Signaling in Inflammation, Stress, and Tumorigenesis

Summary

Principal Investigator: GEORGE ROBERT STARK
Abstract: DESCRIPTION (provided by applicant): Cell and tissue injury are accompanied by responses that serve to limit further damage and initiate processes requisite to repair and restoration of normal structure and function. These include both inflammation as well as cellular stress. These events are, however;also recognized as important contributing features of tumorigenesis though the pathways involved remain poorly understood. Initiation of inflammatory response through stimulation of pattern recognition receptors leads to the production of pro-inflammatory cytokines, which further amplify inflammatory gene expression in multiple target cell populations. Cell stress responses can modify inflammation and contribute significantly to cell and tissue repair. The downstream signals associated with both inflammatory and stress responses lead to altered patterns of transcription factor activation/function, post-transcriptional regulation and target gene expression. Collectively these changes translate into the loss of control of normal cellular proliferation, migration, and neighboring cell-cell interactions and ultimately contribute to the malignant transition. This program will address aspects of pathogen-initiated signaling pathways focusing upon TLRs, stress responses integrated by translational control through elF2a phosphorylation, transcriptional and post-transcriptional control mechanisms, and the causal links between inflammatory signaling and neoplasia. Project 1 is designed to dissect multiple pathways associated with the action of TLR3 and associated factors (TRIF and IRF3) and their control of inflammation linked tumorigenesis. Project 2 is focused upon how nuclear lysine methylation of STATs 1 and 3 and NFkB at the promoter site provides gene-specific inflammatory responses to diverse external signals. Project 3 will assess novel post-transcriptional mechanisms through which cell stress regulates expression of the TIS7/IFRD1 gene and how the distinct cell type specific functions of this gene may influence stress/inflammation driven colon tumor development. Finally Project 4 is to investigate how SIGIRR, a negative regulator for TLR-IL-1R signaling, modulates inflammation-induced tumorigenesis in the colon through its impact on commensal microflora-dependent homeostasis and innate and adaptive immune responses of the colonic epithelium.
Funding Period: 1994-08-15 - 2016-01-31
more information: NIH RePORT

Top Publications

  1. pmc All-trans retinoic acid induces arginase-1 and inducible nitric oxide synthase-producing dendritic cells with T cell inhibitory function
    Sumantha Bhatt
    Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195
    J Immunol 192:5098-108. 2014
  2. pmc Missense mutation in the second RNA binding domain reveals a role for Prkra (PACT/RAX) during skull development
    Benjamin K Dickerman
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
    PLoS ONE 6:e28537. 2011
  3. pmc Caspase-8-mediated cleavage inhibits IRF-3 protein by facilitating its proteasome-mediated degradation
    Nathaniel Sears
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Biol Chem 286:33037-44. 2011
  4. pmc Inhibition of RNase L and RNA-dependent protein kinase (PKR) by sunitinib impairs antiviral innate immunity
    Babal Kant Jha
    Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Biol Chem 286:26319-26. 2011
  5. pmc The dual functions of IL-1 receptor-associated kinase 2 in TLR9-mediated IFN and proinflammatory cytokine production
    Youzhong Wan
    Department of Molecular Genetics, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    J Immunol 186:3006-14. 2011
  6. pmc The functions of signal transducers and activators of transcriptions 1 and 3 as cytokine-inducible proteins
    Hyeonjoo Cheon
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Interferon Cytokine Res 31:33-40. 2011
  7. pmc Lysine methylation of promoter-bound transcription factors and relevance to cancer
    George R Stark
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Cell Res 21:375-80. 2011
  8. pmc Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes
    Jinbo Yang
    School of Life Science, Lanzhou University, Lanzhou, Gansu 73000, People s Republic of China
    Proc Natl Acad Sci U S A 107:21499-504. 2010
  9. pmc Major differences in the responses of primary human leukocyte subsets to IFN-beta
    Anette H H van Boxel-Dezaire
    Department of Molecular Genetics, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    J Immunol 185:5888-99. 2010
  10. pmc The ISG56/IFIT1 gene family
    Volker Fensterl
    Department of Molecular Genetics, The Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Interferon Cytokine Res 31:71-8. 2011

Detail Information

Publications76

  1. pmc All-trans retinoic acid induces arginase-1 and inducible nitric oxide synthase-producing dendritic cells with T cell inhibitory function
    Sumantha Bhatt
    Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195
    J Immunol 192:5098-108. 2014
    ..Thus, we conclude that ATRA enhances both Arg-1 and iNOS expression in IFN-γ-treated DCs, resulting in a tolerogenic phenotype. These findings elucidate mechanisms through which ATRA may contribute to liver immune tolerance. ..
