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)

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) activates the aryl hydrocarbon receptor (AhR) to mediate transcriptional activity of dioxin-responsive genes. The transactivation domain (TAD) of human AhR (hAhR) has potentially distinct acidic, glutamine-rich, and proline/serine/threonine-rich subdomains. Cotransfection of exogenous hAhR into BP8 cells with isolated subdomains of hAhR TAD fused to glutathione S-transferase exhibited squelching of TCDD-dependent dioxin-response element (DRE)-driven luciferase reporter-gene activity with each subdomain. To study the potential cross talk between AhR- and estrogen receptor (ER)-mediated activities, BP8 cells were cotransfected with hAhR TAD subdomain constructs and ERalpha. The three hAhR TAD subdomains inhibited the 17beta-estradiol-induced estrogen-response element-mediated reporter-gene transactivation. Cotransfection of hAhR with the ligand-binding domain (LBD) of ERalpha also squelched TCDD-dependent DRE-driven reporter-gene activity in the presence of 17beta-estradiol. Similar results were observed in T47D cells that express functional AhR and ERalpha. These results indicate that the isolated subdomains of hAhR's TAD and LBD of ERalpha are capable of squelching ligand-dependent transactivation of either the AhR or the ER, by titrating crucial proteins from an existing common pool of cofactors.
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PMID:The subdomains of the transactivation domain of the aryl hydrocarbon receptor (AhR) inhibit AhR and estrogen receptor transcriptional activity. 1248 7

Prostate cancer chemoprevention can be described as the administration of natural products and pharmaceutical agents that inhibit one or more steps in the natural history of prostatic carcinogenesis. The principle components of the chemoprevention strategy are closely connected to this natural history and include: (a) agents and their molecular targets; (b) strategic intermediate endpoint biomarkers (IEBs) and their critical pathways; (c) cohorts identified by genetic and acquired risk factors and (d) efficient designs that combine these elements into a cohesive clinical trial. The primary goal is to find effective noncytotoxic agents that modulate the promotion and progression from normal epithelium to dysplasia to high-grade prostatic intraepithelial neoplasia (HGPIN) to locally invasive cancer and metastatic disease. Another important target for chemoprevention is to modulate progression to clinically aggressive disease and to maintain an androgen-sensitive clinical state and delay the emergence of androgen resistance. There is a rationale for use of antiandrogens as the lead class, e.g., 5 alpha receptor inhibitors (5ARI), for chemoprevention of prostate cancer. Nevertheless, the desire to improve the therapeutic index, achieve synergy (5ARI may have only modest anticancer effects) and prevent the emergence of drug (androgen) resistance provide incentives for developing other effective agents and combinations. The availability of more than a dozen classes of noncytotoxic pharmaceutical and natural products already in clinical development create many opportunities for rational combination therapy. Several agent classes have a pharmacodynamic basis for combination with antiandrogens including antiproliferatives, selective estrogen receptor modulators (SERMs), proapoptotic antioxidant micronutrients and selective cyclo-oxygenase (COX)-2 inhibitors. Many other rational pharmacodynamic combinations without antiandrogens are feasible. It is anticipated that in the future, a selective COX-2 inhibitor may be combined with other agent classes such as proapoptotic antioxidant micronutrients, receptor tyrosine kinase modulators, antiangiogenic modulators, antiproliferative/differentiating agents, NFkappaB modulators, IGF-1 modulators and other novel proapototic nonsteroidal drugs. A novel target for rational combinations is the hypermethylation of GST-PI leading to functional silencing of this key anticarcinogen defense enzyme in precursors (HGPIN) and prostate cancer. Factorial designs are well suited for evaluating the individual and combined effects of each agent in a single trial design. There are a number of moderate to high-risk cohorts and clinical models of primary and secondary prevention that can be employed in both short-term developmental (translational) trials for proof of biologic activity and in intermediate sized longer-term chemoprevention trials for proof of efficacy against prostate cancer. Strategic IEBs are needed to more efficiently monitor short-term biologic activity and validate efficacy. The emergence of new powerful tools such as gene chip cDNA microarrays for multiplex gene expression profiling and proteomic analysis of tissue based and secreted proteins will accelerate the identification of new molecular targets, strategic endpoints, cohorts at risk and the design of rational combination trials.
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PMID:Chemoprevention of prostate cancer: current status and future directions. 1254 68

