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 nuclear peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily and acts as a ligand-dependent transcription factor mediating adipocyte differentiation, cell proliferation and inflammatory processes, and modulation of insulin sensitivity. Members of the 160-kDa protein (SRC-1/TIF2/AIB-1) family of coactivators, CBP/p300 and TRAP220/DRIP205, are shown to interact directly with PPARgamma and potentiate nuclear receptor transactivation function in a ligand-dependent fashion. Because PPARgamma ligands exert partially overlapping but distinct subsets of biological action through PPARgamma binding, we wished to examine whether interactions between PPARgamma and known coactivators were induced to the same extent by different classes of PPARgamma ligand. The natural ligand 15-deoxy-Delta12,14-prostaglandin J(2) induced PPARgamma interactions with all coactivators tested (SRC-1, TIF2, AIB-1, p300, TRAP220/DRIP205) in yeast and mammalian two-hybrid assays, as well as in a glutathione S-transferase pull-down assay. However, under the same conditions troglitazone, a synthetic PPARgamma ligand that acts as an antidiabetic agent, did not induce PPARgamma interactions with any of the coactivators. Our findings suggest that ligand binding may alter PPARgamma structure in a ligand type-specific way, resulting in distinct PPARgamma-coactivator interactions.
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PMID:Ligand type-specific interactions of peroxisome proliferator-activated receptor gamma with transcriptional coactivators. 2414 11

Receptor-interacting protein 140 (RIP140) encodes a histone deacetylase (HDAC) inhibitor-sensitive repressive activity. Direct interaction of RIP140 with HDAC1 and HDAC3 occurs in vitro and in vivo as demonstrated in co-immunoprecipitation and glutathione S-transferase pull-down experiments. The HDAC-interacting domain of RIP140 is mapped to its N-terminal domain, between amino acids 78 and 303 based upon glutathione S-transferase pull-down experiments. In chromatin immunoprecipitation assays, it is demonstrated that histone deacetylation occurs at the chromatin region of the Gal4 binding sites as a result of Gal4 DNA binding domain-tethered RIP expression. The immunocomplexes of RIP140 from cells transfected with RIP140 and HDAC are able to deacetylate histone proteins in vitro. This study presents the first evidence for RIP140 as a negative coregulator for nuclear receptor actions by directly recruiting histone deacetylases and categorizes RIP140 as a novel negative coregulator that is able to directly interact with HDACs.
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PMID:Receptor-interacting protein 140 directly recruits histone deacetylases for gene silencing. 1100 75

Small heterodimer partner (SHP, NR0B2) is an atypical orphan nuclear receptor that inhibits transcriptional activation by several other nuclear receptors. We recently reported that mutations in the SHP gene are associated with insulin resistance. In the present study, we demonstrated that the SHP gene is expressed in adipose tissues. A reporter gene assay showed that a gene product of SHP increased the transcriptional activation of peroxisome proliferator-activated receptor (PPAR) gamma. SHP-mediated activation of PPARgamma was observed both in the presence and absence of the ligand of PPARgamma. Immunoprecipitation and glutathione S-transferase pull-down assay showed that SHP directly bound to PPARgamma and competed with nuclear receptor corepressor for binding to PPARgamma. Serial deletion studies indicated that the C terminus of SHP is important for PPARgamma activation. Mutant SHP proteins, which are found in naturally occurring mutation, showed less enhancing activity for PPARgamma than wild-type SHP. Our results suggest that SHP may act as an endogenous enhancer of PPARgamma.
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PMID:Small heterodimer partner, an orphan nuclear receptor, augments peroxisome proliferator-activated receptor gamma transactivation. 1169 34

The human testicular orphan receptor 4 (TR4) is a member of the nuclear receptor superfamily that shows a broad tissue distribution with higher expression in the nervous system and male reproductive tract. TR4 functions as a transcriptional modulator that controls various target genes via binding to the DNA hormone response elements. Here we report that instead of direct binding to hormone response elements for gene regulation, TR4 can also go through direct protein-protein interaction to repress estrogen receptor (ER)-mediated transactivation. Electrophoretic mobility shift and glutathione S-transferase pull-down assays clearly demonstrate that the direct interaction between TR4 and ER will inhibit the homodimerization of ER and interrupt/prevent ER binding to the estrogen response element. The consequence of these events may then result in the suppression of ER target genes, such as cyclin D1 and pS2 and inhibition of ER-mediated cell proliferation in the MCF-7 cells stably transfected with TR4. Together, our results showing that TR4 can suppress ER function via protein-protein interaction not only represent a unique cross-talk signaling pathway in the nuclear receptor superfamily, it may also provide us with a new strategy to modulate ER function in the breast cancer cells.
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PMID:Modulation of estrogen receptor-mediated transactivation by orphan receptor TR4 in MCF-7 cells. 1184 90

