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)

Benzo[a]pyrene (BaP) is a ubiquitous environmental pollutant, which may contribute to the development of human cancer. The ultimate carcinogenic BaP metabolite produced by cytochrome P450 enzymes (CYP), such as CYP1A1 and CYP1B1, anti-BaP-7,8-diol-9,10-epoxide, binds covalently to DNA and causes mutations. The levels of various CYP isoforms can be significantly modulated under inflammatory conditions. As the chronic inflammation is known to contribute to carcinogenesis, we investigated interactions of a major proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), and BaP in regulation of the expression of CYP1A1/1B1 and induction of DNA damage in rat liver epithelial WB-F344 cells. TNF-alpha enhanced induction of CYP1B1, while it simultaneously suppressed the BaP-induced CYP1A1 expression. The observed deregulation of CYP1 induction was found to be associated with a significantly enhanced formation of DNA adducts. The elevated DNA damage corresponded with increased phosphorylation of p53 tumor suppressor at Ser-15 residue, enhanced accumulation of cells in the S-phase of cell cycle and potentiation of BaP-induced apoptosis. Inhibition of CYP1B1 by fluoranthene significantly decreased both the formation of DNA adducts and the induction of apoptosis in WB-F344 cells treated with BaP and TNF-alpha, thus suggesting that this isoform might be responsible for genotoxic effects of BaP in nonparenchymal liver cells. Our results seem to indicate that inflammatory conditions might enhance genotoxic effects of carcinogenic polycyclic aromatic hydrocarbons through upregulation of CYP1B1 expression.
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PMID:Tumor necrosis factor-alpha potentiates genotoxic effects of benzo[a]pyrene in rat liver epithelial cells through upregulation of cytochrome P450 1B1 expression. 1833 43

The aim of this report is to review and evaluate, in a comprehensive manner, the published data regarding the contribution of genetic polymorphisms to risk of head and neck cancer (HNC). All relevant studies available in MEDLINE and published before July 2007 were identified. Studies carried out in humans that compared HNC patients with at least 1 standard control group were considered for analysis. Two hundred and eighteen publications and 3 published meta-analyses were identified. Seventy-five (34%) studies were conducted in Asian, 72 (33%) in American, and 68 (31%) in European countries. The most widely studied gene was GSTM1 (58 studies), followed by GSTT1 (42 studies), GSTP1 (codon 105, 22 studies) and p53 (codon 72, 20 studies). GSTM1, GSTT1, GSTP1, XRCC1 codons 194 and 399, and CYP1A1 codon 462 were examined by meta-analyses, and significant relations were found between the GSTM1-null genotype and an increased risk for HNC. In addition, increased risk for HNC was associated consistently with the ALDH2*1/*2, p53 codon 72 Pro/Pro and EPHX1 codon 113 Tyr/His and His/His genotypes. Cohort studies that simultaneously consider multiple genetic and environmental factors possibly involved in carcinogenesis of the head and neck are needed to ascertain not only the relative contribution of these factors to tumor development but also the contributions of their putative interactions.
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PMID:Genetic polymorphisms and head and neck cancer risk (Review). 1842 22

A CYP1A1 polymorphism has been associated with an increased risk for gallbladder cancer (GBC) in Japanese women. However, genetic risk factors for GBC in Hungary, where the population has a relatively high GBC incidence, has not been well studied. We therefore tested associations between CYP1A1 T3801C, CYP1A1 Ile462Val, GSTM1deletion, and TP53 Arg72Pro and GBC in Hungary. Genomic DNA was extracted from peripheral blood of 100 controls (52 men and 48 women) and from the tissue embedded in paraffin of 43 cases (6 men and 37 women). The case-control analysis was limited to females due to a small number of males. Of 37 female cases, 21 (56.8%) were diagnosed as adenocarcinoma, and the remaining 16 (43.2%) were classified as non-adenocarcinoma. The odds ratios (ORs) for the Ile/Val genotype and the Val allele were 8.9 (95% CI: 2.9-27.4) and 4.4 (95% CI: 1.7-11.1), respectively. The occurrence of the combined variant genotypes of CYP1A1 Ile462Val and GSTM1 (37.8% vs. 8.3%) or CYP1A1 Ile462Val and TP53 Arg72Pro (24.3% vs. 0%) was significantly higher in the cases than in the controls. The Ile/Val genotype was significantly associated with an increased risk of adenocarcinoma (OR 9.2; 95% CI: 2.6-32.6) and non-adenocarcinoma (OR 8.4; 95% CI: 2.2-32.4). Additionally, the Arg/Pro genotype increased risk of non-adenocarcinoma (OR 3.8; 95% CI: 1.2-12.8). The Val allele may contribute to the development of GBC not only in Japanese but also in Hungarian women. Our results provide a rationale for further studies of genetic variation on the risk of GBC in Hungary.
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PMID:Effect of genetic predisposition on the risk of gallbladder cancer in Hungary. 1899 8

