DOCSLIB.ORG

Cell Death Survey NECROPTOSIS 2 2 1 1 1 S.Gramatikova Phd, K.Gramatiko Phd, J.Mountzouris Phd, T.Gilliam & C.Wu Phd

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Cell Death Survey NECROPTOSIS 2 2 1 1 1 S.Gramatikova Phd, K.Gramatiko Phd, J.Mountzouris Phd, T.Gilliam & C.Wu Phd Cell Death Survey www.abcepta.com NECROPTOSIS 2 2 1 1 1 S.Gramatikova PhD, K.Gramatiko PhD, J.Mountzouris PhD, T.Gilliam & C.Wu PhD (1) Abcepta Inc., 10320 Camino Santa Fe, Ste G, San Diego, CA 92121 (2) Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037 ABGENT has hundreds of cell death/survival-related antibodies which cover key targets for apoptosis, autophagy, necroptosis, and other programed cell death processes. Visit www.abgent.com for a complete listing. Cell Death Selected Abgent Products Comparison of different cell death programs Caspase 8 NECROPTOSIS Caspase 3 Figure Target Tissue/Cell line Cat # A. B. zVAD inhibitor Apoptosome formation CALCIUM- AIF/PARP- A. BAD Human lung carcinoma AP1314b BID CHARACTERISTICS APOPTOSIS NECROPTOSIS AUTOPHAGIC ONCOSIS MEDIATED DEPENDENT B. PUMA Human breast carcinoma AP1317a Cytochrome c DNA BMF release fragmentation C. CASP1 Human hepatocarcinoma AT1400a Chromatin condensation, Mitochondrial dysfunction, Autophagic Membrane whorls Mild chromatin Cellular D. CASP3 Human lung carcinoma AP7563c BAX Morphology nuclear fragmentation, membrane rupture, ER vacuoles, membrane condensation swelling BCL2 BCL2 AIF release apoptotic bodies swelling, increase of ROS rupture E. DNMT1 Human carcinoma (HeLa) AT1805a C. D. BAX F. CBX5 Human carcinoma (HeLa) AT1411a APOPTOSIS Oxidative stress, death Trophotoxicity, TNF, Serum, amino acid Calcium entry, DNA damage, Ischemia, TNFR activation G. CASP6 Mouse liver tissue AP1313b Triggers receptors, viral infections, damage-induced lesions, starvation, protein CDK5 signaling glutamate, NO excitotoxicity NECROPTOSIS hypoxia, etc. ischemia, antimycin A aggregates deg mutants H. MLL3 Transfected 293T cells AP6184a CypD I. AIF1 Human leukemia cells K562 AT1077a Energy collapse Mediators Caspases, BH family, etc. ERK2, NUR77 Atg orthologs Calpains, cathepsins PARP, AIF JNK J. BIRC5 Transfected 293T cells AT1299a ATP depletion E. F. Membrane AIF release CYLD Caspase inhibitors, Necrostatins, Ca2+ chelators, 3-Methyladenine, Calreticulin, PARP inhibitors JNK inhibitors, K. SPP1 Human carcinoma (HeLa) AT4028a permeabilization TOP1 inhibitors, survivin, PARP inhibitors, U0126, bafilomycin A1, mTOR, calpain inhibitors glycine L. JUN Transfected 293T cells AP1984d Deubiquitination Cathepsins Inhibitors 2+ VEGF, zVAD, NO, etc. DN NUR77, CypD inhibitors JNK inhibitors? RIP1 Ca overload PARP M. PARP1 Transfected 293T cells AP6373a C. elegans Some excito- Examples Type I and nuclear pcd Type III and cytoplasmic pcd Type II pcd Ischemic pcd TLR signaling deg mutants toxic pcd Necrostatins Calpains Liver 293T K562 293T HeLa 293T 293T Type 1 IFN family ROS 250 150 250 95 250 72 541 Table 1. Alternative programed cell death (pcd) processes. Necroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli 55 under conditions where apoptotic and/or autophagic execution are prevented. Abbreviations for Fig. 1 and Table 1: AIF, apoptosis-inducing factor; BAX, BCL2-as- 37 55 130 36 25 Fig. 1. Crosstalk between apoptosis and programed necrosis (necropto- sociated X protein; BCL2, B-cell CLL/lymphoma 2; BID, BH3 interacting domain death agonist; BMF, Bcl2 modifying factor; CDK5, cyclin-dependent kinase 5; CYLD, 20 36 sis). Caspase 8-mediated degradation of RIP1 (receptor-interacting protein kinase 1) is a major cylindromatosis (turban tumor syndrome); CypD, cyclophilin D; deg, degenerin; ERK2, mitogen-activated protein kinase 1; IFN, interferon; JNK, mitogen-activated 15 molecular switch between apoptosis and necroptosis. Necroptosis centers on the activation of RIP1. As protein kinase 8; mTOR, mechanistic target of rapamycin; NO, nitric oxide; NUR77, nuclear receptor; DN Nur77, dominant negative Nur77; PARP, poly (ADP- opposed to apoptosis, necroptosis does not engage apoptotic regulators such as caspases, BCL2 family ribose) polymerase; ROS, reactive oxygen species; TLR, Toll-like receptor; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor; TOP1, DNA topoisomerase 17 10 15 55 members, or cytochrome c (1-7). 