The nuclear receptor corepressor (NCoR) was isolated as a peroxisome-proliferator-activated receptor (PPAR) delta interacting protein using the yeast two-hybrid system. NCoR interacted strongly with the ligand-binding domain of PPAR delta, whereas interactions with the ligand-binding domains of PPAR gamma and PPAR alpha were significantly weaker. PPAR-NCoR interactions were antagonized by ligands in the two-hybrid system, but were ligand-insensitive in in vitro pull-down assays. Interaction between PPAR delta and NCoR was unaffected by coexpression of retinoid X receptor (RXR) alpha. The PPAR delta-RXR alpha heterodimer bound to an acyl-CoA oxidase (ACO)-type peroxisome-proliferator response element recruited a glutathione S-transferase-NCoR fusion protein in a ligand-independent manner. Contrasting with most other nuclear receptors, PPAR delta was found to interact equally well with interaction domains I and II of NCoR. In transient transfection experiments, NCoR and the related silencing mediator for retinoid and thyroid hormone receptor (SMRT) were shown to exert a marked dose-dependent repression of ligand-induced PPAR delta-mediated transactivation; in addition, transactivation induced by the cAMP-elevating agent forskolin was efficiently reduced to basal levels by NCoR as well as SMRT coexpression. Our results suggest that the transactivation potential of liganded PPAR delta can be fine-tuned by interaction with NCoR and SMRT in a manner determined by the expression levels of corepressors and coactivators.
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PMID:Nuclear receptor corepressor-dependent repression of peroxisome-proliferator-activated receptor delta-mediated transactivation. 1190 58

Human B1F was cloned from a human liver cDNA library by yeast one-hybrid screening and characterized. It is a transcription factor which belongs to nuclear receptor superfamily. The cDNA segment 450-930 of human liver transcription factor hB1F was cloned into the pGEX-3X expression vector and was expressed in E.coli. The purified GST-fused hB1F, named GST-CS, were used to immunize mice to get polyclonal antibodies to hB1F. The antiserum showed specificity to hB1F after the purification by GST-Sepharose 4B. It can be used in further investigations of the structure and function of hB1F.
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PMID:Fusion Expression and Antibody Preparation of the Human Transcription Factor hB1F. 1211 Sep 6

Isoforms of the thyroid hormone receptor (TR)alpha and TRbeta genes mediate thyroid hormone action. How TR isoforms modulate tissue-specific thyroid hormone (TH) action remains largely unknown. The steroid receptor coactivator-1 (SRC-1) is among a group of transcriptional coactivator proteins that bind to TRs, along with other members of the nuclear receptor superfamily, and modulate the activity of genes regulated by TH. Mice deficient in SRC-1 possess decreased tissue responsiveness to TH and many steroid hormones; however, it is not known whether or not SRC-1-mediated activation of TH-regulated gene transcription in peripheral tissues, such as heart and liver, is TR isoform specific. We have generated mice deficient in TRalpha and SRC-1, as well as in TRbeta and SRC-1, and investigated thyroid function tests and effects of TH deprivation and TH treatment compared with wild-type (WT) mice or those deficient in either TR or SRC-1 alone. The data show that 1) in the absence of TRalpha or TRbeta, SRC-1 is important for normal growth; 2) SRC-1 modulates TRalpha and TRbeta effects on heart rate; 3) two new TRbeta-dependent markers of TH action in the liver have been identified, osteopontin (upregulated) and glutathione S-transferase (downregulated); and 4) SRC-1 may mediate the hypersensitivity to TH seen in liver of TRalpha-deficient mice.
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PMID:Specificity of thyroid hormone receptor subtype and steroid receptor coactivator-1 on thyroid hormone action. 1238 68

