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)

This study shows that the iron-storage protein ferritin is a component of the redox-stress response in the obligate anaerobe Bacteroides fragilis. It is up-regulated at transcriptional level under aerobic conditions but constitutively expressed at low levels under anaerobic conditions. Northern hybridization and primer extension analysis revealed that ftnA is transcribed as a monocistronic mRNA of approximately 600 nt. Under reduced anaerobic conditions, ftnA mRNA levels were not dependent on the iron content of the culture medium. Following oxygen exposure ftnA message increased about 10-fold in iron-replete medium compared to a fourfold increase under low-iron conditions. Addition of the oxidant potassium ferricyanide induced expression of ftnA mRNA anaerobically, suggesting that the oxidation of the medium affected expression of ftnA. Two transcription initiation start sites were identified. Both transcripts were expressed constitutively under anaerobic conditions but one promoter was induced by oxidative stress or the addition of the oxidant potassium ferricyanide. The effect of redox stress on ftnA expression was further investigated by addition of diamide, a thiol-oxidizing agent, which induced ftnA mRNA levels anaerobically, suggesting that an unbalanced cellular redox state also affects ftnA expression. Induction by hydrogen peroxide and oxygen was decreased in an oxyR deletion mutant but some oxygen induction still occurred. This strongly suggests that ftnA is regulated by both the peroxide response transcriptional activator, OxyR, and another unidentified oxygen-dependent regulator. Taken together, these data show that ftnA mRNA levels are controlled by both iron and oxidative stress; this coordinated regulation may be important for survival in an adverse aerobic environment.
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PMID:Transcriptional regulation of the Bacteroides fragilis ferritin gene (ftnA) by redox stress. 1525 55

The SoxR protein of Escherichia coli responds to redox signals by activating the transcription of soxS, which encodes another transcription activator that directly stimulates oxidative stress genes. In contrast, Pseudomonas aeruginosa has an open reading frame (ORF) encoding a putative protein homologous to E. coli SoxR, but not to SoxS. Instead of a soxS homolog, ORFs encoding an unknown hypothetical protein and soxR are arranged divergently with their 5' ends separated by a 78 bp region containing a sequence homologous to the SoxR-binding soxS promoter. In this study, we report the overproduction and purification of SoxR from P. aeruginosa to investigate the mechanism of gene activation by SoxR. The spectroscopic properties of the purified SoxR protein indicate that it contains a redox active iron-sulfur [2Fe-2S] cluster. Redox titration of the SoxR protein revealed a midpoint potential of -290 mV. The SoxR protein specifically binds a fragment of the SoxS promoter-like region in a concentration-dependent fashion, as shown by both gel mobility shift and fluorescence polarization assays. The purified SoxR stimulates the in vitro transcription of the gene encoding the hypothetical protein in P. aeruginosa. This activity was lost following reduction of the SoxR [2Fe-2S] clusters. The levels of mRNA in the hypothetical protein increased in paraquat-treated cells. These results indicate that P. aeruginosa SoxR is a direct transcriptional activator of the hypothetical protein, and suggest that SoxR proteins may play multiple regulatory roles as a transcription factor in addition to its protective role in oxidative stress.
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PMID:Activation of SoxR-dependent transcription in Pseudomonas aeruginosa. 1563

Nitric oxide reduction in Ralstonia eutropha H16 is catalysed by the quinol-dependent NO reductase NorB. norB and the adjacent norA form an operon that is controlled by the sigma(54)-dependent transcriptional activator NorR in response to NO. A NorR derivative containing MalE in place of the N-terminal domain binds to a 73 bp region upstream of norA that includes three copies of the putative upstream activator sequence GGT-(N(7))-ACC. Mutations altering individual bases of this sequence resulted in an 80-90% decrease in transcriptional activation by wild-type NorR. Similar motifs are present in several proteobacteria upstream of genes encoding proteins of NO metabolism. The N-terminal domain of NorR contains a GAF module and is hypothesized to interact with a signal molecule. A NorR derivative lacking this domain activates the norAB promoter constitutively. Amino acid exchanges within the GAF module identified a cysteine residue that is essential for promoter activation by NorR. Signal sensing by NorR is negatively modulated by the iron-containing protein NorA.
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PMID:Transcriptional regulation of nitric oxide reduction in Ralstonia eutropha H16. 1566 4

