DOCSLIB.ORG

Fabienne Le Cann

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Fabienne Le Cann ANNÉE 2017 THÈSE / UNIVERSITÉ DE RENNES 1 sous le sceau de l’Université Bretagne Loire En Cotutelle Internationale avec l’Université de Gand, Belgique pour le grade de DOCTEUR DE L’UNIVERSITÉ DE RENNES 1 Mention : Biologie Ecole doctorale Vie Agro Santé présentée par Fabienne Le Cann Préparée à l’unité de recherche UMR Inserm U1085 IRSET Institut de Recherche en Santé Environnement et Travail UFR Sciences de la Vie et de l’Environnement Thèse soutenue à Rennes Caractérisation de le 2 juin 2017 nouveaux inhibiteurs devant le jury composé de : Mojgan DJAVAHERI-MERGNY de la kinase RIPK1 et CR INSERM, Université de Bordeaux / rapporteur Alicia TORRIGLIA de la nécroptose DR INSERM, Université de Paris Descartes, UPMC / rapporteur Sandy ADJEMIAN-CATANI Junior Scientist, Université de Gand / rapporteur Sandrine RUCHAUD CR CNRS, Sorbonne Universités, UPMC Paris VI / examinateur Tom VANDEN BERGHE Senior Scientist, Université de Gand / examinateur Georges BAFFET DR INSERM, Université de Rennes 1 / examinateur, Président de jury Peter VANDENABEELE Pr, Dr, Université de Gand / co-directeur de thèse Marie-Thérèse DIMANCHE-BOITREL DR INSERM, Université de Rennes 1 / co-directrice de thèse ANNÉE 2017 Fabienne Le Cann Thesis submitted in partial fulfillment of the requirements for the degree of DOCTOR IN BIOLOGY from Rennes 1 University & DOCTOR OF SCIENCES: Biochemistry and Biotechnology from Ghent University Academic year 2016-2017 Rennes 1 University – Faculty of Sciences in Health and Environment under seal of University Bretagne Loire Ghent University – Faculty of Sciences Prepared at the research unit of UMR Inserm U1085 IRSET Institute for Research in Health, Environment and Work UFR Sciences in Health and Environment, Rennes, France and at the VIB research unit for Molecular Signaling and Cell Death, Department of Biomedical Molecular Biology VIB-UGent Center for Inflammation Research, Ghent, Belgium Joint PhD fellowship presented in Rennes Characterization of new on the 2nd june 2017 necroptosis inhibitors Examination Board : targeting RIPK1 Mojgan DJAVAHERI-MERGNY CR INSERM, University of Bordeaux / thesis referee Alicia TORRIGLIA DR INSERM, University of Paris Descartes, UPMC / thesis referee Sandy ADJEMIAN-CATANI Junior Scientist, University of Ghent / thesis referee Sandrine RUCHAUD CR CNRS, Sorbonne Universities, UPMC Paris VI / examiner Tom VANDEN BERGHE Senior Scientist, University of Ghent / examiner Georges BAFFET DR INSERM, University of Rennes 1 / examiner, jury president Peter VANDENABEELE Pr, Dr, University of Ghent / co-promotor Marie-Thérèse DIMANCHE-BOITREL DR INSERM, University of Rennes 1 / co-promotor www.irset.org INSTITUT DE RECHERCHE SANTE, ENVIRONNEMENT & TRAVAIL Inserm Unité 1085 Université de Rennes 1 Campus de Villejean 35043 RENNES Cedex France Marie-Thérèse DIMANCHE-BOITREL, Senior scientist, DR INSERM Tél : +33 (0)2 23 23 48 99 Secrétariat : +33 (0)2 23 23 47 21 Fax : +33 (0)2 23 23 47 94 Email : [email protected] TO WHOM IT MAY CONCERN Subject: Confidentiality of Fabienne Le Cann’s manuscript thesis Fabienne Le Cann defended her joint thesis between the University of Rennes1 and the University of Ghent on the June 02th 2017 at the Faculty of Pharmacy in Rennes. The conditions of this oral defense were confidential. The thesis title was “Characterization of new inhibitors of RIPK1 and necroptosis”. The results of this thesis work having led to the filing of three European patents, the thesis manuscript must be kept confidential for 2 years after the date of this thesis defense. I thank you for respecting these privacy rules in the name of intellectual property. Kind regards Dr Marie-Thérèse Dimanche-Boitrel (co-promotor) Rennes, June 16, 2016 Je dédie cette thèse à mon papa parti trop tôt, ma maman et ma sœur, À mes très chers