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)

Kaposi's sarcoma-associated herpesvirus has been linked to Kaposi's sarcoma, body cavity-based lymphoma, and Castleman's disease. The Kaposi's sarcoma-associated herpesvirus genome contains a cluster of open reading frames encoding proteins (vIRFs) with homology to the cellular transcription factors of the interferon regulatory factor family. vIRF-3, also called LANA2, is a latently expressed nuclear protein. Here we demonstrate that vIRF-3 directly interacts with cellular interferon regulatory factor (IRF) IRF-3, IRF-7, and the transcriptional co-activator CBP/p300. The mapping of the vIRF-3 binding domain revealed that vIRF-3 associates with both IRF-3 and IRF-7 through its C-terminal region. The p300 domain, which interacts with vIRF-3, is distinct from the previously identified IBiD domain, to which both vIRF-1 and IRF-3 bind. Thus, in contrast to vIRF-1, vIRF-3 neither blocks the interaction between IRF-3 and p300 nor inhibits the histone acetylation. Although vIRF-3 is not a DNA-binding protein, it is recruited to the IFNA promoters via its interaction with IRF-3 and IRF-7. The presence of vIRF-3 in the enhanceosome assembled on the IFNA promoters increases binding of IRF-3, IRF-7, and acetylated histone H3 to this promoter region. Consequently, vIRF-3 stimulates the IRF-3- and IRF-7-mediated activation of type I interferon (IFNA and IFNB) genes and the synthesis of biologically active type I interferons in infected B cells. These studies illustrate that vIRF-3 and vIRF-1 have clearly distinct functions. In addition to its co-repressor activity, vIRF-3 can also act as a transcriptional activator on genes controlled by cellular IRF-3 and IRF-7.
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PMID:Kaposi's sarcoma-associated herpesvirus-encoded vIRF-3 stimulates the transcriptional activity of cellular IRF-3 and IRF-7. 1466 46

In eukaryotes, the switch between alternative developmental pathways is mainly attributed to a switch in transcriptional programs. A major mode in this switch is the transition between histone deacetylation and acetylation. In budding yeast, early meiosis-specific genes (EMGs) are repressed in the mitotic cell cycle by active deacetylation of their histones. Transcriptional activation of these genes in response to the meiotic signals (i.e., glucose and nitrogen depletion) requires histone acetylation. Here we follow how this regulated switch is accomplished, demonstrating the existence of two parallel mechanisms. (i) We demonstrate that depletion of glucose and nitrogen leads to a transient replacement of the histone deacetylase (HDAC) complex on the promoters of EMG by the transcriptional activator Ime1. The occupancy by either component occurs independently of the presence or absence of the other. Removal of the HDAC complex depends on the protein kinase Rim15, whose activity in the presence of nutrients is inhibited by protein kinase A phosphorylation. (ii) In the absence of glucose, HDAC loses its ability to repress transcription, even if this repression complex is directly bound to a promoter. We show that this relief of repression depends on Ime1, as well as on the kinase activity of Rim11, a glycogen synthase kinase 3beta homolog that phosphorylates Ime1. We further show that the glucose signal is transmitted through Rim11. In cells expressing the constitutive active rim11-3SA allele, HDAC repression in glucose medium is impaired.
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PMID:Glucose and nitrogen regulate the switch from histone deacetylation to acetylation for expression of early meiosis-specific genes in budding yeast. 1516 85

Copper is an essential cellular cofactor that becomes toxic at high levels. Copper homeostasis is tightly regulated by opposing mechanisms that control copper import, export, and copper binding capacity within the cell. High levels of copper induce the expression of metallothioneins, small sulfhydryl-rich proteins with high metal binding capabilities that serve as neutralizers of toxic levels of metals. In yeast, the CUP1 gene encodes a copper metallothionein that is strongly induced in response to metals and other stress and is subsequently rapidly down-regulated. Activation of CUP1 is mediated by the copper-responsive transcriptional activator AceI, and also requires the histone acetylase Spt10 for full induction. We have examined the role of histone H2A in the normal regulation of the CUP1 gene. We have shown that specific H2A mutations in combination with spt10 deletions result in aberrant regulation of CUP1 expression. Certain lysine mutations in H2A alleviate the transcriptional defect in spt10 Delta strains, though CUP1 activation is still delayed in these mutants; however, CUP1 shutdown is normal. In contrast, serine mutations in H2A prevent CUP1 shutdown when combined with spt10 deletions. In addition, swi/snf mutants exhibit both impaired CUP1 induction and failure to shut down CUP1 normally. Finally, different Spt10-dependent histone acetylation events correlate with induction and shutdown. Taken together, these data indicate that CUP1 transcriptional shutdown, like induction, is an active process controlled by the chromatin structure of the gene. These results provide new insights for the role of chromatin structure in metal homeostasis.
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PMID:Histone H2A and Spt10 cooperate to regulate induction and autoregulation of the CUP1 metallothionein. 1550 26

