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)

Steroid receptor coactivator-1 (SRC-1) specifically bound to the transcription factor AP-1 subunits c-Jun and c-Fos, as demonstrated by the yeast two-hybrid tests and glutathione S-transferase pull down assays. The c-Jun and c-Fos binding sites were localized to the C-terminal subregion of SRC-1 (amino acids 1101-1441) that encompasses the previously described histone acetyltransferase and receptor-binding domains. In mammalian cells, SRC-1, similar to the previous results with CBP-p300 (Arias, J., Alberts, A. S., Brindle, P., Claret, F. X., Smeal, T., Karin, M., Feramisco, J., and Montminy, M. (1994) Nature 370, 226-229; Bannister, A. J., and Kouzarides, T. (1995) EMBO J. 14, 4758-4762), potentiated the AP-1-mediated transactivations in a dose-dependent manner and derepressed the mutual inhibitions between nuclear receptors and AP-1. Furthermore, coexpression of p300 further enhanced this SRC-1-potentiated level of transactivations. Thus, we concluded that at least two distinct coactivator molecules may cooperate to regulate AP-1-dependent transactivations and mediate transrepression between AP-1 and nuclear receptors in vivo.
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PMID:Steroid receptor coactivator-1 coactivates activating protein-1-mediated transactivations through interaction with the c-Jun and c-Fos subunits. 964 16

Using coimmunoprecipitation and glutathione S-transferase pulldown experiments, we found that polyomavirus large T antigen binds to p300 in vivo and in vitro. The N-terminal region of the viral protein, including the pRB binding motif, was dispensable for this interaction, which involved several regions within the C-terminal half of the large T antigen. Interestingly, anti-T antibody coimmunoprecipitated a subspecies of p300 which has high histone acetyltransferase activity.
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PMID:Polyomavirus large T antigen binds the transcriptional coactivator protein p300. 988 90

Whereas the histone acetyltransferase activity of yeast Gcn5p has been widely studied, its structural interactions with the histones and the role of the carboxy-terminal bromodomain are still unclear. Using a glutathione S-transferase pull down assay we show that Gcn5p binds the amino-terminal tails of histones H3 and H4, but not H2A and H2B. The deletion of bromodomain abolishes this interaction and bromodomain alone is able to interact with the H3 and H4 N termini. The amino acid residues of the H4 N terminus involved in the binding with Gcn5p have been studied by site-directed mutagenesis. The substitution of amino acid residues R19 or R23 of the H4 N terminus with a glutamine (Q) abolishes the interaction with Gcn5p and the bromodomain. These residues differ from those known to be acetylated or to be involved in binding the SIR proteins. This evidence and the known dispensability of the bromodomain for Gcn5p acetyltransferase activity suggest a new structural role for the highly evolutionary conserved bromodomain.
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PMID:The bromodomain of Gcn5p interacts in vitro with specific residues in the N terminus of histone H4. 1007 2

Epigenetic mechanisms may be the main driving force for critical changes in gene expression that are responsible for progression of prostate cancers. The three most extensively characterized mechanisms for epigenetic gene-regulation are (i) changing patterns of DNA methylation, (ii) histone acetylations/deacetylations, and (iii) alterations in regulatory feedback loops for growth factors. Several studies have indicated that DNA hypermethylation is an important mechanism in prostate cancer for inactivation of key regulatory genes such as E-cadherin, pi-class glutathione S-transferase, the tumor suppressors CDKN2 and PTEN, and IGF-II. Similarly, histone acetylations and deacetylations are frequently associated respectively with transcriptional activation (e.g. IGFBP-2 and p21) and repression (e.g. Mad:Max dimers) of genes linked to prostate cancer progression. Recently, histone acetyltransferase and deacetylase activities have been shown to be intrinsic with transcriptional coregulator proteins that bind to steroid receptors (e.g. SRC-1 and PCAF). Changes in regulatory feedback loops for growth factors with prostate cancer progression tend toward shifts from paracrine to autocrine control where the receptor and ligand are produced by the same cell. While there are several examples of this progression pattern in prostate tumors such as with IGF, FGF, TGF-alpha and their respective receptors, the precise mechanism (i.e. epigenetic or mutational) is less certain. In the context of treatment options, the contribution of mutational versus epigenetic events to prostate cancer progression is an important consideration. Irreversible genetic changes are likely to be less amenable to therapeutic control than are epigenetic ones.
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PMID:Epigenetic mechanisms for progression of prostate cancer. 1045 84