amis, Et à mes deux amours. Vous me comblez tous de bonheur, merci infiniment. Abréviations AIF Apoptosis Inducing Factor AIM2 Absent in melanoma 2, interferon-inducible protein ALAT Alanine Amino Transférase ANT Adénine nucléotide translocase AP-1 Activator Protein 1 Apaf1 Apoptotic Peptidase Activating Factor 1 ASAT Aspartate Amino Transférase ASK1 Apoptosis signaling kinase-1 Bcl2 B-cell lymphoma-2 BclXL B-cell lymphoma-extra large CAMK Ca2+/calmodulin-dependent protein kinase CARD Caspase Activation Recruitment Domain CD95 Récepteur Fas cFLIP cellular FLICE-Like Inhibitory Protein (cellular Fas-associated death-domain-like IL1-β-converting enzyme inhibitory protein) CHX cycloheximide cIAPs cellular Inhibitors of Apoptosis Proteins / E3 ubiquitin ligases cIAPs CMV Cytomegalovirus CsA Cyclosporine A CYLD Cylindromatosis CypA Cyclophiline A CypD Cyclophiline D DAI/ZBP-1 DNA-dependent activator of IFN regulatory factors / Z-DNA binding protein 1 DAMPs Damage-Associated Molecular Patterns Daxx Death Domain-associated protein DD Death Domain DISC Death-Inducing Signaling Complex DR Death Receptor ERK Extracellular signal-Regulated Kinase (ou MAPK) FADD Fas Associated Death Domain FAK Focal Adhesion Kinase FasL Ligand Fas γGT gamma Glutamyl-Transpeptidase, ou gamma Glutamyl-Transférase GPX4 Glutathione Peroxidase 4 GSH Glutathion HHV8 Herpès Virus Humain de type 8 HMGB1 High Mobility Group Box 1 hTERT human Telomerase Reverse Transcriptase IDO Indoleamine-pyrrole 2,3-dioxygenase IFN Interféron IKK Inhibitor of Kappa B Kinase α/β (IκB kinase α/β) IĸBα Inhibitor of ĸB-alpha IL Interleukine IRFs Interferon-Regulatory Factor proteins IRI Ischemia-Reperfusion Injury JNK c-Jun N-terminal kinase KD Kinase Dead KO knockout LPS Lipopolysaccharide LT Oncoprotéine Large T du virus SV40 LUBAC Linear Ubiquitin Chain Assembly Complex MAPK Mitogen Activated Protein Kinase MAVS Mitochondrial AntiViral-Signaling protein MCMV Murine Cytomegalovirus MEK MAPK kinase / ERK kinase MEKK MAPK kinase kinase MLKL Mixed Lineage Kinase Domain Like MNNG 1-Methyl-3-nitro-1-nitrosoguanidine MOMP Mitochondrial Outer Membrane Permeabilization MPTP Mitochondrial Membrane Permeability Transition Pore NAD Nicotinamide Adénine Dinucléotide NADPH forme réduite du Nicotinamide Adénine Dinucléotide Phosphate Nec-1 Nécrostatine-1 NETs Neutrophil Extracellular Traps NF-ĸB Nuclear Factor-ĸB NK Natural Killer NKT Natural Killer T NLRs NODD Like Receptors NOX NADPH oxidase NSA Nécrosulfonamide PAMPs Pathogen-Associated Molecular Patterns PAR Poly (ADP-ribose) PARP-1 Poly (ADP-ribose) polymerase 1 PIPs Phosphatidyl Inositol Phosphates PKR Protein kinase RNA-activated Poly (I:C) Acide polyinosinique-polycytidylique PPIase Peptidyl-Prolyl cis-trans isomérase PRR Pattern Recognition Receptor RAF Rapidly Accelerated Fibrosarcoma, MAP3K RAIDD RIP-associated ICH-1/CED-3 homologous protein with a death domain Ras rat Sarcoma, a GTPase RHIM RIP Homotypic Interaction Motif RIPK Receptor Interacting Protein Kinase RIG-I Retinoic Acid-Inducible Gene I ROS Reactive Oxygen Species RSL3/5 Ras Selective Lethal 3 or 5 SfA Sangliféhrine A SIRS Syndrome de Réponse Inflammatoire Systémique Smac Second Mitochondrial activator of Caspases ST oncoprotéine Small T du virus SV40 TAK1 TGF-β Activated Kinase 1 TICAM1 Toll Like Receptor-adaptor molecule 1 TLR Toll Like Receptor TNF Tumor Necrosis Factor TNF-α TNF-alpha TNFR TNF Receptor TRADD TNFR1-Associated Death Domain TRAF TNFR Associated Factor TRAIL TNF-Related Apoptosis Inducing Ligand TRAIL-R TRAIL-Receptor TRAMP Tumor necrosis factor receptor superfamily member 25 (or DR3) TRIF TIR-domain-containing adapter inducing IFN-β VDAC Voltage-Dependent Anion Channels vIRA viral Inhibitor of RIP Activation WT Wild Type XIAP X-linked Inhibitor of Apoptosis Protein ZBP-1 Z-DNA binding protein 1 Sommaire Avant-propos ................................................................................................................................. 