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 carcinogenicity associated with chronic inflammation has been attributed to neutrophils and the oxidants they produce. Neutrophils accumulate at sites of chronic inflammation, where they are stimulated to produce hydrogen peroxide which is converted to hypochlorous acid by coreleased myeloperoxidase. We report here that levels of the tumor suppressor protein p53 were increased in cultured human skin fibroblasts that had been incubated with stimulated neutrophils. The increase in p53 required the myeloperoxidase-dependent generation of hypochlorous acid and could be mimicked by exposing cells to a flux of hypochlorous acid produced by purified myeloperoxidase and a hydrogen peroxide-generating system. Levels of p53 were very sensitive to hypochlorous acid, with fluxes as low as 0.2 microM per min being effective. Levels of the p53-dependent protein WAF1/CIP1 were also elevated when fibroblasts were treated with hypochlorous acid. This result indicates that the p53 in the cells treated with hypochlorous acid was transcriptionally active. Hydrogen peroxide alone also elevated p53 and WAF1/CIP1, but the fluxes required were nearly 10-fold higher than those that were effective for hypochlorous acid. Our results implicate hypochlorous acid in the neutrophil-dependent initiation of a signal transduction pathway which could minimize the carcinogenicity of chronic inflammation.
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PMID:Hypochlorous acid activates the tumor suppressor protein p53 in cultured human skin fibroblasts. 979 59

To clarify the mechanism of carcinogenesis by hair dyes, we compared the extent of DNA damage induced by mutagenic m-phenylenediamine and 4-methoxy-m-phenylenediamine, using 32P-5'-end-labeled DNA fragments obtained from the human c-Ha-ras-1 protooncogene and the p53 tumor suppressor gene. Carcinogenic 4-methoxy-m-phenylenediamine caused DNA damage at thymine and cytosine residues in the presence of Cu(II). Catalase and bathocuproine, a Cu(I)-specific chelator, inhibited 4-methoxy-m-phenylenediamine-induced DNA damage, suggesting the involvement of H2O2 and Cu(I). Superoxide dismutase (SOD) enhanced the DNA damage. Formation of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) was induced by 4-methoxy-m-phenylenediamine in the presence of Cu(II). UV-visible spectroscopic studies have shown that Cu(II) mediated autoxidation of 4-methoxy-m-phenylenediamine and SOD accelerated the autoxidation. On the other hand, non-carcinogenic m-phenylenediamine did not cause clear DNA damage and significant autoxidation even in the presence of Cu(II). These results suggest that carcinogenicity of m-phenylenediamines is associated with ability to cause oxidative DNA damage rather than bacterial mutagenicity.
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PMID:DNA damage induced by m-phenylenediamine and its derivative in the presence of copper ion. 980 51

It is now generally accepted that massive neuronal death due to oxidative stress is a regular feature of brains in neurodegenerative diseases. However, much less attention has been given to the death of glial cells. In this study, we examined p53-sensitive apoptosis of cells by using human glioblastoma A172 cells and p53-deficient mouse astrocytes. In human A172 cells, hydrogen peroxide (H2O2) caused cell death in a time- and concentration-dependent manner, accompanied by nucleosomal DNA fragmentation and chromatin condensation. After treatment with H2O2, p53 protein was highly expressed and protein levels of Bak, p21WAF1/CIP1 and GADD45 were also enhanced. However, the protein levels of Bcl-2 and Bax did not change. On the other hand, primary cultured astrocytes from p53-deficient mouse brain grew faster than wild-type and heterozygous astrocytes. In addition, p53-deficient astrocytes were more resistant to H2O2-induced apoptosis than wild-type and heterozygous astrocytes. These results suggest that glial proliferation and the repair of damaged DNA may be regulated by p53-induced p21WAF1/CIP1 and GADD45, and that glial apoptosis caused by oxidative stress may be mediated by p53-induced Bak.
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PMID:Hydrogen peroxide-induced apoptosis mediated by p53 protein in glial cells. 989 Jun 30

Reactive oxygen species (ROS) play an important role in cell death induced by many different stimuli. This study shows that hydrogen peroxide-induced apoptosis in T-cells did not require tyrosine kinase p561ck, phosphatase CD45, the CD95 receptor and its associated Caspase-8. H2O2-triggered cell death led to the induced cleavage and activation of Caspase-3. Hydrogen peroxide-treatment of T-cells resulted in the formation of mitochondrial permeability transition pores, a rapid decrease of the mitochondrial transmembrane potential delta psi(m) and the release of Cytochrome C. Inhibition of the mitochondrial permeability transition by bongkrekic acid (BA), or interference with the mitochondrial electron transport system by rotenone or menadione prevented the cytotoxic effect of H2O2. Antimycin A, a mitochondrial inhibitor that increases the release of mitochondrial ROS (MiROS), enhanced apoptosis. Overexpression of Bcl-2 and the viral anti-apoptotic proteins BHRF-1 and E1B 19K counteracted H2O2-induced apoptosis. Pharmacological and genetic inhibition of transcription factor NF-kappaB protected cells from hydrogen peroxide-elicited cell death. This detrimental effect of NF-kappaB mediating hydrogen peroxide-induced cell death presumably relies on the induced expression of death effector genes such as p53, which was NF-kappaB-dependently upregulated in the presence of H2O2.
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PMID:Hydrogen peroxide-induced apoptosis is CD95-independent, requires the release of mitochondria-derived reactive oxygen species and the activation of NF-kappaB. 998 25