1; U0126, inhibitor of MEK kinase; zVAD, carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone, a caspase inhibitor (1-7). G. H. I. J. K. L. M. Protein Associations Identification Protocol Statistical Distribution Inferred Network Fig. 2 siRNA screening for genes re- quired in necroptosis. siRNA screen of the Oxidoreductase, 10 mouse genome for regulators of necroptosis identified Extracellular matrix, 10 TNF TTRAP SPATA2* TRAF7 a set of 432 genes that regulate necroptosis, a subset siRNA transfection of L929 Protease, 11 Nucleic acid binding, 65 of 32 genes that are associated with RIP1 kinase, 32 genes required for apoptosis, and 7 genes involved in Transporter, 13 cells targeting 16,873 genes both necroptosis and apoptosis. zVAD, carbobenzoxy- valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone; Cytoskeleton, 14 TRAF5 TRAF6 CYLD* n CX, cycloheximide (7). e re Hydrolase, 16 Fig. 3 Classification of 432 selected pro- zVAD - induced c TRAF3 TRAF2 TRAIP teins from the necroptosis screen into (A) y s RIPK1 molecular function and (B) biological process catego- necroptosis r ries. Genes for which no annotations could be assigned a Signaling, 21 TRAF1 HSP90AA1 IKBKG were excluded from the analysis. Categories with at least m Receptors, 50 ten genes are displayed. The number of genes assigned Viability assay pri Transferase, 20 to each category are shown in gray (7). CASP3* TNFRSF1A* CASP8* GRB2 Fig. 4 Molecular interactions of TNF- induced necroptotic proteins. A, Crosstalk Regulatory, 24 Transcription, 43 CASP7* CASP10* between necroptosis-related proteins, positively identi- Selection of 666 genes required A fied in the secondary screen, with apoptotic (*) and other signaling molecules. The network was generated by using data curated from the literature. Number for zVAD - induced necroptosis Lipid, fatty acid, steroid metabolism, 13 Apoptosis, 10 KCNIP1 BCL2* BMF PARP2 B, of protein binding partners for necroptotic proteins se- Carbohydrate metabolism, 13 lected from the secondary screen. Proliferation & differentiation, 13 Signaling, 95 Neuronal activities, 13 Caspase Necroptosis-related TNF-signaling associated Other Protein abbreviations: ATP6V1G2, vacu- n Cell structure & motility, 18 TNF - induced zVAD - induced TNF+CX - induced A olar ATP synthase subunit G2; CASP, caspase; COM- MD4, COMM domain containing 4; EIF5B, eukaryotic ree Intracellular protein traffic, 19 necroptosis necroptosis apoptosis c translation initiation factor 5B; DEFB1, defensin, beta 1; DPYSL4, dihydropyrimidinase-like 4; JPH3, s y s Cell cycle, 18 r >193 r junctophilin 3; HOXA3, homeobox A3; HSPBAP1, tne >43 32 genes 432 genes 32 genes r Molecular interactions heat shock associated protein 1; GALNT5, N-acetyl- Transport, 26 of necroptosis proteins galactosaminyltransferase 5; GRB2, growth factor ein pa Nucleic acid ot r receptor-bound protein 2; KCNIP1, Kv channel inter- metabolism, 80 acting protein 1; MAG, myelin associated glycoprotein; 13 10 seconda Sensory perception, 27 RAB25, RAB25, member RAS oncogene family; SPA- 7 6 6 5 4 4 2 2 2 1 1 1 1 1 1 1 1 1 TA2, spermatogenesis associated 2; TMEM57, trans- 7 genes positive in: of p Number membrane protein 57; TNFAIP8L1, tumor necrosis 7 G A2 5 Immunity & defense, 28 A SL4 AP1 T XA3 PVR BMF factor, alpha-induced protein 8-like 1; , M Y TNFRSF1A B A CYLD JPH3 O TNF / zVAD / TNF+CX B ARP2 GRB2 CNIP1 Protein metabolism EIF5B