Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AfsR is a pleiotropic, global regulator that controls the production of actinorhodin, undecylprodigiosin and calcium-dependent antibiotic in Streptomyces coelicolor A3(2). AfsR, with 993 amino acids, is phosphorylated on serine and threonine residues by a protein serine/threonine kinase AfsK and contains an OmpR-like DNA-binding fold at its N-terminal portion and A- and B-type nucleotide-binding motifs in the middle of the protein. The DNA-binding domain, in-dependently of the nucleotide-binding domain, contributed the binding of AfsR to the upstream region of afsS that locates immediately 3' to afsR and encodes a 63-amino-acid protein. No transcription of afsS in the DeltaafsR background and restoration of afsS transcription by afsR on a plasmid in the same genetic background indicated that afsR served as a transcriptional activator for afsS. Interestingly, the AfsR binding site overlapped the promoter of afsS, as determined by DNase I protection assay and high-resolution S1 nuclease mapping. The nucleotide-binding domain contributed distinct ATPase and GTPase activity. The phosphorylation of AfsR by AfsK greatly enhanced the DNA-binding activity and modulated the ATPase activity. The DNA-binding ability of AfsR was independent of the ATPase activity. However, the ATPase activity was essential for transcriptional activation of afsS, probably because the energy available from ATP hydrolysis is required for the isomerization of the closed complex between AfsR and RNA polymerase to a transcriptionally competent open complex. Thus, AfsR turns out to be a unique transcriptional factor, in that it is modular, in which DNA-binding and ATPase activities are physically separable, and the two functions are modulated by phosphorylation on serine and threonine residues.
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PMID:afsS is a target of AfsR, a transcriptional factor with ATPase activity that globally controls secondary metabolism in Streptomyces coelicolor A3(2). 1195 95

Expression of the Pseudomonas aeruginosa type III secretion system is induced by contact with eukaryotic cells, serum or low Ca2+ concentrations. We report that ExsD, a unique protein, is a negative regulator of the type III regulon. Localization studies indicate that ExsD is not secreted by P. aeruginosa. To determine the role of exsD, a non-polar deletion was returned to the chromosome by allelic exchange. The delta exsD mutant is competent for type III secretion and translocation of the ExoU cytotoxin to eukaryotic host cells. To examine the effect of ExsD on transcription, lacZ transcriptional reporter fusions were integrated into the chromosome. Promoters controlling transcription of genes encoding the type III secretory, regulatory and effector proteins demonstrated significant derepression in the delta exsD background. Expression of ExsD from a multicopy plasmid completely repressed transcription of the regulon. Although a mutant in pscC, encoding a structural component of the type III translocase, is repressed for expression of the regulon, a delta exsD, pscC:: omega double mutant is derepressed. Bacterial two-hybrid data indicate that ExsD binds the transcriptional activator of the regulon, ExsA. We conclude that ExsD is a negative regulator and propose that ExsD functions as an ExsA antiactivator to regulate transcription of the regulon.
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PMID:ExsD is a negative regulator of the Pseudomonas aeruginosa type III secretion regulon. 1242 16

Skeletal muscle adapts to different patterns of motor nerve activity by alterations in gene expression that match specialized properties of contraction, metabolism, and muscle mass to changing work demands (muscle plasticity). Calcineurin, a calcium/calmodulin-dependent, serine-threonine protein phosphatase, has been shown to control programs of gene expression in skeletal muscles, as in other cell types, through the transcription factor nuclear factor of activated T cells (NFAT). This study provides evidence that the function of NFAT as a transcriptional activator is regulated by neuromuscular stimulation in muscles of intact animals and that calcium influx from the transient receptor potential (TRPC3) channel is an important determinant of NFAT activity. Expression of TRPC3 channels in skeletal myocytes is up-regulated by neuromuscular activity in a calcineurin-dependent manner. These data suggest a mechanism for cellular memory in skeletal muscles whereby repeated bouts of contractile activity drive progressively greater remodeling events.
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PMID:TRPC3 channels confer cellular memory of recent neuromuscular activity. 1519 80

