Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The glutathione S-transferases (GSTs) have been implicated in carcinogenesis and tumour drug-therapy resistance. In this study GST pi was the predominant isoenzyme in the fetal human kidney. It was present in differentiated epithelial structures but never in the primitive mesenchyme. By contrast most cases of Wilms' tumours showed GST pi in both epithelial structures and undifferentiated blastema. The level of expression, as assessed by immunostaining, was no more than moderate, and was generally higher in differentiated elements. In only one case was GST alpha found in Wilms' tumour. This study had demonstrated a difference between fetal kidney and Wilms' tumour blastema in terms of GST expression.
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PMID:Glutathione S-transferase expression in fetal kidney and Wilms' tumour. 216 34

Progress over the past 30 years has revealed many strengths of the rainbow trout as an alternative model for environmental carcinogenesis research. These include low rearing costs, an early life-stage ultrasensitive bioassay, sensitivity to many classes of carcinogen, a well-described tumor pathology, responsiveness to tumor promoters and inhibitors, and a mechanistically informative nonmammalian comparative status. Low-cost husbandry, for example, has permitted statistically challenging tumor study designs with up to 10,000 trout to investigate the quantitative interrelationships among carcinogen dose, anticarcinogen dose, DNA adduct formation, and final tumor outcome. The basic elements of the trout carcinogen bioassay include multiple exposure routes, carcinogen response, husbandry requirements, and pathology. The principal known neoplasms occur in liver (mixed hepatocellular/cholangiocellular adenoma and carcinoma, hepatocellular carcinoma), kidney (nephroblastoma), swim bladder (adenopapilloma), and stomach (adenopapilloma). Trout possess a complex but incompletely characterized array of cytochromes P450, transferases, and other enzymic systems for phase I and phase II procarcinogen metabolism. In general, trout exhibit only limited capacity for DNA repair, especially for removal of bulky DNA adducts. This factor, together with a high capacity for P450 bioactivation and negligible glutathione transferase-mediated detoxication of the epoxide, accounts for the exceptional sensitivity of trout to aflatoxin B1 carcinogenesis. At the gene level, all trout tumors except nephroblastoma exhibit variable and often high incidences of oncogenic Ki-ras gene mutations. Mutations in the trout p53 tumor suppressor gene have yet to be described. There are many aspects of the trout model, especially the lack of complete organ homology, that limit its application as a surrogate for human cancer research. Within these limitations, however, it is apparent that trout and other fish models can serve as highly useful adjuncts to conventional rodent models in the study of environmental carcinogenesis and its modulation. For some problems, fish models can provide wholly unique approaches.
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PMID:Fish models for environmental carcinogenesis: the rainbow trout. 872 7

We report a novel human gene whose product specifically associates with the negative regulatory domain of the Wilms' tumor gene product (WT1) in a yeast two-hybrid screen and with WT1 in immunoprecipitation and glutathione S-transferase (GST) capture assays. The gene encodes a 17-kDa protein that has 56% amino acid sequence identity with yeast ubiquitin-conjugating enzyme (yUBC) 9, a protein required for cell cycle progression in yeast, and significant identity with other subfamilies of ubiquitin-conjugating enzymes. The human gene fully complements yeast that have a temperature-sensitive yUBC9 gene mutation to fully restore normal growth, indicating that we have cloned a functionally conserved human (h) homolog of yUBC9. Transcripts of hUBC9 of 4.4 kilobases (kb), 2.8 kb, and 1.3 kb were found in all human tissues tested. A single copy of the hUBC9 gene was found and localized to human chromosome 16p13.3. We conclude that hUBC9 retains striking structural and functional conservation with yUBC9 and suggest a possible link of the ubiquitin/proteosome proteolytic pathway and the WT1 transcriptional repressor system.
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PMID:Molecular cloning of the cDNA and chromosome localization of the gene for human ubiquitin-conjugating enzyme 9. 879 54

The human glutathione transferase (GST, EC 2.5.1.18) alpha class locus comprises several genes and pseudogenes. Genomic DNA encoding several human alpha-class-related genes and pseudogenes was cloned and characterized. Three distinct but highly similar 5'-flanking regions of GST alpha genes as well as a series of 5'-deletions were investigated for promoter activity by fusion to the luciferase reporter gene. Transient transfection of these luciferase constructs into human hepatoblastoma, kidney carcinoma, nephroblastoma or bladder carcinoma cells revealed that the promoters are active and contain both positive and negative regulatory regions that behave in a cell-type specific fashion. The 150 bp proximal promoter regions of the three sequences retained the same relative activities as the full length promoters. Two of them were equally active, whereas the third one showed only 20% of the activity of the two stronger promoters. Site-directed mutagenesis indicated that a conspicuous insertion of three nucleotides (TTT) in the weak promoter is not responsible for the different activities.
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PMID:Positive and negative regulatory regions in promoters of human glutathione transferase alpha genes. 892 12