Glutathione S-transferase pi (GST-pi), a Phase II detoxification enzyme, has recently been implicated in protection against apoptosis. Expression of GST-pi and Bcl-2 protein, an established apoptosis marker, was analyzed by immunohistochemistry in 116 cases of infiltrative ductal breast carcinomas in Singapore women. The markers were correlated with apoptosis detected by the TUNEL method and clinico-pathological parameters. There were 67 (58%) GST-pi-positive breast tumors and 43 (37%) Bcl-2-positive tumors. In a large proportion of GST-pi-positive/Bcl-2-positive tumors, there was a distinct accumulation of the GST-pi enzyme within the nucleus of cancer cells when examined by double immunofluorescence labeling under confocal microscopy. GST-pi immunoreactivity was not significantly correlated with any of the traditional histologic factors known to influence prognosis, whereas Bcl-2 overexpression was associated with reduced size of primary tumor (P =.021) and positive estrogen receptor status (P =.001). Univariate analysis revealed that GST-pi-positive, Bcl-2-positive, and lower histological grade tumors had decreased levels of apoptosis (P =.024, P =.011, and P =.029, respectively). However, multivariate analysis showed that histological grade and Bcl-2, but not GST-pi, immunoreactivity were correlated with apoptotic status. The Kaplan-Meier disease-free survival curves showed a significant difference between GST-pi-positive and GST-pi-negative breast cancer cases (P =.002). Disease-free survival in patients with GST-pi-positive tumors was also worse than that in patients with GST-pi-negative tumors in the group who had adjuvant chemotherapy (P =.04). In patients who were lymph node positive, GST-pi immunopositivity was found to influence disease-free survival. Recurrence of tumors was also significantly affected by GST-pi immunoreactivity (relative risk of 8.1). The findings indicate that GST-pi-positive tumors are more aggressive and have a poorer prognosis than do corresponding GST-pi-negative breast cancers.
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PMID:Prognostic significance of glutathione S-transferase-pi in invasive breast cancer. 1280 61

The truncated estrogen receptor product-1 (TERP-1, or TERP) is a pituitary-specific isoform of estrogen receptor alpha (ERalpha), and its expression is regulated by estrogen. TERP modulates the transcriptional activity of ERalpha but has no independent effect on transcription of estrogen-response element-containing promoters. At low concentrations, TERP stimulates ERalpha transcriptional activity in transient transfection assays. At TERP concentrations equal to or greater than full-length ERalpha, TERP forms dimers with ERalpha and reduces both ligand-dependent and -independent transcription. A dimerization mutant of TERP, TERP L509R, stimulated ERalpha transcription at all concentrations. We hypothesized that TERP stimulates ERalpha transcriptional activity by titrating suppressors of ERalpha activity. We found that repressor of estrogen receptor activity (REA), originally isolated from human breast cancer cells, is present in mouse pituitary gonadotrope cell lines. Levels of REA vary slightly throughout the rat reproductive cycle, but TERP mRNA and protein vary much more dramatically. In transfection experiments, REA suppressed ERalpha transcriptional activity, and TERP L509R was able to alleviate transcriptional suppression by REA. In glutathione S-transferase pull-down assays, TERP bound to REA more efficiently than did ERalpha at equivalent concentrations, suggesting that REA will preferentially bind to TERP. Our findings suggest that the stimulation of pituitary ERalpha activity by low concentrations of TERP can occur by titration of corepressors such as REA.
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PMID:Truncated estrogen receptor product-1 stimulates estrogen receptor alpha transcriptional activity by titration of repressor proteins. 1287 3

The estrogen receptor (ERalpha) is a member of a large superfamily of nuclear receptors that regulates the transcription of estrogen-responsive genes. Several recent studies have demonstrated that human X-box binding protein 1 (XBP-1) mRNA expression is associated with ERalpha status in breast tumors. More recently, two forms of XBP-1 were identified due to their unique splicing. The two splicing variants of XBP-1 were designated XBP-1S and XBP-1U, respectively. In this study, the coding sequences of XBP-1S and XBP-1U were cloned respectively into the expression vector pcDNA3 harboring FLAG epitope, generating the recombinant plasmids pcDNA3-FLAG-XBP-1S and pcDNA3-FLAG-XBP-1U. Western blot analysis showed that both XBP-1S and XBP-1U were expressed in mammalian cells. To determine the effects of XBP-1S and XBP-1U on the transcriptional activity of ERalpha, MDA-MB-231 breast cancer cells were cotransfected with the expression vectors for ERalpha and either pcDNA3-FLAG-XBP-1S or pcDNA3-FLAG-XBP-1U. The results indicated that XBP-1S and XBP-1U enhanced ERalpha-mediated transcriptional activities in a hormone-independent manner. GST pull-down assay showed that both XBP-1S and XBP-1U interacted with ERalpha. These data suggest that XBP-1S and XBP-1U may play an important role in breast cancer growth and progression through ERalpha signaling.
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PMID:[XBP-1 enhances the transcriptional activity of estrogen receptor alpha]. 1295 56

