Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progress in the treatment of colon cancer depends on the development of target-based molecules built on an improved understanding of the molecular biology of the disease. Defining end points for chemotherapy resistance is needed as drug resistance develops quickly and patients demonstrate variation in response to chemotherapy. Many techniques that measure a marker's preponderance have been developed including biochemical, immunohistochemical, genomics, proteomics or a combination thereof. However, standardization of these techniques that measure either genes or their protein products is urgently needed. This article reviews several markers (TS,TP, DPD, FT, EGFR, VEGF, CD44v6, TRAIL, microsatellite instability, allelic deletions, oncogenes and suppressor genes [c-myc, Ki-Ras, p53, p21, Topo I, Topo IIalpha, Fos, hMLH1, Bcl-2/Bax and MDR1], MDR-related proteins [Pgp, MRP and LRP], genomic polymorphisms [XPD, ERCC1, GSTP1 and TS 3 -UTR] and COX-;2) that influence DNA metabolism, DNA damage, programmed cell death, the immune or vascular system, or lead to mutations. When combined together and tested by newly developed genomic and proteomic approaches, many of these markers provide a more sensitive indicative predictor of response than when evaluated separately or by older biochemical, immunohistologic or morphologic methods. A global approach involving the simultaneous testing of several predictive multimarkers will provide critical information for improving chemotherapy to alleviate suffering from this disease.
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PMID:Molecular markers that predict response to colon cancer therapy. 1593 13

Glutathione S-transferase P1(GSTP1) plays an important role in the detoxification and xenobiotics metabolism. Here, we show that GSTP1 is also involved in LPS (lipopolysaccharide)-induced inflammatory response. GSTP1 expression, determined at the transcription and translation levels, were upregulated by the LPS stimulation in RAW264.7 macrophage-like cells. GSTP1 inhibited LPS-induced mitogen-activated protein kinases MAPKs including ERK, JNK and p38 as well as NF-kappaB activation dose- and time-dependently in transient transfected and stable transfected cells. Moreover this inhibition of the signaling pathways resulted in the decrease of tumor necrosis factor alpha (TNF-alpha) and nitric oxide (NO) synthesis. These data suggest that the GSTP1 prevents LPS-induced excessive production of pro-inflammatory factors and plays an anti-inflammatory role in response to LPS.
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PMID:Regulation of lipopolysaccharide-induced inflammatory response by glutathione S-transferase P1 in RAW264.7 cells. 1602 7

Oxidative stress is thought to play an important role in the pathophysiology of pre-eclampsia. A defect in certain enzymes responsible for detoxification may cause prolonged exposure to reactive by-products and contribute to maternal endothelial as well as placental damage. Two polymorphisms affecting the function of the biotransformation enzymes epoxide hydrolase and glutathione S-transferase P1 were shown previously to be associated with pre-eclampsia in a Dutch population. The aim of this study was to determine if these two polymorphisms (maternal or fetal) contribute to pre-eclampsia in an anthropologically distinct population (the Western Cape region of South Africa) with a high incidence of the disease. Genomic DNA of mother - infant pairs with severe pre-eclampsia (n = 144), a population control group (n = 156) and control mother - infant pairs with uncomplicated pregnancy outcome (n = 45) were analysed for the EPHX and GSTP1 polymorphisms by polymerase chain reaction amplification and restriction enzyme digestion. Each polymorphism had a similar distribution in case and control subjects (mother and infant). The Val105/Val105 genotype of GSTP1 occurred at a higher frequency than reported for other populations. Neither maternal nor fetal EPHX Tyr113His and GSTP1 Ile105Val polymorphisms appear to contribute significantly to the pathophysiology of pre-eclampsia in the Coloured population of the Western Cape region of South Africa.
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PMID:Maternal and fetal single nucleotide polymorphisms in the epoxide hydrolase and gluthatione S-transferase P1 genes are not associated with pre-eclampsia in the Coloured population of the Western Cape, South Africa. 1614 38

