UNIPROT:P51532 - FACTA Search

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Query: UNIPROT:P51532 (transcriptional activator)
6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Maturity onset diabetes of the young (MODY) 3 is a monogenic form of diabetes caused by mutations in the transcription factor hepatocyte nuclear factor (HNF)-1 alpha. We investigated the involvement of apoptotic events in INS-1 insulinoma cells overexpressing wild-type HNF-1 alpha (WT-HNF-1 alpha) or a dominant-negative mutant (DN-HNF-1 alpha) under control of a doxycycline-dependent transcriptional activator. Forty-eight h after induction of DN-HNF-1 alpha, INS-1 cells activated caspase-3 and underwent apoptotic cell death, while cells overexpressing WT-HNF-1 alpha remained viable. Mitochondrial cytochrome c release and activation of caspase-9 accompanied DN-HNF-1 alpha-induced apoptosis, suggesting the involvement of the mitochondrial apoptosis pathway. Activation of caspases was preceded by mitochondrial hyperpolarization and decreased expression of the anti-apoptotic protein Bcl-xL. Transient overexpression of Bcl-xL was sufficient to rescue INS-1 cells from DN-HNF-1 alpha-induced apoptosis. Both WT- and DN-HNF-1 alpha-expressing cells demonstrated similar increases in apoptosis when cultured at high glucose (25 mm). In contrast, induction of DN-HNF-1 alpha highly sensitized cells to ceramide toxicity. In cells cultured at low glucose, DN-HNF-1 alpha induction also caused up-regulation of the cell cycle inhibitor p27(KIP1). Therefore, our data indicate that increased sensitivity to the mitochondrial apoptosis pathway and decreased cell proliferation may account for the progressive loss of beta-cell function seen in MODY 3 subjects.
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PMID:Dominant-negative suppression of HNF-1 alpha results in mitochondrial dysfunction, INS-1 cell apoptosis, and increased sensitivity to ceramide-, but not to high glucose-induced cell death. 1172 85

The involvement of chromatin structure and organization in transcriptional regulatory pathways has become evident. One unsolved question concerns the molecular mechanisms of chromatin remodeling during in vivo promoter activation. By using a high resolution in vivo analysis we show that when yeast cells are exposed to a regulatory signal the positions of specific nucleosomes change. The system analyzed consists of the basic elements of the Saccharomyces cerevisiae ADH2 promoter, two nucleosomes of which are shown to change the distribution of their positions by few nucleotides in the direction of transcription when the glucose content of the medium is lowered. Such repositioning does not occur in the absence of the ADH2 transcriptional activator Adr1 or in the presence of its DNA-binding domain alone. A construct consisting of the DNA-binding domain plus a 43-amino acid peptide containing the Adr1 activation domain is sufficient to induce the same effect of the full-length protein. Nucleosome repositioning occurs even when the catalytic activity of the RNA polymerase II is impaired, suggesting that the Adr1 activation domain mediates the recruitment of some factor to correctly preset the relevant sequences for the subsequent transcription steps.
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PMID:In vivo changes of nucleosome positioning in the pretranscription state. 1174 18

The genes of the Escherichia coli maltose regulon are controlled by MalT, the specific transcriptional activator which, together with the inducer maltotriose and ATP, is essential for mal gene transcription. Network regulation in this system affects the function of MalT and occurs on two levels. The first concerns the expression of malT. It has long been known that malT is under catabolite repression and thus under the control of the cAMP/CAP complex. We found that, in addition, the global regulator Mlc is a repressor for malT transcription. The repressor activity of Mlc is controlled by the transport status of the glucose-specific enzyme EIICB of the PTS that causes sequestration (and inactivation as a repressor) of Mlc when glucose is transported. The second level of MalT regulation affects its activity. MalT is activated by maltotriose which is not only formed when the cells are growing on any maltodextrin but also, in low amounts, endogenously when the cells grow on non-maltodextrin carbon sources. Thus, cellular metabolism, for instance degradation of galactose or trehalose, can cause mal gene induction. It was found that unphosphorylated internal glucose takes part in endogenous maltodextrin biosynthesis and is therefore a key element in endogenous mal gene expression. In addition to the maltotriose-dependent activation, MalT can interact with three different enzymes that lead to its inactivation as a transcriptional activator. The first is MaIK, the energy transducing ABC subunit of the maltodextrin transport system. Transport controls the interaction of MalK and MalT thus affecting gene expression. The second enzyme is MalY, a pyridoxal phosphate containing enzyme exhibiting cystathionase activity. The crystal structure of MalY was established and mutations in MalY that reduce mal gene repression map in a hydrophobic MalT interaction patch on the surface of the enzyme. The last enzyme is a soluble esterase of as yet unknown function. When overproduced, this enzyme specifically reduces mal gene expression and affects the activity of MalT in an in vitro transcription assay.
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PMID:Network regulation of the Escherichia coli maltose system. 1193 62