The observation that apoptosis is an inherent pathway in oligodendrocytes development coupled with the notion that wild-type p53 is expressed in these cells, prompted us to investigate the interrelationship between the two phenomena. Using a permanent oligodendroglia-like cell line (OLN 93), we examined the role of p53 protein in apoptosis following a DNA insult induced by a brief exposure to H2O2. A marked translocation of p53 from the cytosolic to the nuclear compartment was notable by 20 min, following a 5 min treatment with 1 mM H2O2 as identified by cell immunostaining. By 48 h following H2O2 addition, nearly 60% of the cells exhibited p53 in the nuclei. At this time, a large proportion of the cells underwent apoptosis as identified by DAPI nuclear staining. The genotoxic-induced p53 relocalization appeared to be cell cycle phase specific; thus OLN 93 cultures enriched for cells in the G0/G1 stage by serum starvation, and abundant in nuclear-associated p53, were more susceptible to H2O2-induced apoptosis than their untreated counterparts and than double thymidine block, G1/S enriched, cultures. Analysis of the expression of p53 downstream genes indicated that p21 and mdm2 were upregulated following p53 nuclear translocation. From the kinetics of protein accumulation, it appears that mdm2 enhancement accelerated the exit of p53 from the nucleus to the cytosol. Our results suggest that following stress, oligodendroglia-like cells are induced to undergo p53-dependent apoptosis, an event that coincides with p53 nuclear translocation and is cell-cycle related.
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PMID:Hydrogen peroxide induces nuclear translocation of p53 and apoptosis in cells of oligodendroglia origin. 1006 87

DNA damage induced by reactive oxygen species (ROS) is considered an important intermediate in the pathogenesis of human conditions such as cancer and aging. By developing an oxidative-induced DNA damage mapping version of the Ligation-mediated polymerase chain reaction (LMPCR) technique, we investigated the il vivo and in vitro frequencies of DNA base modifications caused by ROS in the human p53 and PGK1 gene. Intact human male fibroblasts were exposed to 50mM H2O2, or purified genomic DNA was treated with 5 mM H2O2, 100 microM Ascorbate, and 50 microM, 100 microM, or 100 microM of Cu(II), Fe(II), or Cr(VI) respectively. The damage pattern generated in vivo was nearly identical to the in vitro Cu(II) or Fe(III) damage patterns; damage was non-random with guanine bases heavily damaged. Cr(VI) generated an in vitro damage pattern similar to the other metal ions, although several unique thymine positions were damaged. Also, extra nuclear sites are a major contributor of metal ions (or metal-like ligands). These data show that the local probability of H2O2-mediated DNA damage is determined by the primary DNA sequence, with chromatin structure having a limited effect. The data suggest a model in which DNA-metal ion binding domains can accommodate different metalions. LMPCR's unique aspect is a blunt-end ligation of an asymmetric double-stranded linker, permitting exponential PCR amplification. An important factor limiting the sensitivity of LMPCR is the representation of target gene DNA relative to non-targeted genes; therefore, we recently developed a method to eliminate excess non-targeted genomic DNA. Restriction enzyme-digested genomic DNA is size fractionated by Continuous Elution Electrophoresis (CEE), capturing the target sequence of interest. The amount of target DNA in the starting material for LMPCR is enriched, resulting in a stronger amplification signal. CEE provided a 24-fold increase in the signal strength attributable to strand breaks plus modified bases created by ROS in the human p53 and PGK1 genes, detected by LMPCR. We are currently taking advantage of the enhanced sensitivity of target gene-enriched LMPCR to map DNA damage induced in human breast epithelial cells exposed to non-cytotoxic concentrations of H2O2.
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PMID:Mapping oxidative DNA damage at nucleotide level. 1009 55

We investigated DNA damage induced by aminoacetone, a metabolite of threonine and glycine. Pulsed-field gel electrophoresis revealed that aminoacetone caused cellular DNA cleavage. Aminoacetone increased the amount of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in human cultured cells in a dose-dependent manner. The formation of 8-oxodG in calf thymus DNA increased due to aminoacetone only in the presence of Cu(II). DNA ladder formation was observed at higher concentrations of aminoacetone than those causing DNA cleavage. Flow cytometry showed that aminoacetone enhanced the generation of hydrogen peroxide (H2O2) in cultured cells. Aminoacetone caused damage to 32P-5'-end-labeled DNA fragments, obtained from the human c-Ha-ras-1 and p53 genes, at cytosine and thymine residues in the presence of Cu(II). Catalase and bathocuproine inhibited DNA damage, suggesting that H2O2 and Cu(I) were involved. Analysis of the products generated from aminoacetone revealed that aminoacetone underwent Cu(II)-mediated autoxidation in two different pathways: the major pathway in which methylglyoxal and NH+4 are generated and the minor pathway in which 2,5-dimethylpyrazine is formed through condensation of two molecules of aminoacetone. These findings suggest that H2O2 generated by the autoxidation of aminoacetone reacts with Cu(I) to form reactive species capable of causing oxidative DNA damage.
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PMID:Oxidative DNA damage induced by aminoacetone, an amino acid metabolite. 1022 39