DEFB1 P AIP8I1 P RAB25 H K F S DP TXNL4B GALNT5 OMMD4 tumor necrosis factor receptor superfamily, member 1A; TMEM HSP TP6V1G2 Development, 38 C & modification, 48 TN TNFRSF1A B A TRAIP, TRAF interacting protein; TRAF, TNF receptor- associated factor 1; TTRAP, TRAF and TNF receptor as- Fig. 2 Fig. 3 Fig. 4 sociated protein; TXNL4B, thioredoxin-like 4B. Protein Markers Product Abbreviations TNFα Necroptosis CDK4 APOPTOSIS DNA REPAIR TNFR BAD: BCL2-associated agonist of cell death; BCL-X/BCL-2 binding protein; BCL2-binding component 6; BBC2 Membrane PUMA: BCL2 binding component 3; BBC3 Caspase 1, 3, 6, 7 & 8; p53; DNA ligase III; CASP9 HSP90AA1 CASP1, -3, -6: caspase 1, -3, -6 Granzyme B; PARP3; XRCC1, 5 & 6; PCNA; Death domain RIP1 DNMT1: DNA (cytosine-5-)-methyltransferase 1; CXXC finger protein 9; DNA methyltransferase 1 BCL2; NFκB; CDKN1A Werner syndrome Kinase domain CBX5: chromobox homolog 5 (HP1 alpha homolog, Drosophila); heterochromatin protein 1 homolog alpha Autophagy Lipoxygenases XIAP MLL3: myeloid/lymphoid or mixed-lineage leukemia 3; histone-lysine N-methyltransferase, H3 lysine-4 specific CASP3 DIABLO AIF1: allograft inflammatory factor 1; interferon gamma responsive transcript; ionized calcium-binding adapter poly (ADP-ribose) JNK activation Phospholipase A polymerase 1 (PARP1) Survivin (BIRC5) BIRC5: baculoviral IAP repeat-containing 5; apoptosis inhibitor 4; survivin variant 3 alpha PARP1 & PARP2 ROS formation & Sphingomyelinase SPP1: secreted phosphoprotein 1; bone sialoprotein I; osteopontin protein partners mitochondrial dysfunction Survivin RASA1 CDCA8 JUN: jun oncogene; Jun activation domain binding protein; v-jun avian sarcoma virus 17 oncogene homolog PARP1: poly (ADP-ribose) polymerase 1; ADP-ribosyltransferase (NAD+; poly (ADP-ribose) polymerase) DNA topoisomerase I (TOP1) AURKB TRANSCRIPTION CELL CYCLE CASP7 DNA damage or drugs XPO1 References Transcription factors; CENPA & B; MYBL2; INCENP Retinoid receptors; Nucleophosmin 1; TOP1 cleavage complex CDC2 1. Bredesen DE. (2007) Key note lecture: toward a mechanistic taxonomy
Load more

Recommended publications
  • The Potential Role of Necroptosis in Clinical Diseases (Review)
    INTERNATIONAL JOURNAL OF MOleCular meDICine 47: 89, 2021 The potential role of necroptosis in clinical diseases (Review) WENLI DAI1*, JIN CHENG1*, XI LENG2, XIAOQING HU1 and YINGFANG AO1 1Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, Beijing 100191; 2Medical Imaging Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China Received November 19, 2020; Accepted March 8, 2021 DOI: 10.3892/ijmm.2021.4922 Abstract. As an important type of programmed cell death in 1. Introduction addition to apoptosis, necroptosis occurs in a variety of patho‑ physiological processes, including infections, liver diseases, Necroptosis, an emerging field closely related to apoptosis, is a kidney injury, neurodegenerative diseases, cardiovascular non‑caspase‑dependent cell death that has been implicated in diseases, and human tumors. It can be triggered by a variety the pathological processes of various diseases. It is regulated of factors, such as tumor necrosis factor receptor and Toll‑like by various genes that cause regular and ordered cell death. receptor families, intracellular DNA and RNA sensors, and Through activating specific death signaling pathways, it shares interferon, and is mainly mediated by receptor‑interacting typical characteristics of necrosis, including loss of metabolic protein kinase 1 (RIP1), RIP3, and mixed lineage kinase function and subcellular changes (1,2). Receptor‑interacting domain‑like protein. A better understanding of the mechanism protein kinase 1 (RIP1) was the first signaling molecule of necroptosis may be useful in the development of novel drugs identified in the necrosome (3). RIP1 and RIP3 interact for necroptosis‑related diseases.
