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5 results on '"RR, ribonucleotide reductase"'

1. The diverse roles of RIP kinases in host-pathogen interactions

Author

Vik Ven Eng, Madeleine A. Wemyss, and Jaclyn S. Pearson

Subjects
NSA, necrosulfonamide, T4SS, type IV secretion system, RHIM, RIP homotypic interaction motif, ERK, extracellular signal-regulated kinases, MDP, muramyl dipeptide, TNF, tumour necrosis factor, RIP kinase, 0302 clinical medicine, UPR, unfolded protein response, RIG-I, cytosolic retinoic acid-inducible gene I, T3SS, type III secretion system, TGFβ, transforming growth factor beta, AEC, airway epithelial cell, MCMV, murine cytomegalovirus, NP, nucleoprotein, ZBP1, Z-DNA binding protein, Kgp, lysine-specific protease gingipain, COTV, Cotia poxvirus, COVID-19, coronavirus disease 2019, XIAP, X-linked inhibitor of apoptosis protein, ALRs, AIM2-like receptors, KD, kinase domain, Kinase, Th1, T helper 1, BMDMs, bone marrow-derived macrophages, HFMD, hand foot and mouth disease, BclxL, Bcl-extra large, TRAM, translocating chain-associated membrane protein, dsRNA, double stranded RNA, LMP1, latent membrane protein, Cell biology, Intracellular signal transduction, CARD, caspase activation and recruitment domain, SDH, succinate dehydrogenase, TRPM7, transient receptor potential cation channel subfamily M member 7, IKK, IĸB kinase, MAVS, mitochondrial antiviral signaling proteins, NK, natural killer, TRIF, TIR-domain-containing adapter-inducing interferon-β, ISGF3, IFN-stimulated gene factor 3, Cell signaling, AIM2, absent in melanoma 2, PD, Parkinson disease, Yop, Yersinia outer protein, JEV, Japanese encephalitis virus, Poly(I:C), polyinosinic:polycytidylic acid, Article, PKR, protein kinase R, vIRA, viral inhibitor of RIP activation, RIPK2, 03 medical and health sciences, RIPK1, BAV, BeAn 58058 poxvirus, NLRs, nucleotide-binding domain–like receptors, ORF, open reading frame, IAV, influenza A virus, MyD88, myeloid differentiation factor 88, CD, Crohn’s disease, Humans, SARS, severe acute respiratory syndrome, DAMPs, danger-associated molecular patterns, GSDMD, gasdermin D, TLR, toll-like receptor, UL45/UL48, human CMV envelope protein 45/48, RR, ribonucleotide reductase, OMV, outer membrane vesicle, NO, nitric oxide, Pathogen-associated molecular pattern, TRAILR, TNF-related apoptosis-inducing ligand receptor, COR, C-terminal of Roc, DR, death receptor, GEF, guanidine exchange factor, IĸB, inhibitor of ĸB, WT, wild-type, Saporins, HMGB1, high mobility group box 1, IL, interleukin, MDA5, melanoma differentiation-associated protein 5, 030104 developmental biology, siRNA, small interfering RNA, TBK1, TANK-binding kinase 1, PFT, pore-forming toxins, ISGs, interferon stimulated genes, Cif, cycle inhibiting factor, RSV, respiratory syncytial