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)

Filamentous fungi produce high levels of polysaccharide-degrading enzymes and are frequently used for the production of industrial enzymes. Because of the high secretory capacity for enzymes, filamentous fungi are effective hosts for the production of foreign proteins. Genetic studies with Aspergillus nidulans have shown pathway-specific regulatory systems that control a set of genes that must be expressed to catabolize particular substrates. Besides the pathway-specific regulation, wide domain regulatory systems exist that affect a great many individual genes in different pathways. A molecular analysis of various regulated systems has confirmed the formal models derived from purely genetic data. In general, many genes are subject to more than one regulatory system. In this article, we describe two transcriptional activators, AmyR and XlnR, and an enhancer, Hap complex, in view of their regulatory roles in the expression of the amylolytic and (hemi-)cellulolytic genes mainly in aspergilli. The amyR gene has been isolated as a transcriptional activator involved in the expression of amylolytic genes from A. oryzae, A. niger, and A. nidulans, and the xlnR gene, which has been isolated from A. niger and A. oryzae, activates the expression of xylanolytic genes as well as some cellulolytic genes in aspergilli. Both AmyR and XlnR have a typical zinc binuclear cluster DNA-binding domain at their N-terminal regions. Hap complex, a CCAAT-binding complex, enhances the overall promoter activity and increases the expression levels of many fungal genes, including the Taka-amylase A gene. Hap complex comprises three subunits, HapB, HapC, and HapE, in A. nidulans and A. oryzae as well as higher eukaryotes, whereas HAP complex in Saccharomyces cerevisiae and Kluyveromyces lactis has the additional subunit, Hap4p, which is responsible for the transcriptional activation. Hap complex is suggested to enhance transcription by remodeling the chromatin structure. The regulation of gene expression in filamentous fungi of industrial interest could follow basically the same general principles as those discovered in A. nidulans. The knowledge of regulation of gene expression in combination with traditional genetic techniques is expected to be increasingly utilized for strain breeding. Furthermore, this knowledge provides a basis for the rational application of transcriptional regulators for biotechnological processes in filamentous fungi.
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PMID:Regulation of the amylolytic and (hemi-)cellulolytic genes in aspergilli. 1248 63

The Zap1 transcriptional activator from Saccharomyces cerevisiae induces expression of a series of genes containing an 11 base pair conserved promoter element (ZRE) under conditions of zinc deficiency. This work shows that Zap1 uses four of its seven zinc finger domains to contact the ZRE and that two of these dominate the interaction by contacting the essential ACC-GGT ends. Two Zn finger domains (ZF1 and ZF2) do not contact DNA, and a third ZF3 may be more important for interfinger protein-protein interactions. Zn finger domains important for ZRE contact were identified from triple mutations in Zap1, changing three residues in the alpha helix in each finger known to be important for DNA contacts in Zn finger proteins. Replacement of -1, 3, and 6 helix residues in ZF4 and ZF7 reduced the affinity of Zap1 for the wild-type ZRE. In contrast, triple mutations within the intervening ZF5 and ZF6 domains had minimal effect. The data argue that fingers 4 and 7 contact the ACC-GGT ends while fingers 5 and 6 contact the 5 bp central ZRE sequence. This conclusion is corroborated by decreased Zap1 affinity for a ZRE DNA duplex containing mutations of the AC-GT ends of the ZRE, whereas transversion mutations within the central 5 bp of the ZRE had minimal effect on Zap1 binding affinity.
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PMID:Two of the five zinc fingers in the Zap1 transcription factor DNA binding domain dominate site-specific DNA binding. 1254 26

The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anti- carbonic anhydrase, diuretic, hypoglycemic and antithyroid activity among others. A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial antitumor activity in vitro and in vivo. Although they have a common chemical motif of aromatic/heterocyclic or amino acid sulfonamide, there are a variety of mechanisms of their antitumor action, such as carbonic anhydrase inhibition, cell cycle perturbation in the G1 phase, disruption of microtubule assembly, functional suppression of the transcriptional activator NF-Y, and angiogenesis (matrix metalloproteinase, MMP) inhibition among others. Some of these compounds selected via elaborate preclinical screenings or obtained through computer-based drug design, are currently being evaluated in clinical trials. The review summarizes recent classes of sulfonamides and related sulfonyl derivatives disclosed as effective tumor cell growth inhibitors, or for the treatment of different types of cancer. Another research line that progressed much in the last time regards different sulfonamides with remarkable antiviral activity. Thus, at least two clinically used HIV protease inhibitors possess sulfonamide moieties in their molecules, whereas a very large number of other derivatives are constantly being synthesized and evaluated in order to obtain compounds with less toxicity or activity against drug-resistant viruses. Several non nucleoside HIV reverse transcriptase or HIV integrase inhibitors containing sulfonamido groups were also reported. Another approach to inhibit the growth of retroviruses, including HIV, targets the ejection of zinc ions from critical zinc finger viral proteins, which has as a consequence the inhibition of viral replication in the absence of mutations leading to drug resistance phenotypes. Most compounds with antiviral activity possessing this mechanism of action incorporate in their molecules primary sulfonamide groups. Some small molecule chemokine antagonists acting as HIV entry inhibitors also possess sulfonamide functionalities in their scaffold.
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PMID:Anticancer and antiviral sulfonamides. 1267 81