Heme oxygenase 1 (HO-1) catalyses the oxidation of heme to biliverdin, and its expression is induced by oxidative stress. This study was aimed at assessing the role of metabolic polymorphisms (CYP1A1, CYP1B1, GSTM1, GSTP1, EPHX) in the modulation of HO-1 gene expression in 37 foundry workers. Blood and urine samples were obtained at the beginning (BS) and at the end (ES) of work shift, in February (T1) and June (T2). Urinary 1-hydroxypyrene (1-OHP) was measured as a tracer of PAH exposure. HO-1 gene expression in ES samples normalized to BS values (HO-1 ES/BS) was higher at T2 respect to T1. HO-1 gene induction was related to ES 1-OHP when considering either T2 samples or the combination of the two samplings. HO-1 ES/BS was significantly increased in subjects with at least a mutant allele for GSTP1 as compared to subjects with GSTP1AA genotype (1.23 +/- 0.002 vs 0.88 +/- 0.002, p < 0.05). Only in subjects with at least one vari.nt allele for GSTP1, a positive correlation between HO-1 ET/IT expression and 1-OHP FT levels was observed (r2 = 0.21, p = 0.016). The present study demonstrates a correlation between PAH exposure, as assessed by urinary 1-OHP, and the induction of HO-1 expression. Such a correlation seems to be limited to subjects bearing variant alleles for GSTP1. At the same exposure levels, these subjects showed a greater expression of HO-1 FT as compared to subjects with GSTP1 wild type genotype, possibly due to a higher oxidative stress in the subjects expressing the mutant GSTP1-1 isoform, which could imply a limited scavenging capacity.
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PMID:[Heme oxygenase 1 expression in foundry workers]. 1624 May 85

Quantitative and structural genetic alterations cause the development and progression of prostate cancer. A number of genes have been implicated in prostate cancer by genetic alterations and functional consequences of the genetic alterations. These include the ELAC2 (HPC2), MSR1, and RNASEL (HPC1) genes that have germline mutations in familial prostate cancer; AR, ATBF1, EPHB2 (ERK), KLF6, mitochondria DNA, p53, PTEN, and RAS that have somatic mutations in sporadic prostate cancer; AR, BRCA1, BRCA2, CHEK2 (RAD53), CYP17, CYP1B1, CYP3A4, GSTM1, GSTP1, GSTT1, PON1, SRD5A2, and VDR that have germline genetic variants associated with either hereditary and/or sporadic prostate cancer; and ANXA7 (ANX7), KLF5, NKX3-1 (NKX3.1), CDKN1B (p27), and MYC that have genomic copy number changes affecting gene function. More genes relevant to prostate cancer remain to be identified in each of these gene groups. For the genes that have been identified, most need additional genetic, functional, and/or biochemical examination. Identification and characterization of these genes will be a key step for improving the detection and treatment of prostate cancer.
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PMID:Prevalent mutations in prostate cancer. 1626 36

Styrene oxide (SO), ethylene oxide (EO) and gamma-radiation (G) are agents with a well-described metabolism and genotoxicity. EPHX1 and GSTs play an important role in the detoxification of electrophiles and oxidative stress. Enzymes involved in base excision repair (hOGG1, XRCC1), in rejoining single strand breaks (XRCC1) and in repair of cross-links and chromosomal double strand breaks (XRCC3) might have an impact on genotoxicity as well. In this study we assessed the dose-dependent effect of genetic polymorphisms in biotransforming (EPHX (Tyr113/His113 and His139/Arg139), GSTP1 (Ile105/Val105), GSTM1 and GSTT1) and DNA repair enzymes (hOGG1 (Ser326/Cys326), XRCC1 (Arg194/Trp194, Arg280/His280, Arg399/Gln399), XRCC3 (Thr241/Met241)) on the induced genotoxicity. Peripheral blood mononuclear cells from 20 individuals were exposed to 3 doses per agent (+control). Genotoxicity was evaluated by measuring comet tail length (TL) and micronucleus frequencies in binucleated cells (MNCB). Dose-dependent DNA damage was found for all agents and end-points, with the exception of MNCB induced by EO. Repeated measure ANOVA revealed a significant contribution of hOGG1 and XRCC3 genotypes to the inter-individual variability of TL and MNCB in cells exposed to EO and G. Homozygous hOGG1326 wild cells showed significantly lower EO-induced TL than the heterozygous cells. Significantly higher TL and MNCB were found in EO-exposed cells carrying the XRCC3(241)Met variant and the influence on TL was more pronounced at higher dose. In G-irradiated cells, TL was significantly higher in the hOGG1326 homozygous wild types compared with mutated genotypes. The influence of hOGG1326 on TL was borderline dose-dependent. We conclude that the influence of genetic polymorphisms of enzymes involved in DNA repair on induced genotoxicity depends on exposure dose.
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PMID:Dose-dependent influence of genetic polymorphisms on DNA damage induced by styrene oxide, ethylene oxide and gamma-radiation. 1638 46

