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Journal ArticleDOI

Targeted Disruption of the Mouse Stat1 Gene Results in Compromised Innate Immunity to Viral Disease

09 Feb 1996-Cell (Cell Press)-Vol. 84, Iss: 3, pp 443-450
TL;DR: Cell and tissues from Stat1(-1-1) mice were unresponsive to IFN, but remained responsive to all other cytokines tested, indicating that STAT1 appears to be specific for IFN pathways that are essential for viability in the face of otherwise innocuous pathogens.
About: This article is published in Cell.The article was published on 1996-02-09 and is currently open access. It has received 1554 citations till now. The article focuses on the topics: Leukemia inhibitory factor & Innate immune system.
Citations
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Journal ArticleDOI
TL;DR: The Janus kinases and signal transducers and activators of transcription, and many of the interferon-induced proteins, play important alternative roles in cells, raising interesting questions as to how the responses to the interFERons intersect with more general aspects of cellular physiology and how the specificity of cytokine responses is maintained.
Abstract: Interferons play key roles in mediating antiviral and antigrowth responses and in modulating immune response. The main signaling pathways are rapid and direct. They involve tyrosine phosphorylation and activation of signal transducers and activators of transcription factors by Janus tyrosine kinases at the cell membrane, followed by release of signal transducers and activators of transcription and their migration to the nucleus, where they induce the expression of the many gene products that determine the responses. Ancillary pathways are also activated by the interferons, but their effects on cell physiology are less clear. The Janus kinases and signal transducers and activators of transcription, and many of the interferon-induced proteins, play important alternative roles in cells, raising interesting questions as to how the responses to the interferons intersect with more general aspects of cellular physiology and how the specificity of cytokine responses is maintained.

4,026 citations

Journal ArticleDOI
TL;DR: The current understanding of IFN‐γ ligand, receptor, ignal transduction, and cellular effects with a focus on macrophage responses and to a lesser extent, responses from other cell types that influence macrophages function during infection are reviewed.
Abstract: Interferon-gamma (IFN-gamma) coordinates a diverse array of cellular programs through transcriptional regulation of immunologically relevant genes. This article reviews the current understanding of IFN-gamma ligand, receptor, signal transduction, and cellular effects with a focus on macrophage responses and to a lesser extent, responses from other cell types that influence macrophage function during infection. The current model for IFN-gamma signal transduction is discussed, as well as signal regulation and factors conferring signal specificity. Cellular effects of IFN-gamma are described, including up-regulation of pathogen recognition, antigen processing and presentation, the antiviral state, inhibition of cellular proliferation and effects on apoptosis, activation of microbicidal effector functions, immunomodulation, and leukocyte trafficking. In addition, integration of signaling and response with other cytokines and pathogen-associated molecular patterns, such as tumor necrosis factor-alpha, interleukin-4, type I IFNs, and lipopolysaccharide are discussed.

3,589 citations


Cites background from "Targeted Disruption of the Mouse St..."

  • ...This is supported by the Stat1 KO mouse, which displays loss of only IFN signaling, despite multiple reports of Stat1 activation in response to a range of other cytokines in vitro [106, 151]....

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  • ...This susceptibility has been attributed to defective immune system function as a result of the combined loss of types I and II IFN responses [151]....

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Journal ArticleDOI
TL;DR: Much of the cellular response to IFN-gamma can be described in terms of a set of integrated molecular programs underlying well-defined physiological systems, for example the induction of efficient antigen processing for MHC-mediated antigen presentation, which play clearly defined roles in pathogen resistance.
Abstract: Interferons are cytokines that play a complex and central role in the resistance of mammalian hosts to pathogens. Type I interferon (IFN-alpha and IFN-beta) is secreted by virus-infected cells. Immune, type II, or gamma-interferon (IFN-gamma) is secreted by thymus-derived (T) cells under certain conditions of activation and by natural killer (NK) cells. Although originally defined as an agent with direct antiviral activity, the properties of IFN-gamma include regulation of several aspects of the immune response, stimulation of bactericidal activity of phagocytes, stimulation of antigen presentation through class I and class II major histocompatibility complex (MHC) molecules, orchestration of leukocyte-endothelium interactions, effects on cell proliferation and apoptosis, as well as the stimulation and repression of a variety of genes whose functional significance remains obscure. The implementation of such a variety of effects by a single cytokine is achieved by complex patterns of cell-specific gene regulation: Several IFN-gamma-regulated genes are themselves components of transcription factors. The IFN-gamma response is itself regulated by interaction with responses to other cytokines including IFN-alpha/beta, TNF-alpha, and IL-4. Over 200 genes are now known to be regulated by IFN-gamma and they are listed in a World Wide Web document that accompanies this review. However, much of the cellular response to IFN-gamma can be described in terms of a set of integrated molecular programs underlying well-defined physiological systems, for example the induction of efficient antigen processing for MHC-mediated antigen presentation, which play clearly defined roles in pathogen resistance. A promising approach to the complexity of the IFN-gamma response is to extend the analysis of the less understood IFN-gamma-regulated genes in terms of molecular programs functional in pathogen resistance.

