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

---

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

Previous studies from our group have shown that Foxa1 is expressed in the prostate and interacts with the androgen receptor (AR) to regulate prostate-specific genes such as prostate-specific antigen (PSA) and probasin (PB). We report here that Foxa2 but not Foxa1 is expressed in the epididymis. Further, Foxa2 interacts with the AR to regulate the mouse epididymal retinoic acid binding protein (mE-RABP) gene, an epididymis-specific gene. Binding of Foxa2 to the mE-RABP promoter was confirmed by gel-shift and chromatin immunoprecipitation (ChIP) assays. Overexpression of Foxa2 suppresses androgen activation of the mE-RABP promoter while overexpression of Foxa2 with prostate-specific promoters activates gene expression in an androgen-independent manner. GST pull-down assays determined that both Foxa1 and Foxa2 physically interact with the DNA binding domain of the AR. The interaction between Foxa proteins and AR was further confirmed by gel-shift assays where Foxa protein was recruited to AR binding oligomers even when Foxa binding sites were not present, and AR was recruited to Foxa binding oligomers even in the absence of an AR binding site. Given that Foxa1 and Foxa2 proteins are expressed differentially in the prostate and epididymis, these data suggest that the Foxa proteins have distinct effects on AR-regulated genes in different male reproductive accessory organs.
...
PMID:Foxa1 and Foxa2 interact with the androgen receptor to regulate prostate and epididymal genes differentially. 1646 59

The androgen receptor (AR) is a ligand-activated transcription factor that controls growth and survival of prostate cancer cells. In the present study, we investigated the regulation of AR activity by the receptor-interacting protein 140 (RIP140). We first showed that RIP140 could be coimmunoprecipitated with the receptor when coexpressed in 293T cells. This interaction appeared physiologically relevant because chromatin immunoprecipitation assays revealed that, under R1881 treatment, RIP140 could be recruited to the prostate-specific antigen encoding gene in LNCaP cells. In vitro glutathione S-transferase pull-down assays provided evidence that the carboxy-terminal domain of AR could interact with different regions of RIP140. By means of fluorescent proteins, we demonstrated that ligand-activated AR was not only able to translocate to the nucleus but also to relocate RIP140 from very structured nuclear foci to a diffuse pattern. Overexpression of RIP140 strongly repressed AR-dependent transactivation by preferentially targeting the ligand binding domain-dependent activity. Moreover, disruption of RIP140 expression induced AR overactivation, thus revealing RIP140 as a strong AR repressor. We analyzed its mechanism of transrepression and first demonstrated that different regions of RIP140 could mediate AR-dependent repression. We then showed that the carboxy-terminal end of RIP140 could reverse transcriptional intermediary factor 2-dependent overactivation of AR. The use of mutants of RIP140 allowed us to suggest that C-terminal binding protein played no role in RIP140-dependent inhibition of AR activity, whereas histone deacetylases partly regulated that transrepression. Finally, we provided evidence for a stimulation of RIP140 mRNA expression in LNCaP cells under androgen treatment, further emphasizing the role of RIP140 in androgen signaling.
...
PMID:Receptor-interacting protein 140 is a repressor of the androgen receptor activity. 1652 72

We tested the hypothesis that cell invasiveness and tumorigenesis are driven by hypomethylation of genes involved in tumor progression. Highly invasive human prostate cancer cells PC-3 were treated with either the methyl donor S-adenosylmethionine (SAM) or methyl DNA-binding domain protein 2 antisense oligonucleotide (MBD2-AS). Both treatments resulted in a dose- and time-dependent inhibition of key genes, such as urokinase-type plasminogen activator (uPA), matrix metalloproteinase-2 (MMP-2), and vascular endothelial growth factor expression to decrease tumor cell invasion in vitro. No change in the levels of expression of genes already known to be methylated in late-stage prostate cancer cells, such as glutathione S-transferase P1 and androgen receptor, was seen. Inoculation of PC-3 cells pretreated with SAM and MBD2-AS into the flank of male BALB/c nu/nu mice resulted in the development of tumors of significantly smaller volume compared with animals inoculated with PC-3 cells treated with vehicle alone or MBD2 scrambled oligonucleotide. Immunohistochemical analysis of tumors showed the ability of SAM and MBD2-AS to significantly decrease tumoral uPA and MMP-2 expression along with levels of angiogenesis and survival pathway signaling molecules. Bisulfite sequencing analysis of tumoral genomic DNA showed that inhibition of both uPA and MMP-2 expression was due to methylation of their 5' regulatory region. These studies support the hypothesis that DNA hypomethylation controls the activation of multiple tumor-promoting genes and provide valuable insight into developing novel therapeutic strategies against this common disease, which target the demethylation machinery.
...
PMID:Alteration of the methylation status of tumor-promoting genes decreases prostate cancer cell invasiveness and tumorigenesis in vitro and in vivo. 1698 64

