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)

Molecular epidemiology is a new and evolving area of research, combining laboratory measurement of internal dose, biologically effective dose, biologic effects, and influence of individual susceptibility with epidemiologic methodologies. Biomarkers evaluated were selected according to basic scheme: biomarkers of exposure--metabolites in urine, DNA adducts, protein adducts, and Comet assay parameters; biomarkers of effect--chromosomal aberrations, sister chromatid exchanges, micronuclei, mutations in the hypoxanthine-guanine phosphoribosyltransferase gene, and the activation of oncogenes coding for p53 or p21 proteins as measured on protein levels; biomarkers of susceptibility--genetic polymorphisms of genes CYP1A1, GSTM1, GSTT1, NAT2. DNA adducts measured by 32P-postlabeling are the biomarker of choice for the evaluation of exposure to polycyclic aromatic hydrocarbons. Protein adducts are useful as a biomarker for exposure to tobacco smoke (4-aminobiphenyl) or to smaller molecules such as acrylonitrile or 1,3-butadiene. Of the biomarkers of effect, the most common are cytogenetic end points. Epidemiologic studies support the use of chromosomal breakage as a relevant biomarker of cancer risk. The use of the Comet assay and methods analyzing oxidative DNA damage needs reliable validation for human biomonitoring. Until now there have not been sufficient data to interpret the relationship between genotypes, biomarkers of exposure, and biomarkers of effect for assessing the risk of human exposure to mutagens and carcinogens.
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PMID:Molecular epidemiology studies on occupational and environmental exposure to mutagens and carcinogens, 1997-1999. 1069 23

We have analyzed the tumor biopsies of 45 patients with bladder cancer for p53 mutations by direct sequencing. In addition to N-acetyltransferase-2 (NAT2) and GSTM1 allelisms, which were examined previously, we have analyzed the genetic polymorphisms of GSTT1, GSTP1, COMT, NQO1, TS-SULT and MPO in buffy coat DNA using PCR-based methods. All subjects were interviewed through a questionnaire on smoking, dietary habits and other risk factors. No specific pattern was evident for p53 mutations. Eight out of ten mutations occurred in grade 3 tumors. All p53 mutations occurred in subjects with the COMT mutated allele (p=0.03). The prevalence of cases with p53 mutations was 3.5-fold higher in subjects with wild type than in those with variant GSTP1 alleles (p=0.03). The other polymorphisms investigated were not associated with p53 mutations.
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PMID:Impact of polymorphisms in xeno(endo)biotic metabolism on pattern and frequency of p53 mutations in bladder cancer. 1076 40

The purpose of this study was to establish the frequencies of CYP2D6, CYP1A1, GSTM1 and p53 polymorphic genotypes in Tundra Nentsi, which comprises the small group of indigenous people belonging to Northern Mongoloids and Caucasians of Western Siberia. A total number of 102 Tundra Nentsi individuals and 96 Caucasians of Western Siberia were genotyped by means of polymerase chain reaction-based assays. Mutated alleles comprising CYP2D6*4, CYP1A1Val, GSTM1*0 and p53Pro were analysed along with the wild-type alleles. The results showed the intermedial position of CYP2D6*4 allele frequency in Tundra Nentsi, compared to Caucasians and Orientals (0.07 versus 0.2, P = 0.0003; 0.07 versus 0.003, P = 1 x 10(-6), respectively). Thus, our data indicate that the intermedial position of Tundra Nentsi between Orientals and Caucasians most likely shows the Caucasian ancestral origin of CYP2D6*4 allele. Comparative analysis of p53Pro allele frequency showed the pronounced ethnic differences with geographic gradient. Though the frequency of p53Pro allele ranged from 0.17 in Tundra Nentsi up to 0.3 in Caucasians of Western Siberia (P = 0.002), which is in agreement with the previously reported radial distribution of the known genetic markers. No differences were found in the CYP1A1Val allele distribution among Caucasians of Western Siberia and Caucasoid populations presented in other studies, whereas the frequency of Val allele in Nentsi was 1.5-fold higher (P = 0.076) compared to the Japanese group. It was found that the frequency of GSTM1 null genotype in Tundra Nentsi was only 39.8%. The frequency of GSTM1 null genotype in females was higher than in males (0.27 and 0.50, respectively) but that difference was not statistically significant. Comparative analyses of the distribution of putative markers towards cancer susceptibility, CYP1A1Val, GSTM1*0 and p53Pro alleles, have shown that the healthy Tundra Nentsi population (Northern Mongoloids) have a low number of p53Pro alleles and GSTM1*0/*0 genotypes and a high level of CYP1A1Val alleles. Further investigations of gene polymorphisms in isolated Northern native populations would be valuable in clarifying the origin of Northern natives. All this is important for comparative analyses of pharmacogenetic data in Mongoloid populations.
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PMID:Genetic polymorphisms of CYP2D6, CYP1A1, GSTM1 and p53 genes in a unique Siberian population of Tundra Nentsi. 1097 7