Dlk/ZIP kinase is a newly discovered serine/threonine kinase which, due to its homology to DAP kinase, was named DAP like kinase, Dlk. This kinase is tightly associated with nuclear structures, it undergoes extensive autophosphorylation and phosphorylates myosin light chain and core histones H3, H2A and H4 in vitro. Moreover, it possesses a leucine zipper which mediates interaction with transcription factor ATF-4, therefore it was called ZIP kinase. We employed the yeast two-hybrid system to identify interaction partners of Dlk that might serve as regulators or targets. Besides ATF-4 and others we found Par-4, a modulator of transcription factor WT1 and mediator of apoptosis. Complex formation between Dlk and Par-4 was confirmed by GST pull-down experiments and kinase reactions in vitro and coexpression experiments in vivo. The interaction domain within Dlk was mapped to an arginine-rich region between residues 338 - 417, rather than to the leucine zipper. Strikingly, coexpression of Dlk and Par-4 lead to relocation of Dlk from the nucleus to the cytoplasm, particularly to actin filaments. These interactions provoked a dramatic reorganization of the cytoskeleton and morphological symptoms of apoptosis, thus suggesting a functional relationship between Dlk and Par-4 in the control of apoptosis.
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PMID:Interaction partners of Dlk/ZIP kinase: co-expression of Dlk/ZIP kinase and Par-4 results in cytoplasmic retention and apoptosis. 1060 80

More than 80% of the patients presenting with Wilms' tumor can be cured today. Some patients, however, fail to respond to chemotherapy. The objective of this study was to analyze the immunohistochemical distribution of two markers of cytostatic drug resistance, e.g. DNA topoisomerase II alpha (Topo II alpha) and glutathione S-transferase-pi (GST-pi) in 23 Wilms' tumor patients who had undergone an operation between 1984 and 1997. Eight patients had stage I disease, seven stage II, three stage III, four stage IV, and one stage V disease. Five tumors showed high malignancy histology. Investigations were carried out on formalin-fixed and paraffin-embedded tissue sections using the indirect immunoperoxidase method. Topo II alpha was predominantly present in the epithelial components of the specimens. It was more frequently found in anaplastic tumors. There was no difference in the presence of Topo II alpha in the epithelial components between specimens derived from treated and untreated patients. Topo II alpha was, however, less expressed in the blastemal and stromal elements of specimens after preoperative treatment. If GST-pi was present, it was confined to the epithelial components except for one case. While no expression of GST-pi was found in preoperatively untreated Wilms' tumors, it was present in epithelial compartments in 57% of tumors after chemotherapy. In conclusion, preoperative chemotherapy led to compartment-specific alterations in the expression levels of both markers indicating a contribution to treatment response of Wilms' tumors.
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PMID:Differential expression of the drug resistance markers DNA topoisomerase II alpha and glutathione S-transferase-pi in the histological compartments of Wilms' tumors. 1129 42

We analysed the expression profiles of 70 kidney tumors of different histological subtypes to determine if these subgroups can be distinguished by their gene expression profiles, and to gain insights into the molecular mechanisms underlying each subtype. In all, 39 clear cell renal cell carcinomas (RCC), seven primary and one metastatic papillary RCC, six granular RCC from old classification, five chromophobe RCC, five sarcomatoid RCC, two oncocytomas, three transitional cell carcinomas (TCC) of the renal pelvis and five Wilms' tumors were compared with noncancerous kidney tissues using microarrays containing 19,968 cDNAs. Based on global gene clustering of 3560 selected cDNAs, we found distinct molecular signatures in clear cell, papillary, chromophobe RCC/oncocytoma, TCC and Wilms' subtypes. The close clustering in each of these subtypes points to different tumorigenic pathways as reflected by their histological characteristics. In the clear cell RCC clustering, two subgroups emerged that correlated with clinical outcomes, confirming the potential use of gene expression signatures as a predictor of survival. In the so-called granular cell RCC (terminology for a subtype that is no longer preferred), none of the six cases clusters together, supporting the current view that they do not represent a single entity. Blinded histological re-evaluation of four cases of 'granular RCC' led to their reassignment to other existing histological subtypes, each compatible with our molecular classification. Finally, we found gene sets specific to each subtype. In order to establish the use of some of these genes as novel subtype markers, we selected four genes and performed immunohistochemical analysis on 40 cases of primary kidney tumors. The results were consistent with the gene expression microarray data: glutathione S-transferase alpha was highly expressed in clear cell RCC, alpha methylacyl racemase in papillary RCC, carbonic anhydrase II in chromophobe RCC and K19 in TCC. In conclusion, we demonstrated that molecular profiles of kidney cancers closely correlated with their histological subtypes. We have also identified in these subtypes differentially expressed genes that could have important diagnostic and therapeutic implications.
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PMID:Molecular subclassification of kidney tumors and the discovery of new diagnostic markers. 1455 94

