Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.2.3.23 (GAS)
 957 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A subtraction library of group B streptococcus (GBS) strain O9OR with GAS chromosomal DNA (strain SF370) was constructed and more than 100 plasmid clones sequenced. DNA sequences of the plasmid inserts were analyzed using the BLAST gene search. Most inserts had little or no homology to GAS chromosomal DNA and 26 clones from the library had no gene homologues in the gene bank. The majority of genes discovered represented house keeping GBS genes, but several could be considered as possible virulence factors. Inserts from 21 clones were labeled and used as probes for hybridization with GBS DNA fragments separated by pulsed field electrophoresis. A genetic map of GBS strain O9OR was constructed.
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PMID:Construction of a GBS-GAS DNA subtraction library allows discovery of previously unidentified GBS genes and rapid location of unique regions on the GBS chromosome. 1476 30

Trapidil is a triazolopyrimidine that has been found to prevent restenosis after vascular injury. Although its precise mode of action is still unclear, several biological effects have been described including inhibition of IFN-gamma-induced CD40 expression on monocytes. Herein, we investigated the molecular mechanisms by which Trapidil exerts this inhibitory action. First, we observed that the inhibition of CD40 expression is associated with the suppression of CD40 gene transcription, as demonstrated by a clear decrease of CD40 nuclear RNA (nRNA) levels and unchanged CD40 mRNA half-life. IFN-gamma-induced CD40 transcription has been shown to be mediated by STAT1alpha dimers (p91/p84) which, after nuclear translocation, bind to GAS elements present in the promoter of IFN-gamma responsive genes. Electrophoresis mobility shift assay (EMSA) with both STAT1 consensus and CD40 mGAS probes showed that Trapidil did not affect the DNA binding ability of STAT1 dimers. STAT1 dimerization and activation are conferred by upstream phosphorylation of two amino acid residues of the STAT1 protein. The subsequent studies on these two potential STAT1 phosphorylation sites (Tyr701, Ser727) revealed that Trapidil attenuated IFN-gamma-induced Ser727 but not Tyr701 phosphorylation. The inhibition of CD40 transcription by Trapidil could at least partially owing to the impaired Ser727 phosphorylation of STAT1, since IFN-gamma failed to trigger CD40 expression in U3A S727A cells, a cell line displaying a point mutation at the Ser727 site. Collectively, our results indicate that phosphorylation of STAT1 at the Ser727 site enhances CD40 transcription and that Trapidil might be used as a selective inhibitor that could differentially modulate STAT1 target genes.
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PMID:Trapidil inhibits monocyte CD40 expression by preventing IFN-gamma-induced STAT1 S727 phosphorylation. 1518 26

Streptococcus pyogenes (the group A streptococcus [GAS]) is a medically significant pathogen of humans, causing a range of diseases from pharyngitis to necrotizing fasciitis. Several important GAS virulence genes are under the control of a pleiotropic regulator called Mga, or the multiple gene regulator of GAS, including the gene encoding the streptococcal collagen-like protein, or sclA. Analysis of the genome sequence upstream of sclA revealed two potential Mga-binding sites with homology to the published Mga-binding element, which were called PsclA-I (distal) and PsclA-II (proximal) based on their location relative to a predicted start of transcription. Primer extension was used to confirm that the Mga-dependent transcriptional start site for sclA was located adjacent to the proximal PsclA-II binding site. By using overlapping PsclA promoter probes and purified Mga-His fusion protein, it was shown by electrophoretic mobility shift assays that, unlike other Mga-regulated promoters, Mga binds only to a distal DNA-binding site (PsclA-I). Binding of Mga to PsclA-I could be competed with cold probes corresponding to known Mga-regulated promoters (Pemm, PscpA, and Pmga) but not with a nonspecific probe or the proximal PsclA-II fragment. With the use of a plasmid-based green fluorescent protein transcriptional reporter system, the full-length PsclA was not sufficient to reproduce normal Mga-regulated activation. However, studies using a single-copy gusA transcriptional reporter system integrated at the native sclA chromosomal locus clearly demonstrated that the distal PsclA-I binding site is required for Mga regulation. Therefore, PsclA represents a new class of Mga-regulated promoters that requires a single distal binding site for activation.
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PMID:Transcriptional activation of sclA by Mga requires a distal binding site in Streptococcus pyogenes. 1554 55