The number of reports investigating disease susceptibility based on the carriage of low-penetrance, high-frequency polymorphisms has steadily increased over the last years. Evidence based on meta-analyses of individual case-control studies is accumulating, defining specific individual variations in disease susceptibility. For example, genetic variations of the estradiol metabolism have been described as significant contributors to disease susceptibility with variations depending on ethnic background. In the field of obstetrics and gynecology, the genetic contribution of polymorphic markers to a series of disorders has been characterized. These disorders include recurrent pregnancy loss, pre-eclampsia, endometriosis, breast cancer, and hormone replacement therapy (HRT)-related complications such as thrombosis. Among other genetic markers, thrombophilic genetic variants, such as the Factor V Leiden and prothrombin G20210A polymorphisms, as well as genetic variants of cytochrome P450 (CYP) enzymes, for example, CYP19 and CYP1B1, have been established as genetic risk markers and disease modifiers of recurrent and sporadic pregnancy loss and HRT-independent and -dependent breast cancer, respectively. In addition, meta-analyses of data in the literature established the TGFBR1*6A, GSTP I105V, and TP53 R72P polymorphisms, as well as the GSTM1 gene deletion as low-penetrance genetic risk factors of sporadic breast cancer. With respect to genetic modulation of therapeutic effects, beneficial effects of estrogen replacement therapy and HRT are modulated by the carriage of single nucleotide polymorphisms, for example, osteoprotection and blood lipid changes by the estrogen receptor-alpha (ER-a) PvuII polymorphism. Polymorphisms of the catechol-O-methyltransferase (COMT), ER-alpha, IL-1 receptor antagonist, and Factor V genes have been demonstrated to modulate the timing of natural menopause. Lastly, a strong genetic contribution of polymorphisms to the development and the clinical course of endometriosis has been established with data pointing to polymorphisms of the COMT, GST, NAT-2, and ER-alpha genes as susceptibility markers. In summary, the available evidence points to a number of polymorphisms of a wide variety of genes as strong hereditary determinants of the susceptibility to benign and malignant gynecologic and obstetric conditions.
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PMID:Applications of polymorphisms and pharmacogenomics in obstetrics and gynecology. 1468 20

In the present study, we tested the hypothesis that 17beta-estradiol (betaE2) is a neuroprotectant in the retina, using two experimental approaches: 1) hydrogen peroxide (H(2)O(2))-induced retinal neuron degeneration in vitro, and 2) light-induced photoreceptor degeneration in vivo. We demonstrated that both betaE2 and 17alpha-estradiol (alphaE2) significantly protected against H(2)O(2)-induced retinal neuron degeneration; however, progesterone had no effect. betaE2 transiently increased the phosphoinositide 3-kinase (PI3K) activity, when phosphoinositide 4,5-bisphosphate and [(32)gammaATP] were used as substrate. Phospho-Akt levels were also transiently increased by betaE2 treatment. Addition of the estrogen receptor antagonist tamoxifen did not reverse the protective effect of betaE2, whereas the PI3K inhibitor LY294002 inhibited the protective effect of betaE2, suggesting that betaE2 mediates its effect through some PI3K-dependent pathway, independent of the estrogen receptor. Pull-down experiments with glutathione S-transferase fused to the N-Src homology 2 domain of p85, the regulatory subunit of PI3K, indicated that betaE2 and alphaE2, but not progesterone, identified phosphorylated insulin receptor beta-subunit (IRbeta) as a binding partner. Pretreatment with insulin receptor inhibitor, HNMPA, inhibited IRbeta activation of PI3K. Systemic administration of betaE2 significantly protected the structure and function of rat retinas against light-induced photoreceptor cell degeneration and inhibited photoreceptor apoptosis. In addition, systemic administration of betaE2 activated retinal IRbeta, but not the insulin-like growth factor receptor-1, and produced a transient increase in PI3K activity and phosphorylation of Akt in rat retinas. The results show that estrogen has retinal neuroprotective properties in vivo and in vitro and suggest that the insulin receptor/PI3K/Akt signaling pathway is involved in estrogen-mediated retinal neuroprotection.
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PMID:Involvement of insulin/phosphoinositide 3-kinase/Akt signal pathway in 17 beta-estradiol-mediated neuroprotection. 1471 19

