Functional classification of interferon‐stimulated genes identified using microarrays

Interferons (IFNs) are a family of multifunctional cytokines thatactivate transcription of subsets of genes. The gene products inducedby IFNs are responsible for IFN antiviral, antiproliferative, andimmunomodulatory properties. To obtain a more comprehensive list and abetter understanding of the genes regulated by IFNs, we compiled datafrom many experiments, using two different microarray formats. Thecombined data sets identified >300 IFN‐stimulated genes (ISGs). Toprovide new insight into IFN‐induced cellular phenotypes, we assignedthese ISGs to functional categories. The data are accessible on the World Wide Web at http://www.lerner.ccf.org/labs/williams, including functional categories and individual genes listed in asearchable database. The entries are linked to GenBank and Unigenesequence information and other resources. The goal is to eventuallycompile a comprehensive list of all ISGs. Recognition of the functionsof the ISGs and their specific roles in the biological effects of IFNsis leading to a greater appreciation of the many facets of theseintriguing and essential cytokines. This review focuses on thefunctions of the ISGs identified by analyzing the microarray data andfocuses particularly on new insights into the protein kinaseRNA‐regulated (PRKR) protein, which have been made possible with theavailability of PRKR‐null mice.

[1]  W. Merrick,et al.  A new pathway of translational regulation mediated by eukaryotic initiation factor 3 , 2000, The EMBO journal.

[2]  A. Hovnanian,et al.  Characterization of the gene encoding the 100-kDa form of human 2',5' oligoadenylate synthetase. , 2000, Genomics.

[3]  A N N Gardulf,et al.  Interferon-beta treatment for patients with multiple sclerosis: the patients' perceptions of the side-effects , 2000, Multiple sclerosis.

[4]  S. Akira,et al.  Toll-like receptors: lessons from knockout mice. , 2000, Biochemical Society transactions.

[5]  P. Carmeliet,et al.  Angiogenesis in cancer and other diseases , 2000, Nature.

[6]  B. Williams,et al.  The protein kinase PKR is required for p38 MAPK activation and the innate immune response to bacterial endotoxin , 2000, The EMBO journal.

[7]  M. Crouch,et al.  Nuclear and cytoskeletal translocation and localization of heterotrimeric G‐proteins , 2000, Immunology and cell biology.

[8]  P. Lusso.  Chemokines and viruses: the dearest enemies. , 2000, Virology.

[9]  C. A. de la Motte,et al.  Central Role of Double-Stranded RNA-Activated Protein Kinase in Microbial Induction of Nitric Oxide Synthase1 , 2000, The Journal of Immunology.

[10]  E. Meurs,et al.  PKR Stimulates NF-κB Irrespective of Its Kinase Function by Interacting with the IκB Kinase Complex , 2000, Molecular and Cellular Biology.

[11]  P. Roberts,et al.  Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. , 2000, Immunity.

[12]  Zan Xu,et al.  The B56α Regulatory Subunit of Protein Phosphatase 2A Is a Target for Regulation by Double-Stranded RNA-Dependent Protein Kinase PKR , 2000, Molecular and Cellular Biology.

[13]  John G. Collard,et al.  Rho family proteins in cell adhesion and cell migration. , 2000, European journal of cancer.

[14]  P. Gerwins,et al.  Function of fibroblast growth factors and vascular endothelial growth factors and their receptors in angiogenesis. , 2000, Critical reviews in oncology/hematology.

[15]  R. Vakkalanka,et al.  Induction of Fas ligand-mediated apoptosis by interferon-alpha. , 2000, Clinical immunology.

[16]  T. Di Pucchio,et al.  Type I Interferon as a Powerful Adjuvant for Monocyte-Derived Dendritic Cell Development and Activity in Vitro and in Hu-Pbl-Scid Mice , 2000, The Journal of experimental medicine.

[17]  P. Krammer,et al.  The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems. , 2000, Experimental cell research.

[18]  F. Marincola,et al.  High-fidelity mRNA amplification for gene profiling , 2000, Nature Biotechnology.

[19]  G. Semenza.  HIF-1: mediator of physiological and pathophysiological responses to hypoxia. , 2000, Journal of applied physiology.

[20]  A. Bowie,et al.  The interleukin‐1 receptor/Toll‐like receptor superfamily: signal generators for pro‐inflammatory interleukins and microbial products , 2000, Journal of leukocyte biology.

[21]  D. Kalvakolanu,et al.  Interferons and cell growth control. , 2000, Histology and histopathology.

[22]  A. Israël.  The IKK complex: an integrator of all signals that activate NF-κB? , 2000 .

[23]  M. Esteban,et al.  Activation of NF-κB by the dsRNA-dependent protein kinase, PKR involves the IκB kinase complex , 2000, Oncogene.