2,956 citations

Journal ArticleDOI
TL;DR: The signal transducer and activator of transcription (STAT) proteins are among the most well studied of the latent cytoplasmic signal-dependent transcription-factor pathways.
Abstract: Extracellular proteins bound to cell-surface receptors can change nuclear gene expression patterns in minutes, with far-reaching consequences for development, cell growth and homeostasis. The signal transducer and activator of transcription (STAT) proteins are among the most well studied of the latent cytoplasmic signal-dependent transcription-factor pathways. In addition to several roles in normal cell decisions, dysregulation of STAT function contributes to human disease, making the study of these proteins an important topic of current research.

2,720 citations

Journal ArticleDOI
26 Apr 2001-Nature
TL;DR: It is shown that lymphocytes and IFNγ collaborate to protect against development of carcinogen-induced sarcomas and spontaneous epithelial carcinomas and also to select for tumour cells with reduced immunogenicity, which explains the apparent paradox of tumour formation in immunologically intact individuals.
Abstract: Lymphocytes were originally thought to form the basis of a 'cancer immunosurveillance' process that protects immunocompetent hosts against primary tumour development, but this idea was largely abandoned when no differences in primary tumour development were found between athymic nude mice and syngeneic wild-type mice However, subsequent observations that nude mice do not completely lack functional T cells and that two components of the immune system-IFNgamma and perforin-help to prevent tumour formation in mice have led to renewed interest in a tumour-suppressor role for the immune response Here we show that lymphocytes and IFNgamma collaborate to protect against development of carcinogen-induced sarcomas and spontaneous epithelial carcinomas and also to select for tumour cells with reduced immunogenicity The immune response thus functions as an effective extrinsic tumour-suppressor system However, this process also leads to the immunoselection of tumour cells that are more capable of surviving in an immunocompetent host, which explains the apparent paradox of tumour formation in immunologically intact individuals

2,673 citations

References
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Journal ArticleDOI
TL;DR: A procedure for preparing extracts from nuclei of human tissue culture cells that directs accurate transcription initiation in vitro from class II promoters, including tRNA and Ad 2 VA, is developed.
Abstract: We have developed a procedure for preparing extracts from nuclei of human tissue culture cells that directs accurate transcription initiation in vitro from class II promoters. Conditions of extraction and assay have been optimized for maximum activity using the major late promoter of adenovirus 2. The extract also directs accurate transcription initiation from other adenovirus promoters and cellular promoters. The extract also directs accurate transcription initiation from class III promoters (tRNA and Ad 2 VA).

10,800 citations


"Targeted Disruption of the Mouse St..." refers methods in this paper

  • ...Cytoplasmic and nuclear extracts were prepared from cells as Fujita, T., Sakakibara, J., Sudo, Y., Miyamoto, M., Kimura, Y., and previously described (Dignam et al., 1983)....

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Journal ArticleDOI
03 Jun 1994-Science
TL;DR: A previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that phosphorylate substrate proteins called STATs (signal transducers and activators of transcription).
Abstract: Through the study of transcriptional activation in response to interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma), a previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that then phosphorylate substrate proteins called STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins move to the nucleus, bind specific DNA elements, and direct transcription. Recognition of the molecules involved in the IFN-alpha and IFN-gamma pathway has led to discoveries that a number of STAT family members exist and that other polypeptide ligands also use the Jak-STAT molecules in signal transduction.

5,746 citations

Journal ArticleDOI
TL;DR: Disaggregated mouse embryo cells, grown in monolayers, underwent a progressive decline in growth rate upon successive transfer, the rapidity of the decline depending on the inoculation density, but nearly all cultures developed into established lines within 3 months of culture.
Abstract: Disaggregated mouse embryo cells, grown in monolayers, underwent a progressive decline in growth rate upon successive transfer, the rapidity of the decline depending, among other things, on the inoculation density. Nevertheless, nearly all cultures developed into established lines within 3 months of culture. The first sign of the emergence of an established line was the ability of the cells to maintain a constant or rising potential growth rate. This occurred while the cultures were morphologically unchanged. The growth rate continued to increase until it equaled or exceeded that of the original culture. The early established cells showed an increasing metabolic autonomy, as indicated by decreasing dependence on cell-to-cell feeding. It is suggested that the process of establishment involves an alteration in cell permeability properties. Chromosome studies indicated that the cells responsible for the upturn in growth rate were diploid, but later the population shifted to the tetraploid range, often very rapidly. Still later, marker chromosomes appeared. Different lines acquired different properties, depending on the culture conditions employed; one line developed which is extremely sensitive to contact inhibition.