    [Show full text]
  • Cloning and Sequence Analysis of Canine Apoptosis-Associated Molecules
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2007 Cloning and sequence analysis of canine apoptosis-associated molecules Schade, Benjamin Abstract: The aim of the study was to clone and sequence the coding sequences of a representative set of proteins, primarily from the intrinsic apoptotic pathway in dogs and to assess their conservation with hu- man and murine orthologues. cDNA for these proteins, including Bcl-2 family members (Bcl-XL, Bcl-w, Mcl-1, Bax, Bak, Bad, Noxa), caspases (Caspase-3, Caspase-8, Caspase-9), Inhibitors of Apoptosis Pro- teins (XIAP, cIAP-1, cIAP-2, Survivin), their mitochondrial inhibitors (Smac/ DIABLO, Omi/HtrA2) and p53, were generated by RT-PCR with RNA extracted from two canine non-neoplastic cell lines. Eleven sequences are novel for the dog. Interspecies comparison revealed strongest similarity between the sequences of human and canine intrinsic apoptosis pathway members. Differences with potential func- tional impact, however, were observed in both dogs and mice. In dogs, these changes involve the putative Inhibitor of Apoptosis Protein binding motif of canine Omi/HtrA2, some caspase substrate recognition motifs and some functionally relevant residues of p53. Canine XIAP yields a caspase-cleavage site reported as unique to humans. In conclusion, the generally high degree of similarity of canine apoptosis-associated proteins as compared to human counterparts is supportive of the use of dogs as a model for human dis- eases. Single interspecies sequence variations with potential functional relevance under physiologic and neoplastic conditions do exist, however, and will require further analysis.
    [Show full text]
  • Supplementary Materials For
    Supplementary Materials for Elucidating cellular population dynamics by molecular density function perturbations 1 2,3, Thanneer Malai Perumal ​ and Rudiyanto Gunawan *​ ​ ​ 1 Sage Bionetworks, Seattle, Washington, USA; [email protected] 2 Institute for Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland; [email protected] 3 Swiss Institute of Bioinformatics, Lausanne, Switzerland * Correspondence: [email protected]; Tel.: +41-44-633-2134 Supplementary Material S1. Probability Distance Metrics Signed Engineering Metric: ∞ 2 ∆ (f A (t, x )||f B (t, x )) = sign(∆μ ) ∫ (x f A (t, x ) − x f B (t, x )) dx (S. 1) E Xi i Xi i Xi i Xi i i Xi i i −∞ Signed Jeffrey Divergence: ∞ f A (t,x ) A B A B Xi i ∆ (f (t, x )||f (t, x )) = sgn(∆μ ) ∫ (f (t, x ) − f (t, x ))ln ( B ) )dx (S. 2) JD Xi i Xi i Xi Xi i Xi i f (t,x ) i −∞ Xi i Signed Kullback-Leibler Distance: ∞ f B (t,x ) A B B Xi i ∆ (f (t, x )||f (t, x )) = sgn(∆μ ) ∫ f (t, x )ln ( A ) dx (S. 3) KLD Xi i Xi i Xi Xi i f (t,x ) i −∞ Xi i Signed Jensen-Shannon Divergence: f + (t,x )+f − (t,x ) Xi i Xi i ∆ f (t, x ) = sgn(∆μ ) (S. 4) JSD Xi i Xi 2 Signed Kolmogorov-Smirnov Metric: ∆ (f A (t, x )||f B (t, x )) = sgn(∆μ )sup|F A (t, x ) − F B (t, x )| (S. 5) KS Xi i Xi i Xi Xi i Xi i Supplementary Material S2.