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

Calmodulin (CaM), a ubiquitous calcium-binding protein, regulates diverse cellular functions by modulating the activity of a variety of enzymes and proteins. Plants express numerous CaM isoforms that exhibit differential activation and/or inhibition of CaM-dependent enzymes in vitro. However, the specific biological functions of plant CaM are not well known. In this study, we isolated a cDNA encoding a CaM binding transcription factor, MYB2, that regulates the expression of salt- and dehydration-responsive genes in Arabidopsis. This was achieved using a salt-inducible CaM isoform (GmCaM4) as a probe from a salt-treated Arabidopsis expression library. Using domain mapping, we identified a Ca2+-dependent CaM binding domain in MYB2. The specific binding of CaM to CaM binding domain was confirmed by site-directed mutagenesis, a gel mobility shift assay, split ubiquitin assay, and a competition assay using a Ca2+/CaM-dependent enzyme. Interestingly, the specific CaM isoform GmCaM4 enhances the DNA binding activity of AtMYB2, whereas this was inhibited by a closely related CaM isoform (GmCaM1). Overexpression of Gm-CaM4 in Arabidopsis up-regulates the transcription rate of AtMYB2-regulated genes, including the proline-synthesizing enzyme P5CS1 (Delta1-pyrroline-5-carboxylate synthetase-1), which confers salt tolerance by facilitating proline accumulation. Therefore, we suggest that a specific CaM isoform mediates salt-induced Ca2+ signaling through the activation of an MYB transcriptional activator, thereby resulting in salt tolerance in plants.
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PMID:Direct interaction of a divergent CaM isoform and the transcription factor, MYB2, enhances salt tolerance in arabidopsis. 1556 82

The Streptomyces produce a plethora of secondary metabolites including antibiotics and undergo a complex developmental cycle. As a means of establishing the pathways that regulate secondary metabolite production by this important bacterial genus, the model species Streptomyces coelicolor and its relatives have been the subject of several genetic screens. However, despite the identification and characterization of numerous genes that affect antibiotic production, there is still no overall understanding of the network that integrates the various environmental and growth signals to bring about changes in the expression of biosynthetic genes. To establish new links, we are taking a biochemical approach to identify transcription factors that regulate antibiotic production in S. coelicolor. Here we describe the identification and characterization of a transcription factor, designated AtrA, that regulates transcription of actII-ORF4, the pathway-specific activator of the actinorhodin biosynthetic gene cluster in S. coelicolor. Disruption of the corresponding atrA gene, which is not associated with any antibiotic gene cluster, reduced the production of actinorhodin, but had no detectable effect on the production of undecylprodigiosin or the calcium-dependent antibiotic. These results indicate that atrA has specificity with regard to the biosynthetic genes it influences. An orthologue of atrA is present in the genome of Streptomyces avermitilis, the only other streptomycete for which there is a publicly available complete sequence. We also show that S. coelicolor AtrA can bind in vitro to the promoter of strR, a transcriptional activator unrelated to actII-ORF4 that is the final regulator of streptomycin production in Streptomyces griseus. These findings provide further evidence that the path leading to the expression of pathway-specific activators of antibiotic biosynthesis genes in disparate Streptomyces may share evolutionarily conserved components in at least some cases, even though the final activators are not related, and suggests that the regulation of streptomycin production, which serves an important paradigm, may be more complex than represented by current models.
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PMID:Transcriptional activation of the pathway-specific regulator of the actinorhodin biosynthetic genes in Streptomyces coelicolor. 1616 54

