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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferon regulation of gene expression is dependent on the tyrosine phosphorylation and activation of the DNA-binding activity of two related proteins of 91 kDa (STAT1) and/or 113 kDa (STAT2). Recent studies have suggested that these proteins are substrates of Janus kinases and that proteins related in STAT1 are involved in a number of signalling pathways, including those activated in myeloid cells by erythropoietin and interleukin-3 (IL-3). To clone STAT-related proteins from myeloid cells, degenerate oligonucleotides were used in PCRs to identify novel family members expressed in myeloid cells. This approach allowed the identification and cloning of the Stat4 gene, which is 52% identical to STAT1. Unlike STAT1, Stat4 expression is restricted but includes myeloid cells and spermatogonia. In the erythroid lineage, Stat4 expression is differentially regulated during differentiation. Functionally, Stat4 has the properties of other STAT family genes. In particular, cotransfection of expression constructs for Stat4 and Jak1 and Jak2 results in the tyrosine phosphorylation of Stat4 and the acquisition of the ability to bind to the gamma interferon (IFN-gamma)-activated sequence of the interferon regulatory factor 1 (IRF-1) gene. Stat4 is located on mouse chromosome 1 and is tightly linked to the Stat1 gene, suggesting that the genes arose by gene duplication. Unlike Stat1, neither IFN-alpha nor IFN-gamma activates Stat4. Nor is Stat4 activated in myeloid cells by a number of cytokines, including erythropoietin, IL-3, granulocyte colony-stimulating factor, stem cell factor, colon-stimulating factor 1, hepatocyte growth factor, IL-2, IL-4, and IL-6.
Mol Cell Biol 1994 Jul
PMID:Stat4, a novel gamma interferon activation site-binding protein expressed in early myeloid differentiation. 800 43

Induction by gamma interferon (IFN-gamma) of the gene encoding the human high-affinity Fc gamma receptor (Fc gamma R1) in myeloid cells requires an IFN-gamma response region (GRR) and a myeloid cell-activating transcription element (MATE). GRR and MATE interact with factors to form, respectively, an IFN-gamma-activating complex (GIRE-BP), depending on the phosphorylation of the 91-kDa protein (subunit of ISGF3), and a cell-type-specific complex (MATE-BP). Although GIRE-BP is detected in cells of different origins after IFN-gamma treatment, the presence of MATE-BP was found to be restricted to B- and myeloid cell lines. Sequence analysis of a cDNA encoding a polypeptide recognizing specifically the MATE motif led to the identification of this product as the proto-oncogene PU.1/Spi-1, a transcriptional activator expressed in myeloid and B cells. Expression of this factor in nonhematopoietic cells allowed IFN-gamma-induced expression of a reporter gene under control of the GRR and MATE sequences. The presence of these motifs in other gene promoters indicates that the binding of PU.1/Spi-1 and IFN regulatory proteins to their respective motifs could be part of a general mechanism leading to cell-type-restricted and IFN-induced gene expression.
Mol Cell Biol 1994 Aug
PMID:Involvement of the transcription factor PU.1/Spi-1 in myeloid cell-restricted expression of an interferon-inducible gene encoding the human high-affinity Fc gamma receptor. 803 86

Acute lung injury, characterized as the adult respiratory distress syndrome (ARDS), is a common clinical occurrence following blood loss and injury. We previously found increased levels of transforming growth factor (TGF)-beta 1 mRNA in murine intraparenchymal mononuclear cells and in alveolar macrophages within 1 h after hemorrhage. Because TGF-beta has potent proinflammatory and immunoregulatory properties, we investigated the effect of blocking TGF-beta with mAb on hemorrhage-induced pathology, cytokine mRNA levels in lungs, as well as survival from pneumonia. Mice treated with anti-TGF-beta mAb showed normal pulmonary histology 3 days after hemorrhage and resuscitation in contrast to the mononuclear and neutrophil infiltrates, intraalveolar hemorrhage, and interstitial edema found in hemorrhaged mice either treated with control antibody or not treated with any antibody. Decreased mRNA levels for IL-1 beta, TNF-alpha, IL-6, IL-10, and IFN-gamma as compared with untreated, hemorrhaged controls were present in intraparenchymal pulmonary mononuclear cells following therapy with anti-TGF-beta. In contrast, therapy with anti-TGF-beta increased mRNA levels for IL-1 beta and TNF-alpha in alveolar macrophages and for TGF-beta in peripheral blood mononuclear cells collected 3 days after hemorrhage. Administration of anti-TGF-beta to hemorrhaged mice did not correct the enhanced susceptibility to Pseudomonas aeruginosa pneumonia that exists after hemorrhage. These results suggest that TGF-beta has an important role in hemorrhage-induced acute lung injury, but does not contribute to the post-hemorrhage depression in pulmonary antibacterial response.
Am J Respir Cell Mol Biol 1994 Sep
PMID:Anti-transforming growth factor-beta monoclonal antibodies prevent lung injury in hemorrhaged mice. 808 71

