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)

A direct interaction between the nuclear receptor TR2 and histone deacetylases (HDACs) 3 and 4 is mediated by the DNA binding domain (DBD) of TR2. To test if this interaction is common to members of the nuclear receptor family, the Cys2-Cys2 type zinc finger (ZF) DBDs were subcloned from several nuclear receptors (mRARalpha, mRXRbeta, mTR2, mTR4, RAR, mPPARdelta, and mPPARgamma2). Using GST pull-downs, both HDACs 3 and 4 were found to interact directly with the core DBD from each receptor. The three-dimensional structure of the ZF domains was essential for this interaction as disruption by zinc chelation precluded interaction with HDACs. The results suggest that the ZFs of nuclear receptors provide a general interaction interface for HDACs 3 and 4. Functional significance of this interaction was demonstrated using ChIP assays where a truncated TR2 protein (lacking the LBD) recruited HDACs 3 and 4 to the target DNA causing demonstrable histone deacetylation. GST pull-downs and mammalian two-hybrid interaction tests were then used to define the interaction domains of HDAC3 with TR2. Both the N- and C-terminal portions of HDAC3 showed interaction with the TR2 DBD. Thus, multiple domains of HDAC3 form the interaction surface for the DBD of nuclear receptors.
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PMID:Interaction of nuclear receptor zinc finger DNA binding domains with histone deacetylase. 1294 85

Pulses of the steroid hormone ecdysone trigger the major developmental transitions in Drosophila, including molting and puparium formation. The ecdysone signal is transduced by the EcR/USP nuclear receptor heterodimer that binds to specific response elements in the genome and directly regulates target gene transcription. We describe a novel nuclear receptor interacting protein encoded by rigor mortis (rig) that is required for ecdysone responses during larval development. rig mutants display defects in molting, delayed larval development, larval lethality, duplicated mouth parts, and defects in puparium formation--phenotypes that resemble those seen in EcR, usp, E75A and betaFTZ-F1 mutants. Although the expression of these nuclear receptor genes is essentially normal in rig mutant larvae, the ecdysone-triggered switch in E74 isoform expression is defective. rig encodes a protein with multiple WD-40 repeats and an LXXLL motif, sequences that act as specific protein-protein interaction domains. Consistent with the presence of these elements and the lethal phenotypes of rig mutants, Rig protein interacts with several Drosophila nuclear receptors in GST pull-down experiments, including EcR, USP, DHR3, SVP and betaFTZ-F1. The ligand binding domain of betaFTZ-F1 is sufficient for this interaction, which can occur in an AF-2-independent manner. Antibody stains reveal that Rig protein is present in the brain and imaginal discs of second and third instar larvae, where it is restricted to the cytoplasm. In larval salivary gland and midgut cells, however, Rig shuttles between the cytoplasm and nucleus in a spatially and temporally regulated manner, at times that correlate with the major lethal phase of rig mutants and major switches in ecdysone-regulated gene expression. Taken together, these data indicate that rig exerts essential functions during larval development through gene-specific effects on ecdysone-regulated transcription, most likely as a cofactor for one or more nuclear receptors. Furthermore, the dynamic intracellular redistribution of Rig protein suggests that it may act to refine spatial and temporal responses to ecdysone during development.
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PMID:rigor mortis encodes a novel nuclear receptor interacting protein required for ecdysone signaling during Drosophila larval development. 1464 29

Farnesoid X receptor (FXR) is a nuclear receptor for bile acids. Ligand activated-FXR regulates transcription of genes to allow feedback control of bile acid synthesis and secretion. There are five major bile acids in humans. We have previously demonstrated that lithocholate acts as an FXR antagonist, and here we show that the other four bile acids, chenodeoxycholate (CDCA), deoxycholate (DCA), cholate (CA), and ursodeoxycholate (UDCA), act as selective FXR agonists in a gene-specific fashion. In an in vitro coactivator association assay, CDCA fully activated FXR, whereas CA partially activated FXR and DCA and UDCA had negligible activities. Similar results were also obtained from a glutathione S-transferase pull-down assay in which only CDCA and the synthetic FXR agonist GW4064 significantly increased the interaction of SRC-1 with FXR. In FXR transactivation assays with a bile salt export pump (BSEP) promoter-driven luciferase construct, bile acids showed distinct abilities to activate the BSEP promoter: CDCA, DCA, CA, and UDCA increased luciferase activity by 25-, 20-, 18-, and 8-fold, respectively. Consistently, CDCA increased BSEP mRNA by 750-fold in HepG2 cells, whereas DCA, CA, and UDCA induced BSEP mRNA by 250-, 75-, and 15-fold, respectively. Despite the partial induction of BSEP mRNA, CA, DCA, and UDCA effectively repressed expression of cholesterol 7alpha-hydroxylase, another FXR target. We further showed that all four bile acids significantly increased FXR protein, suggesting the existence of an auto-regulatory loop in FXR signaling pathways. In conclusion, these results suggest that the binding of each bile acid results in a different FXR conformations, which in turn differentially regulates expression of individual FXR targets.
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PMID:The farnesoid X receptor controls gene expression in a ligand- and promoter-selective fashion. 1468 51

