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)

p53 and Rb gene mutations are intermediate biomarkers useful for the prediction of neoplastic progression in bladder cancers. Previously, we have shown that low CYP3A activity, measured by dapsone N-hydroxylation, and high CYP2D6 activity, assessed by debrisoquine 4-hydroxylation, were significant susceptibility risk factors in developing aggressive bladder cancer. However, no information is available about the relationship between drug/xenobiotic metabolizing enzyme activities and p53/Rb mutations that may suggest mechanisms of bladder carcinogenesis. We evaluated in vivo CYP3A activity by the dapsone recovery ratio (DPRR), CYP2D6 activity by the debrisoquine recovery ratio (DBRR), CYP2C19 activity by the mephenytoin R/S ratio (RSR), N-acetyltransferase activity by the monoacetyl dapsone to dapsone ratio and glutathione-S-transferase M1 (GSTM1) genotype by PCR. In immunohistochemical studies of bladder tumor tissue, over expression of p53 protein was detected with antibody pAb1801 and loss of Rb protein expression was evaluated with antibody PMG3-245 in patients with transitional cell carcinoma of the bladder. Low CYP3A activity was significantly associated with over expression of or mutated p53 protein (P < 0.05). High CYP2D6 activity (within the extensive metabolizer group) was significantly associated with loss of expression of or mutated Rb protein (P < 0.05). Positive p53 staining also predicted aggressive bladder cancer histopathology (P < 0.05, odds ratio 2.9), and the lowest tertile of DPRR predicted p53 positivity (P < 0.01, odds ratio 3.9 comparing means of lower tertile versus upper tertile of DPRR). These selective associations are consistent with the hypothesis that an environmental pro-carcinogen fails to be detoxified by CYP3A which may preferentially induce p53 mutations, whereas, an alternative pro-carcinogen that may be activated by CYP2D6, may selectively induce Rb mutations.
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PMID:Association of low CYP3A activity with p53 mutation and CYP2D6 activity with Rb mutation in human bladder cancer. 864 Sep 13

Occurrence or specific types of mutations found in oncogenes or tumor suppressor genes may partially be determined by activities of toxifying or detoxifying enzymes, such as glutathione S-transferases (GST) M1 and T1, arylamine N-acetyltransferase (NAT2), microsomal epoxide hydrolase, and the cytochrome P-450 enzymes 2D6, 1A1, 2A6, and 2E1. In an explorative observational study, 69 bladder cancer patients were analysed for acquired mutations in the p53 tumor suppressor gene. The same patients were studied for the polymorphic traits of xenobiotic metabolism given above which were characterized from blood cell DNA by molecular methods. In 20 patients, single point mutations in p53 were detected whereas five patients carried two mutations; thus in total 25 mutations were detected. Twelve of these were G:C-->A:T transitions, six were A:T-->G:C transitions and seven were transversions (three G:C-->T:A, two A:T-->T:A, one G:C-->C:G, and one A:T-->C:G). There was no correlation between the types of p53 mutations and lifetime smoking or occupational history. In correlation with xenobiotic metabolism, 86% of the seven transversion mutations were found in homozygously deficient individuals for GSTM1 compared to only 44% of GSTM1 deficiency in the carriers of the 18 transition mutations of p53 (p = 0.06). A similar trend was seen for NAT2: six of the seven carriers of transversion mutations had two slow NAT2 alleles. No apparent associations were seen for the other polymorphic traits which were studied. In conclusion, low or deficient activities of two conjugating enzymes of foreign compound metabolism, GSTM1 and NAT2, may influence types of acquired mutations in p53 in bladder cancer.
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PMID:Polymorphic enzymes of xenobiotic metabolism as modulators of acquired P53 mutations in bladder cancer. 901 3

Epidemiologic studies have suggested that smokers of air-cured tobacco (rich in arylamines) are at higher risk of bladder cancer than smokers of flue-cured tobacco. The risk has been shown to be modulated by the N-acetyltransferase genotype. We analyzed the biopsies of 45 patients with bladder cancer. p53 mutations were sought by direct sequencing, and 4-aminobiphenyl-DNA adducts were measured by negative ion gas chromatography-mass spectrometry. 4-Aminobiphenyl-DNA adducts were higher in smokers of air-cured tobacco and in current smokers, but no relationship with the number of cigarettes smoked was found. Adducts were higher in more advanced histologic grades of tumors. No pattern was evident for p53 mutations. Seven of 9 mutations occurred in grade 3 tumors. No association was found between 4-ABP adducts and GSTM1 or NAT2 genetic polymorphisms.
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PMID:4-Aminobiphenyl-DNA adducts and p53 mutations in bladder cancer. 946 49