Recent studies have shown that the p300/CREB binding protein (CBP)-associated factor (PCAF) is involved in transcriptional activation. PCAF activity has been shown strongly associated with histone acetyltransferase (HAT) activity. In this report, we present evidence for a HAT-independent transcription function that is activated in the presence of the human T-cell leukemia virus type 1 (HTLV-1) Tax protein. In vitro and in vivo GST-Tax pull-down and coimmunoprecipitation experiments demonstrate that there is a direct interaction between Tax and PCAF, independent of p300/CBP. PCAF can be recruited to the HTLV-1 Tax responsive element in the presence of Tax, and PCAF cooperates with Tax in vivo to activate transcription from the HTLV-1 LTR over 10-fold. Point mutations at Tax amino acid 318 (TaxS318A) or 319 to 320 (Tax M47), which have decreased or no activity on the HTLV-1 promoter, are defective for PCAF binding. Strikingly, the ability of PCAF to stimulate Tax transactivation is not solely dependent on the PCAF HAT domain. Two independent PCAF HAT mutants, which knock out acetyltransferase enzyme activity, activate Tax transactivation to approximately the same level as wild-type PCAF. In contrast, p300 stimulation of Tax transactivation is HAT dependent. These studies provide experimental evidence that PCAF contains a coactivator transcription function independent of the HAT activity on the viral long terminal repeat.
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PMID:PCAF interacts with tax and stimulates tax transactivation in a histone acetyltransferase-independent manner. 1056 39

We cloned cDNA encoding the chicken p46 polypeptide, chp46, homologous to the p48 subunit of chicken chromatin assembly factor-1, chCAF-1p48. It comprises 424 amino acids including a putative initiation Met, is a member of the WD protein family, with seven WD repeat motifs, and exhibits 90.3% identity to chCAF-1p48 and 94.3% identity to the human and mouse p46 polypeptides (hup46 and mop46). The in vitro immunoprecipitation experiment established that chp46 interacts with histones H2B and H4 and chicken histone acetyltransferase-1, chHAT-1, whereas hup46 interacts with histones H2A and H4 and chHAT-1 and chCAF-1p48 with histone H4 and chHAT-1. The in vitro immunoprecipitation experiment, involving truncated mutants of chp46, revealed not only that two regions comprising amino acids 33-179 and 375-404 are necessary for its binding to H2B, but also that two regions comprising amino acids 1-32 and 405-424 are necessary for its binding to H4. Furthermore, the GST pulldown affinity assay, involving truncated mutants of chp46, revealed that a region comprising amino acids 359-404 (in fact, 375-404) binds to chHAT-1 in vitro. Taken together, these results indicate not only that chp46 should participate differentially in a number of DNA-utilizing processes through interactions of its distinct regions with chHAT-1 and histones H2B and H4, but also that the proper propeller structure of chp46 is not necessary for its interaction with chHAT-1.
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PMID:Distinct regions of the chicken p46 polypeptide are required for its in vitro interaction with histones H2B and H4 and histone acetyltransferase-1. 1111 23

Endothelins exert their biological effects through G protein-coupled receptors. However, the precise mechanism of downstream signaling and trafficking of the receptors is largely unknown. Here we report that the histone acetyltransferase Tip60 and the histone deacetylase HDAC7 interact with one of the ET receptors, ETA, as determined by yeast two-hybrid analysis, glutathione S-transferase pull-down assays, and co-immunoprecipitation from transfected COS-7 cells. In the absence of ET-1, Tip60 and HDAC7 were localized mainly in the cell nucleus while ETA was predominantly confined to the plasma membrane. Stimulation with ET-1 resulted in the internalization of ETA to the perinuclear compartment and simultaneously in the efflux of Tip60 and HDAC7 from the nucleus to the same perinuclear compartment where each protein co-localized with the receptor. Upon co-transfection with ETA into COS-7 cells, Tip60 strongly increased ET-1-induced ERK1/2 phosphorylation, whereas HDAC7 had no significant effect. We thus suggest that protein acetylase and deacetylase interact with ETA in a ligand-dependent fashion and may participate in ET signal transduction.
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PMID:Tip60 and HDAC7 interact with the endothelin receptor a and may be involved in downstream signaling. 1126 86