The present study comprised a biomonitoring study in 95 workers occupationally exposed to styrene and 98 unexposed controls, employing an integrated approach involving biomarkers of exposure, effect, and susceptibility. Airborne styrene was evaluated at workplace, and urinary styrene metabolites, mandelic acid (MA), phenylglyoxylic acid (PGA), vinylphenols (VPTs) and phenylhydroxyethylmercapturic acids (PHEMAs), were measured as biomarkers of internal dose. Cytogenetic alterations were evaluated by analysing the frequency of chromosomal aberrations (CAs) and micronucleated binucleated cells (MNBN) in peripheral blood lymphocytes. The micronucleus assay was coupled with centromeric fluorescence in situ hybridization to distinguish micronuclei (MN) arising from chromosomal breakage (C- MN) from those harboring whole chromosomes (C+ MN). The possible influence of genetic polymorphisms of xenobiotic-metabolizing enzymes involved in styrene biotransformation (EPHX1, GSTT1, GSTM1, GSTP1) and NAT2 on the cytogenetic endpoints was investigated. The exposed workers showed a significantly higher frequency of MNBN (13.8+/-0.5% versus 9.2+/-0.4%; P<0.001) compared to control subjects. The effect appeared to concern both C- and C+ MN. A positive correlation was seen between the frequency of C+ MN and urinary level of MA+PGA (P<0.05) and VPTs (P<0.001). Chromosome-type CAs positively correlated with airborne styrene level and VPTs (P<0.05), whereas chromatid-type CAs correlated with PHEMAs (P<0.05). Workers bearing GSTM1 null genotype showed lowered levels of PHEMAs (P<0.001). The GSTT1 null genotype was associated with increased MNBN frequencies in the exposed workers (P<0.05) and the fast activity EPHX genotype with a moderate decrease in both MNBN and CAs in the controls. Our results suggest that occupational exposure to styrene has genotoxic effects that are potentiated by the GSTT1 gene deletion. These observations may have relevance considering the risk of lymphatic and haematopoietic malignancies tentatively associated with styrene exposure.
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PMID:Cytogenetic biomarkers, urinary metabolites and metabolic gene polymorphisms in workers exposed to styrene. 1642 21

Nitrosamines are mainly mutagenic through methylation of DNA. 7-Methylguanine (m(7)Gua) is a product of base excision repair and spontaneous depurination of such lesions in DNA and a metabolite from RNA. Associations between urinary excretion of m(7)Gua and risk of lung cancer were examined in a population-based cohort of 25,717 men and 27,972 women aged 50-64 years. During 3-7 years follow-up 260 cases with lung cancer were identified and a subcohort of 263 individuals matched on sex, age and smoking duration was selected for comparison. Urine collected at entry was analyzed for m(7)Gua by HPLC. Effect modification by glutathione-S-transferases GSTM1, GSTM3, GSTT1 and GSTP1 was investigated. We found higher excretion of m(7)Gua among current smokers than among former smokers. The IRR (incidence rate ratio) of lung cancer was 1.20 (95% CI: 1.00-1.43) per doubling of m(7)Gua excretion in unadjusted analysis and 1.12 (95% CI: 0.93-1.35) after adjustment for smoking status, intensity and duration at entry. This association was mainly present among current smokers. Comparing the highest with the lowest tertile of m(7)Gua excretion the IRR of lung cancer was 1.75 (95% CI: 1.04-2.95) irrespective of genotype and 2.75 (95% CI: 1.33-5.81) in subjects with GSTM1 null genotype. If not caused by residual confounding by smoking a possible association between m(7)Gua excretion and lung cancer supports the importance of methylation of guanine. The finding of an association between m(7)Gua excretion and lung cancer risk mainly among current smokers and subjects with GSTM1 null genotype supports causality in this respect.
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PMID:Prospective study of urinary excretion of 7-methylguanine and the risk of lung cancer: Effect modification by mu class glutathione-S-transferases. 1756 46