1 Introduction générale ..................................................................................................................... 3 I. Morts cellulaires ..................................................................................................................... 3 A. Mort cellulaire non régulée ou accidentelle, la nécrose .............................................................. 4 B. Morts cellulaires programmées ................................................................................................... 4 1) Apoptose ..................................................................................................................................... 4 2) Nécroses régulées ........................................................................................................................ 7 II. La famille des Receptor Interacting Protein Kinases ....................................................... 16 A. Les différents membres ............................................................................................................. 17 1) RIPK1 ....................................................................................................................................... 17 2) RIPK3 ....................................................................................................................................... 20 3) RIPK2 ....................................................................................................................................... 23 4) RIPK4 ....................................................................................................................................... 24 5) RIPK5, RIPK6, RIPK7 ............................................................................................................
Load more

Recommended publications
  • Evaluating Necroptosis Competency in Malignant Melanoma
    Evaluating necroptosis competency in malignant melanoma Von der Fakultät 4: Energie-, Verfahrens- und Biotechnik der Universität Stuttgart zur Erlangung der Würde eines Doktors der Naturwissenschaften (Dr. rer. nat.) Genehmigte Abhandlung Vorgelegt von Biswajit Podder, M.Sc. aus Narsingdi, Bangladesh Hauptberichter: Prof. Dr. Markus Morrison Mitberichter: Prof. Dr. Jochen Utikal, Universität Heidelberg Prüfungsvorsitzender: Prof. Dr. Roland Kontermann Tag der mündlichen Prüfung: 18.06.2020 Institut für Zellbiologie und Immunologie der Universität Stuttgart Stuttgart, 2020 I II Declarations according to § 2 of the doctoral degree regulations: Eidesstattliche Erklärung Hiermit versichere ich, dass ich diese Arbeit selbst verfasst und dabei keine anderen als die angegeben Quellen und Hilfsmittel verwendet habe. Declaration of Authorship I hereby certify that this Dissertation is entirely my own work, apart from where otherwise indicated. Passages and ideas from other sources have been clearly indicated. Biswajit Podder Stuttgart, 10th of July 2020 III IV This thesis is dedicated to three million freedom fighters who sacrifice their lives for my beloved country Bangladesh “There will be obstacles. There will be doubters. There will be mistakes. But with hard work, there are no limits.” —Michael Phelps I VI Research outputs Journal Article: Podder B., Guttà C., Rožanc J., Gerlach E., Feoktistova M., Panayotova-Dimitrova D, Alexopoulos LG., Leverkus M., Rehm M., TAK1 suppresses RIPK1-dependent cell death and is associated With disease progression in melanoma Cell death and differentiation; 12 February 2019.1 doi: 0.1038/s41418-019-0315-8 Rožanc J., Sakellaropoulos T., Antoranz A., Guttà C., Podder B., Vetma V., Rufo N., Agostinis P., Pliaka V., Sauter T., Kulms D., Rehm M., Alexopoulos LG., Phosphoprotein patterns predict trametinib responsiveness and optimal trametinib sensitisation strategies in melanoma.