The hamster buccal pouch (HBP) carcinogenesis model is one of the most well characterized animal systems for analyzing the development of oral squamous cell carcinoma (OSCC), a common malignancy worldwide. HBP carcinomas that closely mimic human OSCC are useful in understanding the molecular mechanisms of neoplastic transformation. The present study is a comparative evaluation of markers of carcinogen activation, oxidative stress, cell proliferation, apoptosis, invasion, and angiogenesis in human and hamster OSCCs. Enhanced expression of CYP1A1 and CYP1B1 isoforms in both human and hamster oral tumours was associated with significantly increased expression of 8-hydroxy 2-deoxyguanosine (8-OHdG) indicating oxidative DNA damage. Analysis of markers of cell survival and proliferation revealed increased expression of PCNA, GST-P, and NF-kappaB with downregulation of p21, p53 and IkappaB in both human and hamster OSCCs. In addition, both human and hamster oral carcinomas displayed invasive, and angiogenic properties as revealed by dysregulated cytokeratin expression, downregulation of RECK, and increased expression of uPA, MMP-2 and-9, HIF-1alpha, and VEGF. The results reveal aberrant expression of multiple molecules in key signaling pathways in both human OSCCs and HBP carcinomas rendering the HBP model as an important tool for monitoring oral oncogenesis.
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PMID:Of humans and hamsters: a comparative evaluation of carcinogen activation, DNA damage, cell proliferation, apoptosis, invasion, and angiogenesis in oral cancer patients and hamster buccal pouch carcinomas. 1925 Aug 57

The esophageal squamous cell carcinoma is multifactorial disease involving genetic and environmental factors. The paper presents most important human data on the polymorphisms of selected genes that have been linked with higher risk of the neoplasm. The most widely studied group were genes encoded molecules engaged in biotransformations of xenobiotics, in particular potential carcinogens, like alcohol (ADH2) and aldehyde (ALDH2) dehydrogenases, various isoenzymes of cytochrome P450 (CYP1A1, CYP2E1) and glutathione S-transferase (GSTM1, GSTT1, GSTP1). High interest was also put for polymorphism in DNA repair genes, i.e., OGG1, XRCC1, XPD, XPG and MGMT as well as genes associated with nucleotide biosyntesis like methylenotetrahydrofolate reductase and thymidylate synthase and in control of cell cycle and apoptosis e.g., p53, Fas, FasL or TNF. Furthermore, it was revealed that predisposition to cancer in certain individual could be determined by coexistence of unprofitable allele of a few genes. Introduction of genetic screening test allows effective, purpose-oriented methods of prevention and in patients suffered from the cancer--application of optimal therapy and minimization of side-effects.
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PMID:[Genetic base of esophageal squamous cell carcinoma susceptibility]. 1938 10