virus, TRADD, TNFR1-associated death domain protein, Bacterial infection, PAMPs, pathogen associated molecular patterns, 030217 neurology & neurosurgery, Developmental Biology, 0301 basic medicine, NSP, non-structural protein, Bcl-2, B-cell lymphoma 2, CA6, coxsackievirus A6, DENV, dengue virus, E3L, vaccinia virus protein E3 long, TAK1, TGFβ-activated kinase 1, iE-DAP, Ɣ-d-glutamyl-mesodiaminopimelic acid, AP-1, activator protein 1, vICA, viral inhibitor of caspase-8 activation, ZIKV, Zika virus, HIV-1, human immunodeficiency virus type 1, PI3K, PI3 kinase, ATG16L1, autophagy-related 16-like 1, CVB, coxsackievirus B3, PRRs, pattern recognition receptors, SNPs (line 657) ssRNA, single-stranded RNA, MAPKs, mitogen-activated protein kinases, Pathogen, HSV, Herpes simplex virus, DAI, DNA-dependent activator of IRFs, EBV, Epstein-Barr virus, M45, murine CMV virion associated protein M45, PGN, bacterial peptidoglycan, DAP, diaminopimelic acid, UBE2N, ubiquitin-conjugating enzyme E2N, ID, intermediate domain, NleB, non-LEE encoded effector protein B, c-FLIP, cellular FLICE inhibitory protein, DRP1, dynamin-related protein 1, vMLKL, viral MLKL-like proteins, IRG1, immunoresponsive gene 1, LRR, leucine-rich repeat, NF-ĸB, nuclear factor-ĸB, TNFR1, TNF receptor type 1, WNV, West Nile virus, HCV, hepatitis C virus, JNK, c-Jun N-terminal kinase, Host-Pathogen Interactions, LPS, lipopolysaccharide, Roc, Ras-of-complex, PVM, pneumonia virus of mice, NET, neutrophil extracellular traps, HAEC, human aortic endothelial cells, ASC, apoptosis-associated speck-like protein, NLRC4, NLR family CARD domain containing 4, SARS-3a, SARS-CoV ORF protein 3a, Cell death, VSV, vesicular stomatitis virus, PnCW, pneumococcal cell wall, RIPKs, receptor interacting protein kinases, Mtb, Mycobacterium tuberculosis, HBeAg, hepatitis B e antigen, Biology, CNS, central nervous system, cIAPs, cellular inhibitor of apoptosis proteins, ER, endoplasmic reticulum, IFI44L, IFN-induced protein 44-like, NOD, nucleotide-binding oligomerization domain, ROS, reactive oxygen species, DISCs, death-inducing signaling complexes, NoV, norovirus, 3Cpro, viral non-structural protein 3C, IFN, interferon, VV, vaccinia virus, PR, protease, TRAF, TNFR associated factors, Inflammation, CNF1, cytotoxic necrotising factor 1, HCMV, human cytomegalovirus, KO, knockout, NLRP3, NLR family pyrin domain containing 3, Nec-1, necrostatin-1, Autophagy, IRFs, IFN regulatory factors, Cell Biology, CMV, cytomegalovirus, MLKL, mixed-lineage kinase-domain like protein, HPV, human papilloma virus, NAIPs, NLR family apoptosis inhibitory proteins, HBV, hepatitis B virus, PI3P, phosphatidylinositol 3-phosphate, RDA, RIPK1-dependent apoptosis, Viral infection, MKKs, MAPK kinases, LUBAC, linear ubiquitin chain assembly complex, BVDV, bovine viral diarrhoea virus
Abstract