BCL-6 is a POZ domain zinc-finger transcription factor that appears to play important roles in the development of the immune system and its regulation. Mutations within BCL-6 gene can therefore contribute to the genesis of a variety of lymphomas, and can also manifest as a classic Th2-type hyperimmune response. In addition to its roles in B- and T-cell development, and in germinal centre formation, the factor is also critical for the development of peripheral memory T cells. In this study, we report that BCL-6 expression is induced by IFN-gamma in Jurkat cells and in nontransformed T cells polarized toward the Th1 phenotype. The IFN-gamma-responsive region has been mapped within the first exon between nucleotide +180 and +200. In vivo footprinting of the first exon reveals that a stretch of DNA between nucleotide +180 to +195 (which we term the X-box) is constitutively occupied in vivo in the presence or absence of IFN-gamma. A guanine at +195 residing at the boundary of the X-box and a downstream IFN-gamma-activated sequence (GAS 1; between nucleotides +192 to +200) is occupied in IFN-gamma-treated cells, indicating the interaction of an IFN-gamma-inducible/modified factor to this region. Consistent with this, electrophoretic mobility shift assays detect STAT-1alpha interactions with the downstream GAS1 motif. The cumulative data suggest that the X-box-binding protein facilitate the binding of STAT-1alpha to the GAS 1 site. The discovery that the BCL-6 transcription factor is inducible by IFN-gamma may help explain some of the postulated biological roles of BCL-6 in T cell development and differentiation, and help explain the Th2-biased phenotype of BCL-6-deficient mice.
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PMID:Induction of BCL-6 gene expression by interferon-gamma and identification of an IRE in exon I. 1559 57

Streptococcus pyogenes (GAS) is a common bacterial pathogen that has emerged as an increasingly important health concern in many parts of the world. Although GAS may appear harmless in healthy individuals, the ability of this bacterium to take advantage of a weakened or compromised host defense system is extraordinary. Following the recent publication of the genome sequences of several S. pyogenes strains, we undertook an investigation of a specialized gene group in GAS that encodes transcriptional regulators. By screening S. pyogenes transcriptional regulator genes from the complete genome of M1 strain SF370 against other DNA sequences at GenBank by BLAST searches, we identified a gene (i.e., Spy1258) that is uniquely present in the bacterium. Application of PCR primers (spy1258F and spy1258R) derived from this gene facilitated amplification of a 407-bp DNA fragment from S. pyogenes only, but not from other species of the genus Streptococcus and common bacteria. Apart from offering an additional target for specific confirmation of GAS, further analysis of the putative transcriptional regulator gene Spy1258 and its related protein product may lead to new insights into the molecular mechanisms of S. pyogenes maintenance and pathogenicity.
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PMID:Rapid identification of Streptococcus pyogenes with PCR primers from a putative transcriptional regulator gene. 1586 55

Expression of SHP-1 phosphatase, a key negative regulator of cell signaling, is lost in T cell lymphomas and other malignancies due to DNA methylation of the SHP-1 promoter by a currently undefined mechanism. We demonstrate that malignant T cells express DNA methyltransferase (DNMT) 1 and that constantly activated signal transducer and activator of transcription (STAT) 3 is capable of binding in vitro to DNA oligonucleotides corresponding to four STAT3 SIE/GAS binding sites identified in the SHP-1 promoter. STAT3, DNMT1, and histone deacetylase 1 form complexes and bind to the SHP-1 promoter in vivo. Treatment with pharmacologic grade DNMT1 anti-sense oligonucleotides and STAT3 small-interfering RNA induces in the malignant T cells DNA demethylation and expression of SHP-1 gene. These data indicate that STAT3 may, in part, transform cells by inducing epigenetic silencing of SHP-1 in cooperation with DNMT1 and, apparently, histone deacetylase 1. Reversal of such gene silencing represents an attractive aim for novel anticancer therapies.
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PMID:STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. 1587 Jan 98

The CovR/S (CsrR/S) two component system is a global regulator of virulence gene expression in the group A streptococcus (GAS, Streptococcus pyogenes). The response regulator, CovR, regulates about 15% of the genes of GAS, including its own operon. Using in vitro DNA binding assays with purified CovR protein, we found that CovR binds a DNA fragment including the covR promoter (Pcov). DNaseI footprint analyses showed that phosphorylation of CovR enhanced and extended the protected regions. The proposed CovR consensus binding sequence (ATTARA) was present at most, but not all protected regions. The effect of replacing the two thymine residues in the consensus binding sequence (CB) with guanine residues was evaluated both in vitro and in vivo. Most, but not all, CB mutations reduced binding of CovR in vitro. Using a transcriptional reporter introduced in single copy into the GAS chromosome, we found that mutations at each CB completely or partially relieved CovR-mediated repression in vivo. This suggests that CovR regulation of Pcov is direct. Further support for this conclusion comes from use of an in vitro GAS transcription system in which CovR was sufficient to mediate repression of Pcov. This repression was enhanced by phosphorylation of the protein. In addition, we found that the CovR binding region overlapping the promoter was essential for wild type repression of Pcov both in vitro and in vivo, suggesting that promoter occlusion is a primary mechanism of Pcov repression by CovR.
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PMID:The CovR response regulator of group A streptococcus (GAS) acts directly to repress its own promoter. 1588 14