The type III secretion system (TTSS) of Pseudomonas aeruginosa is induced in vivo upon contact with eukaryotic cells and in vitro by calcium depletion in culture medium. We have observed a previously identified protein, PsrA, necessary for full activation of TTSS gene expression in P. aeruginosa. Electrophoretic mobility shift assays showed that recombinant PsrA could bind to the exsCEBA promoter region. A mutant with a deletion in the psrA gene was constructed. Using transcriptional fusions, we demonstrated that PsrA is required for the full activation of transcription of the TTSS regulatory operon exsCEBA and effector exoS, although the deletion mutant still responded to calcium depletion, to serum, and to host cell contact. The psrA mutant showed a marked decrease in the secretion of the type III effectors and weak resistance to phagocyte-like PLB-985 cells. The defect in TTSS transcription and secretion in the psrA mutant could be complemented by expression in trans of psrA. PsrA was previously identified as a transcriptional activator of RpoS, a central regulator during stationary phase. We confirmed with our strain that RpoS has a negative effect on TTSS gene expression. Taken altogether, these results suggest that PsrA is a newly identified activator that is involved in the expression of the TTSS by enhancing the exsCEBA transcriptional level.
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PMID:PsrA is a positive transcriptional regulator of the type III secretion system in Pseudomonas aeruginosa. 1642 60

A significant number of human immunodeficiency virus type 1 (HIV-1)-infected patients are alcoholics. Either alcohol or HIV alone induces morphological and functional damage to the nervous system. HIV-1 Tat is a potent transcriptional activator of the viral promoter, with the ability to modulate a number of cellular regulatory circuits including apoptosis and to cause neuronal injury. To further evaluate the involvement of alcohol in neuronal injury, the authors examined the effect of ethanol on Tat-induced calcium responses in rat cerebral cortical neurons, using microfluorimetric calcium determination. HIV Tat protein (10 or 500 nM) elicited two types of calcium responses in cortical neurons: a fast-onset, short-lasting response and a slow-onset, sustained response. The responses were concentration-dependent and diminished in calcium-free saline. A short exposure to ethanol (50 mM) potentiated both types of calcium response, which was markedly decreased when the cells were pretreated with BAPTA-AM (20 microM). In addition, an increase in the neurotoxic effect of Tat, which was assessed by trypan blue exclusion assay, was observed. The result led the authors to conclude that alcohol exposure significantly potentiates Tat-induced calcium overload and neuronal death.
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PMID:Acute exposure to ethanol potentiates human immunodeficiency virus type 1 Tat-induced Ca(2+) overload and neuronal death in cultured rat cortical neurons. 1659 70

Regulation of Col2a1 is a key event in the cartilage development. Many factors including cell adhesion, hypoxia, growth factors or cytokines regulate various transcription factors or co-factors which influence the expression of Col2a1. Sox9 is a key transcriptional activator that is involved in most of these events by cooperating or interfering with these factors. The balance of positive and negative regulators determines the level of matrix gene expression.
Clin Calcium 2006 Jul
PMID:[Matrix gene regulation in cartilage]. 1681 84

Expression of the Pseudomonas aeruginosa type III secretion system (T3SS) is induced by calcium depletion and is positively regulated by the ExsA transcriptional activator and negatively regulated by the ExsD antiactivator. Under conditions permissive for expression of the T3SS, the negative regulatory activity of ExsD is antagonized by a direct binding interaction with ExsC. In the present study, the ExsC-ExsD binding interaction was characterized. Individually, both ExsC and ExsD form self-associated complexes, as judged by bacterial monohybrid and gel filtration experiments. A mixture of purified ExsC and ExsD readily formed a complex that elutes from gel filtration medium as a single included peak. The calculated molecular weight of the ExsC-ExsD complex is consistent with a complex containing multiple copies of ExsC and ExsD. Isothermic titration calorimetry experiments found formation of the ExsC-ExsD complex to be thermodynamically favorable, with a Kd of approximately 18 nM and a likely binding ratio of 1:1. To identify amino acid residues important for the regulatory activities of ExsC and ExsD, self-association, and complex formation, charged-cluster mutagenesis was performed. Two of the resulting ExsD charged-cluster mutants (DM2 and DM3) demonstrated a hyperrepressive phenotype for expression of the T3SS. By two-hybrid and copurification assays, the DM3 mutant was found to be impaired in its interaction with ExsC. This finding demonstrates that the binding of ExsC to ExsD is required for transcriptional induction of the T3SS under calcium-limiting growth conditions.
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PMID:Characterization of ExsC and ExsD self-association and heterocomplex formation. 1698 Apr 86


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