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)

The gene for the RNA-dependent eIF-2 alpha protein kinase (PKR) was isolated from mouse genomic DNA and characterized. The mouse PKR gene contains 16 exons and spans about 28 kilobase pairs. Exon 1 is untranslated; the AUG translation initiation site is located early in the second exon. Exon 16 includes the UAG translation termination site. ATTAAA polyadenylylation signal, and a putative TA rather than CA 3' cleavage site. Primer extension analysis determined one major as well as multiple minor transcription initiation sites; the major site was 159 bp upstream of the translation initiation site. The complete cDNA of mouse PKR is, therefore, 2334 bp in length excluding the 3' poly(A)+ tail. The PKR gene 5' flanking region was a functional promoter in interferon-treated, transfected cells as measured with chloramphenicol acetyltransferase as the reporter gene. Sequence analysis of the 5' flanking region disclosed numerous potential binding sites for transcription factors including both an ISRE element and a GAS element involved in interferon inducibility; Ets, Myb, MyoD, and E2F sites commonly associated with growth control regulation and differentiation; and NF-kappa B-like sites as well as sites for two types of interleukin 6-activated factors, NF-IL6 and APRF, often associated with acute-phase, immune, and inflammatory response genes.
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PMID:Mechanism of interferon action: structure of the mouse PKR gene encoding the interferon-inducible RNA-dependent protein kinase. 791

GAS (gamma activated sequence) and GAS-like elements are found in a rapidly growing number of genes. Data from EMSA (electromobility shift assay) and transient transfection assays using heterologous promoter systems do not necessarily reflect transcriptional involvement and protein occupation of a binding site in vivo. This has been shown recently by in vivo footprinting of the NF-kappa B site at -40 in the interferon regulatory factor-1 (IRF-1) promoter. Here we show by in vivo footprinting using dimethylsulfate (DMS) that the GAS of the IRF-1 promoter, which also contains an overlapping putative NF-kappa B site, is occupied upon treatment with gamma-interferon (IFN gamma) but not with phorbol 12-myristate 13-acetate (PMA). Irrespective of induction, we detect a very strong DMS hypersensitivity at a guanosine just adjacent to GAS and a less persistent minor DMS hypersensitivity at a central cytosine. Our data confirm the crucial role of GAS in transcriptional activation by IFN gamma and are consistent with induced binding of p91 to GAS. In addition, our data suggest a major conformational distortion of the DNA at the GAS element of the IRF-1 promoter and that this GAS element is not involved in transcriptional activation by PMA.
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PMID:In vivo footprinting of the IRF-1 promoter: inducible occupation of a GAS element next to a persistent structural alteration of the DNA. 806 17

A gene designated BRCA1, implicated in the susceptibility to early-onset familial breast cancer, has recently been localized to chromosome 17q12-q21. To date, the order of DNA markers mapped within this region has been based on genetic linkage analysis. We report the use of multicolor fluorescence in situ hybridization to establish a physically based map of five polymorphic DNA markers and 10 cloned genes spanning this region. Three cosmid clones and Alu-PCR-generated products derived from 12 yeast artificial chromosome clones representing each of these markers were used in two-color mapping experiments to determine an initial proximity of markers relative to each other on metaphase chromosomes. Interphase mapping was then employed to determine the order and orientation of closely spaced loci by direct visualization of fluorescent signals following hybridization of three probes, each detected in a different color. Statistical analysis of the combined data suggests that the order of markers in the BRCA1 region is cen-THRA1-TOP2-GAS-OF2-17HSD-248yg9-RNU 2-OF3-PPY/p131-EPB3-Mfd188- WNT3-HOX2-GP3A-tel. This map is consistent with that determined by radiation-reduced hybrid mapping and will facilitate positional cloning strategies in efforts to isolate and characterize the BRCA1 gene.
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PMID:Multicolor FISH mapping with Alu-PCR-amplified YAC clone DNA determines the order of markers in the BRCA1 region on chromosome 17q12-q21. 824 79