    [Show full text]
  • Targeting RIP Kinases in Chronic Inflammatory Disease
    biomolecules Review Targeting RIP Kinases in Chronic Inflammatory Disease Mary Speir 1,2, Tirta M. Djajawi 1,2 , Stephanie A. Conos 1,2, Hazel Tye 1 and Kate E. Lawlor 1,2,* 1 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; [email protected] (M.S.); [email protected] (T.M.D.); [email protected] (S.A.C.); [email protected] (H.T.) 2 Department of Molecular and Translational Science, Monash University, Clayton, VIC 3168, Australia * Correspondence: [email protected]; Tel.: +61-85722700 Abstract: Chronic inflammatory disorders are characterised by aberrant and exaggerated inflam- matory immune cell responses. Modes of extrinsic cell death, apoptosis and necroptosis, have now been shown to be potent drivers of deleterious inflammation, and mutations in core repressors of these pathways underlie many autoinflammatory disorders. The receptor-interacting protein (RIP) kinases, RIPK1 and RIPK3, are integral players in extrinsic cell death signalling by regulating the production of pro-inflammatory cytokines, such as tumour necrosis factor (TNF), and coordinating the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, which underpin patholog- ical inflammation in numerous chronic inflammatory disorders. In this review, we firstly give an overview of the inflammatory cell death pathways regulated by RIPK1 and RIPK3. We then discuss how dysregulated signalling along these pathways can contribute to chronic inflammatory disorders of the joints, skin, and gastrointestinal tract, and discuss the emerging evidence for targeting these RIP kinases in the clinic. Keywords: apoptosis; necroptosis; RIP kinases; chronic inflammatory disease; tumour necrosis factor; Citation: Speir, M.; Djajawi, T.M.; interleukin-1 Conos, S.A.; Tye, H.; Lawlor, K.E.
    [Show full text]
  • Targeting RIPK1 for the Treatment of Human Diseases INAUGURAL ARTICLE
    Targeting RIPK1 for the treatment of human diseases INAUGURAL ARTICLE Alexei Degtereva,1, Dimitry Ofengeimb,1, and Junying Yuanc,2 aDepartment of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02445; bRare and Neurologic Disease Research Therapeutic Area, Sanofi US, Framingham, MA 01701; and cDepartment of Cell Biology, Harvard Medical School, Boston, MA 02115 This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2017. Edited by Don W. Cleveland, University of California, San Diego, La Jolla, CA, and approved April 8, 2019 (received for review January 21, 2019) RIPK1 kinase has emerged as a promising therapeutic target for carrying different RIPK1 kinase dead knock-in mutations, including the treatment of a wide range of human neurodegenerative, D138N, K45A, K584R, and ΔG26F27,aswellasRIPK3orMLKL autoimmune, and inflammatory diseases. This was supported by knockout mutations, show no abnormality in development or in the extensive studies which demonstrated that RIPK1 is a key mediator adult animals (6–10). Thus, necroptosis might be predominantly of apoptotic and necrotic cell death as well as inflammatory path- activated under pathological conditions, which makes inhibiting ways. Furthermore, human genetic evidence has linked the dysre- this pathway an attractive option for the treatment of chronic gulation of RIPK1 to the pathogenesis of ALS as well as other human diseases. inflammatory and neurodegenerative diseases. Importantly, unique Necroptosis was first defined by a series of small-molecule allosteric small-molecule inhibitors of RIPK1 that offer high selectivity inhibitors (necrostatins), including Nec-1/Nec-1s, Nec-3, Nec-4, have been developed.