Sulfur dioxide (SO(2)) and benzo(a)pyrene (B(a)P) are common industrial and environmental contaminants. However, few data are available on the effects of SO(2) on proto-oncogenes and tumor suppressor genes, as well as the interactions between SO(2) and other xenobiotics regulating proto-oncogenes or tumor suppressor genes expression. To investigate the interactions between SO(2) and B(a)P, male Wistar rats were exposed to intratracheally instilled with B(a)P or SO(2) inhalation alone or together. We detected mRNA expression of CYP1A1 and 1A2, 7-ethoxyresorufin O-deethylase (EROD), and methoxyresorufin O-demethylase (MROD) activities in livers. The mRNA and protein levels of several cancer-related genes were analyzed in livers by real-time RT-PCR and Western blot, respectively. The EROD/MROD activities and CYP1A1/2 expression were down-regulated by SO(2) but up-regulated by B(a)P alone. Exposure of SO(2) alone induced c-fos, c-jun, c-myc, H-ras, and p53 expression, and depressed p16 and Rb expression in livers. The effects of B(a)P on the above gene were similar to SO(2) except c-fos expression. Furthermore, SO(2) + B(a)P exposure increased the expression of c-fos, c-jun, c-myc, and p53, and decreased p16 and Rb expression in livers compared with exposed to SO(2) or B(a)P alone. However, no synergistic effects were observed on H-ras and CYP1A1/2 after SO(2) + B(a)P exposure. Our findings indicate that multiple cell cycle regulatory proteins play key roles in the toxicity of SO(2) and B(a)P in livers. It might involve the activation of c-fos, c-jun, c-myc, and p53. And p16-Rb pathway might also participate in the progress. Although the gene products we studied are classed as oncogenes and tumor suppressor genes, their functions actually relate to more general processes of control of cell proliferation, survival, and/or apoptosis.
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PMID:Sulfur dioxide and benzo(a)pyrene modulates CYP1A and tumor-related gene expression in rat liver. 1940 42

Oral cancer is the most common malignancy in India, where it is epidemiologically linked to the chewing of betel quid and other carcinogens. But various point mutations were detectable in the p53 and p15 genes. Hence, this review was conducted with the aim to find out genetic risks as well as markers for oral cancers and wound healing. Tobacco-related cancers are associated with polymorphisms of the CYP1A1 and GSTM1 genes in terms of genotype frequencies and cigarette smoking dose. Expression of E6/E7 were also found in tumors, most of which were derived from the oropharynx. Presence of homozygous arginine at codon 72 renders p53 about seven times more susceptible to E6-mediated proteolytic degradation. Erythropoietin, vascular permeability factor (VPF, also known as vascular endothelial growth factor or VEGF), and PDGF has been implicated as one of the principal mitogens involved in cutaneous wound healing. Activation of NF-kB is associated with enhanced cell survival. Human papilloma virus status is a significantly favorable prognostic factor in tonsilar cancer and may be used as a marker in order to optimize the treatment of patients with this type of cancer.
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PMID:The genomics of oral cancer and wound healing. 1941 66

We sought to evaluate the molecular markers involved in breast tumorigenesis in a rat model that mimics many essential elements of human breast cancer. Female Sprague-Dawley rats were divided into two groups. Animals in group 1 were given a single dose of 7,12-dimethylbenz[a]anthracene (DMBA) (20 mg/rat) dissolved in 1 ml of sesame oil by intragastric intubation. Group 2 animals received basal diet and served as control. We analyzed DMBA-induced changes in the expression of CYP isoforms (CYP1A1 and 1B1) involved in DMBA metabolism, markers of oxidative stress (4HNE, HEL, and 8-OHdG), cell survival and proliferation (PCNA, NF-kappaB-p50, NF-kappaB-p65, GST-P, and p53), apoptosis (Bcl-2, Bax, caspases, Apaf-1, cytochrome C, and Fas), invasion (uPA, MMP-2, MMP-9, TIMP-2, and RECK), and angiogenesis (VEGF, VEGF-R1, HIF-1alpha, and PLGF) by immunohistochemical localization, Western blot, and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. The present study demonstrates increased carcinogen metabolism, oxidative stress, cell proliferation, together with apoptosis evasion, invasion, metastasis, and neovascularization that may confer a selective growth advantage to DMBA-induced mammary tumors. Aberrant expression of multiple molecules in key signaling pathways in Sprague-Dawley rat mammary tumors renders this model as an important tool for monitoring carcinogenic progression and chemointervention.
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PMID:Evaluation of molecular markers in a rat model of mammary carcinogenesis. 1972 28