Transcription factor GATA-4 plays critical roles in controlling heart development and cardiac hypertrophy. To understand how GATA-4 functions under diverse conditions, we sought to identify its coactivators. We tested p300 as a coactivator in GATA-4-dependent transient transcription assays in NIH3T3 cells and found that p300 synergistically activated GATA-4-dependent transcription on both synthetic and natural promoters. Direct physical interactions between the N- and C-zinc finger domains of GATA-4 and the cysteine/histidine-rich region 3 (C/H3) of p300 were identified in immunoprecipitation and glutathione S-transferase pull-down experiments. Deletion of the C/H3 region of p300 abolished its coactivator activity indicating that the physical interaction was required for functional synergy. Through the use of a series of GATA-4 zinc finger mutants, the amino acids WRR in the C finger were identified as critical to the interaction. The adenoviral E1A protein or a peptide encoding the C/H3 region of p300 could inhibit GATA-4-dependent transcription, presumably by competing for p300 binding. Furthermore, deletion of the region of p300 encoding the histone acetyltransferase activity abolished its effect on GATA-4-dependent transcriptional activity. These results establish that p300 acts as a GATA-4 coactivator and that the p300 histone acetyltransferase activity is necessary for the functional interaction.
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PMID:p300 Functions as a coactivator of transcription factor GATA-4. 1148 22

The rat mineralocorticoid receptor (MR) has two activation functions in distinct regions of the A/B domain, designated activation function 1a (AF-1a; amino acids 1 to 169) and AF-1b (amino acids 451 to 600). Since the p160 family protein TIF2, a known component of the AF-2 coactivator complex, potentiates the transactivation function of AF-1b but not that of AF-1a, it is likely that some other, novel protein complex interacts with the AF-1a region. Therefore, we attempted to identify such coactivator complexes from HeLa nuclear extracts by biochemical purification using a glutathione S-transferase-MR AF-1a fusion protein. Purified AF-1a region-interacting proteins were found to contain RNA helicase A (RHA) and CBP. Further analysis showed that RHA interacted with the AF-1a region directly and then recruited a complex with histone acetyltransferase (HAT) activity that contained CBP. For full-length MR, aldosterone, but not hydrocortisone, was found to induce the binding of RHA/CBP complexes to the AF-1a region, as well as to allow the cooperative potentiation of MR transcriptional activity by RHA and CBP. In addition, a chromatin immunoprecipitation assay showed that aldosterone-bound MR, but not hydrocortisone-bound MR, recruited RHA/CBP complexes to native MR target gene promoters. Our results suggested that an altered conformation of the A/B region induced by aldosterone, but not hydrocortisone, might determine the accessibility of MR AF-1a to RHA/CBP complexes.
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PMID:Ligand-selective potentiation of rat mineralocorticoid receptor activation function 1 by a CBP-containing histone acetyltransferase complex. 2450 61

The role played by histone acetyltransferase (HAT), GCN5, in transcriptional co-activation has been analysed in detail in yeast and mammals. Here, we present the cloning and expression pattern of Zmgcn5, the maize homologue. The enzymatic activity of the recombinant ZmGCN5 was analysed with histone and nucleosome substrates. In situ hybridisation of developing maize kernels using Zmgcn5 as probe shows that the transcript is concentrated in rapidly dividing cells. To investigate the role of ZmGCN5 in the transcription of specific plant genes, direct protein-protein interactions were tested. A cDNA clone encoding a putative interacting partner in GCN5-adapter complexes, ZmADA2, was isolated and the interaction between ZmGCN5 and ZmADA2 was confirmed by a GST-spin down experiment. Co-immunoprecipitation of the plant transcriptional activator Opaque-2 and ZmADA2 in nuclear extracts suggests ADA2/GCN5-containing complexes to mediate transcriptional activation by binding of this bZIP factor. For a more general analysis of the effects of histone acetylation on plant gene expression, 2500 ESTs spotted on filters were hybridised with cDNA probes derived either from maize cell lines treated with Trichostatin A (TSA), or from a transgenic line expressing the ZmGCN5 antisense transcript. Several sequences showing marked changes in abundance were confirmed by RNA blot analysis. Inhibition of histone deacetylation with TSA is accompanied by a decrease in the abundance of ZmGCN5 acetylase protein, but by increases in mRNAs for histones H2A, H2B, H3 and H4. The elevated histone mRNA levels were not reflected in increasing histone protein concentrations, suggesting hyperacetylated histones arising from TSA treatment may be preferentially degraded and substituted by de novo synthesised histones. The ZmGCN5 antisense material showed suppression of the endogenous ZmGCN5 transcript and the profiling analysis revealed increased mRNA levels for H2A, H2B and H4. Furthermore, in the antisense line, a reduction in the amount of the RPD3-type HD1B-I histone deacetylase protein was observed. A model for linked regulation of histone acetylation and histone mRNA transcription is discussed.
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PMID:Alteration of GCN5 levels in maize reveals dynamic responses to manipulating histone acetylation. 1258 4


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