SOX9 is a member of the SOX [Sry-related high-mobility group (HMG) box] family of HMG DNA-binding domain transcription factors and is required for the development and differentiation of multiple cell lineages. This report shows that basal epithelial cells express SOX9 in normal prostate, with no detectable expression in luminal epithelial cells. In contrast, SOX9 is expressed in primary prostate cancers in vivo, at a higher frequency in recurrent prostate cancer and in prostate cancer cell lines (LNCaP, CWR22, PC3, and DU145). SOX9 message and protein levels in prostate cancer cells were increased by treatment with glycogen synthase kinase 3beta inhibitor (SB415286), and SOX9 was reduced when beta-catenin was down-regulated by small interfering RNA (siRNA), indicating that SOX9 expression in prostate cancer is regulated by Wnt/beta-catenin signaling. SOX9 bound specifically to androgen receptor (AR) DNA-binding domain glutathione S-transferase fusion proteins, and this interaction was dependent on a short peptide immediately COOH-terminal to the DNA-binding domain (the C-terminal extension), which is required for interactions between steroid hormone receptors and the architectural HMG proteins. Exogenous SOX9 expressed at high nonphysiologic levels decreased AR expression and activity; however, at lower levels, SOX9 increased AR protein expression. Significantly, down-regulation of SOX9 by siRNA in prostate cancer cells reduced endogenous AR protein levels, and cell growth indicating that SOX9 contributes to AR regulation and decreased cellular proliferation. These results indicate that SOX9 in prostate basal cells supports the development and maintenance of the luminal epithelium and that a subset of prostate cancer cells may escape basal cell requirements through SOX9 expression.
...
PMID:SOX9 is expressed in normal prostate basal cells and regulates androgen receptor expression in prostate cancer cells. 1723 60

Multiple biological effects of tributyltin (TBT) on juvenile salmon have been investigated. Fish were exposed for 7 days to waterborne TBT at nominal concentrations of 50 and 250 microg/L dissolved in dimethyl sulfoxide (DMSO). Hepatic samples were analyzed for gene expression patterns in the hormonal and xenobiotic biotransformation pathways using validated real-time PCR method. Immunochemical and several cytochrome P450 (CYP)-mediated enzyme activity (ethoxyresorufin: EROD, benzyloxyresorufin: BROD, methoxyresorufin: MROD and pentoxyresorufin: PROD) assays were analyzed. Our data show that TBT produced concentration-specific decrease of estrogen receptor-alpha (ERalpha), vitellogenin (Vtg), zona radiata protein (Zr-protein) and increase of estrogen receptor-beta (ERbeta) and androgen receptor-beta (ARbeta) in the hormonal pathway. In the xenobiotic biotransformation pathway, TBT produced apparent increase and decrease at respective low and high concentration, on aryl hydrocarbon receptor-alpha (AhRalpha), AhR nuclear translocator (ARNT) and AhR repressor (AhRR) mRNA. The expression of CYP1A1 and GST showed a TBT concentration-dependent decrease. The AhRbeta, CYP3A and uridine diphosphoglucuronosyl transferase (UGT) mRNA expressions were significantly induced after exposure to TBT. Immunochemical analysis of CYP3A and CYP1A1 protein levels confirmed the TBT effects observed at the transcriptional levels. The effect of TBT on the biotransformation enzyme gene expressions partially co-related but did not directly parallel enzyme activity levels for EROD, BROD, MROD and PROD. In general, these findings confirm previous reports on the endocrine effects of TBT, in addition to effects on hepatic CYP1A isoenzyme at the transcriptional level that transcends to protein and enzymatic levels. The induced expression patterns of CYP3A and UGT mRNA after TBT exposure, suggest the involvement of CYP3A and UGT in TBT metabolism in fish. The effect of TBT on CYP3A is proposed to represent another hormonal effect of TBT not previously reported in any fish or lower vertebrate. The proposed androgenic effect is supported by the observation that TBT also induced ARbeta mRNA expression in a concentration-specific manner. To our knowledge, this is the first study that has simultaneously studied multiple responses after exposure to TBT in fish.
...
PMID:Modulation of xenobiotic biotransformation system and hormonal responses in Atlantic salmon (Salmo salar) after exposure to tributyltin (TBT). 1734 1