We analyzed the activation and changes in the protein level of STAT1 as a consequence of in vivo treatment with superantigens. Ninety minutes after i.p. injection of the staphylococcal enterotoxin B (SEB), a complex containing STAT1 that was able to specifically bind to DNA containing GAS-like sequences was activated in mouse splenocytes. This complex had the same characteristics as that induced by IFN-gamma in several in vitro systems. Activation of the complex was inhibited by cyclosporin A, and Abs against IFN-gamma severely decreased the amount of complex detected. When splenocytes were analyzed 24 h after SEB treatment, a high increase in the amount of the STAT1 isoforms, STAT91 and STAT84, was observed by Western analysis, but binding to GAS-like sequences was clearly decreased when compared with analysis at 90 min. Nevertheless, when SEB was injected a second time 24 h after the first injection, the binding of STAT1 to GAS-like sequences had risen again. This approach corroborates the implication of IFN-gamma in the response to superantigens in vivo and shows the relevance of analysis of transcription factors in defining the molecular events involved in the immune response.
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PMID:Stat1 implication in the immune response to superantigens in vivo. 856 37

The rat homolog of sheep mammary gland factor (MGF)/Stat5 has been isolated and used to study the regulation of Stat5 during mammary gland development and PRL regulation in COS cells transfected with Stat5a and the PRL receptor. Two alternatively spliced isoforms, designated Stat5a1 and Stat5a2, were identified, the latter encoding a carboxy-terminal truncated protein. A polyclonal antibody to a carboxy-terminal peptide of Stat5a1 was generated and used to measure the level of this isoform during mammary gland development and after PRL induction in COS cells transiently transfected with Stat5a and the long form of the PRL receptor. Surprisingly, Stat5a mRNA and protein were readily detected both in virgin rats and after mammary gland involution. The levels of Stat5a increased during pregnancy, were highest in late pregnancy, and then, unexpectedly, decreased during lactation, the time at which the highest levels of milk protein gene expression are observed. Electrophoretic mobility shift assays using the specific anti-Stat5a1 antisera demonstrated that Stat5a1 comprises part of the heterogeneous, PRL-inducible, protein-DNA complex associated with the beta-casein GAS site. Immunocytochemical analysis detected considerable cytoplasmic and some nuclear staining for Stat5a1 during late pregnancy and predominantly nuclear staining during early lactation. The lack of correspondence of Stat5a gene expression and beta-casein gene expression suggests that Stat5 activation may facilitate the interaction of other factors binding within composite response elements identified recently in the milk protein gene promoters that are then responsible for the stable expression of milk protein genes in terminally differentiated mammary epithelial cells.
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PMID:Regulation of mammary gland factor/Stat5a during mammary gland development. 858 36

Binding of many cytokines to their cognate receptors immediately activates Jak tyrosine kinases and their substrates, STAT (signal transducers and activators of transcription) DNA-binding proteins. The DNA binding targets of STATs are sequence elements related to the archetypal gamma interferon activation site, GAS. However, association of interleukin 1 (IL-1) with Jak-STAT signaling has remained unresolved. We now report an element termed LILRE (lipopolysaccharide [LPS] and IL-1-responsive element) in the human prointerleukin 1beta gene (IL1B) which can be immediately induced by either lipopolysaccharide (LPS) or IL-1 protein to bind a tyrosine-phosphorylated protein. This LPS- and IL-1-induced factor (LIL factor) is recognized by an antibody raised against the N terminus of Stat1, but not by those specific for either the C terminus of Stat1 or any other GAS-binding STAT. Phosphotyrosine (P-Tyr) specifically inhibits formation of the LIL factor-DNA complex, suggesting the importance of P-Tyr for the DNA-binding activity, as has been found for all STAT dimers. Analysis of DNA-binding specificity demonstrates that the LIL factor possesses a novel GAS-like binding activity that contrasts with those of other STATs in a requirement for a G residue at position 8 (TTCCTGAGA). Further investigation has revealed that IL-6, but neither IL-4 nor gamma interferon, activates the LIL factor. Thus, the existence of such a STAT-like factor (LIL-Stat) relates the LPS and IL-1 signaling pathway to other cytokine receptor signaling pathways via the activation of STATs. Moreover, the unique DNA-binding specificity and antigenicity of this factor suggest that LPS, IL-1, and IL-6 may use a common signaling pathway.
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PMID:A novel STAT-like factor mediates lipopolysaccharide, interleukin 1 (IL-1), and IL-6 signaling and recognizes a gamma interferon activation site-like element in the IL1B gene. 862 85