Receptor Interacting Protein Kinases (RIPKs) are cellular signaling molecules that are critical for homeostatic signaling in both communicable and non-communicable disease processes. In particular, RIPK1, RIPK2, RIPK3 and RIPK7 have emerged as key mediators of intracellular signal transduction including inflammation, autophagy and programmed cell death, and are thus essential for the early control of many diverse pathogenic organisms. In this review, we discuss the role of each RIPK in host responses to bacterial and viral pathogens, with a focus on studies that have used pathogen infection models rather than artificial stimulation with purified pathogen associated molecular patterns. We also discuss the intricate mechanisms of host evasion by pathogens that specifically target RIPKs for inactivation, and finally, we will touch on the controversial issue of drug development for kinase inhibitors to treat chronic inflammatory and neurological disorders, and the implications this may have on the outcome of pathogen infections.

Published
2020

2. Structure and Function of Viral Deubiquitinating Enzymes

Author

Robert C. M. Knaap, Ben A. Bailey-Elkin, Brian L. Mark, and Marjolein Kikkert

Subjects
0301 basic medicine, ssRNA, single-stranded RNA, eIF4G, eukaryotic translation initiation factor 4 gamma, OTU, ovarian tumor protease, CoV, coronavirus, ERVV, Erve virus, BL2, blocking-loop 2, RIG-I, retinoic acid-inducible gene I, IRF, IFN regulatory factor, innate immune evasion, Deubiquitinating enzyme, cGAS, cyclic-GMP-AMP synthase, PEDV, porcine epidemic diarrhea virus, Ubiquitin, Structural Biology, CCHFV, Crimean-Congo hemorrhagic fever virus, TRAF, TNF receptor-associated factor, MERS-CoV, Middle East respiratory syndrome CoV, viral deubiquitinating enzyme, Ub, ubiquitin, MCMV, murine cytomegalovirus, TNF, tumor necrosis factor, Deubiquitinating Enzymes, RIG-I, ISG15, interferon-stimulated gene 15, Cell biology, DUB, deubiquitinating enzyme, LDV, lactate dehydrogenase-elevating virus, TYMV, turnip yellow mosaic virus, Host-Pathogen Interactions, Viruses, MAVS, mitochondrial antiviral signaling protein, EBV, Epstein–Barr virus, MDA5, melanoma differentiation factor 5, HSV-1, herpes simplex virus 1, IRF3, IFN regulatory factor 3, SARS-CoV, severe acute respiratory syndrome CoV, PRR, pattern-recognition receptor, papain-like protease, UbV, Ub variant, Biology, TF, trans frame, EAV, equine arteritis virus, Article, PLP, papain-like protease, 03 medical and health sciences, Viral Proteins, Immune system, STING, stimulator of IFN genes, ORF, open reading frame, ubiquitin, ISG, interferon-stimulated gene, IBV, avian infectious bronchitis virus, UBL, Ub-like, IFN, interferon, SARS, severe acute respiratory syndrome, CRL, Cullin-RING Ub ligase, AMC, 7-amino-4-methylcoumarin, TLR, toll-like receptor, Molecular Biology, MHV, mouse hepatitis virus, RR, ribonucleotide reductase, HAUSP, herpesvirus-associated USP, NSDV, Nairobi sheep disease virus, Immune Evasion, KSV, Kaposi's sarcoma virus, AdV, adenovirus, HCMV, human cytomegalovirus, nsps, non-structural proteins, Innate immune system, 030102 biochemistry & molecular biology, NEMO, NF-κB essential modulator, USP, Ub-specific protease, MERS, Middle East respiratory syndrome, DUGV, Dugbe virus, SHFV, simian hemorrhagic fever virus, cGAMP, cyclic-GMP-AMP, MDV, Marek's disease virus, ISG15, Virology, TGEV, porcine transmissible gastroenteritis, Protein ubiquitination, Immunity, Innate, TANK, TRAF family member-associated activator, PRRSV, porcine reproductive and respiratory syndrome virus, 030104 developmental biology, Viral replication, TBK1, TANK-binding kinase 1, biology.protein, FMDV, foot-and-mouth disease virus, EVG, Enterovirus species G
Abstract

Post-translational modification of cellular proteins by ubiquitin regulates numerous cellular processes, including innate and adaptive immune responses. Ubiquitin-mediated control over these processes can be reversed by cellular deubiquitinating enzymes (DUBs), which remove ubiquitin from cellular targets and depolymerize polyubiquitin chains. The importance of protein ubiquitination to host immunity has been underscored by the discovery of viruses that encode proteases with deubiquitinating activity, many of which have been demonstrated to actively corrupt cellular ubiquitin-dependent processes to suppress innate antiviral responses and promote viral replication. DUBs have now been identified in diverse viral lineages, and their characterization is providing valuable insights into virus biology and the role of the ubiquitin system in host antiviral mechanisms. Here, we provide an overview of the structural biology of these fascinating viral enzymes and their role innate immune evasion and viral replication., Graphical Abstract Image 1, Highlights • Activation of host innate antiviral responses is largely ubiquitin-dependent. • Virus-encoded DUBs can modulate innate immune signaling. • Analysis of structurally diverse DUBs of DNA and RNA viruses. • Viral DUBs are critical for virus replication and pathogenesis. • Therapeutic strategies and vaccination approaches targeting viral DUBs.

