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  1. Article ; Online: Adenosine Deaminases Acting on RNA (ADARs) and Viral Infections.

    Pfaller, Christian K / George, Cyril X / Samuel, Charles E

    Annual review of virology

    2021  Volume 8, Issue 1, Page(s) 239–264

    Abstract: C6 deamination of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA) is catalyzed by a family of enzymes known as ADARs (adenosine deaminases acting on RNA) encoded by three genes in mammals. Alternative promoters and splicing produce two ADAR1 ... ...

    Abstract C6 deamination of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA) is catalyzed by a family of enzymes known as ADARs (adenosine deaminases acting on RNA) encoded by three genes in mammals. Alternative promoters and splicing produce two ADAR1 proteins, an interferon-inducible cytoplasmic p150 and a constitutively expressed p110 that like ADAR2 is a nuclear enzyme. ADAR3 lacks deaminase activity. A-to-I editing occurs with both viral and cellular RNAs. Deamination activity is dependent on dsRNA substrate structure and regulatory RNA-binding proteins and ranges from highly site selective with hepatitis D RNA and glutamate receptor precursor messenger RNA (pre-mRNA) to hyperediting of measles virus and polyomavirus transcripts and cellular inverted
    MeSH term(s) Adenosine Deaminase/chemistry ; Adenosine Deaminase/genetics ; Adenosine Deaminase/metabolism ; Animals ; RNA Editing ; RNA, Double-Stranded/genetics ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Virus Diseases
    Chemical Substances RNA, Double-Stranded ; RNA-Binding Proteins ; Adenosine Deaminase (EC 3.5.4.4)
    Language English
    Publishing date 2021-04-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2764224-0
    ISSN 2327-0578 ; 2327-056X
    ISSN (online) 2327-0578
    ISSN 2327-056X
    DOI 10.1146/annurev-virology-091919-065320
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: STAT2-dependent induction of RNA adenosine deaminase ADAR1 by type I interferon differs between mouse and human cells in the requirement for STAT1.

    George, Cyril X / Samuel, Charles E

    Virology

    2015  Volume 485, Page(s) 363–370

    Abstract: Expression of adenosine deaminase acting on RNA1 (ADAR1) is driven by alternative promoters. Promoter PA, activated by interferon (IFN), produces transcripts that encode the inducible p150 ADAR1 protein, whereas PB specifies the constitutively expressed ... ...

    Abstract Expression of adenosine deaminase acting on RNA1 (ADAR1) is driven by alternative promoters. Promoter PA, activated by interferon (IFN), produces transcripts that encode the inducible p150 ADAR1 protein, whereas PB specifies the constitutively expressed p110 protein. We show using Stat1(-/-), Stat2(-/-) and IRF9(-/-) MEFs that induction of ADAR1 p150 occurs by STAT2- and IRF9-dependent signaling that is enhanced by, but not obligatorily dependent upon, STAT1. Chromatin immunoprecipitation analysis demonstrated STAT2 at the PA promoter in IFN-treated Stat1(-/-) cells, whereas IFN-treated wild-type cells showed both STAT1 and STAT2 bound at PA. By contrast, with human 2fTGH cells and mutants U3A or U6A, ADAR1 induction by IFN was dependent upon both STAT1 and STAT2. These results suggest that transcriptional activation of Adar1 by IFN occurs in the absence of STAT1 by a non-canonical STAT2-dependent pathway in mouse but not human cells.
    MeSH term(s) Adenosine Deaminase/genetics ; Adenosine Deaminase/metabolism ; Animals ; Cell Line ; Gene Expression Regulation/drug effects ; Gene Knockout Techniques ; Humans ; Interferon Type I/metabolism ; Interferon Type I/pharmacology ; Mice ; Promoter Regions, Genetic ; Protein Binding ; RNA, Messenger/genetics ; STAT1 Transcription Factor/genetics ; STAT1 Transcription Factor/metabolism ; STAT2 Transcription Factor/genetics ; STAT2 Transcription Factor/metabolism ; Transcriptional Activation
    Chemical Substances Interferon Type I ; RNA, Messenger ; STAT1 Transcription Factor ; STAT2 Transcription Factor ; Adenosine Deaminase (EC 3.5.4.4)
    Language English
    Publishing date 2015-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 200425-2
    ISSN 1096-0341 ; 0042-6822
    ISSN (online) 1096-0341
    ISSN 0042-6822
    DOI 10.1016/j.virol.2015.08.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A broad-spectrum synthetic antibiotic that does not evoke bacterial resistance.