Pharmaceuticals are ubiquitous pollutants in the aquatic environment where their potential effects on non-target species like fish has only recently become subject of systematic investigations. In the present study, experiments were undertaken to examine the effects of a synthetic pharmaceutical endocrine disruptor, ethynylestradiol (EE2), given in water at 5 or 50 ng/L and sampled at days 0 (control), 3 and 7 after exposure, on hepatic phase I and II biotransformation and hormonal pathways of juvenile salmon using quantitative (real-time) polymerase chain reaction (qPCR), Vtg ELISA and 7-ethoxyresorufin O-deethylase (EROD) catalytic activity. Our data show that EE2 produced time- and concentration-specific modulation of estrogen receptor isoforms (ERalpha, ERbeta) and androgen receptor-beta (ARbeta). EE2 produced a concentration-specific induction of vitellogenin (Vtg) and zona radiata protein (Zr-protein) at day 3 after exposure. At day 7, Vtg and Zr-protein mRNA (and plasma Vtg protein) expression were significantly decreased in the group given 5 ng EE2/L, compared to dimethyl sulfoxide (DMSO) control group. In the xenobiotic biotransformation pathway, EE2 produced a significant increase of aryl hydrocarbon receptor-alpha (AhRalpha) at day 3 in the group given 5 ng EE2/L and AhRbeta was decreased at the same concentration at day 7. While CYP3A was not significantly affected by EE2 exposure, the CYP1A1, AhR nuclear translocator (Arnt) and AhR repressor (AhRR) mRNA showed an apparent EE2 concentration and time-dependent decrease. The expression of uridine diphosphoglucuronosyl transferase (UGT) and glutathione S-transferase class pi-like (GSTpi-like) mRNA were decreased after exposure to 50ng EE2/L at both day 3 and 7 after exposure. The effect of EE2 on the CYP1A1 gene expressions paralleled effect on EROD and AhRR mRNA, suggesting a direct role of EE2 in controlling cellular detoxification machinery. Interestingly, the carrier vehicle, DMSO produced significant time-dependent induction of estrogenic (ERalpha, Vtg and Zr-protein) responses, compared with blank (i.e. without DMSO) controls at day 7 post-exposure. The effect of DMSO totally underscored the observed EE2 effect at day 7 after exposure. In general, these findings support previous reports on the endocrine effects of EE2, in addition to effects on hepatic biotransformation system. In view of the data presented here and our recent studies, the use of DMSO as carrier vehicle in endocrine toxicological experimental studies should be re-evaluated.
...
PMID:Effects of 17alpha-ethynylestradiol on hormonal responses and xenobiotic biotransformation system of Atlantic salmon (Salmo salar). 1787 31

Sterol regulatory element-binding protein-1c (SREBP-1c) is a basic helix-loop-helix transcription factor that plays an important role in lipid homeostasis. Here, we show that SREBP-1c regulates androgen receptor (AR) transactivation through direct interaction with AR and represses androgen-dependent growth of prostatic cells. Transient transfection studies show that SREBP-1c specifically inhibits the transactivation of AR. Chromatin immunoprecipitation assays reveal that SREBP-1c is recruited with AR onto the endogenous AR target promoter. Moreover, adenovirus-mediated overexpression of SREBP-1c decreases the mRNA level of the prostate-specific antigen gene, an endogenous target gene of AR, supporting SREBP-1c modulation of AR transactivation. In vivo and in vitro protein interaction assays show that SREBP-1c directly interacts with AR through the activation function-1 domain of AR. In addition, transfection studies and glutathione S-transferase pull-down competition experiments reveal that the SREBP-1c-mediated repression of AR transactivation is accomplished through competition with certain AR coactivators for AR interaction. The SREBP-1c-mediated inhibition of AR transactivation also involves the recruitment of histone deacetylase 1. Finally, adenovirus-mediated overexpression of SREBP-1c inhibits androgen-induced proliferation of prostatic cells in vitro and in vivo, and small interfering RNA-mediated down-regulation of SREBP-1 enhances androgen-induced proliferation of prostatic cells as well as the transactivation of AR. Taken together, these results suggest that SREBP-1c acts as an AR corepressor and may play an important role in the regulation of AR-dependent prostatic cell growth.
...
PMID:Sterol regulatory element-binding protein-1c represses the transactivation of androgen receptor and androgen-dependent growth of prostatic cells. 1824 27