Myo-inositol hexaphosphate (IP6, phytate) is a potent anti-nutritional compound occurring in many plant-based staple foods, limiting the bioavailability of important nutrients such as iron and zinc. The objective of the present study was to investigate different strategies to achieve high and constitutive extracellular IP6 degradation by Baker's yeast, Saccharomyces cerevisiae. By deleting either of the genes PHO80 and PHO85, encoding negative regulators of the transcription of the repressible acid phosphatases (rAPs), the IP6 degradation became constitutive, and the biomass specific IP6 degradation was increased manyfold. In addition, the genes encoding the transcriptional activator Pho4p and the major rAP Pho5p were overexpressed in both a wild-type and a pho80delta strain, yielding an additional increase in IP6 degradation. It has previously been proved possible to increase human iron bioavailability by degradation of IP6 using microbial phytase. A high-phytase S. cerevisiae strain, without the use of any heterologous DNA, may be a suitable organism for the production of food-grade phytase and for the direct use in food production.
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PMID:Improved extracellular phytase activity in Saccharomyces cerevisiae by modifications in the PHO system. 1647 97

Adaptation to low oxygen tension (hypoxia) in cells and tissues leads to the transcriptional induction of a series of genes that participate in angiogenesis, iron metabolism, glucose metabolism, and cell proliferation/survival. The primary factor mediating this response is the hypoxia-inducible factor-1 (HIF-1), an oxygen-sensitive transcriptional activator. HIF-1 consists of a constitutively expressed subunit HIF-1beta and an oxygen-regulated subunit HIF-1alpha (or its paralogs HIF-2alpha and HIF-3alpha). The stability and activity of the alpha subunit of HIF are regulated by its post-translational modifications such as hydroxylation, ubiquitination, acetylation, and phosphorylation. In normoxia, hydroxylation of two proline residues and acetylation of a lysine residue at the oxygen-dependent degradation domain (ODDD) of HIF-1alpha trigger its association with pVHL E3 ligase complex, leading to HIF-1alpha degradation via ubiquitin-proteasome pathway. In hypoxia, the HIF-1alpha subunit becomes stable and interacts with coactivators such as cAMP response element-binding protein binding protein/p300 and regulates the expression of target genes. Overexpression of HIF-1 has been found in various cancers, and targeting HIF-1 could represent a novel approach to cancer therapy.
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PMID:Hypoxia-inducible factor-1 (HIF-1). 1688 34

Heme oxygenase-1 (HO-1) degrades heme into biliverdin, iron and CO. The enzyme participates in adaptive and protective responses to oxidative stress and various inflammatory stimuli, and is induced in response to reactive oxygen species (ROS). 2',7'-Dichlorodihydrofluorescin diacetate (DCFH-DA) is a common reagent used to detect ROS by the oxidation of 2',7'-dichlorodihydrofluorescin (DCFH) to fluorescent dichlorodihydrofluorescein. We previously found that rapid oxidation of DCFH occurred with heme-compounds as well as ROS [Ohashi, T. et al. (2002) FEBS Lett. 511, 21-27], and then examined the effect of DCFH-DA on the induction of HO-1 expression by arsenite, cadmium and hemin, which induce oxidative stress and cytotoxicity. We found suppression of the arsenite-, cadmium- and hemin-dependent induction of HO-1 with DCFH-DA. The suppression occurred at the transcriptional level since the promoter activity of the Maf-recognition site of the HO-1 gene decreased with the DCFH-DA treatment. DCFH abolished the phosphorylation of extracellular signal-regulated kinase, the nuclear translocation of a transcriptional activator Nrf2, and cell death. An antioxidant, N-acetylcysteine (NAC), also suppressed the induction by arsenite and cadmium, but not that by hemin, indicating that DCFH blocked a different site in the stress signal pathway from NAC. Considering that the oxidation of DCFH diminishes ROS generated by various stressors, our findings provide a potential strategy for protection of cells from toxic insults using DCFH-like molecules.
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PMID:The antioxidant role of a reagent, 2',7'-dichlorodihydrofluorescin diacetate, detecting reactive-oxygen species and blocking the induction of heme oxygenase-1 and preventing cytotoxicity. 1695 97

In Ralstonia eutropha H16, the nitric oxide (NO)-responsive transcriptional activator NorR controls the expression of a dicistronic operon that encodes a membrane-bound NO reductase, NorB, and a protein of unknown function, NorA. The N-terminal domain (NTD) of NorR is responsible for perception of the signal molecule, nitric oxide. Thirteen out of 29 conserved residues of the NTD were exchanged by site-directed mutagenesis. Replacement of R63, R72, D93, D96, C112, D130, or F137 strongly decreased NorR-dependent promoter activation, while the exchange of Y95 or H110 led to an increase in promoter activity compared to that of the wild type. A purified truncated NorR comprising only the NTD (NorR-NTD) contained one iron atom per molecule and was able to bind NO in the as-isolated state. Based on the iron content of NorR-NTD proteins with single amino acid replacements, residues R72, D93, D96, C112, and D130 are likely candidates for iron ligands. Residues R63, Y95, and H110 appear not to be involved in NO binding but may take part in subsequent steps of the signal transduction mechanism of NorR.
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PMID:Characterization of the signaling domain of the NO-responsive regulator NorR from Ralstonia eutropha H16 by site-directed mutagenesis. 1727 50