    Heithoff, Douglas M / Mahan, Scott P / Barnes V, Lucien / Leyn, Semen A / George, Cyril X / Zlamal, Jaime E / Limwongyut, Jakkarin / Bazan, Guillermo C / Fried, Jeffrey C / Fitzgibbons, Lynn N / House, John K / Samuel, Charles E / Osterman, Andrei L / Low, David A / Mahan, Michael J

    EBioMedicine

    2023  Volume 89, Page(s) 104461

    Abstract: Background: Antimicrobial resistance (AMR) poses a critical threat to public health and disproportionately affects the health and well-being of persons in low-income and middle-income countries. Our aim was to identify synthetic antimicrobials termed ... ...

    Abstract Background: Antimicrobial resistance (AMR) poses a critical threat to public health and disproportionately affects the health and well-being of persons in low-income and middle-income countries. Our aim was to identify synthetic antimicrobials termed conjugated oligoelectrolytes (COEs) that effectively treated AMR infections and whose structures could be readily modified to address current and anticipated patient needs.
    Methods: Fifteen chemical variants were synthesized that contain specific alterations to the COE modular structure, and each variant was evaluated for broad-spectrum antibacterial activity and for in vitro cytotoxicity in cultured mammalian cells. Antibiotic efficacy was analyzed in murine models of sepsis; in vivo toxicity was evaluated via a blinded study of mouse clinical signs as an outcome of drug treatment.
    Findings: We identified a compound, COE2-2hexyl, that displayed broad-spectrum antibacterial activity. This compound cured mice infected with clinical bacterial isolates derived from patients with refractory bacteremia and did not evoke bacterial resistance. COE2-2hexyl has specific effects on multiple membrane-associated functions (e.g., septation, motility, ATP synthesis, respiration, membrane permeability to small molecules) that may act together to negate bacterial cell viability and the evolution of drug-resistance. Disruption of these bacterial properties may occur through alteration of critical protein-protein or protein-lipid membrane interfaces-a mechanism of action distinct from many membrane disrupting antimicrobials or detergents that destabilize membranes to induce bacterial cell lysis.
    Interpretation: The ease of molecular design, synthesis and modular nature of COEs offer many advantages over conventional antimicrobials, making synthesis simple, scalable and affordable. These COE features enable the construction of a spectrum of compounds with the potential for development as a new versatile therapy for an imminent global health crisis.
    Funding: U.S. Army Research Office, National Institute of Allergy and Infectious Diseases, and National Heart, Lung, and Blood Institute.
    MeSH term(s) Mice ; Animals ; Anti-Bacterial Agents/pharmacology ; Bacterial Infections/microbiology ; Anti-Infective Agents/pharmacology ; Bacteria ; Sepsis/drug therapy ; Microbial Sensitivity Tests ; Drug Resistance, Multiple, Bacterial ; Mammals
    Chemical Substances Anti-Bacterial Agents ; Anti-Infective Agents
    Language English
    Publishing date 2023-02-15
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2851331-9
    ISSN 2352-3964
    ISSN (online) 2352-3964
    DOI 10.1016/j.ebiom.2023.104461
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Upon Infection, Cellular WD Repeat-Containing Protein 5 (WDR5) Localizes to Cytoplasmic Inclusion Bodies and Enhances Measles Virus Replication.