Monolayer cultures of renal tubular (hKEC) cells were established. These cells formed empty spheroids after 2-3 weeks of culture in a collagen gel matrix. A subcellular polarity from the apex to basement was induced in these "spheroidal" hKEC cells. The weak expression of laminin at the outer surface was evident on spheroidal but not on monolayered hKEC cells. The regulation of HLA-ABC, DR, and intercellular adhesion molecule-1 (ICAM-1) antigens on hKEC cells in the gel matrix was investigated utilizing digestion of gel matrix by collagenase. Enzymatic digestion of the collagen gel did not significantly affect the surface expression of HLA-ABC and ICAM-1, but reduced HLA-DR expression as shown by flow cytometry. The MHC and ICAM-1 molecules on both spheroid-forming and monolayered hKEC cells were upregulated by adding a supernatant of mixed lymphocyte reaction (MLR) and recombinant human interferon (IFN)-gamma. HLA-DR antigen expression was inconsistently induced on the hKEC cells cultured in collagen gel without MLR supernatant or IFN-gamma. In contrast, no HLA-DR expression was found on monolayered hKEC cells in the absence of MLR supernatant or IFN-gamma. Spheroid-forming hKEC cells, when dispersed by enzymatic digestion, were more susceptible to cytolysis by lymphokine-activated killer (LAK) cells than were the enzymatically dispersed, monolayered cells in the 51Cr-release assay. The LAK cells were seen to migrate into the collagen gel and kill the hKEC cells. Thus, LAK cells may function to favor the acceleration of graft rejection.(ABSTRACT TRUNCATED AT 250 WORDS)
Virchows Arch B Cell Pathol Incl Mol Pathol 1993
PMID:Susceptibility of renal tubular cells to lymphokine-activated killer (LAK) cells: application of culture system using a collagen gel matrix. 809 21

The 84-, 91-, and 113-kDa proteins of the ISGF-3 alpha complex are phosphorylated on tyrosine residues upon alpha interferon (IFN-alpha) treatment and subsequently translocate to the nucleus together with a 48-kDa subunit. In this study, we investigated the presence and the functional status of ISGF-3 alpha subunits and Tyk-2 and JAK1 tyrosine kinases in mutant HeLa cells defective in the IFN-alpha/beta and -gamma response. Stable cell fusion analysis revealed a single complementation group among one class (class B) of mutants. The class B mutants contain detectable level of mRNA and proteins of the 84-, 91-, and 113-kDa proteins, but neither the protein nor mRNA is inducible by IFN-alpha or -gamma. The 91-kDa protein IFN-gamma-activated factor fails to be activated into a DNA-binding state after IFN-alpha or -gamma treatment. In addition, the 91-kDa protein is unable to localize in the nucleus after IFN-alpha and -gamma treatment, and the 113-kDa protein fails to translocate after IFN-alpha treatment. Immunoprecipitation studies document a failure of phosphorylation of the 84- or 91-kDa proteins after IFN-alpha or -gamma treatment. Similarly, no tyrosine-phosphorylated 113-kDa protein was detected after IFN-alpha treatment. The inability of class B mutants to phosphorylate the 84-, 91-, or 113-kDa protein on tyrosine residues correlated with the loss of biological response to IFN-alpha and -gamma. The genetic defect appears to be the absence of the tyrosine kinase JAK1. Our data therefore confirm a recent report that JAK1 plays a critical early signaling role for both IFN-alpha/beta and IFN-gamma systems.
Mol Cell Biol 1994 Mar
PMID:Mutant cell lines unresponsive to alpha/beta and gamma interferon are defective in tyrosine phosphorylation of ISGF-3 alpha components. 811 47