  2. pmc Missense mutation in the second RNA binding domain reveals a role for Prkra (PACT/RAX) during skull development
    Benjamin K Dickerman
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
    PLoS ONE 6:e28537. 2011
    ....
  3. pmc Caspase-8-mediated cleavage inhibits IRF-3 protein by facilitating its proteasome-mediated degradation
    Nathaniel Sears
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Biol Chem 286:33037-44. 2011
    ..An in vitro assay confirms the direct action of caspase-8 cleavage on IRF-3. We also show that caspase-8-mediated cleavage of IRF-3 helps to modulate dsRNA-dependent gene induction...
  4. pmc Inhibition of RNase L and RNA-dependent protein kinase (PKR) by sunitinib impairs antiviral innate immunity
    Babal Kant Jha
    Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Biol Chem 286:26319-26. 2011
    ..Results indicate that sunitinib treatments prevent antiviral innate immune responses mediated by RNase L and PKR...
  5. pmc The dual functions of IL-1 receptor-associated kinase 2 in TLR9-mediated IFN and proinflammatory cytokine production
    Youzhong Wan
    Department of Molecular Genetics, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    J Immunol 186:3006-14. 2011
    ....
  6. pmc The functions of signal transducers and activators of transcriptions 1 and 3 as cytokine-inducible proteins
    Hyeonjoo Cheon
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Interferon Cytokine Res 31:33-40. 2011
    ..Therefore, interferons not only drive short-term expression of proteins that inhibit growth and promote apoptosis and immune surveillance, but also promote long-term expression of proteins that facilitate tumor survival...
  7. pmc Lysine methylation of promoter-bound transcription factors and relevance to cancer
    George R Stark
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Cell Res 21:375-80. 2011
    ....
  8. pmc Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes
    Jinbo Yang
    School of Life Science, Lanzhou University, Lanzhou, Gansu 73000, People s Republic of China
    Proc Natl Acad Sci U S A 107:21499-504. 2010
    ....
  9. pmc Major differences in the responses of primary human leukocyte subsets to IFN-beta
    Anette H H van Boxel-Dezaire
    Department of Molecular Genetics, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    J Immunol 185:5888-99. 2010
    ....
  10. pmc The ISG56/IFIT1 gene family
    Volker Fensterl
    Department of Molecular Genetics, The Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Interferon Cytokine Res 31:71-8. 2011
    ....
  11. pmc Diversity in post-transcriptional control of neutrophil chemoattractant cytokine gene expression
    Thomas Hamilton
    Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    Cytokine 52:116-22. 2010
    ..These pathways target distinct instability sequences that do not contain the AUUUA pentamer motif, do not signal through p38 MAPK, and function independently of TTP...
  12. pmc High-throughput screening for TLR3-IFN regulatory factor 3 signaling pathway modulators identifies several antipsychotic drugs as TLR inhibitors
    Jianzhong Zhu
    Molecular Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
    J Immunol 184:5768-76. 2010
    ..The data presented in this study provide mechanistic explanation of possible anti-inflammatory roles of some antipsychotic drugs...
  13. pmc Viral apoptosis is induced by IRF-3-mediated activation of Bax
    Saurabh Chattopadhyay
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    EMBO J 29:1762-73. 2010
    ..Thus, IRF-3 is a dual-action cytoplasmic protein that, upon activation, translocates to the nucleus or to the mitochondrion and triggers two complementary antiviral responses of the infected cell...
  14. ncbi Monitoring innate immune recruitment by siRNAs in mammalian cells
    Michael P Gantier
    Monash Institute of Medical Research, Monash University, Clayton, Vic, Australia
    Methods Mol Biol 623:21-33. 2010
    ..This chapter provides a brief overview of the current knowledge of siRNA-induced innate immunity, as well as protocols for the rapid identification of siRNAs with innate immune stimulatory activity...