    Ma, Dzwokai / George, Cyril X / Nomburg, Jason L / Pfaller, Christian K / Cattaneo, Roberto / Samuel, Charles E

    Journal of virology

    2018  Volume 92, Issue 5

    Abstract: Replication of negative-strand RNA viruses occurs in association with discrete cytoplasmic foci called inclusion bodies. Whereas inclusion bodies represent a prominent subcellular structure induced by viral infection, our knowledge of the cellular ... ...

    Abstract Replication of negative-strand RNA viruses occurs in association with discrete cytoplasmic foci called inclusion bodies. Whereas inclusion bodies represent a prominent subcellular structure induced by viral infection, our knowledge of the cellular protein components involved in inclusion body formation and function is limited. Using measles virus-infected HeLa cells, we found that the WD repeat-containing protein 5 (WDR5), a subunit of histone H3 lysine 4 methyltransferases, was selectively recruited to virus-induced inclusion bodies. Furthermore, WDR5 was found in complexes containing viral proteins associated with RNA replication. WDR5 was not detected with mitochondria, stress granules, or other known secretory or endocytic compartments of infected cells. WDR5 deficiency decreased both viral protein production and infectious virus yields. Interferon production was modestly increased in WDR5-deficient cells. Thus, our study identifies WDR5 as a novel viral inclusion body-associated cellular protein and suggests a role for WDR5 in promoting viral replication.
    MeSH term(s) Cytoplasm/virology ; HeLa Cells ; Histone-Lysine N-Methyltransferase/genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Humans ; Inclusion Bodies, Viral/physiology ; Measles/metabolism ; Measles/virology ; Measles virus/physiology ; RNA, Viral/genetics ; RNA, Viral/metabolism ; Viral Proteins/genetics ; Viral Proteins/metabolism ; Virus Replication
    Chemical Substances RNA, Viral ; Viral Proteins ; WDR5 protein, human ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43)
    Language English
    Publishing date 2018-02-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.01726-17
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Editing of Cellular Self-RNAs by Adenosine Deaminase ADAR1 Suppresses Innate Immune Stress Responses.

    George, Cyril X / Ramaswami, Gokul / Li, Jin Billy / Samuel, Charles E

    The Journal of biological chemistry

    2016  Volume 291, Issue 12, Page(s) 6158–6168

    Abstract: Adenosine deaminases acting on double-stranded RNA (ADARs) catalyze the deamination of adenosine (A) to produce inosine (I) in double-stranded (ds) RNA structures, a process known as A-to-I RNA editing. dsRNA is an important trigger of innate immune ... ...