We have identified two novel human SCAN domain genes ZNF396 and ZNF397, which are clustered within the region of chromosome 18q12. Three isoforms of ZNF396 transcript, 1.5, 2.5 and 3.9-kb, are expressed highly in liver. Four isoforms of ZNF397 transcript, 1.7, 2.5, 7.0 and 9.0-kb, are expressed in a variety of tissues, with varying levels. The SCAN-(C(2)H(2))(X) genes encode two distinct proteins due to a unique alternative splicing mechanism. Both ZNF396-fu (full zinc fingers) and ZNF397-fu consist of a SCAN domain in the N-terminal region and many consecutive C(2)H(2) zinc finger repeats in the C-terminal region. ZNF396-nf (no zinc fingers) and ZNF397-nf encode 210 and 198 amino acids, respectively, containing the SCAN domain only. ZNF396-fu, ZNF396-nf, ZNF397-fu or ZNF397-nf can homo-associate, while ZNF396-fu hetero-associates with ZNF396-nf, and ZNF397-fu hetero-associates with ZNF397-nf. ZNF396-nf and ZNF397-nf polypeptides are expressed diffusely in the cells, while ZNF396-fu and ZNF397-fu polypeptides target specifically to the nuclei. ZNF396-fu, ZNF396-nf and ZNF397-nf can repress reporter gene transcription, with ZNF397-nf having the strongest repression activity. Deletion analysis revealed that ZNF397-fu is a transcriptional activator without its nine zinc finger repeats.
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PMID:Identification and characterization of two novel human SCAN domain-containing zinc finger genes ZNF396 and ZNF397. 1280 47

Yeast are capable of modifying their metabolism in response to environmental changes. We investigated the activity of the oxygen-dependent high-affinity iron uptake system of Saccharomyces cerevisiae under conditions of heme depletion. We found that the absence of heme, due to a deletion in the gene that encodes delta-aminolevulinic acid synthase (HEM1), resulted in decreased transcription of genes belonging to both the iron and copper regulons, but not the zinc regulon. Decreased transcription of the iron regulon was not due to decreased expression of the iron sensitive transcriptional activator Aft1p. Expression of the constitutively active allele AFT1-1up was unable to induce transcription of the high affinity iron uptake system in heme-depleted cells. We demonstrated that under heme-depleted conditions, Aft1p-GFP was able to cycle normally between the nucleus and cytosol in response to cytosolic iron. Despite the inability to induce transcription under low iron conditions, chromatin immunoprecipitation demonstrated that Aft1p binds to the FET3 promoter in the absence of heme. Finally, we provide evidence that under heme-depleted conditions, yeast are able to regulate mitochondrial iron uptake and do not accumulate pathologic iron concentrations, as is seen when iron-sulfur cluster synthesis is disrupted.
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PMID:Inhibition of heme biosynthesis prevents transcription of iron uptake genes in yeast. 1292 33

The ability of a pathogen to cause infection depends on successful colonization of the host, which, in turn, requires adaptation to various challenges presented by that host. For example, host immune cells use a variety of mechanisms to control infection by bacterial pathogens, including the production of bactericidal reactive oxygen species. Prokaryotic and eukaryotic cells have developed ways of protecting themselves against this oxidative damage; for instance, Borrelia burgdorferi alters the expression of oxidative-stress-related proteins, such as a Dps/Dpr homolog NapA (BB0690), in response to increasing levels of oxygen and reactive oxygen species. These stress-related genes appear to be regulated by a putative metal-dependent DNA-binding protein (BB0647) that has 50.7% similarity to the peroxide-specific stress response repressor of Bacillus subtilis, PerR. We overexpressed and purified this protein from Escherichia coli and designated it Borrelia oxidative stress regulator, BosR. BosR bound to a 50-nt region 180 bp upstream of the napA transcriptional start site and required DTT and Zn2+ for optimal binding. Unlike the Bacillus subtilis PerR repressor, BosR did not require Fe2+ and Mn2+ for binding, and oxidizing agents, such as t-butyl peroxide, enhanced, not eliminated, BosR binding to the napA promoter region. Surprisingly, transcriptional fusion analysis indicated that BosR exerted a positive regulatory effect on napA that is inducible with t-butyl peroxide. On the basis of these data, we propose that, despite the similarity to PerR, BosR functions primarily as a transcriptional activator, not a repressor of oxidative stress response, in B. burgdorferi.
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PMID:Borrelia oxidative stress response regulator, BosR: a distinctive Zn-dependent transcriptional activator. 1297 27