The phase II glutathione S-transferases (GSTs) GSTT1, GSTM1 and GSTP1 catalyse glutathione-mediated reduction of exogenous and endogenous electrophiles. These GSTs have broad and overlapping substrate specificities and it has been hypothesized that allelic variants associated with less effective detoxification of potential carcinogens may confer an increased susceptibility to cancer. To assess the role of GST gene variants in ovarian cancer development, we screened 285 epithelial ovarian cancer cases and 299 unaffected controls for the GSTT1 deletion (null) variant, the GSTM1 deletion (null) variant and the GSTP1 codon 104 A-->G Ile-->Val amino acid substitution variant. The frequencies of the GSTT1, GSTM1 and GSTP1 polymorphic variants did not vary with tumour behaviour (low malignant potential or invasive) or p53 immunohistochemical status. There was a suggestion that ovarian cancers of the endometrioid or clear cell histological subtype had a higher frequency of the GSTT1 and GSTM1 deletion genotype than other histological subgroups. The GSTT1, GSTM1 and GSTP1 genotype distributions did not differ significantly between unaffected controls and ovarian cancer cases (overall or invasive cancers only). However, the GSTM1 null genotype was associated with increased risk of endometrioid/clear cell invasive cancer [age-adjusted OR (95% CI) = 2.04 (1.01-4.09), P = 0.05], suggesting that deletion of GSTM1 may increase the risk of ovarian cancer of these histological subtypes specifically. This marginally significant finding will require verification by independent studies.
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PMID:Polymorphisms at the glutathione S-transferase GSTM1, GSTT1 and GSTP1 loci: risk of ovarian cancer by histological subtype. 1115 43

Although aflatoxin B1 (AFB1) is best known as a hepatocarcinogen, the respiratory system can also be a target of this mycotoxin. In isolated lung cells from rabbits and mice, AFB1 is bioactivated by cytochromes P450, primarily in nonciliated bronchiolar epithelial (Clara) cells. However, mutagenesis experiments suggest that the DNA-binding AFB1 epoxide metabolite can leave the cells of origin, and potentially interact with other cell types. Consistent with DNA adduct studies, AFB1-induced AC3F1 mouse lung tumors contain point mutations at guanine residues in K-ras, with the anticipated bias for the A/J allele. Furthermore, following AFB1 treatment but prior to tumor development, K-ras mutations occur preferentially in mouse Clara cells. However, in contrast to findings with other carcinogens, AFB1-induced mouse lung tumors demonstrate frequent, but heterogeneously distributed, overexpression of p53 protein as well as p53 point mutations, suggesting a carcinogen-specific response. Unlike lung tissue from mice and rabbits, human peripheral lung bioactivates AFB1 primarily by prostaglandin H synthase--and/or lipoxygenase-catalyzed cooxidation, with activity concentrated in macrophages. In addition, although glutathione S-transferase M1-1 has high specific activity for AFB1 epoxide conjugation, lung tissues from GSTM1-null individuals do not demonstrate diminished rates of conjugation, compared to tissues from GSTM1-positive individuals. In summary, AFB1 tumorigenesis in mice demonstrates unique properties, and processes of bioactivation show significant species differences.
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PMID:Mechanisms of aflatoxin B1 lung tumorigenesis. 1119 64

