Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alkylating agents, which are metabolized by glutathione S-transferase (GST), have an important role in the etiology of cancer by forming mutagenic DNA adducts. Previous studies have shown that DNA repair protein, O6-methylguanine DNA methyltransferase, repairs these mutagenic DNA adducts and its activity is correlated with the resistance of human tumors to alkylating agent-based anti-cancer drugs. However, little is known about GST and O6-methylguanine DNA methyltransferase activities in patients with thyroid cancer in vivo. We measured the activities of GST and O6-methylguanine DNA methyltransferase in the leukocytes from patients with papillary thyroid carcinoma and healthy controls. The GST activity was significantly higher in men than in women, and it was negative correlated with age in men whereas it was unchanged in women in the control group. Both GST and O6-methylguanine DNA methyltransferase activities were significantly increased in the patient group. There were no age and sex-related changes in the O6-methylguanine DNA methyltransferase activity in both the control and patient groups. These results suggest that leukocyte GST and O6-methylguanine DNA methyltransferase activities were increased with thyroid cancer. This may be related to the resistance to chemotherapy exhibited by patients with thyroid cancer.
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PMID:Glutathione S-transferase and O6-methylguanine DNA methyl transferase activities in patients with thyroid papillary carcinoma. 1244 29

The differential proteomic approach (2D gel analysis coupled to MALDI-MS analysis) of nuclear proteins can provide an extremely useful tool to understand control of cell proliferation and differentiation. In order to identify possible markers of dedifferentiation between normal and cancerous thyroid cells, we used a differential proteomics approach by comparing nuclear extracts from the normal rat thyroid cell line FRTL-5 and the completely undifferentiated Ki-mol cell line, obtained by transformation with the Ki-ras oncogene. Galectin-3 (Gal-3) was identified as highly expressed, in the nuclear compartment, only in the transformed cell line. By using different human cancer cell lines, we showed that Gal-3 is maximally expressed in nuclei of papillary cancer cells. We focused on the functional relationship existing between Gal-3 and the thyroid-specific transcription factor TTF-1, whose expression is maintained in papillary cancer where it can contribute to the proliferating status. By using gel-retardation and transient tranfection assays, we demonstrate that Gal-3 upregulates the TTF-1 transcriptional activity. GST-pulldown experiments demonstrate the occurrence of interaction between Gal-3 and TTF-1 homeodomain. Since several lines of evidence suggest a role for Gal-3 in controlling proliferation and tumor progression in thyroid cancer, the stimulatory activity played by Gal-3 over TTF-1 would account for a possible molecular mechanism through which the galectin controls proliferation in thyroid cells.
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PMID:Nuclear localization of Galectin-3 in transformed thyroid cells: a role in transcriptional regulation. 1261 69

Since exposure to ionizing radiation, a risk factor for thyroid cancer, may produce genotoxins potentially eliminated by glutathione-S-transferases, we conducted a case control study to evaluate the role of the GSTM1- and GSTT1-null genotypes and GSTP1 polymorphisms in thyroid cancer. The frequency of GSTP1 Ile/Ile, GSTM1-, and GSTT1-null genotypes was increased in cancer patients when compared with control population. Considering the genotypes over-represented in thyroid cancer patients as potential risk genotypes, we carried out an odds ratio (OR) analysis considering the presence of none, one, two, or three risk genotypes. The results obtained showed that the presence of three potentially risk alleles (GSTM1 null, GSTT1 null, and GSTP1 Ile/Ile) lead to a significant OR increase for all the cases, irrespective of the type of tumor (OR=2.91), for papillary (OR=3.64) but not for follicular tumors. The presence of GSTP1 Ile/Ile leads to a significant later age of tumor onset when compared with GSTP1 Ile/Val and Val/Val (P<0.05), suggesting a possible association between GSTP1 Ile/Ile and the age of disease manifestation. These results suggest that combined GST polymorphisms lead to a moderate increased risk for thyroid cancer, especially for the papillary type, and GSTP1 polymorphisms might modulate the age of onset of the disease.
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PMID:Combined effects of glutathione S-transferase polymorphisms and thyroid cancer risk. 1512 Sep 11

A new class of glutathione S-transferase enzymes named omega (GSTO) has been recently identified and shown to be expressed in a wide range of human tissues. A genetic polymorphism of the GSTO1 gene causing an alanine-to-aspartate (A140D) substitution in amino acid 140 produces a variant with lowered enzyme activities in the biotransformation of inorganic arsenic, a common contaminant of drinking water in many regions of the world and a well-known carcinogen. In order to investigate the role of GSTO1 inheritance pattern on thyroid cancer risk we used a polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP)-sequencing approach to compare the genotypes of 173 (87 women, 86 men; 18-81 years old; 47+/-18 years old) healthy control individuals with those of 145 patients with thyroid nodules (84 women, 61 men; 17-81 years old; 49+/-14 years old) including 17 follicular carcinomas, 76 papillary carcinomas, 21 follicular adenomas and 31 multinodular goiters. The incidence of GSTO1 variants was similar in the control population and population with the benign and malignant nodules. There was no association between genotype and the patients' clinical features, tumour parameters of aggressiveness at diagnosis or behaviour during follow-up. We conclude that GSTO1 variants do not influence the risk for thyroid nodules or their pathologic and clinical characteristics.
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PMID:GSTO polymorphism analysis in thyroid nodules suggest that GSTO1 variants do not influence the risk for malignancy. 1590 98