The Yersinia pestis plasmid pCD1-encoded type III secretion system (T3SS) is essential for the pathogenicity of Y. pestis in mammalian hosts. T3SS-associated genes are maximally expressed at 37 degrees C in the absence of extracellular calcium. Expression of T3SS genes requires LcrF, an AraC-like transcriptional activator, and is repressed by YmoA, a small histone-like protein. The mechanism by which temperature regulates T3SS gene expression has not been determined; however, changes in DNA topology have been implicated in this process. We report here that a Y. pestis strain deficient in production of the ClpXP and Lon proteases does not express a functional T3SS partly because of high cytosolic levels of YmoA. YmoA is rapidly degraded at 37 degrees C in wild-type Y. pestis, but remains stable in a clpXPlon deletion mutant. The stability of YmoA in wild-type Y. pestis increased as the growth temperature of the culture decreased; in contrast, YmoA was stable at all temperatures examined in the clpXPlon deletion mutant. These results indicate that the ClpXP and Lon proteases contribute to the environmental regulation of the Y. pestis T3SS system through regulated proteolysis of YmoA.
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PMID:The ATP-dependent ClpXP and Lon proteases regulate expression of the Yersinia pestis type III secretion system via regulated proteolysis of YmoA, a small histone-like protein. 1555 75

HTLV-I is a complex retrovirus that encodes a transcriptional activator, Tax, which regulates expression of the viral promoter. Tax has been shown to be both necessary and sufficient to effect immortalization and transformation of cells in culture and tumorigenesis in animal models. Tax exerts its influence through protein-protein interactions with a variety of molecular targets, including transcription factors and cofactors, histone modifying enzymes and post-translational modifying enzymes. Through these interactions, Tax disrupts cellular regulatory cascades and checkpoints designed to control a variety of systems. The result is untimely activation or repression of gene expression, inappropriate protein modifications, incorrect cell cycling, loss of adequate DNA repair capacity, and potential release of the cell from tumor suppression. Whereas for the virus these functions of Tax provide a means for successful completion of its life cycle, for the cell, they result at best in anarchy, and at worst in death of both the cell and the organism of which that cell is a part.
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PMID:The HTLV-I Tax oncoprotein: hyper-tasking at the molecular level. 1556 4

Histones are essential for packaging of eukaryotic genomic DNA in nucleosomes, and histone gene expression is normally coupled with DNA synthesis. Some of the flowering plant histone genes show strictly male gamete-specific expression. However, mechanisms underlying their male gamete-specific expression have not been elucidated so far. Here we report the isolation of the male gamete-specific histone gcH3 promoter from Lilium longiflorum and its activity in the male gametic cell of the flowering plant. The OCT motif, which is well conserved in plant histone promoters regulating S phase-specific expression, is not conserved in the gcH3 promoter. Instead sequence motifs identical to GC box 1 and GC box 2, the transcriptional activator and suppressor for mammalian testis-specific histone H1t, are present in the gcH3 promoter, suggesting that plants and animals share the mechanism which governs the specificity of gene expression in male gametic cells. Male gamete-specific activation of the gcH3 promoter has been confirmed by microprojectile bombardment in lily pollen. The sperm cell carrying gold particles showed reporter gene expression, while green fluorescent protein (GFP) was absent in the other sperm cell which had no particles, confirming that the gcH3 promoter is activated in the male gametic cell, and sperm cells have transcriptional and translational machinery that is independent of the vegetative cell of pollen.
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PMID:Transcriptional activity of male gamete-specific histone gcH3 promoter in sperm cells of Lilium longiflorum. 1575 44

Major insights into the regulation of chromatin organization have stemmed from biochemical studies using Gal4-VP16, a chimeric transcriptional activator in which the DNA binding domain of Gal4p is fused to the activation domain of viral protein VP16. Unexpectedly, given previous intensive efforts to understand how Gal4-VP16 functions in the context of chromatin, we have uncovered a new mode of chromatin reorganization that is dependent on Gal4-VP16. This reorganization is performed by an activity in a crude DEAE (CD) fraction from budding yeast which also supports ATP-dependent assembly of physiologically spaced nucleosome arrays. Biochemical analysis reveals that the activity tightly associates with chromatin and reorganizes nucleosome arrays by a mechanism which is insensitive to ATP depletion after nucleosome assembly. It generates a chromatin organization in which a nucleosome is stably positioned immediately adjacent to Gal4p binding sites in the template DNA. Individual deletion of genes previously implicated in chromatin assembly and remodeling, namely, the histone chaperones NAP1, ASF1, and CAC1 and the SNF2-like DEAD/H ATPases SNF2, ISW1, ISW2, CHD1, SWR1, YFR038w, and SPT20, does not significantly perturb reorganization. Therefore, Gal4-VP16-directed chromatin reorganization in yeast can occur by an ATP-independent mechanism that does not require SAGA, SWI/SNF, Isw1, or Isw2 chromatin remodeling complexes.
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PMID:Gal4-VP16 directs ATP-independent chromatin reorganization in a yeast chromatin assembly system. 1576 86