Lung cancer is a major cause of cancer-related death in developed countries, and its incidence in developing countries is increasing. In Thailand, cancer incidences differ greatly from region to region, and lung cancer is the most common cancer in the northern Thai population. The polymorphic frequency of 10 genetic susceptibility genes and their association with lung cancer were examined in a northern Thai population: CYP1A1 (MspI), CYP1A1 (Ile462Val), CYP2E1 (PstI), CYP2E1 (DraI), GSTM1, GSTT1, MPO (AciI), OGG1 (Ser326Cys), TP53 (Arg72Pro), and MMP1(AluI). The 173 subjects were 91 lung cancer patients and 82 healthy volunteers. Although no significant association between any single genetic variant and lung cancer risk was observed, when genetic variants were analyzed in combination, a significant effect on lung cancer risk was found for the variant allele in a combination of five genes involved in oxidative stress and inflammatory response: GSTM1 (null), MPO (-463A), OGG1 (326Cys), TP53 (72Pro) (alias p53), MMP1 (2G). With a reference group of individuals carrying at least two wild-type genotypes of these five genes, it was found that an individual carrying three or more variant genotypes is at significantly higher risk of developing lung cancer with the increasing of odds ratios (OR) in concurrence with the number of variant genes. The OR was 2.41 (95% CI = 0.76-7.64), 3.90 (95% CI = 1.23-12.34), and 5.20 (95% CI = 1.31-20.54) for individuals carrying three, four, and five variants, respectively. After stratifying by sex, the OR was higher for women: OR 4.05 (95% CI = 0.44-36.94), 9.00 (95% CI = 0.95-84.89) and 18.00 (95% CI = 1.49-216.62) for three, four, and five variant genotypes, respectively. This augmented effect on lung cancer risk of variant genes involved in oxidative stress and inflammatory response in women with a low prevalence of smoking indicates their modifying effect on other risk factors, such as environmental cigarette smoke, air pollution, radon radiation, or infection of the airway. Confirmation would require further investigations with larger sample sizes.
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PMID:Effect of combined genetic polymorphisms on lung cancer risk in northern Thai women. 1996 14

Lung cancer is one of the most common cancers in the world. While historically, more men than women have died from lung cancer as a result of higher numbers of male smokers, the sex mortality ratio is now showing signs of narrowing. Tumors in women with lung cancer may be slightly different to those in men with lung cancer. This review focuses on biomarkers differentially expressed between female and male patients with lung cancer. There is variation in gene expression between men and women in some genes that encode carcinogen-metabolizing enzymes (CYP1A1, GSTM). Gastrin-releasing peptide (GRP), a bombesin-like peptide, is present in two actively transcribed alleles in women compared with men. Higher prevalence of infection with oncogenic variants human papilloma viruses (HPVs) HPV16 and HPV18 has been suggested in women. A higher frequency of G to T transversion was found in the p53 gene in lung tumors of women. KRAS mutation was found to be more frequent in women with resected non-small cell lung cancer (NSCLC) than in men with resected NSCLC. Epidermal growth factor receptor (EGFR) mutation is more frequently found in lung tumors from women, but the confounding effect of tobacco exposure may explain this difference. Lower levels of ERCC1 and BRCA1 have been reported in women with NSCLC. Lung tumors from women are more likely to express estrogen receptors than those from men. An in silico analysis of transcriptome datasets from lung cancer patients demonstrated that only seven genes (in at least two studies) had significantly different expression patterns in male versus female patients. All of these genes are localized on the sex chromosomes: one on chromosome X and six on chromosome Y. Many areas remain under debate and there are still significant gaps in our understanding, particularly how sex-linked factors relate to lung cancer risk, and to biological and clinical behaviors. Future research into lung cancer needs to address these gender differences more specifically.
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PMID:Differential expression of biomarkers in men and women. 1999 47


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