We have examined the hypothesis that a variable number of tandem repeats in the third cytoplasmic loop of the dopamine D4 receptor influences clinical response to clozapine using a sample of 189 schizophrenic patients. Alleles of the 48-bp repeat, which range from two to ten copies in the normal human population, were analysed by the polymerase chain reaction using genomic DNA as template. Association between these alleles and response to clozapine was tested using the difference in pre- and post-treatment GAS scores as a measure of response. We found no statistically significant variation between genotypic groups and response by analysis of variance. We conclude that the variation of the number of 48-bp repeats alone does not determine response to clozapine. Larger studies are underway to determine if there is a more subtle relationship with sequence variation within the repeats or at other polymorphic sites within the gene that may provide evidence for a component of clozapine's action being at D4 receptors.
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PMID:Analysis of clozapine response and polymorphisms of the dopamine D4 receptor gene (DRD4) in schizophrenic patients. 882 92

Random amplified polymorphic DNA (RAPD) analysis was evaluated for its capacity to distinguish species and strains within species of groups A, C and G streptococci. The 99 strains tested, previously typed by multilocus enzyme electrophoresis (MLEE), included 41 group A streptococci (Streptococcus pyogenes), 25 group G Streptococcus spp. (GGS), seven S. dysgalactiae, 11 S. equisimilis, four S. canis, three S. equi and eight S. zooepidemicus. The combined data obtained with three single primers distinguished 82 types. RAPD analysis provided taxonomic results that were in general agreement with previous species classification based on DNA-DNA homology and MLEE. The intraspecies typing efficiency of the technique was significantly improved by the parallel use of several primers. RAPD analysis had greater discriminatory power than MLEE for GAS and GGS. There was not total agreement between the two techniques as RAPD distinguished strains with identical electrophoretic types, whereas MLEE differentiated strains with identical PCR types. RAPD analysis did not distinguish all GAS strains with different biotypes and its already high discriminatory power was further enhanced by concomitant biotyping.
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PMID:Analysis of genetic relationships among strains of groups A, C and G streptococci by random amplified polymorphic DNA analysis. 884 2

The Gen-probe group A Streptococcus direct test (GASD), a nucleic acid probe assay for detecting GAS from throat swabs, has recently been developed. The test uses an acridium ester-labeled DNA probe which is complementary to the rRNA of Streptococcus pyogenes. In this study, 318 single culturette throat swabs were tested by this method using culture as a "gold standard." After plating onto trypticase soy agar plates with 5% sheep blood, swabs were stored at 4 degrees C for no more than 72 h before the probe assay was performed. Our patient population consisted of symptomatic outpatients seen in the Memorial Hospital Emergency Department and in the Family Care Center. After discrepancy testing, sensitivity, specificity, and positive and negative predictive values were 91.4%, 97%, 91.4%, and 97%. The GASD is a rapid, easy-to-perform method for batch screening for streptococcal pharyngitis.
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PMID:Rapid antigen testing for group A Streptococcus by DNA probe. 914 10

STAT proteins are important transcription factors that regulate cell growth and differentiation. To elucidate the molecular mechanisms of insulin actions, we have studied how insulin activates STAT proteins in Hep3B cells. Insulin rapidly phosphorylated Stat1alpha at tyrosine residues and increased its specific binding activities to a GAS/ISRE consensus oligonucleotide. IL-4 also phosphorylated Stat1alpha and increased DNA binding activities to the same Stat1alpha responsive element. There was no increase in tyrosine phosphorylation of JAK family of kinases following insulin stimulation. In contrast, IL-4 stimulated tyrosine phosphorylation of JAK1, JAK2 and tyk2 in this cell line. These data indicate that insulin receptor signaling can activate the transcriptional regulatory function of STAT protein, and that insulin actions on Stat1alpha are mediated through signaling pathways independent of JAK family of kinases.
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PMID:Novel pathway of insulin signaling involving Stat1alpha in Hep3B cells. 919 89


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