The transcriptional activator NF-Y is a heterotrimeric complex composed of NF-YA, NF-YB, and NF-YC, which specifically binds the CCAAT consensus present in about 30% of eukaryotic promoters. All three subunits contain evolutionarily conserved core regions, which comprise a histone fold motif (HFM) in the case of NF-YB and NF-YC. Our results of in vitro binding studies and nuclear import assays reveal two different transport mechanisms for NF-Y subunits. While NF-YA is imported by an importin beta-mediated pathway, the NF-YB/NF-YC heterodimer is translocated into the nucleus in an importin 13-dependent manner. We define a nonclassical nuclear localization signal (ncNLS) in NF-YA, and mutational analysis indicates that positively charged amino acid residues in the ncNLS are required for nuclear targeting of NF-YA. Importin beta binding is restricted to the monomeric, uncomplexed NF-YA subunit. In contrast, the nuclear import of NF-YB and NF-YC requires dimer formation. Only the NF-YB/NF-YC dimer, but not the monomeric components, are recognized by importin 13 and are imported into the nucleus. Importin 13 competes with NF-YA for binding to the NF-YB/NF-YC dimer. Our data suggest that a distinct binding platform derived from the HFM of both subunits, NF-YB/NF-YC, mediates those interactions.
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PMID:Subunits of the heterotrimeric transcription factor NF-Y are imported into the nucleus by distinct pathways involving importin beta and importin 13. 1596 92

Expression of the insulin gene is nearly exclusive to the beta cells of the pancreatic islets. Although the sequence-specific transcription factors that regulate insulin expression have been well studied, the interrelationship between these factors, chromatin structure, and transcriptional elongation by RNA polymerase II (pol II) has remained undefined. In this regard, recent studies have begun to establish a role for the methylation of histone H3 in the initiation or elongation of transcription by pol II. To determine a role for the transcriptional activator Pdx-1 in the maintenance of chromatin structure and pol II recruitment at the insulin gene, we performed small interfering RNA-mediated knockdown of Pdx-1 in betaTC3 cells and subsequently studied histone modifications and pol II recruitment by chromatin immunoprecipitation. We demonstrated here that the 50% fall in insulin transcription following knockdown of Pdx-1 is accompanied by a 60% fall in dimethylated histone H3-Lys-4 at the insulin promoter. H3-Lys-4 methylation at the insulin promoter may be mediated, at least partially, by the methyltransferase Set9. Immunohistochemical analysis revealed that Set9 is expressed in an islet-enriched pattern in the pancreas, similar to the pattern of Pdx-1 expression. The recruitment of Set9 to the insulin gene appears to be a consequence of its direct interaction with Pdx-1, and small interfering RNA-mediated knockdown of Set9 attenuates insulin transcription. Pdx-1 knockdown was also associated with an overall shift in the recruitment of pol II isoforms to the insulin gene, from an elongation isoform (Ser(P)-2) to an initiation isoform (Ser(P)-5). Our findings therefore suggest a model whereby Pdx-1 plays a novel role in linking H3-Lys-4 dimethylation and pol II elongation to insulin transcription.
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PMID:Pdx-1 links histone H3-Lys-4 methylation to RNA polymerase II elongation during activation of insulin transcription. 1614 Dec 9

Runx2 is an essential transcription factor for skeletal mineralization because it stimulates osteoblast differentiation of mesenchymal stem cells, promotes chondrocyte hypertrophy, and contributes to endothelial cell migration and vascular invasion of developing bones. Runx2 is also expressed during mouse embryo development in nascent mammary gland epithelium. Recent evidence implicates deregulation of Runx2 as a contributing factor in breast cancer-induced osteolysis and invasion, as well as in ectopic vascular calcification. Like other Runt domain proteins, Runx2 is a context-dependent transcriptional activator and repressor of genes that regulate cellular proliferation and differentiation. Proteins that temporally and spatially associate with Runx2 dictate these opposing transcriptional activities. Recent studies have identified several co-repressor proteins that bind to Runx2 to regulate gene expression. These co-factors include histone deacetylases (HDACs), transducin-like enhancer of split (TLE) proteins, mSin3a, and yes-associated protein (YAP). These proteins do not bind DNA themselves and appear to act by preventing Runx2 from binding DNA, altering chromatin structure, and/or by possibly blocking co-activator complexes. The nuclear localization of several of these factors is regulated by extracellular signaling events. Understanding the mechanisms whereby co-repressor proteins affect Runx2 activity during normal cellular development and tumor progression will identify new therapeutic targets for skeletal disorders such as osteoporosis and for bone metastatic cancers.
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PMID:Transcriptional co-repressors of Runx2. 1644 Mar 20


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