It has been demonstrated that proline-rich nuclear receptor coregulatory protein (PNRC) is a nuclear receptor coactivator that interacts with nuclear receptors through an SH3-binding motif located in its C-terminus. In the present report, a physical interaction between PNRC and Grb2 (an adapter protein involved in growth factor/Ras-mediated pathways) has been demonstrated using the GST pull-down assay, the yeast two-hybrid assay, as well as by coimmunoprecipitation. Cotransfection and fluorescence imaging have also confirmed the colocalization of PNRC and Grb2 in mammalian cells. Transient transfection experiments have demonstrated that, by interacting with each other, Grb2 decreases the coactivator activity of PNRC for nuclear receptors, and that PNRC suppresses Grb2-mediated Ras/MAP-kinase activation. Furthermore, it was discovered that HeLa cells overexpressing PNRC grew more slowly when compared to matched controls. Additionally, using a RT-PCR analysis of mRNA on six pairs of cancer/noncancer tissues, PNRC expression was found to be significantly lower in breast cancer tissue than in noncancer tissue. Based on these findings, we believe that PNRC and Grb2, by interacting with each other, can suppress nuclear receptor-mediated regulation and growth factor-mediated regulation in human breast tissue. This is a newly identified crosstalk mechanism for modulating these two important types of regulatory pathways.
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PMID:A novel crosstalk mechanism between nuclear receptor-mediated and growth factor/Ras-mediated pathways through PNRC-Grb2 interaction. 1512 21

RORgamma is a nuclear receptor that binds to DNA motifs as a monomer to constitutively activate target genes. RORgamma plays an important role in thymocyte development and lymph node organogenesis, while the regulation of RORgamma-mediated transcriptional activation is currently unclear. The purpose of this study was to identify other nuclear proteins that interact with RORgamma. A yeast two-hybrid screen with Y190 yeast cells under stringent conditions resulted in the identification of CHD4, also known as Mi-2beta, as a RORgamma-interacting protein. This interaction was confirmed by GST pull-down assays. This interaction occurred within the middle regulatory region (amino acids 719-1164) of Mi-2beta. Transfection of Gal4-RORgamma into HeLa cells resulted in constitutive transactivation of the MH100-tk-luc reporter. The addition of Mi-2beta resulted in a dramatic 50% decrease in Gal4-RORgamma-mediated transactivation. These data demonstrate that RORgamma forms a protein-protein interaction with the regulatory region of Mi-2beta, resulting in inhibition of RORgamma transcriptional activity. These results may provide evidence as to how RORgamma-mediated transactivation is regulated by other nuclear proteins.
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PMID:NuRD complex component Mi-2beta binds to and represses RORgamma-mediated transcriptional activation. 1514 97

Transcriptional repression is a major regulatory mechanism in cell differentiation, organogenesis, and oncogenesis. Two repressors of ligand-dependent transcription factors, nuclear receptor corepressor (N-CoR) and the related protein SMRT were identified as a silencing mediator for thyroid hormone receptor beta and as a silencing mediator for retinoic acid and thyroid hormone receptors, respectively. Nuclear receptor coactivators such as steroid receptor coactivator-1 (SRC-1) contain multiple LXXLL motifs, which are essential and sufficient for its ligand-dependent interaction with nuclear receptors. N-CoR also has an LXXLL motif, located between repressor domains 1 and 2, and conserved between mouse and man. In contrast, SMRT lacks this motif. This paper describes functional implications of the LXXLL motif in N-CoR. A 57-amino acid portion of N-CoR containing the LDNLL sequence (N-CoR(LDNLL)) fused to GST interacted with retinoic acid receptor alpha (RARalpha) and thyroid hormone receptor beta (TRbeta) in vitro. Similarly, [(35)S-methionine]N-CoR(LDNLL) interacted with a RARalpha fusion protein. N-CoR(LDNLL) also bound to RARalpha in vivo as determined in mammalian one-hybrid system in transfected CV-1 cells and by two-hybrid assays in bacteria. The interaction with RARalpha in vitro and in vivo was specific as determined by mutation of the sequence LDNLL to LDNAA. Our data suggest that the LDNLL motif in N-CoR has functional significance because it mediates interaction with nuclear receptors such as RARalpha and TRbeta.
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PMID:Functional analyses of an LXXLL motif in nuclear receptor corepressor (N-CoR). 1533 96