    Abstract Adenosine deaminases acting on double-stranded RNA (ADARs) catalyze the deamination of adenosine (A) to produce inosine (I) in double-stranded (ds) RNA structures, a process known as A-to-I RNA editing. dsRNA is an important trigger of innate immune responses, including interferon (IFN) production and action. We examined the role of A-to-I RNA editing by two ADARs, ADAR1 and ADAR2, in the sensing of self-RNA in the absence of pathogen infection, leading to activation of IFN-induced, RNA-mediated responses in mouse embryo fibroblasts. IFN treatment of Adar1(-/-) cells lacking both the p110 constitutive and p150 IFN-inducible ADAR1 proteins induced formation of stress granules, whereas neither wild-type (WT) nor Adar2(-/-) cells displayed a comparable stress granule response following IFN treatment. Phosphorylation of protein synthesis initiation factor eIF2α at serine 51 was increased in IFN-treated Adar1(-/-) cells but not in either WT or Adar2(-/-) cells following IFN treatment. Analysis by deep sequencing of mouse exonic loci containing A-to-I-editing sites revealed that the majority of editing in mouse embryo fibroblasts was carried out by ADAR1. IFN treatment increased editing in both WT and Adar2(-/-) cells but not in either Adar1(-/-) or Adar1(-/-) (p150) cells or Stat1(-/-) or Stat2(-/-) cells. Hyper-edited sites found in predicted duplex structures showed strand bias of editing for some RNAs. These results implicate ADAR1 p150 as the major A-to-I editor in mouse embryo fibroblasts, acting as a feedback suppressor of innate immune responses otherwise triggered by self-RNAs possessing regions of double-stranded character.
    MeSH term(s) Adenosine Deaminase/physiology ; Animals ; Cells, Cultured ; Cytoplasmic Granules/metabolism ; Deamination ; Eukaryotic Initiation Factor-2/metabolism ; Fibroblasts/metabolism ; Immune Tolerance ; Immunity, Innate ; Interferon-alpha/physiology ; Mice, Knockout ; Phosphorylation ; Protein Processing, Post-Translational ; RNA Editing ; RNA, Double-Stranded/genetics ; RNA, Double-Stranded/metabolism ; RNA-Binding Proteins/physiology ; Signal Transduction
    Chemical Substances Eukaryotic Initiation Factor-2 ; Interferon-alpha ; RNA, Double-Stranded ; RNA-Binding Proteins ; ADAR1 protein, mouse (EC 3.5.4.4) ; ADAR2 protein, mouse (EC 3.5.4.4) ; Adenosine Deaminase (EC 3.5.4.4)
    Language English
    Publishing date 2016-01-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M115.709014
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  6. Article ; Online: Host response to polyomavirus infection is modulated by RNA adenosine deaminase ADAR1 but not by ADAR2.

    George, Cyril X / Samuel, Charles E

    Journal of virology

    2011  Volume 85, Issue 16, Page(s) 8338–8347

    Abstract: Adenosine deaminases acting on RNA (ADARs) catalyze the C-6 deamination of adenosine (A) to produce inosine (I), which behaves as guanine (G), thereby altering base pairing in RNAs with double-stranded character. Two genes, adar1 and adar2, are known to ... ...

    Abstract Adenosine deaminases acting on RNA (ADARs) catalyze the C-6 deamination of adenosine (A) to produce inosine (I), which behaves as guanine (G), thereby altering base pairing in RNAs with double-stranded character. Two genes, adar1 and adar2, are known to encode enzymatically active ADARs in mammalian cells. Furthermore, two size forms of ADAR1 are expressed by alternative promoter usage, a short (p110) nuclear form that is constitutively made and a long (p150) form that is interferon inducible and present in both the cytoplasm and nucleus. ADAR2 is also a constitutively expressed nuclear protein. Extensive A-to-G substitution has been described in mouse polyomavirus (PyV) RNA isolated late times after infection, suggesting modification by ADAR. To test the role of ADAR in PyV infection, we used genetically null mouse embryo fibroblast cells deficient in either ADAR1 or ADAR2. The single-cycle yields and growth kinetics of PyV were comparable between adar1(-/-) and adar2(-/-) genetic null fibroblast cells. While large T antigen was expressed to higher levels in adar1(-/-) cells than adar2(-/-) cells, less difference was seen in VP1 protein expression levels between the two knockout MEFs. However, virus-induced cell killing was greatly enhanced in PyV-infected adar1(-/-) cells compared to that of adar2(-/-) cells. Complementation with p110 protected cells from PyV-induced cytotoxicity. UV-irradiated PyV did not display any enhanced cytopathic effect in adar1(-/-) cells. Reovirus and vesicular stomatitis virus single-cycle yields were comparable between adar1(-/-) and adar2(-/-) cells, and neither reovirus nor VSV showed enhanced cytotoxicity in adar1(-/-)-infected cells. These results suggest that ADAR1 plays a virus-selective role in the host response to infection.
    MeSH term(s) Adenosine Deaminase/genetics ; Adenosine Deaminase/metabolism ; Amino Acid Substitution ; Animals ; Animals, Genetically Modified ; Antigens, Polyomavirus Transforming/biosynthesis ; Antigens, Polyomavirus Transforming/genetics ; Base Pairing ; Capsid Proteins/biosynthesis ; Capsid Proteins/genetics ; Cell Line ; Cytopathogenic Effect, Viral ; Fibroblasts ; Mice ; Polymerase Chain Reaction ; Polyomavirus/growth & development ; Polyomavirus/pathogenicity ; Polyomavirus Infections/virology ; RNA-Binding Proteins ; Reoviridae/growth & development ; Vesiculovirus/growth & development
    Chemical Substances Antigens, Polyomavirus Transforming ; Capsid Proteins ; RNA-Binding Proteins ; VP1 protein, polyomavirus ; ADARB1 protein, human (EC 3.5.4.4) ; Adenosine Deaminase (EC 3.5.4.4)
    Language English
    Publishing date 2011-06-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.02666-10
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  7. Article ; Online: An RNA editor, adenosine deaminase acting on double-stranded RNA (ADAR1).