Arabidopsis ZIM is a putative transcription factor containing an atypical GATA-type zinc-finger motif. Transcriptional activation by ZIM was tested using a transient GAL4 fusion assay and measuring the expression of a luciferase reporter in tobacco BY-2 cells. ZIM functioned as a transcriptional activator, and the transactivation domain was found to occur in its N-terminal acidic region.
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PMID:Arabidopsis ZIM, a plant-specific GATA factor, can function as a transcriptional activator. 1464 19

During sensory organ precursor (SOP) specification, a single cell is selected from a proneural cluster of cells. Here, we present evidence that Senseless (Sens), a zinc-finger transcription factor, plays an important role in this process. We show that Sens is directly activated by proneural proteins in the presumptive SOPs and a few cells surrounding the SOP in most tissues. In the cells that express low levels of Sens, it acts in a DNA-binding-dependent manner to repress transcription of proneural genes. In the presumptive SOPs that express high levels of Sens, it acts as a transcriptional activator and synergizes with proneural proteins. We therefore propose that Sens acts as a binary switch that is fundamental to SOP selection.
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PMID:Senseless acts as a binary switch during sensory organ precursor selection. 1466 71

Aldehyde oxidoreductase of Eubacterium acidaminophilum was purified to homogeneity under strict anaerobic conditions using a four-step procedure. The purified enzyme was present as a monomer with an apparent molecular mass of 67 kDa and contained 6.0 +/- 0.1 iron, 1.1 +/- 0.2 tungsten, about 0.6 mol pterin cofactor and zinc, but no molybdenum. The enzyme activity was induced if a molar excess of electron donors, such as serine and/or formate, were supplied in the growth medium compared to readily available electron acceptors such as glycine betaine. Many aldehydes served as good substrates, thus enzyme activity obtained with acetaldehyde, propionaldehyde, butyraldehyde, isovaleraldehyde and benzaldehyde differed by a factor of less than two. Kinetic parameters were determined for all substrates tested. Oligonucleotides deduced from the N-terminal amino acid sequence were used to isolate the encoding aorA gene and adjacent DNA regions. The deduced amino acid sequence of the aldehyde oxidoreductase exhibited high similarities to other tungsten-containing aldehyde oxidoreductases from archaea. Transcription of the aorA gene was monocistronic and started from a sigma 54-dependent promoter. Upstream of aorA, the gene aorR is localized whose product is similar to sigma 54-dependent transcriptional activator proteins and, thus, AorR is probably involved in the regulation of aorA expression.
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PMID:Tungsten-containing aldehyde oxidoreductase of Eubacterium acidaminophilum. 1468 34

The zinc-responsive transcriptional activator Zap1 regulates the expression of both high- and low-affinity zinc uptake permeases encoded by the ZRT1 and ZRT2 genes. Zap1 mediates this response by binding to zinc-responsive elements (ZREs) located within the promoter regions of each gene. ZRT2 has a remarkably different expression profile in response to zinc compared to ZRT1. While ZRT1 is maximally induced during zinc limitation, ZRT2 is repressed in low zinc but remains induced upon zinc supplementation. In this study, we determined the mechanism underlying this paradoxical Zap1-dependent regulation of ZRT2. We demonstrate that a nonconsensus ZRE (ZRT2 ZRE3), which overlaps with one of the ZRT2 transcriptional start sites, is essential for repression of ZRT2 in low zinc and that Zap1 binds to ZRT2 ZRE3 with a low affinity. The low-affinity ZRE is also essential for the ZRT2 expression profile. These results indicate that the unusual pattern of ZRT2 regulation among Zap1 target genes involves the antagonistic effect of Zap1 binding to a low-affinity ZRE repressor site and high-affinity ZREs required for activation.
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PMID:The Zap1 transcriptional activator also acts as a repressor by binding downstream of the TATA box in ZRT2. 1497 57


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