    [Show full text]
  • Supplemental Table S1
    Entrez Gene Symbol Gene Name Affymetrix EST Glomchip SAGE Stanford Literature HPA confirmed Gene ID Profiling profiling Profiling Profiling array profiling confirmed 1 2 A2M alpha-2-macroglobulin 0 0 0 1 0 2 10347 ABCA7 ATP-binding cassette, sub-family A (ABC1), member 7 1 0 0 0 0 3 10350 ABCA9 ATP-binding cassette, sub-family A (ABC1), member 9 1 0 0 0 0 4 10057 ABCC5 ATP-binding cassette, sub-family C (CFTR/MRP), member 5 1 0 0 0 0 5 10060 ABCC9 ATP-binding cassette, sub-family C (CFTR/MRP), member 9 1 0 0 0 0 6 79575 ABHD8 abhydrolase domain containing 8 1 0 0 0 0 7 51225 ABI3 ABI gene family, member 3 1 0 1 0 0 8 29 ABR active BCR-related gene 1 0 0 0 0 9 25841 ABTB2 ankyrin repeat and BTB (POZ) domain containing 2 1 0 1 0 0 10 30 ACAA1 acetyl-Coenzyme A acyltransferase 1 (peroxisomal 3-oxoacyl-Coenzyme A thiol 0 1 0 0 0 11 43 ACHE acetylcholinesterase (Yt blood group) 1 0 0 0 0 12 58 ACTA1 actin, alpha 1, skeletal muscle 0 1 0 0 0 13 60 ACTB actin, beta 01000 1 14 71 ACTG1 actin, gamma 1 0 1 0 0 0 15 81 ACTN4 actinin, alpha 4 0 0 1 1 1 10700177 16 10096 ACTR3 ARP3 actin-related protein 3 homolog (yeast) 0 1 0 0 0 17 94 ACVRL1 activin A receptor type II-like 1 1 0 1 0 0 18 8038 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 1 0 0 0 0 19 8751 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 1 0 0 0 0 20 8728 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 1 0 0 0 0 21 81792 ADAMTS12 ADAM metallopeptidase with thrombospondin type 1 motif, 12 1 0 0 0 0 22 9507 ADAMTS4 ADAM metallopeptidase with thrombospondin type 1
    [Show full text]
  • Dectin-1-Induced RIPK1 and RIPK3 Activation Protects Host Against Candida Albicans Infection
    Cell Death & Differentiation (2019) 26:2622–2636 https://doi.org/10.1038/s41418-019-0323-8 ARTICLE Dectin-1-induced RIPK1 and RIPK3 activation protects host against Candida albicans infection 1 1 1 1 1 1 1 1 1 Mengtao Cao ● Zhengxi Wu ● Qi Lou ● Wenli Lu ● Jie Zhang ● Qi Li ● Yifan Zhang ● Yikun Yao ● Qun Zhao ● 1 1 1,2 Ming Li ● Haibing Zhang ● Youcun Qian Received: 5 November 2018 / Revised: 5 March 2019 / Accepted: 21 March 2019 / Published online: 3 April 2019 © ADMC Associazione Differenziamento e Morte Cellulare 2019 Abstract Necroptosis is a recently defined type of programmed cell death with the specific signaling cascade of receptor-interacting protein 1 (RIPK1) and RIPK3 complex to activate the executor MLKL. However, the pathophysiological roles of necroptosis are largely unexplored. Here, we report that fungus triggers myeloid cell necroptosis and this type of cell death contributes to host defense against the pathogen infection. Candida albicans as well as its sensor Dectin-1 activation strongly induced necroptosis in myeloid cells through the RIPK1-RIPK3-MLKL cascade. CARD9, a key adaptor in Dectin-1 signaling, was identified to bridge the RIPK1 and RIPK3 complex-mediated necroptosis pathway. RIPK1 and fl 1234567890();,: 1234567890();,: RIPK3 also potentiated Dectin-1-induced MLKL-independent in ammatory response. Both the MLKL-dependent and MLKL-independent pathways were required for host defense against C. albicans infection. Thus, our study demonstrates a new type of host defense system against fungal infection. Introduction antifungal drugs used in clinical application and increased drugs resistance, it is of great importance to investigate how Fungal infections severely influence human life quality host defenses against fungal infection to develop new and are common worldwide health problem.