Bone-specific transcription of the osteocalcin (OC) gene is regulated principally by the Runx2 transcription factor and is further stimulated in response to 1alpha,25-dihydroxyvitamin D3 via its specific receptor (VDR). The rat OC gene promoter contains three recognition sites for Runx2 (sites A, B, and C). Mutation of sites A and B, which flank the 1alpha,25-dihydroxyvitamin D3-responsive element (VDRE), abolishes 1alpha,25-dihydroxyvitamin D3-dependent enhancement of OC transcription, indicating a tight functional relationship between the VDR and Runx2 factors. In contrast to most of the members of the nuclear receptor family, VDR possesses a very short N-terminal A/B domain, which has led to the suggestion that its N-terminal region does not contribute to transcriptional enhancement. Here, we have combined transient-overexpression, coimmunoprecipitation, in situ colocalization, chromatin immunoprecipitation, and glutathione S-transferase pull-down analyses to demonstrate that in osteoblastic cells expressing OC, VDR interacts directly with Runx2 bound to site B, which is located immediately adjacent to the VDRE. This interaction contributes significantly to 1alpha,25-dihydroxyvitamin D3-dependent enhancement of the OC promoter and requires a region located C terminal to the runt homology DNA binding domain of Runx2 and the N-terminal region of VDR. Together, our results indicate that Runx2 plays a key role in the 1alpha,25-dihydroxyvitamin D3-dependent stimulation of the OC promoter in osteoblastic cells by further stabilizing the interaction of the VDR with the VDRE. These studies demonstrate a novel mechanism for combinatorial control of bone tissue-specific gene expression. This mechanism involves the intersection of two major pathways: Runx2, a "master" transcriptional regulator of osteoblast differentiation, and 1alpha,25-dihydroxyvitamin D3, a hormone that promotes expression of genes associated with these terminally differentiated bone cells.
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PMID:Bone-specific transcription factor Runx2 interacts with the 1alpha,25-dihydroxyvitamin D3 receptor to up-regulate rat osteocalcin gene expression in osteoblastic cells. 1545 60

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

TBP-free TAF II-containing-type HAT complex subclasses, which contain hGCN5 HAT and TRRAP, appear to act as common coactivator complexes for nuclear receptors. However, their physiological significance with respect to each nuclear receptor remains to be established. To address this issue, we used hepatic cell lines (HepG2) with reduced endogenous TRRAP expression through antisense RNA expression or with overexpressed TRRAP or other major coactivators. The ligand-induced transactivation function of liver X receptor alpha (LXRalpha) and farnesoid X receptor/bile acid receptor reflected TRRAP expression levels, while that of PPARgamma did not. A GST pull-down assay indicated that TRRAP contains two potential LXRalpha-interacting domains in the C-terminal and central domains. Expression of antisense TRRAP RNA in HepG2 cells abolished the ligand-induced expression of LXRalpha target genes. These results suggested that TRRAP plays an important role as a coactivator, presumably part of a complex, in lipid metabolism through regulation of the LXRalpha-mediated gene cascade in hepatic cells.
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PMID:TRRAP as a hepatic coactivator of LXR and FXR function. 1564 35

Insulin-like growth factor-binding protein-3 (IGFBP-3) induces apoptosis by its ability to bind insulin-like growth factors (IGFs) as well as its IGF-independent effects involving binding to other molecules including the retinoid X receptor-alpha (RXRalpha). Here we describe that in response to IGFBP-3, the RXRalpha binding partner nuclear receptor Nur77 rapidly undergoes translocation from the nucleus to the mitochondria, initiating an apoptotic cascade resulting in caspase activation within 6 h. This translocation is a type 1 IGF receptor-signaling independent event as IGFBP-3 induces Nur77 translocation in R-cells. IGFBP-3 and Nur77 are additive in inducing apoptosis. GFP-Nur77 transfection into RXRalpha wild-type and knock-out mouse embryonic fibroblasts and subsequent treatment with IGFBP-3 show that RXRalpha is required for IGFBP-3-induced Nur77 translocation and apoptosis. Addition of IGFBP-3 to 22RV1 cell lysates enhanced the ability of GST-RXRalpha to "pull down" Nur77, and overexpression of IGFBP-3 enhanced the accumulation of mitochondrial RXRalpha. This unique nongenotropic nuclear pathway supports an emerging role for IGFBP-3 as a novel, multicompartmental signaling molecule involved in induction of apoptosis in malignant cells.
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PMID:Rapid apoptosis induction by IGFBP-3 involves an insulin-like growth factor-independent nucleomitochondrial translocation of RXRalpha/Nur77. 1573 Nov 12


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