39 results found
Hergovits S, Mais C, Haan C, et al., 2017, Oncostatin M induces RIG-I and MDA5 expression and enhances the double-stranded RNA response in fibroblasts, Journal of Cellular and Molecular Medicine, Vol: 21, Pages: 3087-3099, ISSN: 1582-4934
Interleukin (IL)-6-type cytokines have no direct antiviral activity; nevertheless, they display immune-modulatory functions. Oncostatin M (OSM), a member of the IL-6 family, has recently been shown to induce a distinct number of classical interferon stimulated genes (ISG). Most of them are involved in antigen processing and presentation. However, induction of retinoic acid-inducible gene (RIG)-I-like receptors (RLR) has not been investigated. Here we report that OSM has the capability to induce the expression of the DExD/H-Box RNA helicases RIG-I and melanoma differentiation antigen 5 (MDA5) as well as of the transcription factors interferon regulatory factor (IRF)1, IRF7 and IRF9 in primary fibroblasts. Induction of the helicases depends on tyrosine as well as serine phosphorylation of STAT1. Moreover, we could show that the OSM-induced STAT1 phosphorylation is predominantly counter-regulated by a strong STAT3-dependent SOCS3 induction, as Stat3 as well as Socs3 knock-down results in an enhanced and prolonged helicase and IRF expression. Other factors involved in regulation of STAT1 or IRF1 activity, like protein tyrosine phosphatase, non-receptor type 2 (PTPN2), promyelocytic leukaemia protein (PML) or small ubiquitin-related modifier 1 (SUMO1), play a minor role in OSM-mediated induction of RLR. Remarkably, OSM and interferon-γ (IFN-γ) synergize to mediate transcription of RLR and pre-treatment of fibroblasts with OSM fosters the type I interferon production in response to a subsequent encounter with double-stranded RNA. Together, these findings suggest that the OSM-induced JAK/STAT1 signalling is implicated in virus protection of non-professional immune cells and may cooperate with interferons to enhance RLR expression in these cells.
Rutherford C, Speirs C, Williams JJL, et al., 2016, Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling, Science Signaling, Vol: 9, ISSN: 1945-0877
Adenosine 5′-monophosphate–activated protein kinase (AMPK) is a pivotal regulator of metabolism at cellular and organismal levels. AMPK also suppresses inflammation. We found that pharmacological activation of AMPK rapidly inhibited the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway in various cells. In vitro kinase assays revealed that AMPK directly phosphorylated two residues (Ser515 and Ser518) within the Src homology 2 domain of JAK1. Activation of AMPK enhanced the interaction between JAK1 and 14-3-3 proteins in cultured vascular endothelial cells and fibroblasts, an effect that required the presence of Ser515 and Ser518 and was abolished in cells lacking AMPK catalytic subunits. Mutation of Ser515 and Ser518 abolished AMPK-mediated inhibition of JAK-STAT signaling stimulated by either the sIL-6Rα/IL-6 complex or the expression of a constitutively active V658F-mutant JAK1 in human fibrosarcoma cells. Clinically used AMPK activators metformin and salicylate enhanced the inhibitory phosphorylation of endogenous JAK1 and inhibited STAT3 phosphorylation in primary vascular endothelial cells. Therefore, our findings reveal a mechanism by which JAK1 function and inflammatory signaling may be suppressed in response to metabolic stress and provide a mechanistic rationale for the investigation of AMPK activators in a range of diseases associated with enhanced activation of the JAK-STAT pathway.
Schlegel CR, Georgiou ML, Misterek MB, et al., 2015, DAPK2 regulates oxidative stress in cancer cells by preserving mitochondrial function, CELL DEATH & DISEASE, Vol: 6, ISSN: 2041-4889
Schlegel CR, Fonseca A-V, Stoecker S, et al., 2014, DAPK2 is a novel modulator of TRAIL-induced apoptosis, CELL DEATH AND DIFFERENTIATION, Vol: 21, Pages: 1780-1791, ISSN: 1350-9047
Bonito NA, Drechsler J, Stoecker S, et al., 2014, Control of gp130 expression by the mitogen-activated protein kinase ERK2, ONCOGENE, Vol: 33, Pages: 2255-2263, ISSN: 0950-9232
Costa-Pereira AP, 2014, Regulation of IL-6-type cytokine responses by MAPKs, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 42, Pages: 59-62, ISSN: 0300-5127
Costa-Pereira AP, 2013, Cytokine Responses Profiling Using Flow Cytometry-Based Kinome Analyses, Transmembrane Signaling Protocols, Editors: Dhanasekaran, Totowa, USA, Publisher: The Humana Press Inc.