    [Show full text]
  • Neurodevelopmental Signatures of Narcotic and Neuropsychiatric Risk Factors in 3D Human-Derived Forebrain Organoids
    Molecular Psychiatry www.nature.com/mp ARTICLE OPEN Neurodevelopmental signatures of narcotic and neuropsychiatric risk factors in 3D human-derived forebrain organoids 1 1 1 1 2 2 3 Michael Notaras , Aiman Lodhi , Estibaliz✉ Barrio-Alonso , Careen Foord , Tori Rodrick , Drew Jones , Haoyun Fang , David Greening 3,4 and Dilek Colak 1,5 © The Author(s) 2021 It is widely accepted that narcotic use during pregnancy and specific environmental factors (e.g., maternal immune activation and chronic stress) may increase risk of neuropsychiatric illness in offspring. However, little progress has been made in defining human- specific in utero neurodevelopmental pathology due to ethical and technical challenges associated with accessing human prenatal brain tissue. Here we utilized human induced pluripotent stem cells (hiPSCs) to generate reproducible organoids that recapitulate dorsal forebrain development including early corticogenesis. We systemically exposed organoid samples to chemically defined “enviromimetic” compounds to examine the developmental effects of various narcotic and neuropsychiatric-related risk factors within tissue of human origin. In tandem experiments conducted in parallel, we modeled exposure to opiates (μ-opioid agonist endomorphin), cannabinoids (WIN 55,212-2), alcohol (ethanol), smoking (nicotine), chronic stress (human cortisol), and maternal immune activation (human Interleukin-17a; IL17a). Human-derived dorsal forebrain organoids were consequently analyzed via an array of unbiased and high-throughput analytical approaches, including state-of-the-art TMT-16plex liquid chromatography/mass- spectrometry (LC/MS) proteomics, hybrid MS metabolomics, and flow cytometry panels to determine cell-cycle dynamics and rates of cell death. This pipeline subsequently revealed both common and unique proteome, reactome, and metabolome alterations as a consequence of enviromimetic modeling of narcotic use and neuropsychiatric-related risk factors in tissue of human origin.
    [Show full text]
  • Necroptosis in Intestinal Inflammation and Cancer
    biomolecules Review Necroptosis in Intestinal Inflammation and Cancer: New Concepts and Therapeutic Perspectives Anna Negroni 1,* , Eleonora Colantoni 2, Salvatore Cucchiara 2 and Laura Stronati 3 1 Division of Health Protection Technologies, ENEA, 00123 Rome, Italy 2 Maternal Infantile and Urological Sciences Department, Sapienza, University of Rome, 00161 Rome, Italy; [email protected] (E.C.); [email protected] (S.C.) 3 Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-06-3048-3623 Received: 3 September 2020; Accepted: 8 October 2020; Published: 10 October 2020 Abstract: Necroptosis is a caspases-independent programmed cell death displaying intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development such tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis plays a role in many disease conditions and inhibiting necroptosis is currently considered a promising therapeutic strategy. In this review, we focus on the molecular mechanisms of necroptosis as well as its involvement in human diseases. We also discuss the present developing therapies that target necroptosis machinery. Keywords: programmed cell death; inflammation; cancer; intestinal diseases; inhibitors 1. Introduction Cell death is crucial during the development and maintenance of tissue homeostasis in multicellular organisms.