Published
2017

3. Ribonucleotide reductase small subunit M2 serves as a prognostic biomarker and predicts poor survival of colorectal cancers

Author

Lily L. Lai, Shu Zheng, Sofia Loera, Peiguo Chu, Yasheng Huang, Bingsen Zhou, Huiyin He, Lun Zhou, Keqiang Zhang, Rebecca A. Nelson, Xiaochen Wang, Shuya Hu, Hang Zhang, Xiyong Liu, Lijun Xue, Yun Yen, and Suzhan Zhang

Subjects
Oncology, Kaplan-Meier Estimate, Metastasis, 0302 clinical medicine, MLH1, mutL homologue 1, rectum, Neoplasm Metastasis, RNA, Small Interfering, prognostic biomarker, TS, thymidylate synthase, 0303 health sciences, Hazard ratio, General Medicine, Prognosis, PFS, progress-free survival, 3. Good health, FFPE, formalin-fixed paraffin-embedded, MMP, matrix metalloproteinase, TNM, tumour node metastasis, 030220 oncology & carcinogenesis, CRC, colorectal cancer, RRM2, RR small subunit M2, Adenocarcinoma, Immunohistochemistry, Colorectal Neoplasms, IHC, immunohistochemistry, Adult, medicine.medical_specialty, Ribonucleoside Diphosphate Reductase, MTA, multiple tissue array, MMR, mismatch repair, Biology, ribonucleotide reductase, S2, survival, OS, overall survival, 03 medical and health sciences, ROS, reactive oxygen species, Internal medicine, Biomarkers, Tumor, Cell Adhesion, medicine, metastasis, 5-FU, fluorouracil, Humans, RR, ribonucleotide reductase, Cell Proliferation, Retrospective Studies, 030304 developmental biology, Original Paper, adenocarcinoma, COH, City of Hope, colon, MTB, multiple tissue board, Retrospective cohort study, dNTP, deoxyribonucleoside triphosphate, Odds ratio, medicine.disease, HR, hazard ratio, Confidence interval, CI, confidence interval, OR, odds ratio, siRNA, small interfering RNA, Immunology, Cancer cell, ZJU, Zhejiang University
Abstract

The overexpression of RRM2 [RR (ribonucleotide reductase) small subunit M2] dramatically enhances the ability of the cancer cell to proliferate and to invade. To investigate further the relevance of RRM2 and CRCs (colorectal cancers), we correlated the expression of RRM2 with the clinical outcome of CRCs. A retrospective outcome study was conducted on CRCs collected from the COH [(City of Hope) National Medical Center, 217 cases] and ZJU (Zhejiang University, 220 cases). IHC (immunohistochemistry) was employed to determine the protein expression level of RRM2, and quantitative real-time PCR was employed to validate. Multivariate logistic analysis indicated that the adjusted ORs (odds ratios) of RRM2-high for distant metastases were 2.06 [95% CI (confidence interval), 1.01–4.30] and 5.89 (95% CI, 1.51–39.13) in the COH and ZJU sets respectively. The Kaplan–Meier analysis displayed that high expression of RRM2 had a negative impact on the OS (overall survival) and PFS (progress-free survival) of CRC in both sets significantly. The multivariate Cox analysis further demonstrated that HRs (hazard ratios) of RRM2-high for OS were 1.88 (95% CI, 1.03–3.36) and 2.06 (95% CI, 1.10–4.00) in the COH and ZJU sets respectively. Stratification analysis demonstrated that the HR of RRM2 dramatically increased to 12.22 (95% CI, 1.62–258.31) in the MMR (mismatch repair) gene-deficient subgroup in the COH set. Meanwhile, a real-time study demonstrated that down-regulation of RRM2 by siRNA (small interfering RNA) could significantly and specifically reduce the cell growth and adhesion ability in HT-29 and HCT-8 cells. Therefore RRM2 is an independent prognostic factor and predicts poor survival of CRCs. It is also a potential predictor for identifying good responders to chemotherapy for CRCs.