Activation of the phosphatidylinositol 3-kinase (PI3K)-AKT/protein kinase B signaling pathway has been associated with multiple human cancers. Recently we showed that AKT is activated in both the thyroid and metastatic lesions of a mouse model of follicular thyroid carcinoma [thyroid hormone beta receptor (TRbeta)(PV/PV) mice]. This TRbeta(PV/PV) mouse harbors a knock-in mutant TRbeta gene (TRbetaPV mutant) that spontaneously develops thyroid cancer and distant metastasis similar to human follicular thyroid cancer. Here we show that in thyroid tumors, PV mutant bound significantly more to the PI3K-regulatory subunit p85alpha, resulting in a greater increase in the kinase activity than did TRbeta1 in wild-type mice. By GST pull-down assays, the ligand-binding domain of TR was identified as the interaction site with p85alpha. By confocal fluorescence microscopy, p85alpha was shown to colocalize with TRbeta1 or PV mainly in the nuclear compartment of cultured tumor cells from TRbeta(PV/PV) mice, but cytoplasmic p85alpha/PV or p85alpha/TRbeta1 complexes were also detectable. Further biochemical analysis revealed that the activation of the PI3K-AKT-mammalian target of the rapamycin-p70(S6K) pathway was observed in both the cytoplasmic and nuclear compartments, whereas the activation of the PI3K-integrin-linked kinase-matrix metalloproteinase 2 pathway was detected mainly in the extranuclear compartments. These results suggest that PV, via the activation of p85alpha, could act to affect PI3K downstream signaling in both the nuclear and extranuclear compartments, thereby contributing to thyroid carcinogenesis. Importantly, the present study unveils a mechanism by which a mutant TR acts to activate PI3K activity via protein-protein interactions.
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PMID:Activation of phosphatidylinositol 3-kinase signaling by a mutant thyroid hormone beta receptor. 1644 24

Basal and induced frequencies of genetic damage can be modulated by different host factors, including genes involved in phase II metabolism. Since polymorphic variants in the glutathione S-transferase (GST) and N-acetyl transferase (NAT) genes have been associated with cancer risk, we explored the possible links between GSTM1, GSTP1, GSTT1 and NAT2 variants and the frequency of micronuclei (MN) in human lymphocytes. This exploratory study was carried out in 30 thyroid cancer patients, before and after receiving an average dose of 109.9+/-1.3 mCi radioactive iodine as a co-adjuvant therapy. The results indicate that none of the polymorphisms studied show any kind of association with the basal level of micronuclei. When the same patients were followed after radioiodine exposure, a significant increase in the frequency of MN was observed in practically all of them (28/30), indicating the genotoxic activity of the ionising radiation exposure. The increase in MN frequency was not associated with any of the GST polymorphisms evaluated. Nevertheless, the presence of slow acetylator phenotypes and, in particular, the presence of the NAT2*7 allele was significantly associated with a lower increase of the MN frequency after radioiodine treatment.
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PMID:Basal and induced micronucleus frequencies in human lymphocytes with different GST and NAT2 genetic backgrounds. 1662 79

In contrast to most human malignancies, epidemiologic studies have frequently reported a reduced risk of differentiated thyroid cancer in tobacco consumers. Cytochrome P4501A1 (CYP1A1) gene variants may be related to an increased capacity to activate polycyclic aromatic hydrocarbons, producing highly reactive electrophilic intermediates that might damage DNA. Hence, the germline inheritance of a wild-type CYP1A1 gene may decrease the susceptibility for thyroid cancer. The present study was designed to investigate CYP1A1 (m1 and m2) role in thyroid tumorigenesis and its connection with GSTM1, GSTT1, GSTP1, GSTO1, and codon 72 of p53 genotypes. A total of 248 patients with thyroid nodules, including 67 benign goiters, 13 follicular adenomas, 136 papillary carcinomas, and 32 follicular carcinomas, and 277 controls with similar ethnic backgrounds were interviewed on their lifetime dietary and occupational histories, smoking habit, previous diseases, and other anamnestic data. DNA was extracted from a blood sample and submitted to PCR-restriction fragment length polymorphism assays. The wild-type CYP1A1m1 genotype was more frequent among papillary carcinoma patients (74.26%) than in the control population (62.45%; P=0.0147), reducing the risk for this type of cancer (odds ratio=0.564; 95% confidence interval=0.357-0.894). A multiple logistic regression analysis showed an inverse correlation between cigarette smoking (P=0.0385) and CYP1A1 germline inheritance (P=0.0237) with the susceptibility to papillary carcinomas. We were not able to find any correlation between smoking, clinical features, parameters of aggressiveness at diagnosis or during follow-up, and any of the GST or CYP genotypes considered separately or in different combinations. We suggest that CYP1A1 genotype might be associated with the reported reduced risk to papillary carcinomas among smokers.
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PMID:Smoking and susceptibility to thyroid cancer: an inverse association with CYP1A1 allelic variants. 1715 63