    [Show full text]
  • XIAP's Profile in Human Cancer
    biomolecules Review XIAP’s Profile in Human Cancer Huailu Tu and Max Costa * Department of Environmental Medicine, Grossman School of Medicine, New York University, New York, NY 10010, USA; [email protected] * Correspondence: [email protected] Received: 16 September 2020; Accepted: 25 October 2020; Published: 29 October 2020 Abstract: XIAP, the X-linked inhibitor of apoptosis protein, regulates cell death signaling pathways through binding and inhibiting caspases. Mounting experimental research associated with XIAP has shown it to be a master regulator of cell death not only in apoptosis, but also in autophagy and necroptosis. As a vital decider on cell survival, XIAP is involved in the regulation of cancer initiation, promotion and progression. XIAP up-regulation occurs in many human diseases, resulting in a series of undesired effects such as raising the cellular tolerance to genetic lesions, inflammation and cytotoxicity. Hence, anti-tumor drugs targeting XIAP have become an important focus for cancer therapy research. RNA–XIAP interaction is a focus, which has enriched the general profile of XIAP regulation in human cancer. In this review, the basic functions of XIAP, its regulatory role in cancer, anti-XIAP drugs and recent findings about RNA–XIAP interactions are discussed. Keywords: XIAP; apoptosis; cancer; therapeutics; non-coding RNA 1. Introduction X-linked inhibitor of apoptosis protein (XIAP), also known as inhibitor of apoptosis protein 3 (IAP3), baculoviral IAP repeat-containing protein 4 (BIRC4), and human IAPs like protein (hILP), belongs to IAP family which was discovered in insect baculovirus [1]. Eight different IAPs have been isolated from human tissues: NAIP (BIRC1), BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4), BIRC5 (survivin), BIRC6 (apollon), BIRC7 (livin) and BIRC8 [2].
    [Show full text]
  • Die Another Way – Non-Apoptotic Mechanisms of Cell Death
    ß 2014. Published by The Company of Biologists Ltd | Journal of Cell Science (2014) 127, 2135–2144 doi:10.1242/jcs.093575 COMMENTARY Die another way – non-apoptotic mechanisms of cell death Stephen W. G. Tait1,*, Gabriel Ichim1 and Douglas R. Green2,* ABSTRACT apoptosis-resistant cancer cells. In this Commentary, we discuss major forms of non-apoptotic programmed cell death, how they Regulated, programmed cell death is crucial for all multicellular intersect with one another and their occurrence and roles in vivo, organisms. Cell death is essential in many processes, including and we outline outstanding questions. Following this, we ask tissue sculpting during embryogenesis, development of the immune whether it really matter how a cell dies. Specifically, we focus on system and destruction of damaged cells. The best-studied form of how the mode of cell death impacts on immunity and programmed cell death is apoptosis, a process that requires inflammation. activation of caspase proteases. Recently it has been appreciated that various non-apoptotic forms of cell death also exist, such as Necroptosis necroptosis and pyroptosis. These non-apoptotic cell death Various stimuli can engage a non-apoptotic form of cell death called modalities can be either triggered independently of apoptosis or necroptosis (Degterev et al., 2005). Although morphologically are engaged should apoptosis fail to execute. In this Commentary, resembling necrosis, necroptosis differs substantially in that it is a we discuss several regulated non-apoptotic forms of cell death regulated active type of cell death (Galluzzi et al., 2011; Green including necroptosis, autophagic cell death, pyroptosis and et al., 2011).
    [Show full text]
  • Necroptosis: a Novel Manner of Cell Death, Associated with Stroke (Review)
    624 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 41: 624-630, 2018 Necroptosis: A novel manner of cell death, associated with stroke (Review) CHeNglIN lIu*, KAI ZHANg*, Haitao SHeN, XIyANg Yao, QINg SuN and gANg CHeN Department of Neurosurgery, The First Affiliated Hospital of Soochow university, Suzhou, Jiangsu 215006, P.R. China Received December 29, 2015; Accepted October 24, 2017 DOI: 10.3892/ijmm.2017.3279 Abstract. Cell death is indispensable in the physiology, present review, the features, molecular mechanism and iden- pathology, growth, development, senility and death of an tification of necroptosis under pathological conditions are organism. In recent years, the identification of a highly regu- discussed, with particular emphasis on its association with lated form of necrosis, known as necroptosis, has challenged stroke. the traditional concept of necrosis and apoptosis, which are two major modes of cell death. This novel manner of cell death is similar in form to necrosis in terms of morphological Contents features, and it can also be regulated in a caspase‑independent manner. Therefore, necroptosis can be understood initially 1. Introduction as a combination of necrosis and apoptosis. The mechanism 2. Cell death of its regulation, induction and inhibition is complicated, 3. Mechanisms of necroptosis and the TNFα-TNFR1-related and involves a range of molecular expression and regulation. signaling pathway According to the recent literature, necroptosis takes place in 4. Necroptosis in stroke the physiological regulatory processes of an organism and is 5. Necroptosis in other diseases involved in the occurrence, development and prognosis of a 6. Conclusions variety of diseases that have a necrosis phenotype, including neurodegenerative diseases, ischemic disease, hemorrhagic disease, inflammation and viral infectious diseases.