    George, Cyril X / John, Lijo / Samuel, Charles E

    Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research

    2014  Volume 34, Issue 6, Page(s) 437–446

    Abstract: Adenosine deaminase acting on RNA1 (ADAR1) catalyzes the C6 deamination of adenosine (A) to produce inosine (I) in regions of RNA with double-stranded (ds) character. This process is known as A-to-I RNA editing. Alternative promoters drive the expression ...

    Abstract Adenosine deaminase acting on RNA1 (ADAR1) catalyzes the C6 deamination of adenosine (A) to produce inosine (I) in regions of RNA with double-stranded (ds) character. This process is known as A-to-I RNA editing. Alternative promoters drive the expression of the Adar1 gene and alternative splicing gives rise to transcripts that encode 2 ADAR1 protein size isoforms. ADAR1 p150 is an interferon (IFN)-inducible dsRNA adenosine deaminase found in the cytoplasm and nucleus, whereas ADAR1 p110 is constitutively expressed and nuclear in localization. Dependent on the duplex structure of the dsRNA substrate, deamination of adenosine by ADAR can be either highly site-selective or nonspecific. A-to-I editing can alter the stability of RNA structures and the coding of RNA as I is read as G instead of A by ribosomes during mRNA translation and by polymerases during RNA replication. A-to-I editing is of broad physiologic significance. Both the production and the action of IFNs, and hence the subsequent interaction of viruses with their hosts, are among the processes affected by A-to-I editing.
    MeSH term(s) Adenosine Deaminase/metabolism ; Animals ; Humans ; RNA Editing ; RNA, Double-Stranded/metabolism ; RNA-Binding Proteins/metabolism
    Chemical Substances RNA, Double-Stranded ; RNA-Binding Proteins ; ADAR protein, human (EC 3.5.4.37) ; Adenosine Deaminase (EC 3.5.4.4)
    Language English
    Publishing date 2014-06-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1226675-9
    ISSN 1557-7465 ; 1079-9907
    ISSN (online) 1557-7465
    ISSN 1079-9907
    DOI 10.1089/jir.2014.0001
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  8. Article ; Online: Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy.

    Jackson, Jeffrey J / Shibuya, Grant M / Ravishankar, Buvana / Adusumilli, Lavanya / Bradford, Delia / Brockstedt, Dirk G / Bucher, Cyril / Bui, Minna / Cho, Cynthia / Colas, Christoph / Cutler, Gene / Dukes, Adrian / Han, Xinping / Hu, Dennis X / Jacobson, Scott / Kassner, Paul D / Katibah, George E / Ko, Michelle Yoo Min / Kolhatkar, Urvi /
    Leger, Paul R / Ma, Anqi / Marshall, Lisa / Maung, Jack / Ng, Andrew A / Okano, Akinori / Pookot, Deepa / Poon, Daniel / Ramana, Chandru / Reilly, Maureen K / Robles, Omar / Schwarz, Jacob B / Shakhmin, Anton A / Shunatona, Hunter P / Sreenivasan, Raashi / Tivitmahaisoon, Parcharee / Xu, Mengshu / Zaw, Thant / Wustrow, David J / Zibinsky, Mikhail

    Journal of medicinal chemistry

    2022  Volume 65, Issue 19, Page(s) 12895–12924

    Abstract: General control nonderepressible 2 (GCN2) protein kinase is a cellular stress sensor within the tumor microenvironment (TME), whose signaling cascade has been proposed to contribute to immune escape in tumors. Herein, we report the discovery of cell- ... ...

