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)

Transcriptionally regulated growth-response genes play a pivotal role in the determination of the fate of a cell. p53 is known to transcriptionally regulate genes important in regulating cell growth potential. Using differential reverse transcription-PCR analysis of rat embryo fibroblast cells containing a temperature-sensitive p53 allele, we were able to isolate several transcripts up-regulated specifically in cells harboring functional p53 protein. Two of these genes, SM20 and microsomal epoxide hydrolase (mEH), are previously described genes. Two previously uncharacterized cDNAs, cell growth regulatory (CGR) genes CGR11 and CGR19, were isolated. The predicted amino acid sequence of these novel proteins contain known motifs; EF-hand domains (CGR11) and a ring-finger domain (CGR19), suggestive of function. CGR11 and CGR19 appear to be primary response genes expressed to moderate levels in functional p53 cells. Both CGR11 and CGR19 are able to inhibit the growth of several cell lines.
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PMID:Induction of cell growth regulatory genes by p53. 896 90

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

We examined polymorphisms in exons 3 and 4 of microsomal epoxide hydrolase in 101 patients with colon cancer and compared the results with 203 control samples. The frequency of the exon 3 T to C mutation was higher in cancer patients than in controls (odds ratio 3.8; 95% confidence intervals 1.8-8.0). This sequence alteration changes tyrosine residue 113 to histidine and is associated with lower enzyme activity when expressed in vitro. This suggests that putative slow epoxide hydrolase activity may be a risk factor for colon cancer. This appears to be true for both right- and left-sided tumours, but was more apparent for tumours arising distally (odds ratio 4.1; 95% confidence limits 1.9-9.2). By contrast, there was no difference in prevalence of exon 4 A to G transition mutation in cancer vs controls. This mutation changes histidine residue 139 to arginine and produces increased enzyme activity. There was no association between epoxide hydrolase genotype and abnormalities of p53 or Ki-Ras.
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PMID:Microsomal epoxide hydrolase gene polymorphism and susceptibility to colon cancer. 1040 10

Malignant gliomas are the main cause of death from primary brain tumors. Despite surgery, radiation, and chemotherapy, patients have a median survival of less than a few years; therefore, it is clearly imperative to investigate new ways of treatment. The development of new therapeutic strategies for brain tumors is dependent on a better understanding of the differences between normal and tumoral brain cells. Our group had described previously a Mr 48,000 antigen defined by reactivity with two monoclonal antibodies (GE2 and BF7) obtained by immunization of mice with human glioblastoma cells. Here, we describe the identification of the GE2/BF7 antigen as microsomal epoxide hydrolase (mEH), a drug-metabolizing enzyme that is involved both in toxification and detoxification of carcinogens. We initially used immunoaffinity purification using GE2 and BF7 and analyzed the purified proteins by microsequencing. Edman degradation identified 15 amino acids of the NH2-terminal sequence that were 100% identical to mEH. To further confirm the identity of the BF7/GE2 antigen as mEH, we showed that the protein immunopurified with GE2 and BF7 was recognized by an anti-mEH antibody and that in vitro and in vivo synthesized human mEH is recognized by BF7 and GE2 antibodies. Furthermore, anti-mEH antibody recognizes an antigen expressed both in gliomas and reactive astrocytes, as do BF7 and GE2. Finally, we demonstrate that in contrast to what has been reported in rat embryo fibroblasts, p53 does not regulate mEH mRNA expression in glioma cells.
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PMID:Identification of the putative brain tumor antigen BF7/GE2 as the (de)toxifying enzyme microsomal epoxide hydrolase. 1072 6

Functional significance has been demonstrated in vitro for the exon 3 T-->C Tyr113His amino acid substitution polymorphism of the microsomal epoxide hydrolase (EPHX) gene. The higher activity or fast TT genotype was previously reported to be associated with an increased risk of ovarian cancer, and this association may reflect enhanced activation of endogenous or exogenous substrates to more reactive and mutagenic derivatives. Components of cigarette smoke are examples of exogenous substrates subject to such bioactivation, and smoking exposure may thus modify the risk associated with the EPHX polymorphism. We examined 545 cases of epithelial ovarian cancer and 287 unaffected controls for this EPHX T-C genetic variant to investigate whether, in the Australian population, the TT genotype was associated with (i) specific ovarian tumor characteristics; (ii) risk of ovarian cancer, overall or for specific subgroups; and (iii) risk of ovarian cancer in smokers specifically. Genotyping was carried out using the Perkin-Elmer ABI Prism 7700 Sequence Detection System for fluorogenic polymerase chain reaction allelic discrimination. Stratification of the ovarian cancer cases according to tumor behavior (low malignant potential or invasive), grade, stage, and p53 immunohistochemical status failed to show any heterogeneity with respect to the genotype defined by the EPHX polymorphism. There was a suggestion of heterogeneity with respect to histologic subtype (P=0.03), largely due to a decreased frequency of the TT genotype in endometrioid tumors. EPHX genotype distribution did not differ significantly between unaffected controls and ovarian cancer cases (overall, low malignant potential, or invasive) either overall or after stratification by smoking status. However, the TT genotype was associated with a decreased risk of invasive ovarian cancer of the endometrioid subtype specifically (age-adjusted odds ratio=0.38, 95% confidence interval=0.17-0.87). The results suggest that the proposed EPHX-mediated bioactivation of components of cigarette smoke to mutagenic forms is unlikely to be involved in the etiology of ovarian cancer in general but that a greater rate of EPHX-mediated detoxification may decrease the risk of endometrioid ovarian cancer. Mol. Carcinog. 30:71-78, 2001.
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PMID:The microsomal epoxide hydrolase Tyr113His polymorphism: association with risk of ovarian cancer. 1125 66

