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)

Hypoxia-inducible factor 1 (HIF-1) is an oxygen-regulated transcriptional activator that plays essential roles in mammalian development, physiology and disease pathogenesis. The HIF-1 alpha subunit is subjected to oxygen-dependent ubiquitination and proteasomal degradation that is mediated by the von Hippel-Lindau protein. Interaction of HIF-1 alpha transactivation domains with coactivators is induced by hypoxia. The signal transduction pathway remains enigmatic, but involves generation of reactive oxygen species. Nitric oxide induces HIF-1 alpha under non-hypoxic conditions but inhibits hypoxia-induced HIF-1 alpha expression.
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PMID:HIF-1 and mechanisms of hypoxia sensing. 1124 50

The mutagenicity of three nitric oxide (NO) donors, 3-morpholinosydnonimine (SIN-1), a compound generating the precursors of peroxynitrite NO and superoxide, diethylamine/NO (DEA/NO) and spermine/NO (SPER/NO), both releasing authentic NO was analyzed using Escherichia coli tester strains IC203, carrying a deletion of the oxyR gene, and its oxyR(+) parent IC188 (the alternative name of WP2 uvrA/pKM101). The OxyR protein is a redox-sensitive transcriptional activator of genes encoding antioxidant enzymes. Strains IC203 and IC188 contain error-prone DNA polymerases polV, encoded by the chromosomal umuDC genes, and polRI, encoded by mucAB genes carried by pKM101. SIN-1 was determined to be an oxidative mutagen giving a positive response only in IC203, whereas DEA/NO and SPER/NO induced similar positive responses in IC203 and IC188 and were considered as non-oxidative mutagens. The spectrum of ochre suppressors in Trp(+) revertants induced by SIN-1 in IC203 was characterized by a higher number of TA-->AT transversions and GC-->AT transitions, and a lower number of GC-->TA transversions, with respect to the untreated control. The mutagenicity of SIN-1 in IC203, probably induced by peroxynitrite through reactive derivatives, was enhanced in the presence of plumbagin (PLB), a superoxide generator. Superoxide generation by PLB, as well as formation of peroxynitrite in cells treated with SIN-1, evaluated by monitoring the oxidation, respectively, of dihydroethidium and dihydrorhodamine 123, were greater in IC203 than in IC188. Formation of peroxynitrite in IC203 treated with SIN-1 was stimulated by PLB. After treatment with DEA/NO and SPER/NO the number of revertants scored in IC188 was higher than in strains IC187, containing only polV, and IC204, deficient in both polV and polRI. For these compounds, induced suppressor revertants in IC187 and IC204 were almost exclusively GC-->AT transitions, whereas in IC188 significant levels of GC-->TA and TA-->AT transversions were also induced. Mutagenesis by both DEA/NO and SPER/NO was partially inhibited in the presence of PLB. The results show the usefulness of the new tester strain IC203 to differentiate NO-promoted mutagenic mechanisms that involve or do not involve oxygen radicals.
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PMID:Mutagenicity of nitric oxide-releasing compounds in Escherichia coli: effect of superoxide generation and evidence for two mutagenic mechanisms. 1152 19

Escherichia coli flavorubredoxin is a new type of cytoplasmic nitric oxide (NO) reductase, which shows NO reductase activity within the range of the canonical membrane-bound heme b(3)-iron NO reductases. Using reverse-transcription polymerase chain reaction we show that although the flavorubredoxin gene (flrd) is transcribed in both aerobic and anaerobic conditions, anaerobiosis induced transcription up to 12-fold, under fermentative conditions; a 28-fold stimulation was observed in an E. coli fnr mutant strain, showing that the flavorubredoxin gene is negatively regulated by FNR. The level of anaerobic transcription was repressed three-fold by nitrate, but induced 47-fold by nitrite. The transcription factors NarL and NarP are not essential for flrd expression. Furthermore, the addition of NO within the physiological range of concentrations does not induce anaerobic transcription of flrd. Since two other E. coli proteins are known to exhibit NO reductase activity, flavohemoglobin and the pentaheme cytochrome c nitrite reductase, we have also compared the concentrations of their mRNAs with those of flavorubredoxin, under the same growth conditions. Transcription of the putative transcriptional activator of flavorubredoxin, ygaA, is also regulated by the absence of oxygen and the presence of nitrite. Levels of FlRd protein did not correlate with mRNA levels. The results reveal that a complex regulation of flavorubredoxin expression is operative, possibly by both transcriptional and post-transcriptional mechanisms.
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PMID:Regulation of the flavorubredoxin nitric oxide reductase gene in Escherichia coli: nitrate repression, nitrite induction, and possible post-transcription control. 1258 21

NnrR, a transcriptional activator and member of the CRP/FNR family of regulators, is responsible for controlling the expression of a number of denitrification genes in Rhodobacter sphaeroides 2.4.3. The apparent effector for NnrR is nitric oxide, and in its presence NnrR activates expression of the nirK gene and the nor operon, encoding nitrite reductase and nitric oxide reductase, respectively. Whether nitric oxide directly interacts with NnrR to activate transcription is unknown. Other denitrifiers carry putative orthologs of NnrR. To gain insight into NnrR function, a number of conserved residues were mutagenized. The impact of these changes on NnrR function was assessed by monitoring expression of a nirK-lacZ fusion. In this way a region spanning from Tyr93 to Cys103 that contains residues critical for NnrR activity was identified.
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PMID:Site-directed mutagenesis of NnrR: a transcriptional regulator of nitrite and nitric oxide reductase in Rhodobacter sphaeroides. 1468 Jun 95

Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator that functions as a master regulator of cellular and systemic oxygen homeostasis. It consists of two constitutively produced subunits: HIF-1alpha and HIF-1beta. Under normoxic conditions HIF-1alpha undergoes hydroxylation at specific prolyl residues which leads to an immediate ubiquitination and subsequent proteasomal degradation of the alpha subunit. Additionally, hydroxylation of an asparaginyl residue blocks the transcriptional activity of HIF-1 due to inhibition of its interaction with co-activators. In contrast, under hypoxic conditions, abolition of prolyl hydroxylation results in HIF-1alpha stabilization, whereas the lack of asparaginyl hydroxylation allows the transcriptional activity. Additionally, the transcriptional activity may be modulated by phosphorylation or redox modification of HIF-1. Despite its name, HIF-1 is induced not only in response to reduced oxygen availability but also by other stimulants, such as nitric oxide, various growth factors, or direct inhibitors of prolyl and asparaginyl hydroxylases. Therefore, it seems to be a crucial transcription factor elicited by a wide range of stresses such as impaired oxygenation, inflammation, energy deprivation, or intensive proliferation. However, the mechanisms of normoxic activation, as well as of oxygen sensing, are not yet fully known. Further understanding of the processes that control HIF-1 activity will be crucial for the development of new diagnostic and therapeutic strategies.
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PMID:HIF-1: the knowns and unknowns of hypoxia sensing. 1544 22

Transglutaminase 2 (TGase 2) expression is increased in inflammatory diseases. We demonstrated previously that inhibitors of TGase 2 reduce nitric oxide (NO) generation in a lipopolysaccharide (LPS)-treated microglial cell line. However, the precise mechanism by which TGase 2 promotes inflammation remains unclear. We found that TGase 2 activates the transcriptional activator nuclear factor (NF)-kappaB and thereby enhances LPS-induced expression of inducible nitric-oxide synthase. TGase 2 activates NF-kappaB via a novel pathway. Rather than stimulating phosphorylation and degradation of the inhibitory subunit alpha of NF-kappaB (I-kappaBalpha), TGase2 induces its polymerization. This polymerization results in dissociation of NF-kappaB and its translocation to the nucleus, where it is capable of up-regulating a host of inflammatory genes, including inducible nitric-oxide synthase and tumor necrosis factor alpha (TNF-alpha). Indeed, TGase inhibitors prevent depletion of monomeric I-kappaBalpha in the cytosol of cells overexpressing TGase 2. In an LPS-induced rat brain injury model, TGase inhibitors significantly reduced TNF-alpha synthesis. The findings are consistent with a model in which LPS-induced NF-kappaB activation is the result of phosphorylation of I-kappaBalpha by I-kappaB kinase as well as I-kappaBalpha polymerization by TGase 2. Safe and stable TGase2 inhibitors may be effective agents in diseases associated with inflammation.
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PMID:Transglutaminase 2 induces nuclear factor-kappaB activation via a novel pathway in BV-2 microglia. 1547 61

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

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

During antidiuresis, renal medullary cells adapt to the hyperosmotic interstitial environment by increased expression of osmoprotective genes, which is driven by a common transcriptional activator, tonicity-responsive enhancer binding protein (TonEBP). Because nitric oxide (NO) is abundantly produced in the renal medulla, the present studies addressed the effect of NO on expression of osmoprotective genes and TonEBP activation in MDCK cells. Several structurally unrelated NO donors blunted tonicity-induced up-regulation of TonEBP target genes involved in intracellular accumulation of organic osmolytes. These effects were mediated by reduced transcriptional activity of TonEBP, as assessed by tonicity-responsive elements- and aldose reductase promoter-driven reporter constructs. Neither total TonEBP abundance nor nuclear translocation of TonEBP was affected by NO. Furthermore, 8-bromo-cGMP and peroxynitrite failed to reproduce the inhibitory effect of NO, indicating that NO acts directly on TonEBP rather than through classical NO signaling pathways. In support of this notion, electrophoretic mobility shift assays showed reduced binding of TonEBP to its target sequence in nuclear extracts prepared from MDCK cells treated with NO in vivo and in nuclear extracts exposed to NO in vitro. Furthermore, immunoprecipitation of S-nitrosylated proteins and the biotin-switch method identified TonEBP as a target for S-nitrosylation, which correlates with reduced DNA binding and transcriptional activity. These observations disclose a novel direct inhibitory effect of NO on TonEBP, a phenomenon that may be relevant for regulation of osmoprotective genes in the renal medulla.
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PMID:Nitric oxide decreases expression of osmoprotective genes via direct inhibition of TonEBP transcriptional activity. 1856 63

Campylobacter jejuni is a zoonotic Gram-negative bacterial pathogen that is exposed to reactive nitrogen species, such as nitric oxide, from a variety of sources. To combat the toxic effects of this nitrosative stress, C. jejuni upregulates a small regulon under the control of the transcriptional activator NssR, which positively regulates the expression of a single-domain globin protein (Cgb) and a truncated globin protein (Ctb). Cgb has previously been shown to detoxify nitric oxide, but the role of Ctb remains contentious. As C. jejuni is amenable to genetic manipulation, and its globin proteins are easily expressed and purified, a combination of mutagenesis, complementation, transcriptomics, spectroscopic characterisation and structural analyses has been used to probe the regulation, function and structure of Cgb and Ctb. This ability to study Cgb and Ctb with such a multi-pronged approach is a valuable asset, especially since only a small fraction of known globin proteins have been functionally characterised.
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PMID:The globins of Campylobacter jejuni. 2405 96


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