of Cu and 100 microM Zn, was decreased to 50% of control with the addition of 500 microM Zn in Cu-treated cells, and to 10% of control with 700 microM Zn. Consistent with its role as a transcription factor, both Western analysis and immunocytochemistry showed significant increases in nuclear p53 protein levels in Cu toxicity. The role of p53 in Cu-mediated apoptosis was further confirmed by elimination of apoptosis in Cu-treated cells that had been transfected with a dominant-negative p53 construct to prevent p53 expression. Furthermore, the addition of 500-700 microM Zn prevented the movement of p53 into the nucleus suggesting that Zn not only protects neurons from Cu toxicity by regulating p53 mRNA abundance but also by preventing the translocation of p53 to the nucleus.
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PMID:Zinc inhibits the nuclear translocation of the tumor suppressor protein p53 and protects cultured human neurons from copper-induced neurotoxicity. 1209 59

Free radicals generated by chemicals can cause sequence-specific DNA damage and play important roles in mutagenesis and carcinogenesis. Carbamoyl group (CONH2) and its derived groups (CONR2) occur as natural products and synthetic chemical compounds. We have investigated the DNA damage by carbamoyl radicals .(CONH2), one of carbon-centered radicals. Electron spin resonance (ESR) spectroscopic study has demonstrated that carbamoyl radicals were generated from formamide by treatment with H2O2 plus Cu(II), and from azodicarbonamide by treatment with Cu(II). We have investigated sequence specificity of DNA damage induced by carbamoyl radicals using 32P-labeled DNA fragments obtained from the human c-Ha-ras-1 and p53 genes. Treatment of double-stranded DNA with carbamoyl radicals induced an alteration of guanine residues, and subsequent treatment with piperidine or Fpg protein led to chain cleavages at 5'-G of GG and GGG sequences. Carbamoyl radicals enhanced Cu(II)/H2O2-mediated formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in double-stranded DNA more efficiently than that in single-stranded DNA. These results shows that carbamoyl radicals specifically induced hydroxylation of deoxyguanosine at 5' site of GG and GGG sequences in double-stranded DNA.
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PMID:Hydroxylation of deoxyguanosine at 5' site of GG and GGG sequences in double-stranded DNA induced by carbamoyl radicals. 1218 Jan 92


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