To understand the mechanism by which estrogen receptor (ER) activates transcription in a tissue specific fashion, we isolated ERalpha binding protein (ERBP) by performing yeast two-hybrid screening with human mammary gland cDNA library. ERBP is a nuclear protein and its mRNA is ubiquitously expressed. The in vitro interaction of ERBP with ERalpha was demonstrated by GST pull-down assay and this interaction was enhanced by estrogen. In addition, ERBP also bound to PPARgamma, RXRalpha, and ERbeta. ERBP interacted with the DNA binding domain and the hinge region of ERalpha. There are two ERalpha binding regions on ERBP. The binding of ERBP region at C-terminus to ERalpha is increased by estrogen while the binding of ERBP region at N-terminus is not affected by estrogen. The interaction of ERBP with ERalpha was further confirmed in vivo by immunoprecipitation. Transient transfection experiment demonstrated that ERBP enhanced the transcriptional activity of ERalpha.
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PMID:ERBP, a novel estrogen receptor binding protein enhancing the activity of estrogen receptor. 1504 47

New World primates (NWPs) exhibit a compensated form of resistance to gonadal steroid hormones. We demonstrated recently that estrogen resistance in NWP cells was associated with the overexpression of two proteins, a nonreceptor-related, dominant-negative-acting estrogen response element (ERE)-binding protein (ERE-BP) and an intracellular estradiol-binding protein (IEBP). Based on the N-terminal sequences of tryptic fragments of IEBP isolated from a 17beta-estradiol (E2) affinity column we cloned a full-length cDNA for IEBP from the estrogen-resistant NWP cell line, B95-8. Subsequent sequence analysis revealed 87% sequence identity between the deduced peptide for IEBP and human Hsp27. When hormone-responsive, wild-type Old World primate (OWP) cells were transiently transfected with IEBP cDNA, E2-directed ERE reporter luciferase activity was reduced by 50% compared with vector only-transfected OWP cells (p < 0.0018). When IEBP and ERE-BP were cotransfected, ERE promoter-reporter activity was reduced by a further 60% (p < 0.0001). Electrophoresis mobility shift analyses showed that IEBP neither bound to ERE nor competed with the estrogen receptor (ER) for binding to ERE. However, there was evidence of protein-protein interaction of IEBP and ERalpha; IEBP was coimmunoprecipitated with anti-ERalpha antibody in wild-type cells stably transfected with IEBP. A specific interaction between ERalpha and IEBP was confirmed in glutathione S-transferase pull-down and yeast two-hybrid assays. Data indicate that the Hsp27-related IEBP interacts with the ligand binding domain of the ERalpha. In summary, by inhibiting the ERalpha-E2 interaction, IEBP acts to squelch ERalpha-directed ERE-regulated transactivation and promote estrogen resistance in NWP cells.
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PMID:An Hsp27-related, dominant-negative-acting intracellular estradiol-binding protein. 1512 1

Estrogen receptor-alpha (ER-alpha) is a nuclear transcriptional factor that is part of the nuclear receptor superfamily. In this study, we isolated and identified a new LXXLL-containing protein that interacts with the ER-alpha via a yeast two-hybrid assay. We have termed this protein estrogen receptor repressor-10 (ERR-10). The ERR-10 cDNA is predicted to encode a polypeptide of 94 amino acids, with a molecular mass of about 10 kDa. Although the ERR-10 mRNA transcript is expressed in a wide range of normal human tissues, higher expression levels are found in endocrinal tissues relative to other tissues. We have demonstrated, through immunoprecipitation, Western blot and GST pull-down assays, that ERR-10 associates with ER-alpha. Moreover, ERR-10 decreased 17beta-estrodial-induced activation of ER-alpha transcriptional activity in transient transfection assays of mammalian cells. The ERR-10 N-terminus, which resembles two LXXLL motifs, is essential for ER-alpha binding and repression activity. Estrogen modulation of estrogen-responsive gene expression was markedly blocked by ERR-10. These results suggest that ERR-10 is a novel mediator in ER transcriptional activation.
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PMID:ERR-10: a new repressor in transcriptional signaling activation of estrogen receptor-alpha. 1547 36


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