ortho-Phenylphenol (OPP) and its sodium salt, which are used as fungicides and antibacterial agents, have been found to cause carcinomas in the urinary tract of rats. To clarify the carcinogenic mechanism of OPP, we compared the DNA damage inducing ability of an OPP metabolite, phenyl-1,4-benzoquinone (PBQ) with that of another metabolite, phenylhydroquinone (PHQ). Pulsed field gel electrophoresis showed that PBQ and PHQ induced DNA strand breakage in cultured human cells, but PBQ did it more efficiently than PHQ. Significant increases in 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) were observed in cells treated with PBQ and PHQ, and the increase of 8-oxodG induced by PBQ was significantly higher than that induced by PHQ. Using 32P-5'-end-labeled DNA fragments obtained from human p53 tumor suppressor gene and c-Ha-ras-1 protooncogene, we showed that PBQ plus NADH, and also PHQ, induced DNA damage frequently at thymine residues, in the presence of Cu(II). The intensity of DNA damage by PBQ was stronger than that by PHQ, showing higher importance of PBQ than other OPP metabolites. Catalase and bathocuproine inhibited Cu(II)-mediated DNA damage by PBQ plus NADH and PHQ, suggesting that H2O2 reacts with Cu(I) to produce active species causing DNA damage. Electron spin resonance and UV-visible spectroscopic studies have demonstrated generation of semiquinone radical and superoxide from the reaction of PBQ with NADH or the Cu(II)-mediated autoxidation of PHQ. The present results suggest that these OPP metabolites cause oxidative DNA damage through H2O2 generation in cells, and the damage may lead to mutation and carcinogenesis. It is concluded that PBQ may play a more important role in the expression of OPP carcinogenicity than other OPP metabolites.
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PMID:Oxidative damage to cellular and isolated DNA by metabolites of a fungicide ortho-phenylphenol. 1033 3

Genotoxic chemicals not only damage cellular DNA, but may also induce cell apoptosis if they are lethal to the cell. p53, Bcl-2 and Bax play important roles in the regulation of genotoxic chemical induced cell apoptosis. Since the mechanisms by which cellular DNA damaged by different DNA-damaging chemicals may not be the same, we studied the involvement of p53, Bcl-2 and Bax in apoptosis induced by methyl methanesulfonate (MMS) and hydrogen peroxide (H2O2). H2O2 damages DNA by free radical generation and MMS damages DNA by DNA methylation. At non-lethal doses, both H2O2 and MMS induced high level of p53 protein accumulation. Nevertheless, while the amount of p53 protein increased with the dose of MMS and the occurrence of apoptotic cell death events, H2O2 doses that induce cell apoptosis attenuated the p53 protein accumulation level. Lethal MMS treatment also increased Bax, but not Bcl-2 expression, whereas in H2O2 induced apoptosis, the level of both Bcl-2 and Bax declined. These results indicate that toxic chemicals differentially regulate the accumulation of p53 protein. Thus, the pathways of toxic chemicals induced cell apoptosis are different and independent.
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PMID:Methyl methanesulfonate and hydrogen peroxide differentially regulate p53 accumulation in hepatoblastoma cells. 1040 64

Gene mutations in invertebrates have been identified that extend life span and enhance resistance to environmental stresses such as ultraviolet light or reactive oxygen species. In mammals, the mechanisms that regulate stress response are poorly understood and no genes are known to increase individual life span. Here we report that targeted mutation of the mouse p66shc gene induces stress resistance and prolongs life span. p66shc is a splice variant of p52shc/p46shc (ref. 2), a cytoplasmic signal transducer involved in the transmission of mitogenic signals from activated receptors to Ras. We show that: (1) p66shc is serine phosphorylated upon treatment with hydrogen peroxide (H2O2) or irradiation with ultraviolet light; (2) ablation of p66shc enhances cellular resistance to apoptosis induced by H2O2 or ultraviolet light; (3) a serine-phosphorylation defective mutant of p66shc cannot restore the normal stress response in p66shc-/- cells; (4) the p53 and p21 stress response is impaired in p66shc-/- cells; (5) p66shc-/- mice have increased resistance to paraquat and a 30% increase in life span. We propose that p66shc is part of a signal transduction pathway that regulates stress apoptotic responses and life span in mammals.
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PMID:The p66shc adaptor protein controls oxidative stress response and life span in mammals. 1058 Apr 90


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