2,654 citations


"Targeted Disruption of the Mouse St..." refers methods in this paper

  • ..., 1995); however, they also show distinct Cell Culture and Protein Extracts patterns of binding to natural enhancer elements, possiMouse embryo fibroblasts were prepared from individual 12–13 day bly explaining an inability of STAT3 to substitute for embryos by standard methods (Todaro and Green, 1963) and were STAT1 in mutant animals....

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  • ...…Cell Culture and Protein Extractspatterns of binding to natural enhancer elements, possiMouse embryo fibroblasts were prepared from individual 12–13 day bly explaining an inability of STAT3 to substitute for embryos by standard methods (Todaro and Green, 1963) and were STAT1 in mutant animals....

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Journal ArticleDOI
24 Jun 1994-Science
TL;DR: Comparison of mice lacking either type I or type II IFN receptors showed that, at least in response to some viruses, both IFN systems are essential for antiviral defense and are functionally nonredundant.
Abstract: Mice lacking the known subunit of the type I interferon (IFN) receptor were completely unresponsive to type I IFNs, suggesting that this receptor chain is essential for type I IFN-mediated signal transduction. These mice showed no overt anomalies but were unable to cope with viral infections, despite otherwise normal immune responses. Comparison of mice lacking either type I or type II IFN receptors showed that, at least in response to some viruses, both IFN systems are essential for antiviral defense and are functionally nonredundant.

2,438 citations


"Targeted Disruption of the Mouse St..." refers background in this paper

  • ...…infections and the requirement of IFNg receptors for resistance to vaccinia capable of binding and activating the enhancer of the IRF-1 gene (Pine et al., 1994; Sims et al., 1993; Lamb etvirus infection (Huang et al., 1993; Müller et al., 1994; Schijns et al., 1994; Steinhoff et al., 1995)....

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Journal ArticleDOI
TL;DR: This review will examine how two receptor associated tyrosine kinases from the JAK family mediate the transduction of signal directly from receptor to nucleus.
Abstract: Cytokines and growth factors regulate multiple aspects of cell growth through their interactions with specific receptors. These receptors initiate signals directed at both the cytoplasmic and the nuclear compartments. Many of the nuclear signals culminate in the induction of new genes. Characterization of the ability of IFN-alpha to rapidly induce new genes has led to the identification of a new signaling paradigm, the JAK-STAT (Signal Transducers and Activators of Transcription) pathway. In the IFN-alpha pathway, two receptor associated tyrosine kinases from the JAK family, Jak1 and Tyk2, mediate the activation of two latent cytoplasmic transcription factors, Stat1 and Stat2. More recent studies have not only determined that this pathway is used extensively, but have led to the identification of additional components (e.g., Jak2, Jak3, Stat3, Stat4, Stat5, and Stat6). This review will examine how these components mediate the transduction of signal directly from receptor to nucleus.

1,878 citations


"Targeted Disruption of the Mouse St..." refers background or methods in this paper

  • ...cate to the nucleus, where they recognize discrete cisChemically mutagenized human fibrosarcoma cells acting regulatory sequences in DNA (for reviews see defective in STAT1 have been isolated and used to demDarnell et al., 1994; Schindler and Darnell, 1995; Levy, onstrate the requirement for STAT1 in IFN responses 1995)....

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  • ...…they recognize discrete cis- Chemically mutagenized human fibrosarcoma cells acting regulatory sequences in DNA (for reviews see defective in STAT1 have been isolated and used to demDarnell et al., 1994; Schindler and Darnell, 1995; Levy, onstrate the requirement for STAT1 in IFN responses 1995)....

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  • ...Functional redundancy could be provided by STAT3, a closely related protein phosphorylated by RNA Isolation and Analysis many of the same cytokines that activate STAT1, includTotal RNA was isolated from cells disrupted in guanidinium isothioing LIF, IL-6, CSF-1, PDGF, and EGF, as well as IFN cyanate by centrifugation through CsCl, fractionated on formalde(Schindler and Darnell, 1995)....

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  • ...…by RNA Isolation and Analysis many of the same cytokines that activate STAT1, includ- Total RNA was isolated from cells disrupted in guanidinium isothioing LIF, IL-6, CSF-1, PDGF, and EGF, as well as IFN cyanate by centrifugation through CsCl, fractionated on formalde(Schindler and Darnell, 1995)....

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