RNA interference (RNAi) has revolutionised the way we interrogate the role of particular molecules in specific molecular processes. Unsurprisingly, its discovery awarded the Nobel Prize of Medicine and Physiology in 2006 to Craig Mello and Andrew Fire, a mere eight years after they stumbled upon it (1). RNAi can be induced using short interfering (si) or short hairpin (sh) RNA molecules and it permits the downregulation of a specific protein by interfering/ degrading its corresponding mRNA. siRNA molecules are typically 21-23 nucleotide long, an important characteristic, as longer dsRNAs are interpreted by mammalian cells as intermediaries of a viral infection, which quickly activate an antiviral response leading to their destruction (2). Indeed, up to 2001 this phenomenon was ‘easily’ achievable in a variety of organisms such as D. melanogaster and C. elegans but remained a challenge in mammalian cells until Tuschl and co-workers (2) managed to successfully induce RNAi in cultured mammalian cells without significantly triggering the Interferon (IFN) system.Despite high redundancy in mammalian cells, RNAi screens using siRNA molecules offer tremendous potential to identify new players in well-defined pathways (3). This chapter will describe in great depth flow cytometry-based kinome-wide siRNA screens designed to identify additional molecules involved in signalling triggered downstream of the IFN-γ and IFN-α receptors (IFNGR and IFNAR, respectively).
Santos CI, Costa-Pereira AP, 2011, The role of ATM in the regulation of Interferon-gamma responses, 9th Joint Meeting of the International-Cytokine-Society/International-Society-for-Interferon-and-Cytokine-Research, Publisher: ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, Pages: 23-23, ISSN: 1043-4666
Costa-Pereira AP, do Carmo CR, Lyons-Lewis J, et al., 2011, A Novel Requirement for Janus Kinases as Mediators of Drug Resistance Induced by Fibroblast Growth Factor-2 in Human Cancer Cells, 9th Joint Meeting of the International-Cytokine-Society/International-Society-for-Interferon-and-Cytokine-Research, Publisher: ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, Pages: 52-52, ISSN: 1043-4666
Walter S, Hintzen C, Costa-Pereira AP, et al., 2011, Oncostain M induces the expression of the DExD/H-box helicases RIG-I and MDA5, 9th Joint Meeting of the International-Cytokine-Society/International-Society-for-Interferon-and-Cytokine-Research, Publisher: ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, Pages: 90-90, ISSN: 1043-4666
Santos CI, Costa-Pereira AP, 2011, Signal transducers and activators of transcription-from cytokine signalling to cancer biology, BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER, Vol: 1816, Pages: 38-49, ISSN: 0304-419X
Chen E, Beer PA, Godfrey AL, et al., 2011, DISTINCT CLINICAL PHENOTYPES ASSOCIATED WITH JAK2V617F REFLECT DIFFERENTIAL STAT1 SIGNALING, EXPERIMENTAL HEMATOLOGY, Vol: 39, Pages: S46-S46, ISSN: 0301-472X
Carmo CR, Lyons-Lewis J, Seckl MJ, et al., 2011, A Novel Requirement for Janus Kinases as Mediators of Drug Resistance Induced by Fibroblast Growth Factor-2 in Human Cancer Cells, PLOS ONE, Vol: 6, ISSN: 1932-6203
The development of resistance to chemotherapy is a major cause of cancer-related death. Elucidating the mechanisms of drug resistance should thus lead to novel therapeutic strategies. Fibroblast growth factor (FGF)-2 signaling induces the assembly of a multi-protein complex that provides tumor cells with the molecular machinery necessary for drug resistance. This complex, which involves protein kinase C (PKC) ε, v-raf murine sarcoma viral oncogene homolog B1 (B-RAF) and p70 S6 kinase β (S6K2), enhances the selective translation of anti-apoptotic proteins such as B-cell leukaemia/lymphoma-2 (BCL-2) and inhibitors of apoptosis protein (IAP) family members and these are able to protect multiple cancer cell types from chemotherapy-induced cell death. The Janus kinases (JAKs) are most noted for their critical roles in mediating cytokine signaling and immune responses. Here, we show that JAKs have novel functions that support their consideration as new targets in therapies aimed at reducing drug resistance. As an example, we show that the Janus kinase TYK2 is phosphorylated downstream of FGF-2 signaling and required for the full phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Moreover, TYK2 is necessary for the induction of key anti-apoptotic proteins, such as BCL-2 and myeloid cell leukemia sequence (MCL) 1, and for the promotion of cell survival upon FGF-2. Silencing JAK1, JAK2 or TYK2 using RNA interference (RNAi) inhibits FGF2-mediated proliferation and results in the sensitization of tumor cells to chemotherapy-induced killing. These effects are independent of activation of signal transducer and activator of transcription (STAT) 1, STAT3 and STAT5A/B, the normal targets of JAK signaling. Instead, TYK2 associates with the other kinases previously implicated in FGF-2-mediated drug resistance. In light of these findings we hypothesize that TYK2 and other JAKs are important modulators of FGF-2-driven cell survival and that inhibitors of t
Costa-Pereira AP, Bonito NA, Seckl MJ, 2011, Dysregulation of janus kinases and signal transducers and activators of transcription in cancer, AMERICAN JOURNAL OF CANCER RESEARCH, Vol: 1, Pages: 806-816, ISSN: 2156-6976
Chen E, Beer PA, Godfrey AL, et al., 2010, Distinct Clinical Phenotypes Associated with JAK2V617F Reflect Differential STAT1 Signaling, CANCER CELL, Vol: 18, Pages: 524-535, ISSN: 1535-6108
do Carmo CR, Lyons-Lewis J, Seckl MJ, et al., 2010, A novel requirement for the Janus kinase TYK2 as a mediator of drug resistance induced by fibroblast growth factor-2 in cancer cells, 8th Joint Conference of the International-Cytokine-Society/International-Society-for-and-Cytokine-Research, Publisher: ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, Pages: 74-74, ISSN: 1043-4666
do Carmo CR, Seckl MJ, Costa-Pereira AP, 2009, A role for janus kinases in chemoresistance, Tri-Society Annual Conference of the International-Cytokine-Society/International-Society-of-Interferon-and-Cytokine-Research/Society-of-Leukocyte-Biology, Publisher: ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, Pages: 126-126, ISSN: 1043-4666
do Carmo CR, Seckl MJ, Costa-Pereira AP, 2008, A role for JAKs and STATs in chemoresistance?, 7th Joint Conference of the International-Cytokine-Society/International-Society-for-Interferon-and-Cytoklin-Research, Publisher: ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD, Pages: 238-238, ISSN: 1043-4666
Watling D, Carmo CR, Kerr IM, et al., 2008, Multiple kinases in the interferon-gamma response, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 105, Pages: 6051-6056, ISSN: 0027-8424
Costa-Pereira AP, 2008, CASLAT - Teaching Portfolio and Reflective Commentary
Watling D, Carmo CR, Kerr IM, et al., 2007, ATM is required for the interferon-gamma response, JOURNAL OF INTERFERON AND CYTOKINE RESEARCH, Vol: 27, Pages: 701-701, ISSN: 1079-9907
Christova R, Jones T, Wu PJ, et al., 2007, P-STAT1 mediates higher-order chromatin remodelling of the human MHC in response to IFN-gamma, J.Cell Sci.
Qing Y, Costa-Pereira AP, Watling D, et al., 2005, Role of tyrosine 441 of interferon-gamma receptor subunit 1 in SOCS-1-mediated attenuation of STAT1 activation, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 280, Pages: 1849-1853, ISSN: 0021-9258
Kerr IM, Costa-Pereira AP, Lillemeier BF, et al., 2003, Of JAKs, STATs, blind watchmakers, jeeps and trains, FEBS LETTERS, Vol: 546, Pages: 1-5, ISSN: 0014-5793
Costa-Pereira AP, Strobl B, Lillemeier BF, et al., 2003, JAK/STAT signalling: a tale of jeeps and trains, Signal transducers and activators of transcription (STATs): activation and biology, Editors: Sehgal, Levy, Hirano, London, UK., Publisher: Kluwer Academic Publishers, Pages: 355-365, ISBN: 9781402016196
Schlaak JF, Hilkens CMU, Costa-Pereira AP, et al., 2002, Cell-type and donor-specific transcriptional responses to interferon-alpha - Use of customized gene arrays, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 277, Pages: 49428-49437, ISSN: 0021-9258
Costa-Pereira AP, Tininini S, Strobl B, et al., 2002, Mutational switch of an IL-6 response to an interferon-gamma-like response, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 99, Pages: 8043-8047, ISSN: 0027-8424
Strobl B, Arulampalam V, Is'harc H, et al., 2001, A completely foreign receptor can mediate an interferon-gamma-like response, EMBO JOURNAL, Vol: 20, Pages: 5431-5442, ISSN: 0261-4189
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