We cloned a novel splicing variant for nuclear coactivator p120(alpha), designated as p120beta and studied its function and expression in several human prostate diseases. Transfection assays demonstrated that p120beta functions as a strong coactivator for androgen receptor (AR), but weakly for other nuclear receptors. GST-pull down assay showed that a glutamine-rich region of the p120 bound to the ligand-binding domain of AR. Interestingly, p120beta mRNAs were expressed predominantly in the normal prostate, androgen-responsive prostate cancers and an androgen-sensitive prostate cancer cell line, LNCaP, but weakly in recurrent cancers and the androgen-insensitive prostate cancer cell lines PC3 and DU145. Furthermore, knockdown of p120alpha by siRNA abolished coactivator activity on thyroid hormone receptors (TR) and PPARgamma, but did not affect that of ARs in PC3 cells. In addition, competitive assay with other nuclear receptors demonstrated that TR and PPARgamma did not inhibit p120beta-induced stimulation. These findings suggested that while p120alpha was essential for ligand-dependent stimulation of TRs and PPARgamma, p120beta acted as a coactivating protein predominantly for AR.
...
PMID:A novel splice variant of the nuclear coactivator p120 functions strongly for androgen receptor: characteristic expression in prostate disease. 1856 Feb 2

A novel mutation F826L located within the ligand binding domain (LBD) of the human androgen receptor (AR) was investigated. This mutation was found in a boy with severe penoscrotal hypospadias (classified as 46,XY DSD). The AR mutant F826L appeared to be indistinguishable from the wild-type AR, with respect to ligand binding affinity, transcriptional activation of MMTV-luciferase and ARE2-TATA-luciferase reporter genes, protein level in genital skin fibroblasts (GSFs), and sub-cellular distribution in transfected cells. However, an at least two-fold higher NH2-/COOH-terminal domain interaction was found in luciferase and GST pull-down assays. A two-fold increase was also observed for TIF2 (transcription intermediary factor 2) co-activation of the AR F826L COOH-terminal domain. This increase could not be explained by a higher stability of the mutant protein, which was within wild-type range. Repression of transactivation by the nuclear receptor co-repressor (N-CoR) was not affected by the AR F826L mutation. The observed properties of AR F826L would be in agreement with an increased activity rather than with a partial defective AR transcriptional activation. It is concluded that the penoscrotal hypospadias in the present case is caused by an as yet unknown mechanism, which still may involve the mutant AR.
...
PMID:A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH2-/COOH-terminal domain interaction and TIF2 co-activation. 1865 23

Prostate cancer is one of the most commonly diagnosed cancers in men. The number of affected men is expected to rapidly increase as the population of males over the age of 50 grows worldwide. For patients who are not cured by local treatment and experience metastatic disease, neither androgen ablation nor chemotherapy can abrogate progression and death from androgen-independent/hormone-refractory disease. Therefore, finding strategies for the prevention of prostate cancer initiation and disease progression is a medical challenge. Consumption of cruciferous vegetables has been reported to be associated with reduced incidence of prostate cancer cases. The isothiocyanates, including phenethyl isothiocyanate (PEITC), from cruciferous vegetables have been demonstrated as active components responsible for chemoprevention. In this review, we summarize the recent findings of PEITC on prostate cancer prevention with an emphasis on epigenetic mechanisms. Studies have indicated that PEITC mediates gene regulation, such as downregulation of androgen receptor expression and induction of endogenous cyclin-dependent kinase inhibitors, p21 and p27. The gene for detoxifying enzyme pi-class glutathione S-transferase (GSTP1), silenced in the vast majority of prostate tumor cells, could be reactivated and the enzymatic function recovered. This may be through epigenetic mechanisms as PEITC is a dual inhibitor of histone deacetylases and aberrant CpG island methylation of various genes. The epigenetic regulation may play a critical role, along with interactive mechanisms including the disruption of microtubule polymerization, in prostate cancer prevention by PEITC. These mechanisms target and correct the aberrations fundamental to the initiation and progression of carcinogenesis in cells, and restoring the cells to a more normal state. Inhibiting and eliminating cancer cells forms the basis of cancer prevention.
...
PMID:Prostate cancer chemopreventive activity of phenethyl isothiocyanate through epigenetic regulation (review). 2066 22


<< Previous 1 2 3 4 5 6 7 Next >>

---