[24]  G. Sen,et al.  Characterization of the Interaction between the Interferon-Induced Protein P56 and the Int6 Protein Encoded by a Locus of Insertion of the Mouse Mammary Tumor Virus , 2000, Journal of Virology.

[25]  B. Williams,et al.  NF-κB Activation by Double-Stranded-RNA-Activated Protein Kinase (PKR) Is Mediated through NF-κB-Inducing Kinase and IκB Kinase , 2000, Molecular and Cellular Biology.

[26]  P. Roberts,et al.  Alpha/Beta Interferons Potentiate Virus-Induced Apoptosis through Activation of the FADD/Caspase-8 Death Signaling Pathway , 2000, Journal of Virology.

[27]  M. Tyers,et al.  Proteolysis and the cell cycle: with this RING I do thee destroy. , 2000, Current opinion in genetics & development.

[28]  Michael Karin,et al.  The IκB kinase (IKK) and NF-κB: key elements of proinflammatory signalling , 2000 .

[29]  L. Peso,et al.  The Ras family of GTPases in cancer cell invasion , 2000, Cellular and Molecular Life Sciences CMLS.

[30]  G. Semenza,et al.  Hypoxia, Clonal Selection, and the Role of HIF-1 in Tumor Progression , 2000, Critical reviews in biochemistry and molecular biology.

[31]  M. Karin,et al.  JNK2 and IKKbeta are required for activating the innate response to viral infection. , 1999, Immunity.

[32]  A. Goldberg,et al.  Proteolysis and class I major histocompatibility complex antigen presentation , 1999, Immunological reviews.

[33]  B. Williams,et al.  PKR; a sentinel kinase for cellular stress , 1999, Oncogene.

[34]  D. Templeton,et al.  Deficiency of transporter for antigen presentation (TAP) in tumor cells allows evasion of immune surveillance and increases tumorigenesis. , 1999, Journal of immunology.

[35]  H. Kwon,et al.  Interferon regulatory factors: the next generation. , 1999, Gene.

[36]  H. Stenmark,et al.  Regulation of endocytic membrane traffic by phosphatidylinositol 3-phosphate. , 1999, Biochemical Society transactions.

[37]  S. Akira,et al.  Unresponsiveness of MyD88-deficient mice to endotoxin. , 1999, Immunity.

[38]  B. Williams,et al.  Interferon action in triply deficient mice reveals the existence of alternative antiviral pathways. , 1999, Virology.

[39]  M. Katze,et al.  The emerging role of the interferon-induced PKR protein kinase as an apoptotic effector: a new face of death? , 1999, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[40]  F. Sallusto.  The role of chemokines and chemokine receptors in T cell priming and Th1/Th2-mediated responses. , 1999, Haematologica.

[41]  N. Sonenberg,et al.  Regulatable expression of the interferon-induced double-stranded RNA dependent protein kinase PKR induces apoptosis and fas receptor expression. , 1999, Virology.

[42]  Bernard Roizman.  HSV gene functions: what have we learned that could be generally applicable to its near and distant cousins? , 1999, Acta virologica.

[43]  L. Lau,et al.  Fisp12/Mouse Connective Tissue Growth Factor Mediates Endothelial Cell Adhesion and Migration through Integrin αvβ3, Promotes Endothelial Cell Survival, and Induces Angiogenesis In Vivo , 1999, Molecular and Cellular Biology.

[44]  J. Carton,et al.  Interferon-induced guanylate binding protein-1 (GBP-1) mediates an antiviral effect against vesicular stomatitis virus and encephalomyocarditis virus. , 1999, Virology.

[45]  I. Weissman,et al.  Cyclophilin C-associated protein: a normal secreted glycoprotein that down-modulates endotoxin and proinflammatory responses in vivo. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[46]  G. Kochs,et al.  Interferon-induced human MxA GTPase blocks nuclear import of Thogoto virus nucleocapsids. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[47]  G. Kochs,et al.  GTP-bound Human MxA Protein Interacts with the Nucleocapsids of Thogoto Virus (Orthomyxoviridae)* , 1999, The Journal of Biological Chemistry.

[48]  E. Reddy,et al.  Modulation of life and death by the TNF receptor superfamily , 1998, Oncogene.

[49]  B. Williams,et al.  Identification of genes differentially regulated by interferon α, β, or γ using oligonucleotide arrays , 1998 .

[50]  T. Mak,et al.  Activation of the dsRNA‐dependent protein kinase, PKR, induces apoptosis through FADD‐mediated death signaling , 1998, The EMBO journal.

[51]  G. Stark,et al.  How cells respond to interferons. , 1998, Annual review of biochemistry.

[52]  P. Moore,et al.  Role of the interferon regulatory factors (IRFs) in virus-mediated signaling and regulation of cell growth. , 1998, Biochimie.

[53]  S. Akira,et al.  Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. , 1998, Immunity.

[54]  S Pestka,et al.  Biological properties of recombinant alpha-interferons: 40th anniversary of the discovery of interferons. , 1998, Cancer research.