Acute pulmonary injury occurs frequently following hemorrhage and injury. In order to better examine the sequence of events leading to lung injury in this setting, we investigated lung histology as well as in vivo mRNA levels for cytokines with proinflammatory and immunoregulatory properties (IL-1 beta, IL-6, IL-10, TNF-alpha, TGF-beta, IFN-gamma) over the 3 days following hemorrhage and resuscitation. Significant increases in mRNA levels for IL-1 beta, IL-6, IL-10, and IFN-gamma, but not TNF-alpha, were present among intraparenchymal pulmonary mononuclear cells obtained 1 and 3 days after hemorrhage. Among alveolar macrophages, TNF-alpha and IL-1 beta mRNA levels were increased 3 days after hemorrhage. Few changes in cytokine mRNA levels, with the exception of TNF-alpha at 3 days after hemorrhage, were present among peripheral blood mononuclear cells. Histologic examination of lungs from hemorrhaged animals showed no alterations 1 day after hemorrhage, but neutrophil and mononuclear cell infiltrates, edema, intra-alveolar hemorrhage, and fibrin generation were present 3 days after hemorrhage. These results suggest that hemorrhage-induced enhancement of proinflammatory cytokine gene transcription may be an important mechanism contributing to the frequent development of acute lung injury following blood loss and injury.
Am J Respir Cell Mol Biol 1994 Mar
PMID:Hemorrhage and resuscitation induce alterations in cytokine expression and the development of acute lung injury. 811 48

Interleukin-6 (IL-6), leukemia inhibitory factor, oncostatin M, IL-11, and ciliary neurotropic factor are a family of cytokines and neuronal differentiation factors which bind to composite plasma membrane receptors sharing the signal transducing subunit gp130. We have shown recently that IL-6 and leukemia inhibitory factor rapidly activate a latent cytoplasmic transcription factor, acute-phase response factor (APRF), by tyrosine phosphorylation, which then binds to IL-6 response elements of various IL-6 target genes. Here we demonstrate that APRF is activated by all cytokines acting through gp130 and is detected in a wide variety of cell types, indicating a central role of this transcription factor in gp130-mediated signaling. APRF activation is also observed in vitro upon addition of IL-6 to cell homogenates. Protein tyrosine kinase inhibitors block both the tyrosine phosphorylation and DNA binding of APRF. The factor was purified to homogeneity from rat liver and shown to consist of a single 87-kDa polypeptide, while two forms (89 and 87 kDa) are isolated from human hepatoma cells. As reported earlier, the binding sequence specificity of APRF is shared by gamma interferon (IFN-gamma) activation factor, which is formed by the Stat91 protein. Partial amino acid sequence obtained from purified rat APRF demonstrated that it is likely to be related to Stat91. In fact, an antiserum raised against the amino-terminal portion of Stat91 cross-reacted with APRF, suggesting the relatedness of APRF and Stat91. Altogether, these data indicate that APRF belongs to a growing family of Stat-related proteins and that IFN-gamma and IL-6 use similar signaling pathways to activate IFN-gamma activation factor and APRF, respectively.
Mol Cell Biol 1994 May
PMID:The interleukin-6-activated acute-phase response factor is antigenically and functionally related to members of the signal transducer and activator of transcription (STAT) family. 816 74

Based on our finding that HIV-1 gp41 independently of CD4 can bind to several proteins (gp41 binding protein: GBP) on the human T-cell line H9, B-cell line Raji and monocyte-cell line U937, we examined the effect of mitogens and cytokines on binding of gp41 to H9, Raji and U937 cells. Flow cytometry (FACS) analysis demonstrated that PWM and LPS, IFN-gamma and IL-6, but not Con A, IFN-alpha, -beta, -omega and IL-2, could increase gp41 binding to Raji cells. In controls, none of the regulators (IFN-alpha, -beta, -gamma, -omega, IL-2, IL-6, Con A, PWM, LPS) could modify the binding potential of H9 and U937 cells. Our data suggest that the expression of HIV-1 binding proteins is subject to regulation by PWM, LPS, IFN-gamma and IL-6 in the case of B-cells, while on T-cells and macrophages, the binding proteins may be constitutively expressed.
Mol Immunol 1993 Dec
PMID:Enhancement of HIV-1 gp41 binding to Raji cells by PWM, LPS, interferon-gamma and interleukin-6. 824 28