  15. pmc The single IgG IL-1-related receptor controls TLR responses in differentiated human intestinal epithelial cells
    Mohammed A Khan
    Division of Pediatric Gastroenterology, BC Children s Hospital, Vancouver, British Columbia V6H 3V4, Canada
    J Immunol 184:2305-13. 2010
    ..Our findings show that Sigirr broadly regulates innate responses in differentiated human IECs; therefore, it may modulate epithelial involvement in infectious and inflammatory bowel diseases...
  16. pmc Stress-sensitive regulation of IFRD1 mRNA decay is mediated by an upstream open reading frame
    Chenyang Zhao
    Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
    J Biol Chem 285:8552-62. 2010
    ..These features of decay collectively define a distinct upstream ORF-mediated instability mechanism whereby cellular stress can modulate specific gene expression through alteration of mRNA half-life...
  17. pmc IL-17 regulates CXCL1 mRNA stability via an AUUUA/tristetraprolin-independent sequence
    Shyamasree Datta
    Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    J Immunol 184:1484-91. 2010
    ..These findings suggest that IL-17-mediated chemokine mRNA stabilization in nonmyeloid cells uses a mechanism that is distinct from that operating to control AU-rich mRNA stability in myeloid cells...
  18. pmc A TRIF-independent branch of TLR3 signaling
    Michifumi Yamashita
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    J Immunol 188:2825-33. 2012
    ..This study also provides a rare example of TLR-mediated cellular effects that do not require gene induction and the first example, to our knowledge, of an adaptor-independent effect of any TLR...
  19. pmc Pellino 2 is critical for Toll-like receptor/interleukin-1 receptor (TLR/IL-1R)-mediated post-transcriptional control
    Tae Whan Kim
    Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
    J Biol Chem 287:25686-95. 2012
    ..Taken together, this study demonstrated that Pellino 2 plays a critical role for TLR/IL-1R-mediated post-transcriptional control...
  20. pmc Meet the terminator: The phosphatase PP2A puts brakes on IRF-3 activation
    Saurabh Chattopadhyay
    Department of Molecular Genetics, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    Mol Cell 54:210-1. 2014
    ..2014) identify protein phosphatase 2A (PP2A) as a deactivator of phospho-interferon regulatory factor 3, the key transcription factor for interferon synthesis, thus providing one basis for the observed transiency...
  21. pmc MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases
    Minjia Yu
    Department of Immunology, 2 Department of Cellular and Molecular Medicine, 3 Department of Pathobiology, 4 Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH 44195
    J Exp Med 211:887-907. 2014
    ..Collectively, these results implicate a critical MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases. ..
  22. pmc An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis
    Bertrand Boisson
    St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA Electronic address
    Immunity 39:676-86. 2013
    ..Overall, human IL-17A and IL-17F depend on ACT1 to mediate protective mucocutaneous immunity. Moreover, other ACT1-dependent IL-17 cytokines seem to be largely redundant in host defense. ..
  23. pmc STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor
    Yuxin Wang
    School of Life Sciences, Lanzhou University, Lanzhou, Gansu 730000, People s Republic of China
    Proc Natl Acad Sci U S A 110:16975-80. 2013
    ..This second wave of STAT3 activation supports sustained expression of a subset of IL-6-induced proteins, several of which play important roles in inflammation and cancer, in which both IL-6 secretion and EGFR levels are often elevated. ..
  24. pmc IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage
    Hyeonjoo Cheon
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
    EMBO J 32:2751-63. 2013
    ....
  25. pmc IL-17 family: cytokines, receptors and signaling
    Chunfang Gu
    Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
    Cytokine 64:477-85. 2013
    ..This review will give an overview and recent updates on the IL-17 family, the activation and regulation of IL-17 signaling as well as diseases associated with this cytokine family. ..
  26. pmc Act1 mediates IL-17-induced EAE pathogenesis selectively in NG2+ glial cells
    Zizhen Kang
    1 Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China 2 Department of Immunology, Cleveland Clinic, Cleveland, Ohio, USA
    Nat Neurosci 16:1401-8. 2013
    ..The sensitivity of oligodendrocyte lineage cells to IL-17-mediated toxicity further suggests a direct link between inflammation and neurodegeneration in multiple sclerosis. ..