    Abstract General control nonderepressible 2 (GCN2) protein kinase is a cellular stress sensor within the tumor microenvironment (TME), whose signaling cascade has been proposed to contribute to immune escape in tumors. Herein, we report the discovery of cell-potent GCN2 inhibitors with excellent selectivity against its closely related Integrated Stress Response (ISR) family members heme-regulated inhibitor kinase (HRI), protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase (PERK), as well as good kinome-wide selectivity and favorable PK. In mice, compound
    MeSH term(s) Animals ; Heme ; Mice ; Mice, Knockout ; Myeloid-Derived Suppressor Cells ; Protein Serine-Threonine Kinases ; T-Lymphocytes/metabolism ; eIF-2 Kinase/metabolism
    Chemical Substances Heme (42VZT0U6YR) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1)
    Language English
    Publishing date 2022-09-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.2c00736
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  9. Article ; Online: Protein kinase PKR and RNA adenosine deaminase ADAR1: new roles for old players as modulators of the interferon response.

    Pfaller, Christian K / Li, Zhiqun / George, Cyril X / Samuel, Charles E

    Current opinion in immunology

    2011  Volume 23, Issue 5, Page(s) 573–582

    Abstract: Double-stranded RNA (dsRNA) plays a centrally important role in antiviral innate immunity, both for the production of interferon (IFN) and also in the actions of IFN. Among the IFN-inducible gene products are the protein kinase regulated by RNA (PKR) and ...

    Abstract Double-stranded RNA (dsRNA) plays a centrally important role in antiviral innate immunity, both for the production of interferon (IFN) and also in the actions of IFN. Among the IFN-inducible gene products are the protein kinase regulated by RNA (PKR) and the adenosine deaminase acting on RNA 1 (ADAR1). PKR is an established key player in the antiviral actions of IFN, through dsRNA-dependent activation and subsequent phosphorylation of protein synthesis initiation factor eIF2α thereby altering the translational pattern in cells. In addition, PKR plays an important role as a positive effector that amplifies the production of IFN. ADAR1 catalyzes the deamination of adenosine (A) in RNA with double-stranded (ds) character, leading to the destabilization of RNA duplex structures and genetic recoding. By contrast to the antiviral and proapoptotic functions associated with PKR, the actions of ADAR1 in some instances are proviral and cell protective as ADAR1 functions as a suppressor of dsRNA-mediated antiviral responses including activation of PKR and interferon regulatory factor 3.
    MeSH term(s) Adenosine/metabolism ; Adenosine Deaminase/genetics ; Adenosine Deaminase/immunology ; Adenosine Deaminase/metabolism ; Animals ; Eukaryotic Initiation Factor-2/genetics ; Eukaryotic Initiation Factor-2/immunology ; Eukaryotic Initiation Factor-2/metabolism ; Gene Expression Regulation/immunology ; Humans ; Immunity, Innate ; Interferon Regulatory Factor-3/genetics ; Interferon Regulatory Factor-3/immunology ; Interferon Regulatory Factor-3/metabolism ; Interferons/genetics ; Interferons/immunology ; Interferons/metabolism ; Mice ; Phosphorylation ; Protein Structure, Tertiary ; RNA Virus Infections/genetics ; RNA Virus Infections/immunology ; RNA Virus Infections/virology ; RNA Viruses/immunology ; RNA, Double-Stranded/immunology ; RNA, Viral/immunology ; Signal Transduction/immunology ; eIF-2 Kinase/genetics ; eIF-2 Kinase/immunology ; eIF-2 Kinase/metabolism
    Chemical Substances Eukaryotic Initiation Factor-2 ; IRF3 protein, human ; Interferon Regulatory Factor-3 ; RNA, Double-Stranded ; RNA, Viral ; Interferons (9008-11-1) ; eIF-2 Kinase (EC 2.7.11.1) ; Adenosine Deaminase (EC 3.5.4.4) ; Adenosine (K72T3FS567)
    Language English
    Publishing date 2011-09-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1035767-1
    ISSN 1879-0372 ; 0952-7915
    ISSN (online) 1879-0372
    ISSN 0952-7915
    DOI 10.1016/j.coi.2011.08.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Organization of the mouse RNA-specific adenosine deaminase Adar1 gene 5'-region and demonstration of STAT1-independent, STAT2-dependent transcriptional activation by interferon.