Published
2013

4. Substrate specificity and phosphorylation of antiviral and anticancer nucleoside analogues by human deoxyribonucleoside kinases and ribonucleoside kinases

Author

Magnus Johansson, An R. Van Rompay, and Anna Karlsson

Subjects
dCK, deoxycytidine kinase, Deoxyribonucleosides, Deoxyribonucleotides, 5′-NT, 5′-nucleotidase, FIAU, 1-(2′-deoxy-2′-fluoro-β-d-arabinofuranosyl)-5-iodouracil (Fialuridine), AIDS, aquired immunodeficiency syndrome, NA, nucleoside analogue, rNK, ribonucleoside kinase, Antiviral therapy, Substrate Specificity, dGK, deoxyguanosine kinase, d4T, 2′,3′-didehydro-3′-deoxythymidine (Stavudine), Prodrugs, dFdC, 2′,2′-difluorodeoxycytidine (Gemcitabine), Pharmacology (medical), Phosphorylation, Kinase, Anticancer therapy, Nucleosides, TK1, thymidine kinase 1, Nucleoside analogue, Prodrug, UCK1, uridine-cytidine kinase 1, F-AraA, 2-fluoro-9-β-d-arabinofuranosyladenine (Fludarabine), ddI, 2′,3′-dideoxyinosine (Didanosine), HIV, human immunodeficiency virus, Phosphotransferases (Alcohol Group Acceptor), Biochemistry, Organ Specificity, RT, reverse transcriptase, Intracellular, medicine.drug, CdA, 2-chloro-2′-deoxyadenosine (Cladribine), Molecular Sequence Data, CAFdA, 2-chloro-2′-fluoro-9-β-d-arabinofuranosyladenine (Clofarabine), Antineoplastic Agents, Biology, Antiviral Agents, Article, Deoxyribonucleoside kinase, TK2, thymidine kinase 2, ADK, adenosine kinase, medicine, Animals, Humans, Chemotherapy, Amino Acid Sequence, RR, ribonucleotide reductase, Pharmacology, NDPK, nucleoside diphosphate kinase, AraG, 9-β-d-arabinofuranosylguanine (Nelarabine), Ribonucleotides, AZT, 3′-azido-2′,3′-dideoxythymidine (Zidovudine), Ribonucleoside, FDA, Food and Drug Administration, 3TC, 2′-deoxy-3′-thiacytidine (Lamivudine), mtDNA, mitochondrial DNA, HBV, hepatitis B virus, Ribonucleoside kinase, ddC, 2′,3′-dideoxycytidine (Zalcitabine), dNK, deoxyribonucleoside kinase, NMPK, nucleoside monophosphate kinase, AraC, 1-β-d-arabinofuranosylcytosine (Cytarabine), UCK2, uridine-cytidine kinase 2, Nucleoside
Abstract

Structural analogues of nucleosides, nucleoside analogues (NA), are used in the treatment of cancer and viral infections. Antiviral NAs inhibit replication of the viral genome, whereas anticancer NAs inhibit cellular DNA replication and repair. NAs are inactive prodrugs that are dependent on intracellular phosphorylation to their pharmacologically active triphosphate form. The deoxyribonucleoside kinases (dNK) and ribonucleoside kinases (rNK) catalyze the first phosphorylation step, converting deoxyribonucleosides and ribonucleosides to their corresponding monophosphate form. The dNKs have been studied intensively, whereas the rNKs have not been as thoroughly investigated. This overview is focused on the substrate specificity, tissue distribution, and subcellular location of the mammalian dNKs and rNKs and their role in the activation of NAs.