  27. pmc The protein kinase double-stranded RNA-dependent (PKR) enhances protection against disease cause by a non-viral pathogen
    Pauline Sebby Ogolla
    Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America
    PLoS Pathog 9:e1003557. 2013
    ....
  28. pmc SIGIRR, a negative regulator of TLR/IL-1R signalling promotes Microbiota dependent resistance to colonization by enteric bacterial pathogens
    Ho Pan Sham
    Division of Gastroenterology, BC s Children s Hospital, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
    PLoS Pathog 9:e1003539. 2013
    ..Thus, SIGIRR expression by IEC reflects a strategy that sacrifices maximal innate responsiveness by IEC in order to promote commensal microbe based colonization resistance against bacterial pathogens...
  29. pmc Role of lysine methylation of NF-κB in differential gene regulation
    Tao Lu
    Department of Molecular Genetics, Cleveland Clinic, Cleveland, OH 44195, USA
    Proc Natl Acad Sci U S A 110:13510-5. 2013
    ..Thus, the K218/221Q and K37Q mutations have dramatically different effects because methylations of these residues affect different genes by distinct mechanisms. ..
  30. pmc PRMT5 dimethylates R30 of the p65 subunit to activate NF-κB
    Han Wei
    Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Proc Natl Acad Sci U S A 110:13516-21. 2013
    ..PRMT5 is overexpressed in many types of cancer, often to a striking degree, indicating that high levels of this enzyme may promote tumorigenesis, at least in part by facilitating NF-κB-induced gene expression. ..
  31. pmc Spontaneous loss of tolerance of autoreactive B cells in Act1-deficient rheumatoid factor transgenic mice
    Natalia V Giltiay
    Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    J Immunol 191:2155-63. 2013
    ..Our results support the important role of Act1 in the regulation of self-reactive B cells and reveal how Act1 functions to prevent the production of autoantibodies. ..
  32. pmc PHF20 regulates NF-κB signalling by disrupting recruitment of PP2A to p65
    Tiejun Zhang
    Department of Pharmacology, Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon 301 747, South Korea
    Nat Commun 4:2062. 2013
    ..Our work identifies PHF20 as a novel regulator of NF-κB activation and suggests that elevated expression of PHF20 may drive constitutive NF-κB activation in some cancers. ..
  33. pmc IRAK-M mediates Toll-like receptor/IL-1R-induced NFκB activation and cytokine production
    Hao Zhou
    Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    EMBO J 32:583-96. 2013
    ....
  34. pmc Inactivation of the enzyme GSK3α by the kinase IKKi promotes AKT-mTOR signaling pathway that mediates interleukin-1-induced Th17 cell maintenance
    Muhammet F Gulen
    Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    Immunity 37:800-12. 2012
    ..Thus, IKKi has a critical role in Th17 cell maintenance and/or proliferation through the GSK-AKT-mTOR pathway, implicating the potential of IKKi as a therapeutic target...
  35. pmc β-TrCP-mediated IRAK1 degradation releases TAK1-TRAF6 from the membrane to the cytosol for TAK1-dependent NF-κB activation
    Wei Cui
    State Key Laboratory of Protein and Plant Gene Research, LSC, Peking University, Beijing, China
    Mol Cell Biol 32:3990-4000. 2012
    ..Taken together, these results implicate a positive role of β-TrCP-mediated IRAK1 degradation in IL-1-induced TAK1 activation...
  36. pmc Epidermal growth factor receptor is essential for Toll-like receptor 3 signaling
    Michifumi Yamashita
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NE20, Cleveland, OH 44195, USA
    Sci Signal 5:ra50. 2012
    ..Thus, these results reveal a connection between antiviral innate immunity and cell growth regulators...
  37. pmc STAT-phosphorylation-independent induction of interferon regulatory factor-9 by interferon-beta
    M R Sandhya Rani
    Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Interferon Cytokine Res 30:163-70. 2010
    ..These studies provide the first evidence that signaling pathways leading to gene transcription are activated by IFN-beta independent of STAT phosphorylation...
  38. pmc Roles of IKK-beta, IRF1, and p65 in the activation of chemokine genes by interferon-gamma
    David B Shultz
    Department of Molecular Genetics, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Interferon Cytokine Res 29:817-24. 2009
    ..Therefore, IKK-beta has a novel role in IFN-gamma-dependent activation of chemokine gene expression through its activation of IRF1 and p65...