[55]  P. Ratcliffe,et al.  Oxygen sensing, hypoxia-inducible factor-1 and the regulation of mammalian gene expression. , 1998, The Journal of experimental biology.

[56]  B. Williams,et al.  Signal transduction in the interferon system. , 1998, Seminars in oncology.

[57]  C. Parkos.  Molecular events in neutrophil transepithelial migration , 1997, BioEssays : news and reviews in molecular, cellular and developmental biology.

[58]  M J Clemens,et al.  The double-stranded RNA-dependent protein kinase PKR: structure and function. , 1997, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[59]  D. Grandér,et al.  How does interferon exert its cell growth inhibitory effect? , 1997, European journal of haematology.

[60]  David M. Rothwarf,et al.  A cytokine-responsive IκB kinase that activates the transcription factor NF-κB , 1997, Nature.

[61]  G. Kroemer.  The proto-oncogene Bcl-2 and its role in regulating apoptosis , 1997, Nature Medicine.

[62]  P. Sims,et al.  Molecular Cloning of Human Plasma Membrane Phospholipid Scramblase , 1997, The Journal of Biological Chemistry.

[63]  D. Lancet,et al.  GeneCards: integrating information about genes, proteins and diseases. , 1997, Trends in genetics : TIG.

[64]  S. Der,et al.  A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[65]  Eric J. Brown,et al.  Decreased Resistance to Bacterial Infection and Granulocyte Defects in IAP-Deficient Mice , 1996, Science.

[66]  P. Cresswell,et al.  Processing and delivery of peptides presented by MHC class I molecules. , 1996, Current opinion in immunology.

[67]  A. Aguzzi,et al.  Deficient signaling in mice devoid of double‐stranded RNA‐dependent protein kinase. , 1995, The EMBO journal.

[68]  M. Tymms,et al.  A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons alpha and beta and alters macrophage responses. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[69]  T. Taniguchi.  IRF-1 and IRF-2 as regulators of the interferon system and cell growth. , 1995, Indian journal of biochemistry & biophysics.

[70]  J. Gamble,et al.  Transendothelial migration of neutrophils involves integrin-associated protein (CD47). , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[71]  Z. Bi,et al.  Inhibition of vesicular stomatitis virus infection by nitric oxide , 1995, Journal of virology.

[72]  D. Chaudhary,et al.  The c-myc promoter binding protein (MBP-1) and TBP bind simultaneously in the minor groove of the c-myc P2 promoter. , 1995, Biochemistry.

[73]  M Aguet,et al.  Functional role of type I and type II interferons in antiviral defense. , 1994, Science.

[74]  R. Zinkernagel,et al.  Immune response in mice that lack the interferon-gamma receptor. , 1993, Science.

[75]  H. W. Chang,et al.  The E3L and K3L vaccinia virus gene products stimulate translation through inhibition of the double-stranded RNA-dependent protein kinase by different mechanisms , 1993, Journal of virology.

[76]  I. Kerr,et al.  Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon , 1990, Cell.

[77]  W. Boll,et al.  Mx protein: Constitutive expression in 3T3 cells transformed with cloned Mx cDNA confers selective resistance to influenza virus , 1986, Cell.

[78]  B. Williams,et al.  NF-kappaB activation by double-stranded-RNA-activated protein kinase (PKR) is mediated through NF-kappaB-inducing kinase and IkappaB kinase. , 2000, Molecular and cellular biology.

[79]  Lili Feng.  Role of chemokines in inflammation and immunoregulation , 2000, Immunologic research.

[80]  M. Esteban,et al.  Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex. , 2000, Oncogene.

[81]  M. Karin,et al.  Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. , 2000, Annual review of immunology.

[82]  A. Israël.  The IKK complex: an integrator of all signals that activate NF-kappaB? , 2000, Trends in cell biology.

[83]  M. Katze,et al.  Evading the interferon response: hepatitis C virus and the interferon-induced protein kinase, PKR. , 2000, Current topics in microbiology and immunology.

[84]  M. Karin,et al.  The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling. , 2000, Seminars in immunology.

[85]  J. Hiscott,et al.  Triggering the interferon response: the role of IRF-3 transcription factor. , 1999, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[86]  C. Betsholtz,et al.  Role of platelet-derived growth factors in angiogenesis and alveogenesis. , 1999, Current topics in pathology. Ergebnisse der Pathologie.

[87]  S H Kaufmann,et al.  Mammalian caspases: structure, activation, substrates, and functions during apoptosis. , 1999, Annual review of biochemistry.

[88]  B. Williams,et al.  Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[89]  E. Zandi,et al.  A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. , 1997, Nature.

[90]  M. G. Santoro.  Viral infection. , 1996, EXS.

[91]  B. Vogelstein,et al.  Prevalence of ras gene mutations in human colorectal cancers , 1987, Nature.