The PrnA transcriptional activator of Aspergillus nidulans binds as a dimer to CCGG-N-CCGG inverted repeats and to CCGG-6/7N-CCGG direct repeats. The binding specificity of the PrnA Zn cluster differs from that of the Gal4p/Ppr1p/UaY/Put3p group of proteins. Chimeras with UaY, a protein that strictly recognizes a CGG-6N-CCG motif, show that the recognition of the direct repeats necessitates the PrnA dimerization and linker elements, but the recognition of the CCGG-N-CCGG inverted repeats depends crucially on the PrnA Zn binuclear cluster and/or on residues amino-terminal to it. Three high-affinity sites in two different promoters have been visualized by in vivo methylation protection. Proline induction is essential for in vivo binding to these three sites but, as shown previously, not for nuclear entry. Simultaneous repression by ammonium and glucose does not affect in vivo binding to these high-affinity sites. PrnA differs from the isofunctional Saccharomyces cerevisiae protein Put3p, both in its unique binding specificity and in the requirement of induction for in vivo DNA binding.
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PMID:PrnA, a Zn2Cys6 activator with a unique DNA recognition mode, requires inducer for in vivo binding. 1197 93

The subcellular localization of Msn2, a transcriptional activator of STRE (stress response element)-regulated genes, is modulated by carbon source availability. In cells growing in glucose, Msn2 is located mainly in the cytosol, whereas in carbon source-starved cells, Msn2 is located largely inside the nucleus. However, in cells lacking Reg1 (the regulatory subunit of the Reg1/Glc7 protein phosphatase complex), the regulation of subcellular distribution is absent, Msn2 being constitutively present in the cytosol. The localization defect in these mutants is specific for carbon starvation stress, and it is because of the presence of an abnormally active Snf1 protein kinase that inhibits the nuclear localization of Msn2 upon carbon starvation. Active Snf1 kinase is also able to avoid the effects of rapamycin, a drug that by inhibiting the TOR kinase pathway leads to a nuclear localization of Msn2 in wild type cells. Therefore, active Snf1 and the TOR kinase pathway may affect similar cytosolic steps in the regulation of the subcellular localization of Msn2.
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PMID:Convergence of the target of rapamycin and the Snf1 protein kinase pathways in the regulation of the subcellular localization of Msn2, a transcriptional activator of STRE (Stress Response Element)-regulated genes. 1209 9

The yeast transcriptional activator Adr1 controls the expression of genes required for ethanol, glycerol, and fatty acid utilization. We show that Adr1 acts directly on the promoters of ADH2, ACS1, GUT1, CTA1, and POT1 using chromatin immunoprecipitation assays. The yeast homolog of the AMP-activated protein kinase, Snf1, promotes Adr1 chromatin binding in the absence of glucose, and the protein phosphatase complex, Glc7.Reg1, represses its binding in the presence of glucose. A post-translational process is implicated in the regulation of Adr1 binding activity. Chromatin binding by Adr1 is not the only step in ADH2 transcription that is regulated by glucose repression. Adr1 can bind to chromatin in repressed conditions in the presence of hyperacetylated histones. To study steps subsequent to promoter binding we utilized miniAdr1 transcription factors to characterize Adr1-dependent transcription in vitro. Yeast nuclear extracts prepared from glucose-repressed and glucose-derepressed cells are equally capable of supporting miniAdr1-dependent transcription and pre-initiation complex formation. Nuclear extracts prepared from a snf1 mutant support miniAdr1-dependent transcription but are partially defective in the formation of pre-initiation complexes with Mediator components being particularly depleted. We conclude that Snf1 regulates Adr1-dependent transcription primarily at the level of chromatin binding.
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PMID:Snf1 protein kinase regulates Adr1 binding to chromatin but not transcription activation. 1216 49

The maltose ATP-binding cassette transporter of Salmonella typhimurium is composed of a membrane-associated complex (MalFGK2) and a periplasmic receptor (MalE). In addition to its role in transport, the complex acts as a repressor of maltose-regulated gene expression and is subject to inhibition in the process of inducer exclusion. These activities are thought to be mediated by interactions of the ATPase subunit, MalK, with the transcriptional activator, MalT, and nonphosphorylated enzyme IIA of the glucose phosphotransferase system, respectively. To gain further insight in protein regions that are critical for these functions, we have generated nine MalK-specific monoclonal antibodies. These bind to four nonoverlapping linear epitopes: 60-LFig-63 (5B5), 113-RVNQVAEVLQL-123 (represented by 4H12), 309-GHETQI-314 (2F9) and 352-LFREDGSACR-361 (represented by 4B3). All mAbs recognize their epitopes in soluble MalK and in the MalFGK2 complex with Kd values ranging from 10-6 to 10-8 m. ATP reduced the affinity of the mAbs for soluble MalK, indicating a conformational change that renders the epitopes less accessible. 4H12 and 5B5 inhibit the ATPase activity of MalK and the MalE/maltose-stimulated ATPase activity of proteoliposomes, while their Fab fragments displayed no significant effect. The results suggest a similar solvent-exposed position of helix 3 in the MalK dimer and in the intact complex and might argue against a direct role in the catalytic process. 4B3 and 2F9 exhibit reduced binding to the MalFGK2 complex in the presence of MalT and enzyme IIAGlc, respectively, thereby providing the first direct evidence for the C-terminal domain of MalK being the site of interaction with the regulatory proteins.
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PMID:Functional characterization of the maltose ATP-binding-cassette transporter of Salmonella typhimurium by means of monoclonal antibodies directed against the MalK subunit. 1218 Sep 84

