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: UNIPROT:P51532 (transcriptional activator)
6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mammalian DNA is methylated at many CpG dinucleotides. The biological consequences of methylation are mediated by a family of methyl-CpG binding proteins. The best characterized family member is MeCP2, a transcriptional repressor that recruits histone deacetylases. Our report concerns MBD2, which can bind methylated DNA in vivo and in vitro and has been reported to actively demethylate DNA (ref. 8). As DNA methylation causes gene silencing, the MBD2 demethylase is a candidate transcriptional activator. Using specific antibodies, however, we find here that MBD2 in HeLa cells is associated with histone deacetylase (HDAC) in the MeCP1 repressor complex. An affinity-purified HDAC1 corepressor complex also contains MBD2, suggesting that MeCP1 corresponds to a fraction of this complex. Exogenous MBD2 represses transcription in a transient assay, and repression can be relieved by the deacetylase inhibitor trichostatin A (TSA; ref. 12). In our hands, MBD2 does not demethylate DNA. Our data suggest that HeLa cells, which lack the known methylation-dependent repressor MeCP2, use an alternative pathway involving MBD2 to silence methylated genes.
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PMID:MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. 1047 84

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) open reading frame 50 (ORF50) encodes a viral transcriptional activator, which binds to the KSHV promoter and stimulates the transcription of viral early and late genes, thus activating the lytic cycle of KSHV. We report here that KSHV ORF50 binds to the cellular proteins CREB-binding protein (CBP) and histone deacetylase (HDAC) and these binding events modulate ORF50-activated viral transcription. Binding of ORF50 to CBP and HDAC activates and represses, respectively, ORF50-mediated viral transcription. KSHV ORF50 was shown to bind to the C/H3 domain and the C-terminal transcriptional activation domain of CBP, while CBP bound to the amino-terminal basic domain and the carboxyl-terminal transactivation domain of ORF50. The LXXLL motif within the transcriptional activation domain of ORF50 is reminiscent of the CBP-binding sequence found in nuclear receptor proteins. The adenovirus E1A protein, which also binds to the C/H3 domain of CBP, repressed the transcriptional activation activity of ORF50. The cellular protein c-Jun, which binds to the kinase-induced activation domain of ORF50, stimulated ORF50-mediated viral transcription. The HDAC1-interacting domain of ORF50 was shown to be a central proline-rich sequence. Our data provide a framework for delineating the regulatory mechanisms used by KSHV to modulate its transcription and replication through interaction with both histone acetyltransferases and HDACs.
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PMID:CREB-binding protein and histone deacetylase regulate the transcriptional activity of Kaposi's sarcoma-associated herpesvirus open reading frame 50. 1116 Jun 90

The mSin3A corepressor complex contains 7 to 10 tightly associated polypeptides and is utilized by many transcriptional repressors. Much of the corepressor function of mSin3A derives from associations with the histone deacetylases HDAC1 and HDAC2; however, the contributions of the other mSin3A-associated polypeptides remain largely unknown. We have purified an mSin3A complex from K562 erythroleukemia cells and identified three new mSin3A-associated proteins (SAP): SAP180, SAP130, and SAP45. SAP180 is 40% identical to a previously identified mSin3A-associated protein, RBP1. SAP45 is identical to mSDS3, the human ortholog of the SDS3p component of the Saccharomyces cerevisiae Sin3p-Rpd3p corepressor complex. SAP130 does not have detectable homology to other proteins. Coimmunoprecipitation and gel filtration data suggest that the new SAPs are, at the very least, components of the same mSin3A complex. Each new SAP repressed transcription when tethered to DNA. Furthermore, repression correlated with mSin3A binding, suggesting that the new SAPs are components of functional mSin3A corepressor complexes. SAP180 has two repression domains: a C-terminal domain, which interacts with the mSin3A-HDAC complex, and an N-terminal domain, which functions independently of mSin3A-HDAC. SAP130 has a repression domain at its C terminus that interacts with the mSin3A-HDAC complex and an N-terminal domain that probably mediates an interaction with a transcriptional activator. Together, our data suggest that these novel SAPs function in the assembly and/or enzymatic activity of the mSin3A complex or in mediating interactions between the mSin3A complex and other regulatory complexes. Finally, all three SAPs bind to the HDAC-interaction domain (HID) of mSin3A, suggesting that the HID functions as the assembly interface for the mSin3A corepressor complex.
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PMID:Identification and characterization of three new components of the mSin3A corepressor complex. 1272 4