    George, Cyril X / Das, Sonali / Samuel, Charles E

    Virology

    2008  Volume 380, Issue 2, Page(s) 338–343

    Abstract: The p150 form of the RNA-specific adenosine deaminase ADAR1 is interferon-inducible and catalyzes A-to-I editing of viral and cellular RNAs. We have characterized mouse genomic clones containing the promoter regions required for Adar1 gene transcription ... ...

    Abstract The p150 form of the RNA-specific adenosine deaminase ADAR1 is interferon-inducible and catalyzes A-to-I editing of viral and cellular RNAs. We have characterized mouse genomic clones containing the promoter regions required for Adar1 gene transcription and analyzed interferon induction of the p150 protein using mutant mouse cell lines. Transient transfection analyses using reporter constructs led to the identification of three promoters, one interferon-inducible (P(A)) and two constitutively active (P(B) and P(C)). The TATA-less P(A) promoter, characterized by the presence of a consensus ISRE element and a PKR kinase KCS-like element, directed interferon-inducible reporter expression in rodent and human cells. Interferon induction of p150 was impaired in mouse cells deficient in IFNAR receptor, JAK1 kinase or STAT2 but not STAT1. Whereas Adar1 gene organization involving multiple promoters and alternative exon 1 structures was highly preserved, sequences of the promoters and exon 1 structures were not well conserved between human and mouse.
    MeSH term(s) Adenosine Deaminase/biosynthesis ; Adenosine Deaminase/genetics ; Animals ; Artificial Gene Fusion ; Base Sequence ; Binding Sites ; Cell Line ; Conserved Sequence ; Genes, Reporter ; Humans ; Interferons/metabolism ; Janus Kinase 1/deficiency ; Luciferases/biosynthesis ; Luciferases/genetics ; Mice ; Molecular Sequence Data ; Promoter Regions, Genetic ; RNA-Binding Proteins ; Receptor, Interferon alpha-beta/deficiency ; STAT1 Transcription Factor/deficiency ; STAT1 Transcription Factor/metabolism ; STAT2 Transcription Factor/deficiency ; STAT2 Transcription Factor/metabolism ; Sequence Analysis, DNA ; Transcription, Genetic
    Chemical Substances Ifnar1 protein, mouse ; RNA-Binding Proteins ; STAT1 Transcription Factor ; STAT2 Transcription Factor ; Stat1 protein, mouse ; Stat2 protein, mouse ; Receptor, Interferon alpha-beta (156986-95-7) ; Interferons (9008-11-1) ; Luciferases (EC 1.13.12.-) ; Jak1 protein, mouse (EC 2.7.10.2) ; Janus Kinase 1 (EC 2.7.10.2) ; ADARB1 protein, human (EC 3.5.4.4) ; Adenosine Deaminase (EC 3.5.4.4)
    Language English
    Publishing date 2008-09-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 200425-2
    ISSN 1096-0341 ; 0042-6822
    ISSN (online) 1096-0341
    ISSN 0042-6822
    DOI 10.1016/j.virol.2008.07.029
    Database MEDical Literature Analysis and Retrieval System OnLINE

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