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)

Human 8-oxoguanine DNA glycosylase 1 (hOGG1) plays a major role in the repair of 8-hydroxyguanine, one of the major forms of DNA damage generated by reactive oxygen species in tobacco smoke. If left unrepaired by hOGG1, 8-hydroxyguanine can produce G:C-to-T:A transversions. Recent studies have suggested that the hOGG1 Ser326Cys polymorphism is associated with both a decrease in enzyme activity and an increased risk of lung cancer. To define the interaction between tobacco carcinogens, hOGG1-mediated DNA repair and DNA damage, we examined the role of the hOGG1 Ser326Cys polymorphism in mutation of the p53 gene in non small cell lung cancer (NSCLC). Tumor and nonneoplastic DNA were collected from 141 cigarette smokers with NSCLC. p53 mutations were detected by direct dideoxy sequencing and/or the GeneChip p53 assay in 74 of the 141 (52%) tumors. hOGG1 codon 326 polymorphisms were identified by polymerase chain reaction-restriction fragment length polymorphism analysis. The distribution of hOGG1 codon 326 genotypes was Ser/Ser, 90 of 141 (64%); Ser/Cys, 45 of 141 (32%); and Cys/Cys, 6 of 141 (4%). p53 mutations were significantly (p = 0.04) less common in NSCLC from patients with codon 326 Ser/Cys or Cys/Cys genotypes (21 of 51; 41%) than in NSCLC from Ser/Ser homozygotes (53 of 90; 59%). The decrease in p53 mutation frequency among carriers of the Cys allele was more evident in lung squamous cell cancer [7 of 17 (41%) for Cys/Cys and Ser/Cys vs. 27 of 38 (71%) for Ser/Ser; p = 0.04] than in nonbronchoalveolar adenocarcinoma [11 of 26 (42%) for Cys/Cys and Ser/Cys vs. 20 of 35 (57%) for Ser/Ser; p = 0.25]. The prevalence of G:C-to-T:A transversions was similar among hOGG1 codon 326 genotypes. In summary, the hOGG1 codon 326 Cys allele was associated with a decrease in p53 mutations and no effect on G:C-to-T:A transversions in NSCLC. This decrease in p53 mutations in vivo is not consistent with a decrease in the repair of 8-hydroxyguanine among carriers of the hOGG1 codon 326 Cys allele in vitro.
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PMID:hOGG1 Ser326Cys polymorphism and G:C-to-T:A mutations: no evidence for a role in tobacco-related non small cell lung cancer. 1555 30

Developmental pathologies may result from endogenous or xenobiotic-enhanced formation of reactive oxygen species (ROS), which oxidatively damage cellular macromolecules and/or alter signal transduction. This minireview focuses upon several model drugs (phenytoin, thalidomide, methamphetamine), environmental chemicals (benzo[a]pyrene) and gamma irradiation to examine this hypothesis in vivo and in embryo culture using mouse, rat and rabbit models. Embryonic prostaglandin H synthases (PHSs) and lipoxygenases bioactivate xenobiotics to free radical intermediates that initiate ROS formation, resulting in oxidation of proteins, lipids and DNA. Oxidative DNA damage and embryopathies are reduced in PHS knockout mice, and in mice treated with PHS inhibitors, antioxidative enzymes, antioxidants and free radical trapping agents. Thalidomide causes embryonic DNA oxidation in susceptible (rabbit) but not resistant (mouse) species. Embryopathies are increased in mutant mice deficient in the antioxidative enzyme glucose-6-phosphate dehydrogenase (G6PD), or by glutathione (GSH) depletion, or inhibition of GSH peroxidase or GSH reductase. Inducible nitric oxide synthase knockout mice are partially protected. Inhibition of Ras or NF-kB pathways reduces embryopathies, implicating ROS-mediated signal transduction. Atm and p53 knockout mice deficient in DNA damage response/repair are more susceptible to xenobiotic or radiation embryopathies, suggesting a teratological role for DNA damage, consistent with enhanced susceptibility to methamphetamine in ogg1 knockout mice with deficient repair of oxidative DNA damage. Even endogenous embryonic oxidative stress carries a risk, since untreated G6PD- or ATM-deficient mice have increased embryopathies. Thus, embryonic processes regulating the balance of ROS formation, oxidative DNA damage and repair, and ROS-mediated signal transduction may be important determinants of teratological risk.
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PMID:Molecular and biochemical mechanisms in teratogenesis involving reactive oxygen species. 1608 Nov 18