    [Show full text]
  • RIP1, a Kinase on the Crossroads of a Cell's Decision to Live Or
    Cell Death and Differentiation (2007) 14, 400–410 & 2007 Nature Publishing Group All rights reserved 1350-9047/07 $30.00 www.nature.com/cdd Review RIP1, a kinase on the crossroads of a cell’s decision to live or die N Festjens1,2, T Vanden Berghe1, S Cornelis1 and P Vandenabeele*,1 Binding of inflammatory cytokines to their receptors, stimulation of pathogen recognition receptors by pathogen-associated molecular patterns, and DNA damage induce specific signalling events. A cell that is exposed to these signals can respond by activation of NF-jB, mitogen-activated protein kinases and interferon regulatory factors, resulting in the upregulation of antiapoptotic proteins and of several cytokines. The consequent survival may or may not be accompanied by an inflammatory response. Alternatively, a cell can also activate death-signalling pathways, resulting in apoptosis or alternative cell death such as necrosis or autophagic cell death. Interplay between survival and death-promoting complexes continues as they compete with each other until one eventually dominates and determines the cell’s fate. RIP1 is a crucial adaptor kinase on the crossroad of these stress-induced signalling pathways and a cell’s decision to live or die. Following different upstream signals, particular RIP1-containing complexes are formed; these initiate only a limited number of cellular responses. In this review, we describe how RIP1 acts as a key integrator of signalling pathways initiated by stimulation of death receptors, bacterial or viral infection, genotoxic stress and T-cell homeostasis. Cell Death and Differentiation (2007) 14, 400–410. doi:10.1038/sj.cdd.4402085 Receptor interacting protein (RIP) kinases constitute a family sufficient for interaction of RIP1 with RIP3.1 RIP4 (DIK/PKK) of seven members, all of which contain a kinase domain (KD) and RIP5 (SgK288) are characterized by the presence of (Figure 1a).
    [Show full text]
  • Interacting Protein Kinase 1 (RIPK1) As a Therapeutic Target
    REVIEWS Receptor- interacting protein kinase 1 (RIPK1) as a therapeutic target Lauren Mifflin 1, Dimitry Ofengeim2 and Junying Yuan 1 ✉ Abstract | Receptor-interacting serine/threonine- protein kinase 1 (RIPK1) is a key mediator of cell death and inflammation. The unique hydrophobic pocket in the allosteric regulatory domain of RIPK1 has enabled the development of highly selective small-molecule inhibitors of its kinase activity, which have demonstrated safety in preclinical models and clinical trials. Potential applications of these RIPK1 inhibitors for the treatment of monogenic and polygenic autoimmune, inflammatory, neurodegenerative, ischaemic and acute conditions, such as sepsis, are emerging. This article reviews RIPK1 biology and disease- associated mutations in RIPK1 signalling pathways, highlighting clinical trials of RIPK1 inhibitors and potential strategies to mitigate development challenges. NF-κ B Receptor-interacting serine/threonine-protein kinase 1 peripherally restricted GSK′772 is being developed for (Nuclear factor κ light chain (RIPK1) is a master regulator of the cellular decision peripheral autoimmune diseases, including psoriasis, enhancer of activated B cells). between pro- survival NF- κB signalling and death in rheumatoid arthritis (RA) and ulcerative colitis12–14. A protein complex whose response to a broad set of inflammatory and pro-death The brain- penetrant DNL747 is in human clinical trial pathway, which can be 1,2 15,16 activated in response to stimuli in human diseases . RIPK1 kinase activation phase Ib/IIa for amyotrophic lateral sclerosis (ALS) . cytokines, free radicals, viral or has been demonstrated in post- mortem human patho- These trials have laid the groundwork for advancing bacterial antigens and other logical samples of autoimmune and neurodegenerative clinical applications of RIPK1 inhibitors.