The large use of simple and effective diagnostic tools has significantly contributed to the increase in diagnosis of thyroid cancer over the past years. However, there is compelling evidence that most micropapillary carcinomas have an indolent behavior and may never evolve into clinical cancers. Therefore, there is an urgent need for new tools able to predict which thyroid cancers will remain silent, and which thyroid cancers will present an aggressive behavior. There are a number of well-established clinical predictors of malignancy and recent studies have suggested that some of the patients laboratory data and image methods may be useful. Molecular markers have also been increasingly tested and some of them appear to be very promising, such as BRAF, a few GST genes and p53 polymorphisms. In addition, modern tools, such as immunocytochemical markers, and the measure of the fractal nature of chromatin organization may increase the specificity of the pathological diagnosis of malignancy and help ascertain the prognosis. Guidelines designed to select nodules for further evaluation, as well as new methods aimed at distinguishing carcinomas of higher aggressiveness among the usually indolent thyroid tumors are an utmost necessity.
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PMID:Identifying a risk profile for thyroid cancer. 1789 Dec 34

Genetic polymorphisms have shown to be susceptibility factors playing an important role in the development of most cancers. Nevertheless, as far as we know, only few studies have been conducted linking thyroid cancer incidence and GST polymorphisms, and no data are available on the possible association between NAT2 polymorphisms and thyroid cancer risk. The possible relationship between polymorphism at the GSTM1, GSTT1, GSTP1, and NAT2 genes and increased susceptibility to thyroid cancer has been evaluated in 176 thyroid cancer patients and 167 healthy controls, all from the urban district of Barcelona (Spain). The results indicate a clear role of the C481T change, present in several NAT2*5 alleles [odds ratio (OR)=0.58; 95% confidence interval (95% CI)=0.35-0.98]. Thus, those individuals carrying this change are less prone to develop thyroid cancer, mainly of the papillary type. In addition, there is a tendency towards the over-representation of the GSTM1 null genotype among thyroid cancer patients, particularly in those patients with papillary type tumor. The same is observed for the GSTM1 and GSTT1 null genotypes combination, and for other combinations with different NAT2 polymorphisms. The combinations involving the NAT2*6 and NAT2*7 genotypes showed the most important effect, and individuals carrying both alleles present a higher risk of thyroid cancer (OR=7.36; 95% CI=0.85-63.47), mainly for the follicular type (OR=17.94; 95% CI=1.34-238.70). The combination of NAT2*5 with NAT2*7 was also found to increase 5.26 (95% CI=1.07-25.76) times the risk of thyroid cancer. In conclusion, our results show that NAT2 polymorphisms play a significant role in thyroid cancer risk modulation.
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PMID:Role of GST and NAT2 polymorphisms in thyroid cancer. 1916 61

Differentiated thyroid cancers and their metastases frequently exhibit reduced iodide uptake, impacting on the efficacy of radioiodine ablation therapy. PTTG binding factor (PBF) is a proto-oncogene implicated in the pathogenesis of thyroid cancer. We recently reported that PBF inhibits iodide uptake, and have now elucidated a mechanism by which PBF directly modulates sodium iodide symporter (NIS) activity in vitro. In subcellular localisation studies, PBF overexpression resulted in the redistribution of NIS from the plasma membrane into intracellular vesicles, where it colocalised with the tetraspanin CD63. Cell-surface biotinylation assays confirmed a reduction in plasma membrane NIS expression following PBF transfection compared with vector-only treatment. Coimmunoprecipitation and GST-pull-down experiments demonstrated a direct interaction between NIS and PBF, the functional consequence of which was assessed using iodide-uptake studies in rat thyroid FRTL-5 cells. PBF repressed iodide uptake, whereas three deletion mutants, which did not localise within intracellular vesicles, lost the ability to inhibit NIS activity. In summary, we present an entirely novel mechanism by which the proto-oncogene PBF binds NIS and alters its subcellular localisation, thereby regulating its ability to uptake iodide. Given that PBF is overexpressed in thyroid cancer, these findings have profound implications for thyroid cancer ablation using radioiodine.
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PMID:A novel mechanism of sodium iodide symporter repression in differentiated thyroid cancer. 1970 88


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