The aim of our study was to identify occupational risk of irradiation exposure in the Czech nuclear power plant workers. We analyzed levels of chromosomal aberrations, a well-known biomarker of early biological effects and a predictor of cancer risk. We applied the conventional method of cytogenetic analysis and fluorescence in situ hybridization (FISH, whole chromosome painting for chromosomes 1 and 4, combined with a pancentromeric probe) to three groups: 123 subjects in the Temelin nuclear power plant (2 years in use), 114 subjects in the Dukovany nuclear power plant (20 years in use), and 53 matched controls from Ceske Budejovice. Nuclear power plant workers were divided into two groups: subjects with admittance into the monitored zone, and others. Following factors were also analyzed: GSTM1, GSTT1, GSTP1, XPD, XRCC1, hOGG1, p53, MTHFR, and MS gene polymorphisms, levels of vitamins A, C, E, and folate in plasma, and level of cotinine in urine. Long-term exposure to ionizing radiation in the monitored zone was 0.47+/-1.50 mSv (miliSievert) in the Temelin nuclear power plant and 5.74+/-9.57 mSv in the Dukovany nuclear power plant. Using the conventional cytogenetic analysis, we observed 1.90+/-0.95 and 1.82+/-1.19% AB.C. (percent of aberrant cells) in the Temelin nuclear power plant, and 2.39+/-1.01 and 2.33+/-1.04% AB.C. in the Dukovany nuclear power plant, for monitored zone workers and others, respectively. In the control group, we found 2.25+/-0.82% AB.C. Genomic frequency of translocations F(G)/100 measured by FISH was 1.89+/-1.40 and 2.01+/-1.68 in the Temelin nuclear power plant, and 2.48+/-1.93 and 2.14+/-1.62 in the Dukovany nuclear power plant for monitored zone workers and others, respectively. In the control group, F(G)/100 was 1.83+/-1.19. Following factors were identified as potential confounders by the conventional cytogenetic analysis: XPD-6, by the FISH: age, GSTP1 and p53Bst genotypes, long-term use of medication, alcohol consumption, and smoking. No association between the dose of irradiation and the level of chromosomal aberrations in any nuclear power plant was detected either by the conventional cytogenetic analysis or by FISH.
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PMID:Possible genetic damage in the Czech nuclear power plant workers. 1619 33

Recent evidence indicates that in vitro p53 augments base excision repair (BER) activities in mammalian cells. To understand the role of p53 in BER, we analyzed the repair activity of hOgg1 in isogenic cell lines HCT116p53+/+ and HCT116p53-/-. We found that hOgg1 activity was significantly decreased in HCT116p53-/- cells as compared with HCT116p53+/+ cells, indicating a functional role for p53 in the regulation of hOGG1. Using gel-shift assays, we showed that p53 binds to its putative cis-elements within the hOGG1 promoter. In addition we demonstrated that supplementing p53 in HCT116p53-/- cells enhanced the transcription of hOGG1. To further strengthen our findings, we used p53-RNAi to study the effects of decreased p53 levels on hOgg1 activity. We observed that p53-RNAi resulted in decreased hOGG1 expression both at the mRNA and protein levels. This decrease in hOGG1 expression was associated with reduced cell viability upon oxidative damage and reduced hOgg1 activity as evidenced by the 8-oxoG incision assay. Taken together, our results indicate that loss of p53 function can lead to decreased hOgg1 repair activity.
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PMID:The effect of p53-RNAi and p53 knockout on human 8-oxoguanine DNA glycosylase (hOgg1) activity. 1629 9