    [Show full text]
  • A RIPK2 Inhibitor Delays NOD Signalling Events Yet Prevents Inflammatory Cytokine Production
    ARTICLE Received 9 Sep 2014 | Accepted 29 Jan 2015 | Published 17 Mar 2015 DOI: 10.1038/ncomms7442 A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production Ueli Nachbur1,2, Che A. Stafford1,2, Aleksandra Bankovacki1,2, Yifan Zhan1,2, Lisa M. Lindqvist1,2, Berthe K. Fiil3,4, Yelena Khakham1,2, Hyun-Ja Ko1,2, Jarrod J. Sandow1,2, Hendrik Falk1,2,5, Jessica K. Holien6, Diep Chau1,2, Joanne Hildebrand1,2, James E. Vince1,2, Phillip P. Sharp1,2, Andrew I. Webb1,2, Katherine A. Jackman7, Sabrina Mu¨hlen8, Catherine L. Kennedy8, Kym N. Lowes1,2, James M. Murphy1,2, Mads Gyrd-Hansen3,4, Michael W. Parker6,9, Elizabeth L. Hartland8, Andrew M. Lew1,2, David C.S. Huang1,2, Guillaume Lessene1,2,* & John Silke1,2,* Intracellular nucleotide binding and oligomerization domain (NOD) receptors recognize antigens including bacterial peptidoglycans and initiate immune responses by triggering the production of pro-inflammatory cytokines through activating NF-kB and MAP kinases. Receptor interacting protein kinase 2 (RIPK2) is critical for NOD-mediated NF-kB activation and cytokine production. Here we develop and characterize a selective RIPK2 kinase inhibitor, WEHI-345, which delays RIPK2 ubiquitylation and NF-kB activation downstream of NOD engagement. Despite only delaying NF-kB activation on NOD stimulation, WEHI-345 prevents cytokine production in vitro and in vivo and ameliorates experimental autoimmune encephalomyelitis in mice. Our study highlights the importance of the kinase activity of RIPK2 for proper immune responses and demonstrates the therapeutic potential of inhibiting RIPK2 in NOD-driven inflammatory diseases. 1 The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
    [Show full text]
  • RIP Kinase Is Involved in Arsenic-Induced Apoptosis in Multiple Myeloma Cells
    Apoptosis 2004; 9: 561–571 C 2004 Kluwer Academic Publishers RIP kinase is involved in arsenic-induced apoptosis in multiple myeloma cells O. Bajenova, B. Tang, R. Pearse, R. Feinman, B. H. Childs and J. Michaeli† The Myeloma Service, Division of Hematology-Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA (O. Bajenova, B. Tang, B. H. Childs, J. Michaeli); New York Presbyterian Hospital, Weil Cornell Medical College of Cornell University, New York, NY 10021, USA (R. Pearse); New Jersey Medical School, Newark, NJ 07103, USA (R. Feinman) 1 These studies explore the molecular effect of arsenicals expanding. Recently arsenic trioxide (AT, As2O3) at- on MM cells. Freshly isolated cells derived from patients tracted a lot of attention as a cancer treatment agent. with advanced, chemo-refractory myeloma as well as hu- At physiologically tolerable concentrations (<5 µMin man myeloma cell lines, ARP-1, RPMI-8226 and H929 were exposed to the organic arsenical melarsoprol and plasma), As2O3 causes complete remission of newly diag- to the inorganic compound AT. Both agents potently in- nosed and relapsed acute promyelocytic leukemia cancer duced apoptosis in myeloma cells. Exposure to 1–5 µM patients through a mechanism which involves the degra- AT or melarsoprol for 6 hours suppressed NF-κB DNA dation of the PML-RAR alfa ∼ fusion oncoprotein, gen- binding and enhanced of c-Jun kinase (JNK) activity. Ar- erally expressed in this type of leukemia. AT has been senic also activated caspase-3 resulting in the cleavage of poly (ADP-ribose) polymerase (PARP) and Fas/TNFα utilized as salvage treatment for relapsed and/or refrac- related receptor interacting protein (RIP).