The human p300/CBP-associating factor, PCAF, mediates transcriptional activation through its ability to acetylate nucleosomal histone substrates as well as transcriptional activators such as p53. We have determined the 2.3 A crystal structure of the histone acetyltransferase (HAT) domain of PCAF bound to coenzyme A. The structure reveals a central protein core associated with coenzyme A binding and a pronounced cleft that sits over the protein core and is flanked on opposite sides by the N- and C-terminal protein segments. A correlation of the structure with the extensive mutagenesis data for PCAF and the homologous yeast GCN5 protein implicates the cleft and the N- and C-terminal protein segments as playing an important role in histone substrate binding, and a glutamate residue in the protein core as playing an essential catalytic role. A structural comparison with the coenzyme-bound forms of the related N-acetyltransferases, HAT1 (yeast histone acetyltransferase 1) and SmAAT (Serratia marcescens aminoglycoside 3-N-acetyltransferase), suggests the mode of substrate binding and catalysis by these enzymes and establishes a paradigm for understanding the structure-function relationships of other enzymes that acetylate histones and transcriptional regulators to promote activated transcription.
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PMID:Crystal structure of the histone acetyltransferase domain of the human PCAF transcriptional regulator bound to coenzyme A. 1039 69

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 state of chromatin (the packaging of DNA in eukaryotes) has long been recognized to have major effects on levels of gene expression, and numerous chromatin-altering strategies-including ATP-dependent remodeling and histone modification-are employed in the cell to bring about transcriptional regulation. Of these, histone acetylation is one of the best characterized, as recent years have seen the identification and further study of many histone acetyltransferase (HAT) proteins and their associated complexes. Interestingly, most of these proteins were previously shown to have coactivator or other transcription-related functions. Confirmed and putative HAT proteins have been identified from various organisms from yeast to humans, and they include Gcn5-related N-acetyltransferase (GNAT) superfamily members Gcn5, PCAF, Elp3, Hpa2, and Hat1: MYST proteins Sas2, Sas3, Esa1, MOF, Tip60, MOZ, MORF, and HBO1; global coactivators p300 and CREB-binding protein; nuclear receptor coactivators SRC-1, ACTR, and TIF2; TATA-binding protein-associated factor TAF(II)250 and its homologs; and subunits of RNA polymerase III general factor TFIIIC. The acetylation and transcriptional functions of these HATs and the native complexes containing them (such as yeast SAGA, NuA4, and possibly analogous human complexes) are discussed. In addition, some of these HATs are also known to modify certain nonhistone transcription-related proteins, including high-mobility-group chromatin proteins, activators such as p53, coactivators, and general factors. Thus, we also detail these known factor acetyltransferase (FAT) substrates and the demonstrated or potential roles of their acetylation in transcriptional processes.
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PMID:Acetylation of histones and transcription-related factors. 1083 22

Genetic polymorphisms of the carcinogen-metabolizing enzymes cytochrome P450 (CYP), glutathione S-transferase (GST) M1 and N-acetyltransferase (NAT2) as well as p53 polymorphisms have been studied experimentally as susceptibility markers for hepatocellular carcinoma development in hepatocellular carcinoma cell lines and in mouse hepatocellular carcinomas. In addition, these susceptibility markers have been studied in hepatocellular carcinoma patients, in the context of coexisting alcohol consumption, smoking and/or HBV infection. To date, there is no clear evidence that susceptibility markers have an overall impact on hepatocarcinogenesis, but in subgroups of individuals, such as smokers, susceptibility markers are emerging indicators for hepatocellular carcinoma risk definition.
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PMID:Hepatocellular carcinoma: susceptibility markers. 1122 Jun 63