The capital city of Prague is one of the most polluted localities of the Czech Republic. Therefore, the effect of exposure to carcinogenic polycyclic aromatic hydrocarbons (c-PAHs) adsorbed onto respirable air particles (<2.5mum) on chromosomal aberrations was studied in a group of policemen (males, aged 22-50 years) working in the downtown area of Prague and spending daily >8h outdoors (N=53). Age- and sex-matched healthy volunteers spending >90% daily time indoors were chosen as controls (N=52). Ambient air particles (PM10, PM2.5) and c-PAHs were monitored using versatile air pollution sampler (VAPS), and personal exposure was evaluated using personal samplers during working shift. Chromosomal aberrations were analyzed by conventional cytogenetic analysis and fluorescent in situ hybridization (FISH). Urinary cotinine plasma levels of vitamins A, E and C, folate, total cholesterol, HDL, LDL cholesterols and triglycerides were also analyzed as possible effect modifiers. Genotypes CYP1A1*2A, CYP1A1*2C, GSTM1, GSTP1, GSTT1, EPHX1, NAT2, hOGG1, XRCC1, XPD, p53 BstI, p53 MspI, MTHFR677, and MS2656 were determined by PCR-based RFLP assays. The following levels of air pollution were recorded during the study period (mean from HiVol sampling): PM10 62.6microg/m(3), c-PAHs 24.7ng/m(3), B[a]P 3.50ng/m(3). The conventional cytogenetic analysis did not reveal any differences between the group of policemen exposed to the ambient air pollution and the control group. The cytogenetic analysis by FISH analysis used the whole chromosome painting probes for chromosomes #1 and #4 (Cambio, UK). It detected a significant increase in all studied endpoints in the policemen compared to controls (% AB.C.=0.33+/-0.25 versus 0.24+/-0.18, p<0.05, F(G)/100=1.72+/-1.57 versus 1.25+/-1.11, p<0.05, AB/1000 (aberrations/1000 cells)=5.58+/-4.62 versus 3.90+/-3.06, p<0.05). CYP1A1*2C (Ile/Ile), XPD 23 (Lys/Lys), and XPD 6 (CC) genotypes were associated with an increase of aberrant cells by conventional method. Factors associated with an increased level of translocations by FISH included age, smoking, B[a]P-like DNA adducts (corresponding to the exposure of c-PAHs), folate, polymorphisms of CYP1A1*2C, GSTP1, EPHX1, p53 MspI and MTHFR. Ambient air exposure to c-PAHs significantly increased FISH cytogenetic parameters in nonsmoking policemen. We may conclude that FISH indicates that the city policemen in Prague represent a group of increased genotoxic risk. This is the first study that has reported a relationship between DNA adducts (biomarker of exposure) and chromosomal aberrations by FISH (biomarker of effect).
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PMID:Chromosomal aberrations in environmentally exposed population in relation to metabolic and DNA repair genes polymorphisms. 1741 42