A hospital-based case-control study was conducted near a former black-foot disease (BFD)-endemic area in southwestern Taiwan to examine the possible risk factors and genetic susceptibility for urinary transitional cell carcinoma (TCC). A total of 221 patients with pathologically confirmed TCC and 223 age-sex-matched control subjects from urology outpatient clinics were recruited between 1998 and 2002. The results showed that residency in the BFD area and consumption of well water for more than 10 years was a strong factor on urinary cancer risk (odds ratio [OR],8.16, 95% confidence interval [CI],3.34-19.90, p<0.0001). Dose response relationship between average arsenic concentration in well water and TCC risk was also observed. Cigarette smoking played a relatively minor role in urinary carcinogenesis in this study. The GSTP1 Ile105Val A-->G polymorphism was significantly associated with cancer risk (A/G+G/G: OR=0.60, 95%CI=0.39-0.94, p=0.02), and the effect of Val105 allele was largely confined to the subjects diagnosed earlier than 55 years old (A/G+G/G: OR,0.29; 95% CI, 0.09-0.87, p=0.03). The results suggest that GSTP1 is a candidate for susceptibility locus and Ile105 allele may predispose individuals to early-onset urinary TCC. The GSTM1 null genotype was associated with tumors of high-invasiveness (OR,2.21; 95% CI, 1.34-4.73) as well as with early-onset TCC risk (OR,2.53; 95% CI, 0.97-6.59). Our preliminary results showed the XRCC1 Arg194Trp were associated with arsenic-related urinary TCC and the interaction between the genotype and the exposure was statistically significant. The modulating effect of the GSTM1, GSTT1, GSTP1 Ile105Val, EPHX Tyr113His and XRCC1 Arg280His on arsenic-related TCC risk was also suggestive. These observations implied that impaired metabolism of carcinogenic exposure as well as impaired DNA repair function play an important role in arsenic-related urinary transitional cell carcinogenesis.
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PMID:SNPs of GSTM1, T1, P1, epoxide hydrolase and DNA repair enzyme XRCC1 and risk of urinary transitional cell carcinoma in southwestern Taiwan. 1819 64

The human placenta is prerequisite for the development of gestational hypertensive diseases like early-onset preeclampsia (PE) and Hemolysis, Elevated Liver enzymes and Low platelets (HELLP) syndrome. Both syndromes are associated with extensive maternal and perinatal mortality, and morbidity with life long consequences. We aimed to investigate differences in gene expression between placental tissue obtained from normotensive pregnant women and women with PE and HELLP syndrome. Firstly, comparison of Serial Analysis of Gene Expression profiles of 28 weeks' control placenta (available after idiopathic premature delivery) to a HELLP/PE placenta matched for gestational age identified 404 differentially expressed transcripts. Secondly, using sqPCR, the expression levels of 37 of these transcripts were analyzed in placentas of 36 pregnant women, 22 with preeclampsia and HELLP syndrome. Thirdly, nearest centroid classification determined the HELLP specific molecular signature consisting of the upregulated expression of genes encoding the vascular endothelial growth factor receptor (FLT1), leptin (LEP), pappalysin 2 (PAPPA2), and WW domain containing transcription regulator 1 (WWTR1) combined with down regulated expression of the genes encoding cadherin-associated protein (CTNNAL), glutathione S-transferase pi (GSTP1) and calgranulin A (S100A8). This set discriminates HELLP placenta from control and PE placenta with a 24% misclassification rate (95% CI 8.3-41.9%), independent from known risk factors like parity and ethnicity. The transcripts involved correspond to diverse molecular pathways, exemplifying the multigenic molecular basis of the disorder. This distinct placental molecular signature suggests that HELLP is not a PE variant but a separate disease entity. Our data may prove fundamental for the further molecular analysis of PE and HELLP syndrome.
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PMID:Seven placental transcripts characterize HELLP-syndrome. 1837 11


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