  39. ncbi Fine-tuning of the innate immune response by microRNAs
    Michael P Gantier
    Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia
    Immunol Cell Biol 85:458-62. 2007
    ..In this review, we present an overview of what is currently known of the involvement of miRNA and RNA interference components in the fine-tuning of innate immune responses...
  40. pmc Tissue-specific and inducer-specific differential induction of ISG56 and ISG54 in mice
    Fulvia Terenzi
    Department of Molecular Genetics NE20, The Lewrnert research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    J Virol 81:8656-65. 2007
    ..Furthermore, our findings provide the first evidence of a differential pattern of expression of ISG54 and ISG56 genes by IFN-alpha and IFN-beta...
  41. ncbi Signal transducer and activator of transcription 1 is required for optimal foam cell formation and atherosclerotic lesion development
    Sudesh Agrawal
    Department of Cell Biology, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA
    Circulation 115:2939-47. 2007
    ..The present study investigated a novel role for Stat1 in foam cell formation and atherosclerosis...
  42. pmc Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB
    Jinbo Yang
    Department of Molecular Genetics, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
    Genes Dev 21:1396-408. 2007
    ....
  43. pmc A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity
    Tae Whan Kim
    Department of Immunology, Cleveland Clinic Foundation, Indianapolis, IN 46285, USA
    J Exp Med 204:1025-36. 2007
    ..Collectively, our results indicate that IRAK4 kinase activity plays a critical role in TLR-dependent immune responses...
  44. pmc Dose-dependent cross-talk between the transforming growth factor-beta and interleukin-1 signaling pathways
    Tao Lu
    Department of Molecular Genetics, Lerner Research Institute, and Brain Tumor Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Proc Natl Acad Sci U S A 104:4365-70. 2007
    ....
  45. ncbi Signaling in lipopolysaccharide-induced stabilization of formyl peptide receptor 1 mRNA in mouse peritoneal macrophages
    Palash Mandal
    Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    J Immunol 178:2542-8. 2007
    ..These findings demonstrate that LY2/LY3 targets a novel TLR4-linked signaling pathway that selectively couples to the stabilization of FPR1 mRNA...
  46. ncbi Enlarged spleens without enlarged lymph nodes in tlr3-/- pkr-/- mice
    Christine L White
    Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    J Interferon Cytokine Res 27:6-12. 2007
    ..These data also suggest that PKR may have a role in preventing progression from splenomegaly to lymphadenopathy in these mice...
  47. ncbi Two tyrosine residues of Toll-like receptor 3 trigger different steps of NF-kappa B activation
    Saumendra N Sarkar
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Biol Chem 282:3423-7. 2007
    ..Thus, two phosphotyrosine residues of TLR3 activate two distinct pathways, one leading to NF-kappaB release and the other leading to its phosphorylation...
  48. ncbi Phosphorylation of specific serine residues in the PKR activation domain of PACT is essential for its ability to mediate apoptosis
    Gregory A Peters
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
    J Biol Chem 281:35129-36. 2006
    ..These results indicate that phosphorylation of specific serine residues in the activation domain of PACT is the major mode of transmission of cellular stress response to PKR...
  49. ncbi Complex modulation of cell type-specific signaling in response to type I interferons
    Anette H H van Boxel-Dezaire
    Department of Molecular Genetics, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
    Immunity 25:361-72. 2006
    ..The type I IFNs use this complexity to regulate many different biological functions in different types of cells, by activating different specific signals and patterns of gene expression...
  50. ncbi Human telomerase RNA degradation by 2'-5'-linked oligoadenylate antisense chimeras in a cell-free system, cultured tumor cells, and murine xenograft models
    Jayashree M Paranjape
    Department of Cancer Biology and Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
    Oligonucleotides 16:225-38. 2006
    ....
  51. ncbi Distinct induction patterns and functions of two closely related interferon-inducible human genes, ISG54 and ISG56
    Fulvia Terenzi
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Biol Chem 281:34064-71. 2006
    ..Thus, although similar in structure, the human P54 and P56 proteins are induced differently and function differently...