The effect of exposure to organic compounds adsorbed onto respirable air particles (<2.5microm) on DNA adducts in lymphocytes was studied in a group of non-smoking policemen (N=109, aged 35+/-0.9 years) working in the downtown area of Prague and spending >8h daily outdoors. Personal exposure to carcinogenic polycyclic aromatic hydrocarbons (c-PAHs) adsorbed on respirable particles was monitored in each subject for 48h before biological sampling. DNA adducts were analyzed by a (32)P-postlabelling assay, and total DNA adduct levels and B[a]P-like spots were determined. Further biomarkers included cotinine levels in urine to control for exposure to tobacco smoke, plasma levels of vitamins A, E and C and polymorphisms of metabolic genotypes (GSTM1, GSTP1, GSTT1, CYP 1A1-Msp I and Ile/Val, MTHFR, MS), DNA repair genotypes (XRCC1, hOGG1 and XPD exons 6 and 23) and the p53 gene (p53 Msp I and BstU I). All the biomarkers of exposure and effect were analyzed repeatedly during a period of one year at 2-3 month intervals (January, March, June, September 2004) to cover periods with high (winter) and low (summer) levels of air pollution. The highest personal exposure to c-PAHs was found in January (8.1+/-8.8ng/m(3)), while the other three sampling periods exhibited 3-4-fold lower c-PAH exposure. The total DNA adducts were only slightly elevated in January (2.08+/-1.60) compared to March (1.66+/-0.65), June (1.96+/-1.73) and September (1.77+/-1.77). B[a]P-like DNA adducts, however, were significantly higher in January than in the March and June sampling periods (0.26+/-0.14 vs. 0.19+/-0.12 and 0.22+/-0.13, respectively; p<0.0001 and p=0.017) indicating that c-PAH exposure probably plays a crucial role in DNA adduct formation in lymphocytes. No effect of individual metabololic or DNA repair genotypes on DNA adduct levels was observed. However, the combination of two genotypes encoding enzymes metabolizing c-PAHs - CYP 1A1 and GSTM1 - was associated with the levels of total and B[a]P-like DNA adducts under conditions of increased exposure to c-PAHs. Our study suggests that DNA adducts in the lymphocytes of subjects exposed to increased c-PAH levels are an appropriate biomarker of a biologically effective dose, directly indicating whether or not the extent of exposure to these compounds is related to an increased mutagenic and carcinogenic risk.
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PMID:Biomarkers of air pollution exposure--a study of policemen in Prague. 1749 40

Human 8-oxoguanine DNA glycosylase (hOGG1) is the main defense enzyme against mutagenic effects of cellular 7,8-dihydro-8-oxoguanine. In this study, we investigated the biological role of hOGG1 in DNA damage-related apoptosis induced by hydrogen peroxide (H(2)O(2))-derived oxidative stress. The down-regulated expression of hOGG1 by its small interfering RNA prominently triggers the H(2)O(2)-induced apoptosis in human fibroblasts GM00637 and human lung carcinoma H1299 cells via the p53-mediated apoptotic pathway. However, the apoptotic responses were specifically inhibited by hOGG1 overexpression. The p53-small interfering RNA transfection into the hOGG1-deficient GM00637 markedly inhibited the H(2)O(2)-induced activation of p53-downstream target proteins such as p21, Noxa, and caspase-3/7, which eventually resulted in the increased cell viability. Although the cell viability of hOGG1-knockdown H1299 p53 null cells was similar to that of the hOGG1 wild-type H1299, after the overexpression of p53 the hOGG1-knockdown H1299 showed the significantly decreased cell viability compared with that of the hOGG1 wild-type H1299 at the same experimental condition. Moreover, the array comparative genome hybridization analyses revealed that the hOGG1-deficient GM00637 showed more significant changes in the copy number of large regions of their chromosomes in response to H(2)O(2) treatment. Therefore, we suggest that although p53 is a major modulator of apoptosis, hOGG1 also plays a pivotal role in protecting cells against the H(2)O(2)-induced apoptosis at the upstream of the p53-dependent pathway to confer a survival advantage to human fibroblasts and human lung carcinomas through maintaining their genomic stability.
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PMID:Human 8-oxoguanine DNA glycosylase suppresses the oxidative stress induced apoptosis through a p53-mediated signaling pathway in human fibroblasts. 1795 8