The objective of this study was to determine whether the association between GSTM1 null/GSTTI null and survival in ovarian cancer is mediated by the influence of these genes on p53 expression. In 81 women with pure invasive ovarian cancer, GSTM1 null and GSTT1 null genotypes were identified using polymerase chain reaction and p53 expression was assessed using immunohistochemistry. The association of these factors with survival was examined using Cox's proportional hazards regression models. Performance status (P < 0.001), operative stage (P = 0.004), residual disease (P = 0.001), histologic subtype (P = 0.05), tumor grade (P = 0.007), and the combined GSTMI null/GSTTl null genotype (P = 0.023) were all individually associated with survival. p53 expression was not associated with survival (P = 0.45). In a multivariate analysis, the effects of GSTM1 null/GSTT1 null on survival were lost when residual disease and tumor grade were included. The effects of p53 expression on survival were unchanged when residual disease, tumor grade, operative stage, and performance score were included. GSTM1 null/GSTT1null did not influence the effects of p53 expression on survival and vice versa. The GSTM1 null/GSTT1 null genotype was associated with response to primary chemotherapy (P = 0.007) but p53 expression was not. We conclude that the association of GSTM1 null/GSTTl null with survival appears to be mediated through different mechanisms to p53 expression in ovarian cancer and in addition, may be a better predictor of outcome.
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PMID:Glutathione S-transferase GSTM1 and GSTT1 genotypes in ovarian cancer: association with p53 expression and survival. 1132 8

Tobacco use is causally associated with head and neck squamous cell cancer (HNSCC). Here, we present the results of a case-control study that investigated the effects that the genetic variants of the cytochrome (CYP)1A1, CYP1B1, glutathione-S-transferase (GST)M1, GSTT1, and GSTP1 genes have on modifying the risk of smoking-related HNSCC. Allelisms of the CYP1A1, GSTT1, GSTM1, and GSTT1 genes alone were not associated with an increased risk. CYP1B1 codon 432 polymorphism was found to be a putative susceptibility factor in smoking-related HNSCC. The frequency of CYP1B1 polymorphism was significantly higher (P < 0.001) in the group of smoking cases when compared with smoking controls. Additionally, an odds ratio (OR) of 4.53 (2.62-7.98) was discovered when investigating smoking and nonsmoking cases for the susceptible genotype CYP1B1*2/*2, when compared with the presence of the genotype wild type. In combination with polymorphic variants of the GST genes, a synergistic-effect OR was observed. The calculated OR for the combined genotype CYP1B1*2/*2 and GSTM1*2/*2 was 12.8 (4.09-49.7). The calculated OR for the combined genotype was 13.4 (2.92-97.7) for CYP1B1*2/*2 and GSTT1*2/*2, and 24.1 (9.36-70.5) for the combination of CYP1B1*2/*2 and GSTT1-expressors. The impact of the polymorphic variants of the CYP1B1 gene on HNSCC risk is reflected by the strong association with the frequency of somatic mutations of the p53 gene. Smokers with susceptible genotype CYP1B1*2/*2 were 20 times more likely to show evidence of p53 mutations than were those with CYP1B1 wild type. Combined genotype analysis of CYP1B1 and GSTM1 or GSTT1 revealed interactive effects on the occurrence of p53 gene mutations. The results of the present study indicate that polymorphic variants of CYP1B1 relate significantly to the individual susceptibility of smokers to HNSCC.
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PMID:Association of CYP1B1 codon 432 mutant allele in head and neck squamous cell cancer is reflected by somatic mutations of p53 in tumor tissue. 1138 67