Deletions were made in Streptomyces lividans in either of two genes (zwf1 and zwf2) encoding isozymes of glucose-6-phosphate dehydrogenase, the first enzyme in the oxidative pentose phosphate pathway (PPP). Each mutation reduced the level of Zwf activity to approximately one-half that observed in the wild-type strain. When the mutants were transformed with multicopy plasmids carrying the pathway-specific transcriptional activator genes for either the actinorhodin (ACT) or undecylprodigiosin (RED) biosynthetic pathway, they produced higher levels of antibiotic than the corresponding wild-type control strains. The presumed lower flux of carbon through the PPP in each of the Deltazwf mutants may allow more efficient glucose utilization via glycolysis, resulting in higher levels of antibiotic production. This appears to occur without lowering the concentration of NADPH (the major biochemical product of the oxidative PPP activity) to a level that would limit antibiotic biosynthesis. Consistent with this hypothesis, deletion of the gene (devB) encoding the enzyme that catalyzes the next step in the oxidative PPP (6-phosphogluconolactonase) also resulted in increased antibiotic production. However, deletion of both zwf genes from the devB mutant resulted in reduced levels of ACT and RED production, suggesting that some of the NADPH made by the PPP is utilized, directly or indirectly, for antibiotic biosynthesis. Although applied here to the model antibiotics ACT and RED, such mutations may prove to be useful for improving the yield of commercially important secondary metabolites.
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PMID:Engineering of primary carbon metabolism for improved antibiotic production in Streptomyces lividans. 1232 14

The insulin gene is specifically expressed in beta-cells of the Langerhans islets of the pancreas, and its transcription is regulated by the circulating glucose level. Previous reports have shown that an unidentified beta-cell-specific nuclear factor binds to a conserved cis-regulatory element called RIPE3b and is critical for its glucose-regulated expression. Based on the sequence similarity of the RIPE3b element and the consensus binding sequence of the Maf family of basic leucine zipper transcription factors, we here identified mammalian homologue of avian MafA/L-Maf, an eye-specific member of the Maf family, as the RIPE3b-binding transcriptional activator. Reverse transcription-PCR analysis showed that mafA mRNA is detected only in the eyes and in pancreatic beta-cells and not in alpha-cells. MafA protein as well as its mRNA is up-regulated by glucose, consistent with the glucose-regulated binding of MafA to the RIPE3b element in beta-cell nuclear extracts. In transient luciferase assays, we also showed that expression of MafA greatly enhanced insulin promoter activity and that a dominant-negative form of MafA inhibited it. Therefore, MafA is a beta-cell-specific and glucose-regulated transcriptional activator for insulin gene expression and thus may be involved in the function and development of beta-cells as well as in the pathogenesis of diabetes.
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PMID:MafA is a glucose-regulated and pancreatic beta-cell-specific transcriptional activator for the insulin gene. 1236 92

The arginine deiminase (AD) system (ADS) is one of two major ammonia-generating pathways in the oral cavity that play important roles in oral biofilm pH homeostasis and oral biofilm ecology. To initiate a study of the Streptococcus gordonii ADS, the ADS gene cluster was isolated from subgenomic DNA libraries of S. gordonii DL1 by using an arcB-specific probe. Nucleotide sequence analysis revealed six open reading frames (ORFs) that were arranged contiguously; the first five ORFs were transcribed in the same direction, as an apparent operon, and the sixth was transcribed in the opposite direction. The ORFs were found to share significant homologies and to correspond closely in molecular mass to previously characterized arc genes; thus, they were designated arcA (AD), arcB (ornithine carbamyltransferase), arcC (carbamate kinase), arcD (arginine-ornithine antiporter), arcT (dipeptidase), and arcR (regulator). A putative sigma(70) promoter (ParcA [TTGTGT-N(19)-TAGAAT]) was mapped 5' to arcA by primer extension, and the expression of ParcA was shown to be inducible by arginine and repressible by glucose, in agreement with AD specific activities measured in the wild-type strain. To investigate the function of ArcR in the differential expression of the arc operon, arcR was insertionally inactivated by a KM resistance marker flanked by T4 transcription/translation termination signals, and the expression of ParcA was monitored by primer extension in the wild-type and ArcR-deficient strains. Lower levels of arcA expression, as well as lower levels of AD activity, were consistently observed in the ArcR-deficient strain compared to wild-type cells, regardless of the growth conditions. Thus, ArcR is a transcriptional activator that is required for induction and optimal expression of the S. gordonii ADS gene cluster.
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PMID:Isolation and molecular analysis of the gene cluster for the arginine deiminase system from Streptococcus gordonii DL1. 1240 48

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