Anthocyanins are a class of flavonoids, widely spread throughout the plant kingdom, exhibiting important antioxidant and anti-inflammatory actions as well as chemotherapeutic effects; nonetheless, little is known about the molecular mechanisms by which these activities are exerted. The present study is aimed at investigating molecular mechanisms involved in the chemotherapeutic effects induced by both cyanidin-3-O-beta glucopyranoside (CY3G) and its aglycon form, cyanidin chloride (CY), in human colon cancer cells (CaCo2). The effect on cell growth, reactive oxygen species (ROS) formation and cell cycle/stress proteins modification, including ataxia teleangectasia mutated protein (ATM), p53, p21, 8-oxoguanine DNA glycosylase (OGG1), 70 kDa heat shock protein (HSP70) and topoisomerase IIbeta, as well as on DNA fragmentation, was determined. CY and CY3G treatment affect cell growth and cell proliferation, this latter in a moderately dose-dependent way. Interestingly, ROS level is decreased by any concentration of CY and, only at the lowest concentration, by CY3G. Moreover, the two molecules exert their activities increasing ATM, topoisomerase II, HSP70 and p53 expression. The analysis of DNA fragmentation by Comet assay evidences: (1) a dose-dependent increase in DNA damage only after treatment with CY3G; (2) a more evident trend in the DNA fragmentation when the treatment is performed on agarose embedded cells (cellular atypical Comet); (3) a highly dose-dependent DNA fragmentation induced by CY when the treatment is carried out on agarose embedded naked DNA (acellular atypical Comet). The present findings substantiate a possible chemotherapeutic role of anthocyanins and suggest that CY and CY3G act on CaCo2 by different mechanisms, respectively, ROS-dependent and ROS-independent.
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PMID:Response of cell cycle/stress-related protein expression and DNA damage upon treatment of CaCo2 cells with anthocyanins. 1805 7

The increased incidence of malignant neoplasms in the elderly is related to the accumulation of damaged DNA. We focused on the molecular mechanisms of the DNA repair system and examined its relationship to malignant neoplasms in the elderly. Hypermethylation of the promoter region of a mismatch repair gene is strongly associated with gastric and colorectal carcinomas occurring in the elderly. These tumors have characteristic features such as the absence of hMLH1 expression, microsatellite instability, poorly differentiated histology, low incidence of lymph node metastasis and favorable prognosis. On the other hand, we analyzed single nucleotide polymorphism (SNP) of the genes in the DNA repair system such as hOGG1, p53, XRCC1 and hMLH1 in autopsy cases. Although no significant associations were found between the SNP and the number of malignant neoplasms, a few SNP were associated with specific tumors. These findings suggest that epigenetic changes in the DNA mismatch repair genes play important roles in the development of gastric and colorectal carcinomas and that the SNP of DNA repair genes have little influence on the occurrence of carcinoma in the elderly.
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PMID:Role of DNA repair systems in malignant tumor development in the elderly. 1871 57

8-hydroxy-2'-deoxyguanosine (8-OHdG) is one of the main mutagenic modifications induced in DNA by oxidative stress. Elevated levels of 8-OHdG have been regarded as an independent prognostic factor in different types of cancer. Various enzymes, such as human 8-oxoguanine DNA-glycosylase 1 (hOGG1) and glucose-6-phosphate dehydrogenase (G6PD), act as protection against oxidative stress. The low activity of such enzymes has been consistently associated with increased risk of progression in several tumor types. The aim of this study was to investigate whether 8-OHdG, hOGG1 and G6PD expression in tumor tissues might be a predictor of survival in melanoma patients. The expression of 8-OHdG, hOGG1 and G6PD was immunohistochemically investigated in primary cutaneous melanoma and the effect on survival was analyzed. Furthermore, the immunostaining for p53 and survivin was evaluated and the relationship among 8-OHdG, hOGG1, G6PD, p53 and survivin expression was analyzed. Kaplan-Meier analysis demonstrated that patients with low expression of nuclear 8-OHdG had significantly longer survival time compared with those with a high expression (P=0.032), whereas cancer-specific survival of patients was not associated with hOGG1 or G6PD expression. These results suggest an involvement of oxidative DNA damage in the process of melanoma pathogenesis and demonstrate that 8-OHdG expression in nuclei of tumor cells could be useful as an early independent prognostic marker in patients with primary cutaneous melanoma.
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PMID:Nuclear 8-hydroxy-2'-deoxyguanosine as survival biomarker in patients with cutaneous melanoma. 2004 92


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