Lung cancer is a major cause of cancer-related death in the developed countries and the overall survival rate has still an extremely poor. Cigarette smoking is an established risk factor for lung cancer although a possible role for genetic susceptibility in the development of lung cancer has been inferred from familial clustering of the disease and segregation analyzes. Everyone may have a unique combination of polymorphic traits that modify genetic susceptibility and response to drugs, chemicals and carcinogens. Developments in molecular biology have led to growing interest in investigation of biological markers, which may increase predisposition to lung carcinogenesis. Therefore, the high-risk genotype of an individual could be determined easily. As there are the great number of carcinogen-activating and -detoxifying enzymes, the variation in their expression and the complexity of exposures to tobacco carcinogens, the existence of multiple alleles at loci of those enzymes may result in differential susceptibilities of individuals. This review summarize data addressing the relationships of lung cancer to markers of genetic susceptibility genes, including metabolic polymorphisms other than well-investigated cytochrome P450s or glutathione S-transferases, DNA repair genes and the p53 tumor suppressor gene. Among genetic polymorphisms reviewed here, myeloperoxidase gene (a G to A mutation) and microsomal epoxide hydrolase exon 4 polymorphism (substitution of Arg for His) were significantly associated with lung cancer risk. As lung cancer is a multifactorial disease, an improved understanding of the interplay of environmental and genetic polymorphisms at multiple loci may help identify individuals who are at increased risk for lung cancer. Hopefully, in the future we will be able to screen for lung cancer susceptibility by using specific biomarkers.
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PMID:Genetic polymorphisms and lung cancer susceptibility: a review. 1223 92

Tobacco-associated carcinogens are catalyzed by microsomal epoxide hydrolase (mEH). Combinations of the Y113H and H139R polymorphic EPHX1 variants have been assumed to alter the enzyme activity and thus the risk of squamous cell head and neck cancer (SCCHN). Based on in vitro data, a putative low, medium and high mEH activity has been associated with combinations of these genotypes, and the respective activity categories have been frequently used in the estimation of risks for smoking-related cancers. We investigated the SCCHN risk for EPHX1 genotypes among 280 cases and 289 controls. We could not detect main effects of the EPHX1 genotypes, but a smaller risk of the 139HR genotype in smokers (odds ratio, OR, 0.57; 95% confidence interval, CI, 0.34-0.95). We could not confirm an increase of the SCCHN risk for genotype combinations according to a putative medium and high enzyme activity (OR 1.28, 95% CI 0.84-1.96; OR 0.98, 95% CI 0.58-1.64, respectively), but a significant heterogeneity of the estimated risks for the singular genotypes within these categories among smokers ( P=0.02). Further, p53 mutations among smoking cases were less frequent in the group with a putative high enzyme activity, although insignificant due to small numbers (OR 0.54, 95% CI 0.13-2.17). This supports uncertainties in categorizing genotypes with respect to limited enzyme activity data, especially when taken from in vitro experiments.
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PMID:Association between head and neck cancer and microsomal epoxide hydrolase genotypes. 1249 Oct 39

Enzymes involved in benzene metabolism are likely genetic determinants of benzene-induced toxicity. Polymorphisms in human microsomal epoxide hydrolase (mEH) are associated with an increased risk of developing leukemia, specifically those associated with benzene. This study was designed to investigate the importance of mEH in benzene-induced toxicity. Male and female mEH-deficient (mEH-/-) mice and background mice (129/Sv) were exposed to inhaled benzene (0, 10, 50, or 100 ppm) 5 days/week, 6 h/day, for a two-week duration. Total white blood cell counts and bone marrow cell counts were used to assess hematotoxicity and myelotoxicity. Micronucleated peripheral blood cells were counted to assess genotoxicity, and the p21 mRNA level in bone marrow cells was used as a determinant of the p53-regulated DNA damage response. Male mEH-/- mice did not have any significant hematotoxicity or myelotoxicity at the highest benzene exposure compared to the male 129/Sv mice. Significant hematotoxicity or myelotoxicity did not occur in the female mEH-/- or 129/Sv mice. Male mEH-/- mice were also unresponsive to benzene-induced genotoxicity compared to a significant induction in the male 129/Sv mice. The female mEH-/- and 129/Sv mice were virtually unresponsive to benzene-induced genotoxicity. While p21 mRNA expression was highly induced in male 129/Sv mice after exposure to 100-ppm benzene, no significant alteration was observed in male mEH-/- mice. Likewise, p21 mRNA expression in female mEH-/- mice was not significantly induced upon benzene exposure whereas a significant induction was observed in female 129/Sv mice. Thus mEH appears to be critical in benzene-induced toxicity in male, but not female, mice.
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PMID:Male mice deficient in microsomal epoxide hydrolase are not susceptible to benzene-induced toxicity. 1265 32