Brain natriuretic peptide (BNP) gene expression is a well documented marker of hypertrophy in the cardiac myocyte. Triiodothyronine (T(3)), the bioactive form of thyroid hormone, triggers a unique form of hypertrophy in cardiac myocytes that accompanies the selective activation or suppression of specific gene targets. In this study, we show that the BNP gene is a target of T(3) action. BNP secretion was increased 6-fold, BNP mRNA levels 3-fold, and BNP promoter activity 3-5-fold following T(3) treatment. This was accompanied by an increase in myocyte size, sarcomeric organization, and protein synthesis. Of note, several of the responses to T(3) synergized with those to the conventional hypertrophic agonist endothelin. The response to the liganded thyroid hormone receptor (TR) was mediated by an unusual thyroid hormone response element located between -1000 and -987 relative to the transcription start site. Both TR homodimers and TR.retinoid X receptor heterodimers associated with this element in an electrophoretic mobility shift assay. Protein fragments harboring the LXXLL motifs of the coactivators GRIP1 and SRC1 or TRAP220 interacted predominantly with the TR.retinoid X receptor heterodimeric pair in a ligand-dependent fashion. Both TR homodimers and heterodimers in the unliganded state selectively associated with glutathione S-transferase-nuclear receptor corepressor fragments harboring one of three receptor interaction domains containing the sequence (I/L)XX(I/V)I. These interactions were dissociated following the addition of T(3). Collectively, these findings identify the BNP gene as a potential model for the investigation of TR-dependent gene regulation in the heart.
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PMID:Triiodothyronine increases brain natriuretic peptide (BNP) gene transcription and amplifies endothelin-dependent BNP gene transcription and hypertrophy in neonatal rat ventricular myocytes. 1256 79

We have shown previously that the transforming growth factor-beta (TGFbeta)-regulated Sma-Mad (Smad) protein 3 and Smad4 proteins transactivate the apolipoprotein C-III promoter in hepatic cells via a hormone response element that binds the nuclear receptor hepatocyte nuclear factor 4 (HNF-4). In the present study, we show that Smad3 and Smad4 but not Smad2 physically interact with HNF-4 via their Mad homology 1 domains both in vitro and in vivo. The synergistic transactivation of target promoters by Smads and HNF-4 was shown to depend on the specific promoter context and did not require an intact beta-hairpin/DNA binding domain of the Smads. Using glutathione S-transferase interaction assays, we established that two regions of HNF-4, the N-terminal activation function 1 (AF-1) domain (aa 1-24) and the C-terminal F domain (aa 388-455) can mediate physical Smad3/HNF-4 interactions in vitro. In vivo, Smad3 and Smad4 proteins enhanced the transactivation function of various GAL4-HNF-4 fusion proteins via the AF-1 and the adjacent DNA binding domain, whereas a single tyrosine to alanine substitution in AF-1 abolished coactivation by Smads. The findings suggest that the transcriptional cross talk between the TGFbeta-regulated Smads and HNF-4 is mediated by specific functional domains in the two types of transcription factors. Furthermore, the specificity of this interaction for certain target promoters may play an important role in various hepatocyte functions, which are regulated by TGFbeta and the Smads.
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PMID:Mechanism of a transcriptional cross talk between transforming growth factor-beta-regulated Smad3 and Smad4 proteins and orphan nuclear receptor hepatocyte nuclear factor-4. 1263 40

Assessment of the risk of human exposure to man-made chemicals that bind to hormone receptors has emerged as a major public health issue. Among hormone receptors, nuclear receptors tend to be targets of xenobiotics because their endogenous ligands are small, fat-soluble molecules. Nuclear receptors are ligand-inducible transcriptional factors and regulate the transcriptional activity of various target genes. At the start of the initiation step of transcription, nuclear receptors interact with coactivators (TIF2, SRC1, ACTR, CBP/p300, etc.) in an agonist-dependent manner. Using the interaction of the nuclear receptor with a coactivator, we have developed a novel rapid ligand in vitro screening method that is easy to use and has high sensitivity. This method, called by us the CoA-BAP system, is applicable to most nuclear receptors and is suitable for high-throughput screening because the entire experimental operation can be carried out on a microplate. We used human TIF2 as a coactivator including LXXLL motifs expressed in Escherichia coli as a fusion protein with BAP and nuclear receptor LBD expressed in E. coli as a fusion protein with GST. On a GSH-coupled microplate these proteins were incubated with chemicals and the protein-protein interactions were detected as alkaline phosphatase activity. To date we have examined seven nuclear receptors (ERalpha/beta, TRalpha, RARalpha/gamma, RXRalpha,and VDR) and confirmed that the method works well.
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PMID:Basis of a high-throughput method for nuclear receptor ligands. 1286 36


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