    [Show full text]
  • 3 in Renal Tubulointerstitial Fibrosis Ying
    Targeting receptor-interacting serine/threonine- protein kinase (RIPK)3 in renal tubulointerstitial fibrosis Ying Shi A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy Sydney Medical School The University of Sydney 2019 Statement of originality This thesis is submitted to The University of Sydney in fulfilment of the requirement for the degree of Doctor of Philosophy. This is to certify that to the best of my knowledge and belief, the content of this thesis is my own work and that all the assistance received in preparing this thesis and sources have been acknowledged. This thesis has not been submitted for any degree or other purposes. Ying Shi 1 Abstract Chronic kidney disease (CKD) affects almost 10% of the adult population worldwide. Regardless of the initial cause of renal injury, renal fibrosis is the final common pathway of all forms of CKD, including diabetic kidney disease (DKD). However, current therapies to attenuate the development of progressive renal fibrosis are limited to blockade of the renin- angiotensin-aldosterone system (RAAS), achievement of blood pressure targets and in the case of DKD, blood glucose control. More recently inhibition of sodium-glucose linked transporter-2 has shown impressive renoprotective benefits in secondary analyses of major cardiovascular end-point trials. However, studies, where renal disease is a primary endpoint, are awaited. Given the personal and societal impacts of the increasing burden of CKD, it is of utmost importance to identify novel interventions for preventing the progressive renal fibrosis and thus progressive CKD. Receptor-interacting serine/threonine-protein kinase (RIPK) 3, known as a necroptotic kinase, is recognised to be involved in various innate immune responses, including necroptosis and activation of the toll-like receptor (TLR) 2 and 4 pathways and the pyrin domain-containing protein (NLRP) 3 inflammasome.
    [Show full text]
  • RIP1 Suppresses Innate Immune Necrotic As Well As Apoptotic Cell Death During Mammalian Parturition
    RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition William J. Kaisera,1, Lisa P. Daley-Bauera, Roshan J. Thapab, Pratyusha Mandala, Scott B. Bergerc, Chunzi Huanga, Aarthi Sundararajana, Hongyan Guoa, Linda Robacka, Samuel H. Specka, John Bertinc, Peter J. Goughc,1, Siddharth Balachandranb, and Edward S. Mocarskia,1 aDepartment of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; bImmune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA 19111; and cPattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426 Edited by Michael Karin, University of California, San Diego School of Medicine, La Jolla, CA, and approved April 16, 2014 (received for review February 27, 2014) The pronecrotic kinase, receptor interacting protein (RIP1, also called architecture facilitates convergent death domain-dependent and RIPK1) mediates programmed necrosis and, together with its partner, RHIM-dependent pathways. RIP1 partners with death domain- RIP3 (RIPK3), drives midgestational death of caspase 8 (Casp8)-deficient containing proteins, particularly fas-associated death domain pro- embryos. RIP1 controls a second vital step in mammalian development tein (FADD), as well as RHIM-containing proteins, such as the immediately after birth, the mechanism of which remains unresolved. pronecrotic kinase RIP3 and the TLR3/TLR4 adapter TIR- −/− Rip1 mice display perinatal lethality, accompanied by gross immune domain–containing adapter-inducing IFN (TRIF) (8, 9). RIP1 is system abnormalities. Here we show that RIP1 K45A (kinase dead) essential for TNF-induced necroptosis but dispensable for other knockin mice develop normally into adulthood, indicating that devel- forms of RIP3 kinase-dependent death (10, 11).