Autocrine granulocyte macrophage-colony stimulating factor (GM-CSF) sequentially activates intracellular components in monocyte/macrophage production of the pro-inflammatory and immunoregulatory prostanoid, prostaglandin E2 (PGE2). GM-CSF first induces STAT5 signaling protein phosphorylation, then prostaglandin synthase 2 (COX2/PGS2) gene expression, and finally IL-10 production, to downregulate the cascade. Without activation, monocytes of at-risk, type 1 diabetic (T1D), and autoimmune thyroid disease (AITD) humans, and macrophages of nonobese diabetic (NOD) mice have aberrantly high GM-CSF, PGS2, and PGE2 expression, but normal levels of IL-10. After GM-CSF stimulation, repressor STAT5A and B isoforms (80-77kDa) in autoimmune human and NOD monocytes and activator STAT5A (96-94kDa) and B (94-92kDa) isoforms in NOD macrophages stay persistently tyrosine phosphorylated. This STAT5 phosphorylation persisted despite treatment in vitro with IL-10, anti-GM-CSF antibody, or the JAK2/3 inhibitor, AG490. Phosphorylated STAT5 repressor isoforms in autoimmune monocytes had diminished DNA binding capacity on GAS sequences found in the PGS2 gene enhancer. In contrast, STAT5 activator isoforms in NOD macrophages retained their DNA binding capacity on these sites much longer than in healthy control strain macrophages. These findings suggest that STAT5 dysfunction may contribute to dysregulation of GM-CSF signaling and gene activation, including PGS2, in autoimmune monocytes and macrophages.
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PMID:Signal transduction activator of transcription 5 (STAT5) dysfunction in autoimmune monocytes and macrophages. 1592 92

The MHC class II transactivator (CIITA), the master regulator of MHC class II (MHC II) expression, is a co-activator that controls MHC II transcription. Human B lymphocytes express MHC II constitutively due to persistent activity of CIITA promoter III (pIII), one of the four potential promoters (pI-pIV) of this gene. Although increases in MHC II expression in B cells in response to cytokines have been observed and induction of MHC II and CIITA by IFN-gamma has been studied in a number of different cell types, the specific effects of IFN-gamma on CIITA expression in B cells have not been studied. To investigate the regulation of CIITA expression by IFN-gamma in B cells, RT-PCR, in vivo and in vitro protein/DNA binding studies, and functional promoter analyses were performed. Both MHC II and CIITA type IV-specific RNAs increased in human B lymphocytes in response to IFN-gamma treatment. CIITA promoter analysis confirmed that pIV is IFN-gamma inducible in B cells and that the GAS and IRF-E sites are necessary for full induction. DNA binding of IRF-1 and IRF-2, members of the IFN regulatory factor family, was up-regulated in B cells in response to IFN-gamma and increased the activity of CIITA pIV. In vivo genomic footprint analysis demonstrated proteins binding at the GAS, IRF-E and E box sites of CIITA pIV. Although CIITA pIII is considered to be the hematopoietic-specific promoter of CIITA, these findings demonstrate that pIV is active in B lymphocytes and potentially contributes to the expression of CIITA and MHC II in these cells.
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PMID:Expression of the MHC class II transactivator (CIITA) type IV promoter in B lymphocytes and regulation by IFN-gamma. 1595 Feb 83

Patients with acute group A- strepotococcal pharyngotonsillitis were randomly assigned to treatment for 10 d with either phenoxymethylpenicillin (PcV), loracarbef or clindamycin. The concentrations of the drugs, respectively, were determined in tonsillar surface fluid (TSF), serum and the saliva in each patient on altogether 5 occasions; before, during and 4 d after end of therapy. On the same occasions blood was drawn for analysis of C-reactive protein (CRP) and orosomucoid. On the last d of treatment PcV could be detected in TSF in 1 of 6 patients only. Loracarbef had a slower decrease in TSF during therapy and measurable levels did occur 2 d after end of therapy corresponding to MIC 100 for GAS. This may be related to the somewhat better clinical results of the cephalosporins than of PcV, and possibly indicates that an extended therapy with these drugs in primary GAS pharyngotonsillitis for more than the arbitrarily chosen 10 d could reduce the number of recurrent episodes. PcV and loracarbef were not detected in serum after the end of treatment. The concentration of clindamycin in both TSF and the saliva was fairly longstanding during therapy and reached levels exceeding MIC 100 for GAS, in both TSF and serum 2 d after the end of treatment. Several investigations have shown that GAS, especially in the stationary phase may invade respiratory epithelial cells and are present intracellularly in patients with acute pharyngotonsillitis as well as in asymptomatic carriers. The same T-type, identical DNA fingerprints and arbitrarily primed patterns are found in GAS before and after treatment failure indicating that the primary episode and the failures are caused by the same strain. The longstanding concentrations of clindamycin in TSF, roughly independent of the degree of the local inflammation combined with its intracellular accumulation and activity against resting GAS seem to explain the efficiency of the drug in recurrent GAS pharyngotonsillitis. CRP and orosomucoid were of limited value in differing between bacterial and viral pharyngtonsillitis and a correlation between antibiotic concentration and CRP/orosomucoid levels was not found.
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PMID:Penicillin V, loracarbef and clindamycin in tonsillar surface fluid during acute group A streptococcal pharyngotonsillitis. 1601 2


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