In most of the studies about molecular alterations in squamous cell carcinomas of the head and neck there is not distinction between the different subsites of this area. The objective of this study is to describe the molecular alterations in squamous cell carcinomas of the oropharynx. Twenty-nine oropharyngeal carcinomas, with a minimum follow-up of 36 months, were studied. The molecular alterations analyzed were: the amplification of 11q13 region (in the 29 cases), and the MYC and ERBB1 oncogenes (in 22 cases); the integration of Human Papillomavirus (HPV) types 6b and 16 (in 22 cases); the loss of heterozygosity (LOH) of p53 and N-acetyltransferase-2 (NAT2) gene (in 12 and 13 informative cases, respectively); and the cellular DNA content (in 13 cases). The most frequent alterations found were the LOH at p53 (67%), and NAT2 (54%) locus, followed by 11q13 amplification (49%). ERBB1 amplification was found in 14% of the cases, and MYC amplification only in one (5%). Integration of the HPV was found in 23% of the cases. Nine (69%) of the 13 analyzed cases were aneuploid. The only alteration with a prognostic significance was 11q13 amplification that showed a tendency to be associated with a higher frequency of nodal metastases and tumor recurrence.
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PMID:[Molecular changes in epidermoid carcinoma of the oropharynx]. 1126 75

Treatment-related leukemias are one of the most devastating late complications of cancer therapy. Patients with rare cancer predisposition syndromes including neurofibromatosis type 1 and inherited p53 mutations are at an increased risk for this complication. Other patients may have increased susceptibility because they possess common genetic polymorphisms in drug-metabolizing enzymes that result in impaired detoxification of chemotherapy or inefficient repair of drug-induced genetic damage. We review studies that have identified a potential role for polymorphisms in the genes encoding the glutathione-S-transferases (GSTs), NAD(P) H: quinone oxidoreductase, myeloperoxidase, N-acetyltransferase (NATs), cytochrome P450 (CYP) 1A1 and 3A4, methylenetetrahydrofolate reductase (MTHFR), cystathionine-beta-synthase (CBS), and others in the etiology of primary or secondary acute leukemias, and therapy-related complications. The identification of high risk polymorphisms and use of pharmacogenetically-guided therapies holds promise to improve the outcome of cancer therapy and reduce the risk of treatment-related leukemias.
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PMID:Genetic predisposition and treatment-related leukemia. 1134 Jun 9

Bladder cancer is associated with smoking, occupational exposures, and glutathione S-transferase (GST) M1 and N-acetyltransferase (NAT) 2 polymorphisms that may influence carcinogen metabolism, but somatic p53mutations are often CpG dinucleotide G:C-A:T transitions that can occur spontaneously. We conducted a case-control study to determine whether p53mutation characteristics might distinguish cases with environmental versus endogenous causes. p53exons 4-9 were amplified from 146 bladder tumors by PCR, screened by single-strand conformational polymorphism analysis, and sequenced. Thirty-one cases were p53-positive, and 112 were p53-negative (germ line or silent). G:C-A:T transitions were also subclassified as CpG or non-CpG. Cases and 215 clinic controls were interviewed. GSTM1, NAT1, and NAT2 polymorphisms were assayed from peripheral blood. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic and polytomous regression. Case-control ORs for smoking, occupations, and NAT1*10genotype were similar for p53-positive and p53-negative cases. Associations with GSTM1-null and NAT2-slow genotypes were somewhat stronger for p53-positive [OR, 3.3; CI, 1.4-7.8 (GSTM1 null); OR, 1.8; CI, 0.8-4.0 (NAT2 slow)] than p53-negative cases [OR, 1.5; CI:0.9-2.3 (GSTM1 null); OR, 0.9; CI, 0.6-1.4 (NAT2 slow)]. Smoking was strongly associated with CpG G:C-A:T (OR, 15.3; CI:3.6-65) versus other G:C-A:T (OR, 1.8; CI, 0.3-9.8). NAT2 slow genotypes were also associated with CpG G:C-A:T (OR, 6.2; CI:0.7-52), whereas GSTM1 null was associated with non-CpG G:C-A:T (OR, 7.8; CI, 0.9-65). Associations were not substantially different for case subtypes defined by p53mutation status alone. Estimates for p53 subtypes were imprecise but support in vitro evidence that some CpG G:C-A:T transitions may be caused by smoking and other environmental mutagens.
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PMID:p53 mutations in bladder cancer: evidence for exogenous versus endogenous risk factors. 1461 56


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