    [Show full text]
  • Anti-Smac / Diablo Antibody (ARG54653)
    Product datasheet [email protected] ARG54653 Package: 50 μg anti-Smac / Diablo antibody Store at: -20°C Summary Product Description Rabbit Polyclonal antibody recognizes Smac / Diablo Tested Reactivity Hu, Ms, Rat Tested Application ELISA, ICC/IF, IHC, IP, WB Host Rabbit Clonality Polyclonal Isotype IgG Target Name Smac / Diablo Immunogen Synthetic peptide (16 aa) within the last 50 aa of Mouse Smac. Conjugation Un-conjugated Alternate Names Smac; Second mitochondria-derived activator of caspase; Diablo homolog, mitochondrial; SMAC; Direct IAP-binding protein with low pI; DFNA64 Application Instructions Application table Application Dilution ELISA Assay-Dependent ICC/IF 10 μg/mL IHC 2 μg/mL IP Assay-Dependent WB 1 μg/mL Application Note * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Positive Control Mouse Heart Tissue Lysate Calculated Mw 27 kDa Properties Form Liquid Purification Affinity purification with immunogen. Buffer PBS and 0.02% Sodium azide Preservative 0.02% Sodium azide Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot and store at -20°C or below. Storage in frost free freezers is not recommended. Avoid repeated freeze/thaw cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed before use. www.arigobio.com 1/3 Note For laboratory research only, not for drug, diagnostic or other use. Bioinformation Database links GeneID: 56616 Human GeneID: 66593 Mouse Swiss-port # Q9JIQ3 Mouse Swiss-port # Q9NR28 Human Gene Symbol Diablo Gene Full Name diablo homolog (Drosophila) Background Smac Antibody: The inhibitor of apoptosis proteins (IAPs) regulate programmed cell death by inhibiting members of the caspase family of enzymes.
    [Show full text]
  • An IFN-STAT Axis Augments Tissue Damage and Inflammation in A
    ORIGINAL RESEARCH published: 20 May 2021 doi: 10.3389/fmed.2021.644244 An IFN-STAT Axis Augments Tissue Damage and Inflammation in a Mouse Model of Crohn’s Disease Iris Stolzer 1, Anja Dressel 1, Mircea T. Chiriac 1, Markus F. Neurath 1,2 and Claudia Günther 1* 1 Medizinische Klinik 1, Universitäts-Klinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany, 2 Deutsches Zentrum Immuntherapie, Universitäts-Klinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany Blocking interferon-function by therapeutic intervention of the JAK-STAT-axis is a novel promising treatment option for inflammatory bowel disease (IBD). Although JAK inhibitors have proven efficacy in patients with active ulcerative colitis (UC), they failed to induce clinical remission in patients with Crohn’s disease (CD). This finding strongly implicates a differential contribution of JAK signaling in both entities. Here, we dissected the contribution of different STAT members downstream of JAK to inflammation and barrier dysfunction in a mouse model of Crohn’s disease like ileitis and colitis (Casp8IEC mice). Deletion of STAT1 in Casp8IEC mice was associated with reduced cell death and a partial rescue of Paneth cell function in the small intestine. Likewise, organoids derived from the small intestine of these mice were less sensitive to cell death triggered by Edited by: IBD-key cytokines such as TNFα or IFNs. Further functional in vitro and in vivo analyses Fernando Gomollón, revealed the impairment of MLKL-mediated necrosis as a result of deficient STAT1 University of Zaragoza, Spain function, which was in turn associated with improved cell survival. However, a decrease Reviewed by: Hiroshi Nakase, in inflammatory cell death was still associated with mild inflammation in the small Sapporo Medical University, Japan intestine.
    [Show full text]