    [Show full text]
  • Full Text (PDF)
    Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2018/03/19/jpet.117.247163.DC1 1521-0103/365/2/354–367$35.00 https://doi.org/10.1124/jpet.117.247163 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 365:354–367, May 2018 Copyright ª 2018 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. Identification and Characterization of Novel Receptor-Interacting Serine/Threonine‐Protein Kinase 2 Inhibitors Using Structural Similarity Analysis s Mohamed Salla, Rodrigo Aguayo-Ortiz, Gaddafi I. Danmaliki, Alaa Zare, Ahmed Said, Jack Moore, Vrajeshkumar Pandya, Robin Manaloor, Sunny Fong, Anna R. Blankstein, Spencer B. Gibson, Laura Ramos Garcia, Pascal Meier, Khushwant S. Bhullar, Basil P. Hubbard, Yahya Fiteh, Harissios Vliagoftis, Ing Swie Goping, Dion Brocks, Peter Hwang, Carlos A. Velázquez-Martínez, and Shairaz Baksh Downloaded from Departments of Biochemistry (M.S., G.I.D., A.S., J.M., V.P., I.S.G., P.H., S.B.), Pediatrics (A.Z., R.M., S.F., S.B.), Pharmacology (K.S.B., B.P.H.), Oncology (S.B.) Medicine (Y.F., H.V., P.H.), and Faculty of Pharmacy and Pharmaceutical Sciences (R.A.-O., D.B., C.A.-V.M.), University of Alberta, Edmonton, Alberta, Canada; Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Mexico City, Mexico (R.A.-O.); Departments of Biochemistry and Medical Genetics and Immunology, University of Manitoba, Winnipeg, Manitoba, Canada (A.R.B., S.B.G.);
    [Show full text]
  • The Role of Map Kinases in Immune Response
    ADVANCES IN CELL BIOLOGY VOL. 2, ISSUE 3/2010 (125–138) THE ROLE OF MAP KINASES IN IMMUNE RESPONSE Malgorzata KRZYZOWSKA, Weronika SWIATEK, Beata FIJALKOWSKA, Marek NIEMIALTOWSKI, Ada SCHOLLENBERGER Division of Immunology, Department of Pre-clinical Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences DOI: 10.2478/v10052-010-0007-5 Summary: The MAP kinases (MAPKs), including ERK, JNK and p38 families comprise part of the intracellular signalling network, which is essential for signal transduction from receptors and stimuli to the biological reaction. Activity of MAPKs plays a crucial role in normal functioning of the immune system. By taking part in cytokine production upon signalling from activated TLR receptors, MAPKs are involved in initiation of innate immunity and in responses to binding of cytokines by appropriate receptors. MAPKs activity is also important for T and B lymphocyte differentiation, by the ITAM signalling pathway. Moreover, their involvement in apoptosis supports lymphocyte T cytotoxicity and enables the removal of damaged, infected or transformed cells. Correct functioning of the MAPK signalling is crucial for effective immune response, and therefore MAPKs’ inhibitors constitute a promising therapeutic goal. Key words: MAP kinases, ERK, JNK, p38 MAP KINASES Intracellular signal transduction allows cells to respond to signals from the extracellular environment, detected by appropriate receptors. This response involves changes in genes expression and cell functioning [41]. MAP kinases (mitogen activated protein kinases, MAPK) are serine/threonine kinases activated by mitogens, which were first described as the proteins activated by growth factors [26]. All the MAPKs posses a Thr-X-Tyr (TXY) motif within their activation loop.
    [Show full text]
  • Concluding Remarks
    Concluding Remarks Volume 3 of the set of textbooks devoted to Circulatory and Ventilatory Sys- tems in the framework of Biomathematical and Biomechanical Modeling gives the basic knowledge on the first phases of signal transduction triggered by extracellular messengers. Signaling determines cell behavior. Numerous process can be modeled to quickly assess effects of parameters, all other agents remaining constant, once the mathematical model has been vali- dated. Advantage of mathematical models is to provide the complete quantity fields, whereas measurements are made in some points or corresponds to averages of ex- ploration windows of the field of the investigated variable. Mathematical description of large, complex biochemical reaction networks, in which molecules are nodes, and modeling of the dynamics of interactions (scaffold- ing, reaction, transcription, etc.) relies on computational simulations. A biochemical reaction network is defined by: (1) a set of variables — the state variables — that de- fine the state of the system and (2) rules of temporal changes and possible transport of involved variables. The network behavior can be analyzed in a single cells and extended to multicellular systems, especially in tumor models. Mathematical models of cascades of chemical reactions are aimed at describing evolution of molecular concentrations 1 using the mass action law or a reaction– diffusion equation set. A given reaction occurs with a certain probability. Stochastic models rely on a stochastic update of system variables. On the other hand, determin- istic models are carried out in systems with a large number of molecules, the time and variable states uniquely defining the state at the next time step.
    [Show full text]