The expression of selected gene products involved in cell differentiation and cell growth and genetic polymorphism of detoxifying genes was examined in 105 surgically resected nonsmall cell lung cancer (NSCLC) patients, and the relationship of these factors was correlated with cigarette smoking and patient survival. Genotyping of peripheral blood lymphocytes from 87 patients was performed for CYP2E1, GSTM1, GSTT1, mEH, and MPO detoxifying genes using polymerase chain reaction. Formalin-fixed, paraffin-embedded tissue was immunostained with antibodies to p53, p27, phospho-AKT, and bcl-2 using the avidin-biotin-peroxidase method and tissue microarray technique. Tumors were assigned a positive or negative score based on more than 10% of tumor cells staining positive with the antibody. The subtypes of NSCLC included 48 adenocarcinomas, 47 squamous cell carcinomas, and 10 large cell undifferentiated carcinomas. A total of 54 tumors were pathologic stage I, 23 were stage II, and 26 were stage III. All subjects smoked (range, 10-175 pack-years; mean, 60 pack-years). The mean overall survival was 112 weeks (median, 129 weeks). Patients with p53-positive tumors had significantly fewer pack-years of smoking (52 pack-years vs 72 pack-years; P = 0.021), smoked fewer years (34 years vs 40 years; P = 0.018), and had significantly better survival compared with those with p53-negative tumors (P = 0.045). When smoking history was further analyzed, the authors found that p53 expression was associated with the number of years smoked and not the number of packs smoked per day. Patients with squamous cell carcinoma had smoked longer compared with those with adenocarcinoma (P = 0.011). Significant association was seen between the CYP2E1 wild-type allele and better survival (P = 0.016). Patients with stage I tumors had better survival compared with stages II and III (P = 0.032). No association was found between survival and tumor type; tumor differentiation; expression of phospho-AKT, p27, and bcl-2; and polymorphic metabolizing genes other than CYP2E1. The significant association of long duration of smoking (>40 years) with loss of p53 expression and poor survival suggests inactivation of the protective p53 pathway in those who had a history of more than 40 years of smoking.
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PMID:CYP2E1 polymorphism, cigarette smoking, p53 expression, and survival in non-small cell lung cancer: a long term follow-up study. 1553 30

The tumor suppressor protein p53 is a transcription factor that regulates apoptotic responses produced by genotoxic agents. Previous studies have reported that 7,12-dimethylbenz[a]anthracene (DMBA)-induced bone marrow toxicity is p53-dependent in vivo. Our laboratory has shown that DMBA-induced splenic immunosuppression is CYP1B1- and microsomal epoxide hydrolase (mEH)-dependent, demonstrating that the DMBA-3,4-dihydrodiol-1,2-epoxide metabolite (DMBA-DE) is probably responsible for DMBA-induced immunosuppression. DMBA-DE is known to bind to DNA leading to strand breaks. Therefore, we postulated that a p53 pathway is required for DBMA-induced immunosuppression. In the present studies, our data show that activated p53 accumulated in the nuclei of spleen cells in WT and AhR-null mice after DMBA treatment, but not in CYP1B1-null or mEH-null mice. These results suggest that DMBA activates p53 in a CYP1B1- and mEH-dependent manner in vivo but is not AhR-dependent. Ataxia telangiectasia mutated (ATM) and ATM and Rad3-related protein (ATR) are sensors for DNA damage that signal p53 activation. Increased ATM, phospho-ATM (Ser(1987)), and ATR levels were observed after DMBA treatment in WT, p53-null, and AhR-null mice but not in CYP1B1-null or mEH-null mice. Therefore, ATM and ATR seem to act upstream of p53 as sensors of DNA damage. Ex vivo immune function studies demonstrated that DMBA-induced splenic immunosuppression is p53-dependent at doses of DMBA that produce immunosuppression in the absence of cytotoxicity. High-dose DMBA cytotoxicity may be associated with p53-independent pathways. This study provides new insights into the requirement of genotoxicity for DMBA-induced immunosuppression in vivo and highlights the roles of ATM/ATR in signaling p53.
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PMID:p53 and ATM/ATR regulate 7,12-dimethylbenz[a]anthracene-induced immunosuppression. 1792 58


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