  52. ncbi Functional annotation of IFN-alpha-stimulated gene expression profiles from sensitive and resistant renal cell carcinoma cell lines
    Michelle Holko
    Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    J Interferon Cytokine Res 26:534-47. 2006
    ..However, no difference in Stat1 activation was observed between the cell lines. Analysis of ISG expression patterns suggests that subtle differences in transcription profiles contribute to differences in IFN responsiveness...
  53. pmc Molecular basis for PKR activation by PACT or dsRNA
    Shoudong Li
    Department of Molecular Genetics NE20, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Proc Natl Acad Sci U S A 103:10005-10. 2006
    ..Furthermore, a short decoy peptide, representing PBM, was able to activate PKR by interfering with the intramolecular interaction. These observations suggest a model for PKR activation upon binding of dsRNA or PACT...
  54. ncbi A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells
    Joao Trindade Marques
    Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
    Nat Biotechnol 24:559-65. 2006
    ..These findings will enable the rational design of siRNAs that avoid nonspecific effects or, alternatively, that induce bystander effects to potentially increase the efficacy of siRNA-based treatments of viral infections or cancer...
  55. pmc A role of the double-stranded RNA-binding protein PACT in mouse ear development and hearing
    Theresa M Rowe
    Departments of Molecular Genetics, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    Proc Natl Acad Sci U S A 103:5823-8. 2006
    ..Our study demonstrated an essential role of PACT in mammalian ear development and produced the first animal model for studying human microtia...
  56. pmc How cells respond to interferons revisited: from early history to current complexity
    George R Stark
    Department of Molecular Genetics, Cleveland Clinic, Cleveland OH 44195, United States
    Cytokine Growth Factor Rev 18:419-23. 2007
    ....
  57. pmc The response of mammalian cells to double-stranded RNA
    Michael P Gantier
    Monash Institute of Medical Research, Monash University, Clayton, Vic, Australia
    Cytokine Growth Factor Rev 18:363-71. 2007
    ..Here, we present an overview of the current knowledge of dsRNA-mediated pathways in mammalian cells and introduce a link between these pathways and application of RNAi...
  58. pmc ATF3 transcription factor and its emerging roles in immunity and cancer
    Matthew R Thompson
    Monash Institute of Medical Research, Monash University, Melbourne, Australia
    J Mol Med (Berl) 87:1053-60. 2009
    ..Moreover, the role of ATF3 in the regulation of the cell cycle and apoptosis has important implications for understanding susceptibility to and progression of several cancers...
  59. pmc Biochemical analysis of PKR activation by PACT
    Gregory A Peters
    Department of Molecular Genetics, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
    Biochemistry 48:7441-7. 2009
    ..These results indicate that stress-induced phosphorylation of specific serine residues in domain 3 of PACT increases its affinity for PKR, which leads to better activation of PKR and resultant eIF-2alpha phosphorylation...
  60. pmc The double-stranded RNA-binding protein, PACT, is required for postnatal anterior pituitary proliferation
    Gregory A Peters
    Department of Molecular Genetics, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    Proc Natl Acad Sci U S A 106:10696-701. 2009
    ..Our study revealed a physiologically significant role for PACT in cell proliferation and an essential role of a dsRNA-binding protein in mammalian pituitary expansion...
  61. pmc Promyelocytic leukemia zinc finger protein regulates interferon-mediated innate immunity
    Dakang Xu
    Monash Institute of Medical Research, Monash University, Melbourne, Australia
    Immunity 30:802-16. 2009
    ..These results provide new insights into the regulatory mechanisms of IFN signaling and the induction of innate antiviral immunity...
  62. pmc IL-17 signaling for mRNA stabilization does not require TNF receptor-associated factor 6
    Justin Hartupee
    Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    J Immunol 182:1660-6. 2009
    ..Because the most potent effects of IL-17 on gene expression are obtained in cooperation with other cytokines such as TNF-alpha, these findings suggest that this pathway is a major contributing mechanism for response to IL-17...
  63. pmc Differential expression in clear cell renal cell carcinoma identified by gene expression profiling
    Brian R Lane
    Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Urol 181:849-60. 2009
    ..We present data using a custom kidney cancer cDNA array that can predict the outcome in patients with unilateral and bilateral renal cell carcinoma...