CooA is a CO-dependent transcriptional activator and transmits a CO-sensing signal to a DNA promoter that controls the expression of the genes responsible for CO metabolism. CooA contains a b-type heme as the active site for sensing CO. CO binding to the heme induces a conformational change that switches CooA from an inactive to an active DNA-binding form. Here, we report the crystal structure of an imidazole-bound form of CooA from Carboxydothermus hydrogenoformans (Ch-CooA). In the resting form, Ch-CooA has a six-coordinate ferrous heme with two endogenous axial ligands, the alpha-amino group of the N-terminal amino acid and a histidine residue. The N-terminal amino group of CooA that is coordinated to the heme iron is replaced by CO. This substitution presumably triggers a structural change leading to the active form. The crystal structure of Ch-CooA reveals that imidazole binds to the heme, which replaces the N terminus, as does CO. The dissociated N terminus is positioned approximately 16 A from the heme iron in the imidazole-bound form. In addition, the heme plane is rotated by 30 degrees about the normal of the porphyrin ring compared to that found in the inactive form of Rhodospirillum rubrum CooA. Even though the ligand exchange, imidazole-bound Ch-CooA remains in the inactive form for DNA binding. These results indicate that the release of the N terminus resulting from imidazole binding is not sufficient to activate CooA. The structure provides new insights into the structural changes required to achieve activation.
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PMID:Crystal structure of CO-sensing transcription activator CooA bound to exogenous ligand imidazole. 1729 14

Iron is both essential for bacterial growth and toxic at higher concentrations; thus, iron homeostasis is tightly regulated. In Neisseria meningitidis the majority of iron-responsive gene regulation is mediated by the ferric uptake regulator protein (Fur), a protein classically defined as a transcriptional repressor. Recently, however, microarray studies have identified a number of genes in N. meningitidis that are iron and Fur activated, demonstrating a new role for Fur as a transcriptional activator. Since Fur has been shown to indirectly activate gene transcription through the repression of small regulatory RNA molecules in other organisms, we hypothesized that a similar mechanism could account for Fur-dependent, iron-activated gene transcription in N. meningitidis. In this study, we used a bioinformatics approach to screen for the presence of Fur-regulated small RNA molecules in N. meningitidis MC58. This screen identified one small RNA, herein named NrrF (for neisserial regulatory RNA responsive to iron [Fe]), which was demonstrated to be both iron responsive and Fur regulated and which has a well-conserved orthologue in N. gonorrhoeae. In addition, this screen identified a number of other likely, novel small RNA transcripts. Lastly, we utilized a new bioinformatics approach to predict regulatory targets of the NrrF small RNA. This analysis led to the identification of the sdhA and sdhC genes, which were subsequently demonstrated to be under NrrF regulation in an nrrF mutant. This study is the first report of small RNAs in N. meningitidis and the first to use a bioinformatics approach to identify, a priori, regulatory targets of a small RNA.
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PMID:A novel fur- and iron-regulated small RNA, NrrF, is required for indirect fur-mediated regulation of the sdhA and sdhC genes in Neisseria meningitidis. 1735 Oct 36

Monothiol glutaredoxins with the CGFS sequence at the active site are widespread among prokaryotes and eukaryotes. Two subclasses exist, those with a single glutaredoxin domain and those with a thioredoxin-like region followed by one or more glutaredoxin domains. Studies in Saccharomyces cerevisiae have demonstrated the role of the Grx5 protein in the biogenesis of iron-sulfur clusters. Grx5 homologues in other eukaryotes could carry out similar functions. Two S. cerevisiae monothiol glutaredoxins with the thioredoxin-like extension, Grx3 and Grx4, are modulators of the transcriptional activator Aft1, which regulates iron uptake in yeast. The human PICOT protein is a Grx3/Grx4 homologue with the same hybrid primary structure that regulates protein kinase C activity and may participate in physiological processes such as control of cardiac function. Therefore, monothiol glutaredoxins share a common basic structural motif and biochemical mechanism of action, while participating in a diversity of cellular functions as protein redox regulators.
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PMID:Monothiol glutaredoxins: a common domain for multiple functions. 1741 23


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