Transcription of the PDGF-A chain gene is regulated by multiple promoter and silencer elements that are GC-rich and exhibit considerable single-stranded character. In this study, the 42 kDa single-stranded DNA and RNA binding protein, Puralpha, was investigated with respect to its ability to bind and interact functionally with single-stranded DNA elements in the PDGF-A gene. Recombinant GST-Puralpha bound with high affinity and sequence-specificity to the G-rich strands of two such transcriptional control elements, the 5'-S1 nuclease-hypersensitive silencer (5'SHS; -1418 to -1388) and the nuclease-hypersensitive element (NHE; -92 to -48). Ethylation interference footprinting localized binding of Puralpha to a region between nucleotides -91 and -77 within the NHE element, which contains binding sites for the double-stranded DNA-binding transcription factors Sp1, EGR-1 and WT1. Forced expression of Puralpha upregulated transcriptional activity of the PDGF-A promoter but not the 5'SHS silencer in HepG2 cells, demonstrating Puralpha has the potential to activate PDGF-A gene expression. Targeted disruption of the Puralpha gene reduced NHE activity and PDGF-A mRNA expression in mouse embryo fibroblasts, consistent with a physiological role for Puralpha in maintaining optimal transcription of the PDGF-A gene. These results indicate Puralpha enhances transcription of the PDGF-A gene through its interactions with single-stranded, G-rich strands in the promoter, perhaps by stabilizing non-B-form DNA conformations.
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PMID:Puralpha activates PDGF-A gene transcription via interactions with a G-rich, single-stranded region of the promoter. 1577 9

Many mammalian proteins are multifunctional proteins with biological activities whose characterization often requires in vitro studies. However, these studies depend on generation of sufficient quantities of recombinant protein and many mammalian proteins cannot be easily expressed and purified as full-length products. One example is the Wilm's tumor gene product, WT1, which has proven difficult to express as a full-length purified recombinant protein using standard approaches. To facilitate expression of full-length WT1 we have developed approaches that optimized its expression and purification in Escherichia coli and mammalian cells. First, using a bicistronic vector system, we successfully expressed and purified WT1 containing a C-terminal tandem affinity tag in 293T cells. Second, using a specific strain of E. coli transformed with a modified GST vector, we successfully expressed and purified N-terminal GST tagged and C-terminal 2x FLAG tagged full-length human WT1. The benefits of these approaches include: (1) two-step affinity purification to allow high quality of protein purification, (2) large soluble tags that can be used for a first affinity purification step, but then conveniently removed with the highly site-specific TEV protease, and (3) the use of non-denaturing purification and elution conditions that are predicted to preserve native protein conformation and function.
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PMID:Two methods for improved purification of full-length mammalian proteins that have poor expression and/or solubility using standard Escherichia coli procedures. 1652 45

Glutathione-S-transferase placental form (GST-P) is markedly and specifically inducible in rat chemical hepatocarcinogenesis and is a reliable marker protein for pre-neoplasia. To gain insights into the molecular mechanisms at the early stage of hepatocarcinogenesis and hepatotoxicity, we investigated the gene expression profile by DNA microarray analysis. We prepared RNA from GST-P-positive foci in three individual rats and compared with normal liver sections from three individual rats, and labeled RNA was individually hybridized onto Affymetrix GeneChip Rat Expression Array 230A. DNA microarray analysis showed distinctly different profiles of dysregulated gene expression and supported the previous finding that some enzymes involved in metabolism and detoxification are overexpressed and suppressed. Here we discovered that several DNA-binding transcription factors and cofactors, including sterol-regulatory-element binding protein 1 (SREBP1) and Wilms' tumour 1 (WT1)-interacting protein, and their target genes were dysregulated in GST-P-positive foci. Moreover, genes involved in chromatin components, histone modification enzymes, and centrosome duplication were highly expressed. These genes were not previously known to be up-regulated during chemically induced hepatocarcinogenesis. DNA microarray analysis using RNA prepared from tumor marker-positive foci and control tissues provided a candidate gene link to the early stage of carcinogenesis and hepatotoxicity.
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PMID:Altered gene expression of transcriptional regulatory factors in tumor marker-positive cells during chemically induced hepatocarcinogenesis. 1699 13


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