Glutathione S-transferases (GSTs) are metabolic phase II enzymes that promote reactive metabolite elimination by conjugating them to glutathione (GSH). Because of their important role in xenobiotic metabolism and detoxification, they have been implicated in carcinogenesis processes, especially epithelium transformation. Moreover, their influence on response to chemotherapy in cancer patients has been demonstrated. Genetic polymorphisms for GSTM1, GSTT1 and GSTP1 have been found in human populations and have been shown to have phenotypic consequences. To investigate the role of GST enzymes in carcinogenesis and in response to chemotherapy in patients with head and neck squamous cell carcinoma (HNSCC), GSTP1, GSTM1 and GSTT1 were studied prospectively in a large series of HNSCC patients. Correlations between GST alterations, p53 mutation status and clinical response to chemotherapy were investigated. We showed that the risk of developing laryngeal cancer was increased by 2.6-fold [95% CI 1.6--6.1] in patients with the GSTM1 null genotype and by 2.8-fold [95% CI 0.9--8.1] in patients with the homozygous GSTP1 val105 genotype. Furthermore, individuals with this latter genotype were over-represented in the p53 mutation group (p = 0.05). After storage duration and hemolysis adjustment, a significantly lower plasmatic GSTP1 level was observed in complete responders compared with partial and non-responders (mean: 4.4 +/- 0.06 microg/l, 4.7 +/- 0.06 microg/l and 4.7 +/- 0.07 microg/l; p = 0.05), respectively. The prevalence of p53-mutated tumors was significantly higher in the group of non-responders (81%) compared with partial (60%) and complete responders (64%) (p = 0.05). Two types of multivariate analysis were performed including parameters that have been shown to influence response to chemotherapy significantly in univariate analysis. p53 mutations and high tumor stage are independent factors of non-response to chemotherapy, whereas plasmatic GSTP1 levels and low tumor stage are independent factors of complete response. Our data suggest that GST enzymes are associated with larynx cancer and that their use as predictive factors and treatment targets should be further explored.
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PMID:Glutathione-associated enzymes in head and neck squamous cell carcinoma and response to cisplatin-based neoadjuvant chemotherapy. 1147 86

Complete data on the polymorphisms of CYP1A1, GSTM1 and p53 genes in Tundra Nentsi population, with known genealogical history are essential for the analysis of the "cancer susceptibility gene markers" distribution among different Oriental populations. The cytochrome P4501A subfamily is known to be responsible for the metabolic activation of aromatic compounds occurring in the products of gas mixture combustion, the main environmental pollutants in the north of western Siberia. Recently a close correlation was reported between development of some types of cancer and polymorphisms of human CYP1A1, GSTM1 and p53 genes. The frequency of the CYP1A1 Vol allele in the healthy part of the Tundra Nentsi population differs from those previously reported for Japanese and is more than 1.5 times higher. It is necessary to underline that homozygote Val genotype was present in 26% of non-healthy Tundra Nentsi, the incidence being 2.7-times higher in comparison with healthy population. GSTM1 gene deletion is present in 40% of Orientals and in 39% of Tundra Nentsi. Moreover, the share of individuals with null genotype among a group with chromosomal abnormalities and cancer was 63%, or 1.5 fold higher. Thus the prevalence of two polymorphic genes CYP1A1 and GSTM1 responsible for the biotransformation of polycyclic aromatic hydrocarbons was too high in the non-healthy group.
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PMID:Genetic polymorphisms of CYP1A1, GSTM1 and P53 genes in a unique Siberian population of Tundra Nentsi and its pharmacogenetic importance. 1150 74

The glutathione S-transferase (GST) genes are involved in the metabolism of various carcinogens. Deletion polymorphisms in the GSTM1 and GSTT1 genes and an A-G polymorphism in the GSTP1 gene were investigated in relation to breast cancer risk in 500 breast cancer patients and 395 controls. The effects of the GST genotypes on the frequency and pattern of p53 mutations in 388 breast carcinomas were also studied. A suggestive trend of increasing risk of breast cancer with increasing number of G alleles of the GSTP1 was observed (P for trend, 0.11). The GSTM1 and GSTT1 polymorphisms did not show an association with breast cancer. No increase in risk was observed with a combination of genotypes. A statistically significant association was observed between the GSTT1 genotype and p53 mutation status of the tumors, with patients carrying the GSTT1 null genotype more frequently having mutations in the p53 gene compared with patients with a GSTT1 gene present (24.6% versus 12.4%; P = 0.019). There was also a suggestive trend for the GG genotype of the GSTP1 gene, but it was not statistically significant (P = 0.19). No association was observed with the type or location of mutations. We conclude that the GSTP1 and GSTT1 genes could play a role in carcinogenesis in the breast, possibly through increased frequency of mutations in tumor suppressor genes such as p53.
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PMID:GSTM1, GSTT1, and GSTP1 genotypes in relation to breast cancer risk and frequency of mutations in the p53 gene. 1170 Feb 65

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