Published
2003

5. A novel strategy for combination of clofarabine and pictilisib is synergistic in gastric cancer

Author

Shayan Khalafi, Shoumin Zhu, Rimpi Khurana, Ines Lohse, Silvia Giordano, Simona Corso, Hassan Al-Ali, Shaun P. Brothers, Claes Wahlestedt, Stephan Schürer, and Wael El-Rifai

Subjects
Cancer Research, PVDF, Polyvinylidene difluoride, P/S, Penicillin/streptomycin, Pictilisib, DSSmod, Modified drug sensitivity score, RR, Ribonucleotide reductase, GC, Gastric Cancer, Annexin, PI3K, Phosphoinositide 3-kinase, EMT, Epithelial-mesenchymal transition, DST, Drug sensitivity testing, FDA, Federal Drug Administration, Clofarabine, GO, Gene ontology, DEG, Differentially expressed genes, SDS-PAGE, sodium dodecyl sulfate–polyacrylamide gel electrophoresis, RC254-282, Original Research, EBV, Epstein-Barr virus, BLC2, B-cell lymphoma 2, Chemistry, CIB, Clofarabine, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, EDTA, Ethylenediaminetetraacetic acid, AKT, Protein Kinase B, ER, Estrogen receptor, STAD, Stomach adenocarcinoma, RPS6KB1, ribosomal protein S6 kinase beta-1, IP, Intraperitoneal, Oncology, RIPA, Radioimmunoprecipitation assay, RPM, Rotations per minute, sDSSmod, Selective modified drug sensitivity score, HER2, Human epidermal growth factor receptor 2, Combination therapy, Drug synergy, Gastric cancer, RNAseq, RNA sequencing, DR, Discordance ratio, ANOVA, Analysis of variance, BAD, BCL2-associated agonist of cell death, IC50, 50% inhibitory concentration, GBM, Glioblastoma multiforme, medicine.drug, HRP, Horseradish peroxidase, FITC, Fluorescein isothiocyanate, Programmed cell death, CI, Combination index, DNA damage, H2AX, H2A histone family member X, NCI DTP, National Cancer institute drug testing program, PBS, Phosphate buffered saline, ATCC, American type cell culture collection, RPMI, Roswell Park memorial institute, HPRT, Hypoxanthine-guanine phosphoribosyltransferase, OG, Oral gavage, qRT-PCR, Quantitative real time polymerase chain reaction, cDNA, complementary DNA, TCGA, The cancer genome atlas, PARP, Poly ADP-ribose polymerase, KEGG, Kyoto encyclopedia of genes and genomes, medicine, PI, Prodidium iodide, DMSO, Dimethylsulfoxide, Protein kinase B, STAR, Spliced transcripts alignment to a reference, DSB, Double strand breaks, mTOR, Mechanistic target of rapamycin, PUMA, p53 upregulated modulator of apoptosis, PTEN, Phosphatase and tensin homolog, HDAC, Histone deacetylase, Cancer, PCA, Principle component analysis, medicine.disease, LINCS, Library of integrated network-based cellular signatures, STR, Short tandem repeat, ALL, Acute lymphoblastic leukemia, BAX, BCL2-associated X, AML, Acute myeloid leukemia, Cell culture, PICT, Pictilisib, FBS, Fetal bovine serum, Cancer research, CHK2, Checkpoint kinase 2, FDR, False discovery rate, PDX, Patient derived xenograft, 5-FU, 5-fluorouracil, DAPI, 4′,6-diamidino-2-phenylindole
Abstract

Highlights • Drug sensitivity testing identified novel drugs like clofarabine effective in treating gastric cancer. • mRNA sequencing can be used to identify agents with synergistic activity to a reference compound. • Pictilisib sensitizes gastric cancer to clofarabine treatment through AKT inhibition. • The combination of clofarabine and pictilisib inhibits tumor growth in cell lines and PDX models., Gastric cancer (GC) is frequently characterized by resistance to standard chemotherapeutic regimens and poor clinical outcomes. We aimed to identify a novel therapeutic approach using drug sensitivity testing (DST) and our computational SynerySeq pipeline. DST of GC cell lines was performed with a library of 215 Federal Drug Administration (FDA) approved compounds and identified clofarabine as a potential therapeutic agent. RNA-sequencing (RNAseq) of clofarabine treated GC cells was analyzed according to our SynergySeq pipeline and identified pictilisib as a potential synergistic agent. Clonogenic survival and Annexin V assays demonstrated increased cell death with clofarabine and pictilisib combination treatment (P

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