The cytokines tumor necrosis factor (TNF), beta interferon (IFN-beta), and IFN-gamma increase major histocompatibility complex class I molecule expression. A greater than additive (i.e., synergistic) induction of class I heavy-chain mRNA is observed in HeLa cells treated with TNF in combination with either type of IFN. To define the cis-acting elements mediating cytokine synergy, the promoter of a human major histocompatibility complex class I heavy-chain gene (HLA-B7) was placed in front of a reporter gene and transfected into HeLa cells. Deletion analysis mapped the elements required for synergy to a 40-bp region containing a kappa B-like element, which is necessary for the response to TNF, and an interferon consensus sequence (ICS), which is necessary for the responses to IFNs. When the orientation of these elements was reversed or their normal 20-bp spacing was reduced by 5 or 10 bp, i.e., one half or one full turn of the DNA helix, essentially equivalent responses were obtained, suggesting that these parameters are not critical. In electromobility shift assays, a p50-containing NF-kappa B nuclear factor from TNF-treated cells binds kappa B-containing probes, and ISGF-2 from IFN-gamma-treated cells binds ICS-containing probes. A probe containing both the kappa B and ICS elements (kappa B-ICS) forms a novel complex with nuclear factors isolated from cells treated with both TNF and IFN-gamma; this complex also forms when nuclear factors from individually cytokine-treated cells are mixed in vitro. The natural variant ICS found in HLA-A responds to IFN-gamma and can mediate synergy with TNF. However, the variant kappa B found in HLA-C does not respond to TNF, nor can it mediate synergy between TNF and IFN-gamma. These observations suggest that synergy between TNF and IFNs in the induction of HLA class I gene expression results from the sum of individual interactions of cytokine-activated enhancer-binding factors with the transcription initiation complex.
Mol Cell Biol 1994 Feb
PMID:HLA class I heavy-chain gene promoter elements mediating synergy between tumor necrosis factor and interferons. 828 10

To define the molecular mechanisms involved in the action of gamma interferon (IFN-gamma), we have analyzed the transcriptional regulation of the mig (monokine induced by gamma interferon) gene, a member of the platelet factor 4-interleukin-8 cytokine family that is expressed in murine macrophages specifically in response to IFN-gamma. Analysis of mig/CAT chimeric constructs transiently transfected into the RAW 264.7 mouse monocytic cell line revealed a unique IFN-gamma-responsive element (gamma RE-1). The sequence of this cis regulatory element defined by deletion analysis contains an imperfect inverted repeat extending 27 bp. Examination of mig/CAT constructs with mutations in gamma RE-1 revealed that the palindromic positions in the element were essential for activity. Consistent with its function as an enhancer, a single copy of gamma RE-1 conferred IFN-gamma inducibility to a heterologous (herpes simplex virus thymidine kinase) promoter. Exonuclease III protection assays demonstrated symmetrical protection of a mig promoter fragment centered about the gamma RE-1 palindromic sequence. Using the gel electrophoretic mobility shift assay, we identified a factor (gamma RF-1) present in nuclear extracts prepared from IFN-gamma-stimulated RAW 264.7 cells which binds to gamma RE-1. The activation of gamma RF-1 occurred rapidly (within 1 min) in response to IFN-gamma and was independent of protein synthesis. Similar to the expression of mig mRNA, the formation of gamma RF-1 was selectively induced by IFN-gamma and not IFN-alpha. The regulation of gene expression through gamma RF-1 and gamma RE-1 may explain the preferential activation of a subset of interferon-inducible genes by IFN-gamma.
Mol Cell Biol 1994 Feb
PMID:A unique palindromic element mediates gamma interferon induction of mig gene expression. 828 31


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