The switch from latent to lytic infection of Kaposi's sarcoma-associated herpesvirus is initiated by the immediate early transcriptional activator protein Rta/open reading frame 50 (ORF50). We examined the transcriptional regulation of the ORF50 core promoter in response to lytic cycle stimulation. We show that the ORF50 promoter is highly responsive to sodium butyrate (NaB) and trichostatin A (TSA), two chemicals known to inhibit histone deacetylases. The NaB and TSA responsive element was mapped to a 70-bp minimal promoter containing an essential GC box that binds Sp1/Sp3 in vitro and in vivo. Micrococcal nuclease mapping studies revealed that a nucleosome is positioned over the transcriptional initiation and the Sp1/3 binding sites. Stimulation with NaB or TSA increased histone acetylation and restriction enzyme accessibility of the ORF50 promoter transcription initiation site. Chromatin immunoprecipitation assay was used to demonstrate that the ORF50 promoter is associated with several different histone deacetylase proteins (including HDAC1, 5, and 7) in latently infected cells. NaB treatment led to the rapid association of Ini1/Snf5, a component of the Swi/Snf family of chromatin remodeling proteins, with the ORF50 promoter. Ectopic expression of the CREB-binding protein (CBP) histone acetyltransferase (HAT) stimulated plasmid-based ORF50 transcription in a HAT-dependent manner, suggesting that CBP recruitment to the ORF50 promoter can be an initiating event for transcription and viral reactivation. Together, these results suggest that remodeling of a stably positioned nucleosome at the transcriptional initiation site of ORF50 is a regulatory step in the transition from latent to lytic infection.
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PMID:Chromatin remodeling of the Kaposi's sarcoma-associated herpesvirus ORF50 promoter correlates with reactivation from latency. 1455 28

Post-translational modifications of proteins have critical roles in many cellular processes because they can cause rapid changes in the functions of preexisting proteins, multiprotein complexes and subcellular structures. Sumoylation, a ubiquitin-like dynamic and reversible post-translational modification system, is an enzymatic cascade leading to the covalent attachment of SUMO to it target proteins. This modification involves three steps and different enzymes: SUMO-activating enzyme E1 (SAE1/SAE2), SUMO-conjugating enzyme E2 (UBC9), SUMO ligases E3s, and SUMO cleaving enzymes. Although the identification of SUMO-modified substrates has progressed rapidly, the biological function of SUMO and regulation of SUMO conjugation are still not well understood. Some viral proteins have been identified as substrates for SUMO modification as well as altering the sumoylation status of host cell proteins. We have been studying an unusual adenoviral protein, Gam1, a strong and global transcriptional activator of both viral and cellular genes that inactivates HDAC1. We have recently expanded the known functions of Gam1 by demonstrating that Gam1 also inhibits the SUMO pathway by interfering with the activity of E1 heterodimer (SAE1/SAE2), leading to the accumulation of SUMO-unmodified substrates. Our data provides a clear example of the effects of a viral infection on host sumoylation and supports the idea that viruses have multifunctional protein that can target essential biochemical pathways.
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PMID:Gam1 and the SUMO pathway. 1587 61

PU.1, a hematopoietic Ets transcription factor, is required for development of the lymphoid and myeloid lineages. We have previously shown that PU.1 functions as both a transcriptional activator and repressor through complex formation with CBP/p300 and HDAC1/mSin3A/MeCP2, respectively. To determine whether modification of PU.1 is responsible for switching its association between co-activators and co-repressors, we examined whether acetylation regulates the physical and functional activities of PU.1. PU.1 was acetylated in vivo and its repressor activity was reduced when the putative acetylation motifs in the Ets domain were mutated. The mutant cooperated with CBP similar to wild type PU.1, but insufficiently with GATA-1 and mSin3A. Whereas overexpression of wild type PU.1 induced differentiation block, growth inhibition, and apoptotic cell death in MEL erythroleukemia cells as we reported previously, overexpression of the mutant-acetylation motif PU.1 did not. Taken together, our data suggest that acetylation might regulate the biological functions of PU.1 in erythroid cells.
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PMID:Impaired repressor activity and biological functions of PU.1 in MEL cells induced by mutations in the acetylation motifs within the ETS domain. 1609 14