  64. pmc Interferon-inducible protein, P56, inhibits HPV DNA replication by binding to the viral protein E1
    Fulvia Terenzi
    Department of Molecular Genetics, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    EMBO J 27:3311-21. 2008
    ..In vitro, recombinant P56, or a small fragment derived from it, inhibited the DNA helicase activity of E1 and E1-mediated HPV DNA replication. These observations delineate the molecular mechanism of IFN's antiviral action against HPV...
  65. pmc Novel characteristics of the function and induction of murine p56 family proteins
    Volker Fensterl
    Department of Molecular Genetics NE20, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    J Virol 82:11045-53. 2008
    ..These results revealed novel cell type-, inducer-, and gene-specific regulation of the ISG56 family of genes...
  66. pmc Protein kinase R-dependent regulation of interleukin-10 in response to double-stranded RNA
    Arindam Chakrabarti
    Departments of Cancer Biology and Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH 44195, USA
    J Biol Chem 283:25132-9. 2008
    ..Together, our data demonstrate the role of PKR in regulating an anti-inflammatory cytokine. The findings have significance in antiviral as well as broader innate immune responses...
  67. pmc Interferon-inducible antiviral effectors
    Anthony J Sadler
    Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia
    Nat Rev Immunol 8:559-68. 2008
    ..Ongoing research continues to expose additional activities for these effector proteins and has revealed unanticipated functions of the antiviral response...
  68. ncbi Determinants of cytokine induction by small interfering RNA in human peripheral blood mononuclear cells
    Maryam Zamanian-Daryoush
    Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    J Interferon Cytokine Res 28:221-33. 2008
    ..In accordance with this, specific chemical modifications differentially altered cytokine production, suggesting recruitment of different TLRs in a sequence-dependent manner...
  69. pmc Select paramyxoviral V proteins inhibit IRF3 activation by acting as alternative substrates for inhibitor of kappaB kinase epsilon (IKKe)/TBK1
    Lenette L Lu
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    J Biol Chem 283:14269-76. 2008
    ....
  70. ncbi TLR7 is involved in sequence-specific sensing of single-stranded RNAs in human macrophages
    Michael P Gantier
    Centre for Cancer Research, Monash Institute of Medical Research, Monash University, 246 Clayton Road, Clayton, Victoria 3168, Australia
    J Immunol 180:2117-24. 2008
    ..Our results suggest that differential sequence-specific sensing of RNA oligonucleotides between human and mouse macrophages is due to the modulation of TLR7 sensing by human TLR8...
  71. pmc IRF-3 activation by Sendai virus infection is required for cellular apoptosis and avoidance of persistence
    Kristi Peters
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Virol 82:3500-8. 2008
    ..These results demonstrated that in our model system, IRF-3 controlled the fate of the SeV-infected cells by promoting apoptosis and preventing persistence...
  72. ncbi Interferons at age 50: past, current and future impact on biomedicine
    Ernest C Borden
    Taussig Cancer Center, Case Comprehensive Cancer Center, Mellen Center for Multiple Sclerosis, and Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA
    Nat Rev Drug Discov 6:975-90. 2007
    ..Our goal is to offer a molecular and clinical perspective that will enable IFNs or their TLR agonist inducers to reach their full clinical potential...
  73. ncbi Negative regulation of TLR-signaling pathways by activating transcription factor-3
    Mark M Whitmore
    Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    J Immunol 179:3622-30. 2007
    ..ATF3 dysregulation merits further exploration in diseases such as type I diabetes and cancer, where altered innate immunity has been implicated in their pathogenesis...
  74. ncbi Viral stress-inducible genes
    Ganes C Sen
    Department of Molecular Genetics, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
    Adv Virus Res 70:233-63. 2007
    ..Thus, in an infected cell, equilibrium is reached between the virus and the cell with regards to the viral stress-inducible genes...
  75. ncbi Binding of the influenza A virus NS1 protein to PKR mediates the inhibition of its activation by either PACT or double-stranded RNA
    Shoudong Li
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    Virology 349:13-21. 2006
    ..In addition, we demonstrated that PKR activation is inhibited in cells infected with a recombinant influenza A virus expressing NS1A mutant protein that cannot bind RNA, as is the case in cells infected with wild-type influenza A virus...