The Myc/Max/Mad network of transcription factors regulates cell proliferation, differentiation, and transformation. Similar to other proteins of the network, Mnt forms heterodimers with Max and binds CACGTG E-Box elements. Transcriptional repression by Mnt is mediated through association with mSin3, and deletion of the mSin3-interacting domain (SID) converts Mnt to a transcriptional activator. Mnt is coexpressed with Myc in proliferating cells and has been suggested to be a modulator of Myc function. We report that Mnt is expressed both in growth-arrested and proliferating mouse fibroblasts and is phosphorylated when resting cells are induced to re-enter the cell cycle. Importantly, the interaction between Mnt and mSin3 is disrupted upon serum stimulation resulting in decreased Mnt-associated HDAC activity. Furthermore, we demonstrate that Mnt binds and recruits mSin3 to the Myc target gene cyclin D2 in quiescent mouse fibroblasts. Interference with Mnt expression by RNAi resulted in upregulation of cyclin D2 expression in growth-arrested fibroblasts, supporting the view that Mnt represses cyclin D2 transcription in quiescent cells. Our data suggest a model in which phosphorylation of Mnt at cell cycle entry results in disruption of Mnt-mSin3-HDAC1 interaction, which allows induction of Myc target genes by release of Mnt-mediated transcriptional repression.
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PMID:Mnt transcriptional repressor is functionally regulated during cell cycle progression. 1610 76

Heat shock factor 1 (HSF1), the transcriptional activator of the heat shock genes, is increasingly implicated in cancer. We have shown that HSF1 binds to the corepressor metastasis-associated protein 1 (MTA1) in vitro and in human breast carcinoma samples. HSF1-MTA1 complex formation was strongly induced by the transforming ligand heregulin and complexes incorporated a number of additional proteins including histone deacetylases (HDAC1 and 2) and Mi2alpha, all components of the NuRD corepressor complex. These complexes were induced to assemble on the chromatin of MCF7 breast carcinoma cells and associated with the promoters of estrogen-responsive genes. Such HSF1 complexes participate in repression of estrogen-dependent transcription in breast carcinoma cells treated with heregulin and this effect was inhibited by MTA1 knockdown. Repression of estrogen-dependent transcription may contribute to the role of HSF1 in cancer.
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PMID:Heat shock factor 1 represses estrogen-dependent transcription through association with MTA1. 1792 35

The peripheral nervous system is required for animals to detect and to relay environmental stimuli to central nervous system for the information processing. In Drosophila, the precise spatial and temporal expression of two proneural genes achaete (ac) and scute (sc), is necessary for development of the sensory organs. Here we present an evidence that the transcription co-repressor, dCtBP acts as a negative regulator of sensory organ prepattern. Loss of dCtBP function mutant exhibits ectopic sensory organs, while overexpression of dCtBP results in a dramatic loss of sensory organs. These phenotypes are correlated with mis-emerging of sensory organ precursors and perturbated expression of proneural transcription activator Ac. Mammalian CtBP-1 was identified via interaction with the consensus motif PXDLSX(K/R) of adenovirus E1A oncoprotein. We demonstrated that dCtBP binds directly to PLDLS motif of Drosophila Friend of GATA-1 protein, U-shaped and sharpens the adult sensory organ development. Moreover, we found that dCtBP mediates multivalent interaction with the GATA transcriptional activator Pannier and acts as a direct co-repressor of the Pannier-mediated activation of proneural genes. We demonstrated that Pannier genetically interacts with dCtBP-interacting protein HDAC1, suggesting that the dCtBP-dependent regulation of Pannier activity could utilize a repressive mechanism involving alteration of local chromatine structure.
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PMID:Drosophila C-terminal binding protein, dCtBP is required for sensory organ prepattern and sharpens proneural transcriptional activity of the GATA factor Pnr. 1877 87

It is becoming increasingly evident that histone deacetylases (HDACs) have a prominent role in the alteration of gene expression during the growth remodeling process of cardiac hypertrophy. HDACs are generally viewed as corepressors of gene expression. However, we demonstrate that class I and class II HDACs play an important role in the basal expression and up-regulation of the sodium calcium exchanger (Ncx1) gene in adult cardiomyocytes. Treatment with the HDAC inhibitor trichostatin A (TSA) prevented the pressure-overload-stimulated up-regulation of Ncx1 expression. Overexpression of HDAC5 resulted in the dose-dependent up-regulation of basal and alpha-adrenergic stimulated Ncx1 expression. We show that Nkx2.5 recruits HDAC5 to the Ncx1 promoter, where HDAC5 complexes with HDAC1. Nkx2.5 also interacts with transcriptional activator p300, which is recruited to the Ncx1 promoter. We demonstrate that when Nkx2.5 is acetylated, it is found associated with HDAC5, whereas deacetylated Nkx2.5 is in complex with p300. Notably, TSA treatment prevents p300 from being recruited to the endogenous Ncx1 promoter, resulting in the repression of Ncx1 expression. We propose a novel model for Ncx1 regulation in which deacetylation of Nkx2.5 is required for the recruitment of p300 and results in up-regulation of exchanger expression.
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PMID:Histone deacetylases facilitate sodium/calcium exchanger up-regulation in adult cardiomyocytes. 1963 1


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