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https://www.readbyqxmd.com/read/27906189/distinct-outcomes-of-crl-nedd8-pathway-inhibition-reveal-cancer-cell-plasticity
#1
Anastasia V Rulina, Frédérique Mittler, Patricia Obeid, Sophie Gerbaud, Laurent Guyon, Eric Sulpice, Frédérique Kermarrec, Nicole Assard, Monika E Dolega, Xavier Gidrol, Maxim Y Balakirev
Inhibition of protein degradation by blocking Cullin-RING E3 ligases (CRLs) is a new approach in cancer therapy though of unknown risk because CRL inhibition may stabilize both oncoproteins and tumor suppressors. Probing CRLs in prostate cancer cells revealed a remarkable plasticity of cells with TMPRSS2-ERG translocation. CRL suppression by chemical inhibition or knockdown of RING component RBX1 led to reversible G0/G1 cell cycle arrest that prevented cell apoptosis. Conversely, complete blocking of CRLs at a higher inhibitor dose-induced cytotoxicity that was amplified by knockdown of CRL regulator Cand1...
December 1, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27901050/the-use-of-the-nedd8-inhibitor-mln4924-pevonedistat-in-a-cyclotherapy-approach-to-protect-wild-type-p53-cells-from-mln4924-induced-toxicity
#2
Lara J Bou Malhab, Simon Descamps, Benedicte Delaval, Dimitris P Xirodimas
Targetting the ubiquitin pathway is an attractive strategy for cancer therapy. The inhibitor of the ubiquitin-like molecule NEDD8 pathway, MLN4924 (Pevonedistat) is in Phase II clinical trials. Protection of healthy cells from the induced toxicity of the treatment while preserving anticancer efficacy is a highly anticipated outcome in chemotherapy. Cyclotherapy was proposed as a promising approach to achieve this goal. We found that cytostatic activation of p53 protects cells against MLN4924-induced toxicity and importantly the effects are reversible...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27864145/myd88-neddylation-negatively-regulates-myd88-dependent-nf-%C3%AE%C2%BAb-signaling-through-antagonizing-its-ubiquitination
#3
Fangxue Yan, Junhong Guan, Yanyan Peng, Xiaofeng Zheng
Myeloid differentiation factor 88 (MyD88) plays a central role in innate immunity response, however, how its activity is tightly regulated remains largely unknown. In this study, we identify MyD88 as a novel substrate of NEDD8, and demonstrate that MyD88 NEDDylation antagonizes its ubiquitination. Interestingly, in response to the stimulation of IL-1β, MyD88 NEDDylation is downregulated while its ubiquitination is upregulated. We also show that deNEDDylase NEDP1 serves as a regulator of this process. Furthermore, we demonstrate that NEDD8 negatively regulates the dimerization of MyD88 and suppresses MyD88-dependent NF-κB signaling...
November 15, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27834018/nuclear-localization-signal-sequence-is-required-for-vacm-1-cul5-dependent-regulation-of-cellular-growth
#4
Angelica N Willis, Shirley E Bradley Dean, Joe A Habbouche, Brian T Kempers, Megan L Ludwig, Aaron D Sayfie, Steven P Lewis, Stephanie Harrier, Zachary J DeBruine, Richard Garrett, Maria A Burnatowska-Hledin
VACM-1/CUL5 is a member of the cullin family of proteins involved in the E3 ligase-dependent degradation of diverse proteins that regulate cellular proliferation. The ability of VACM-1/CUL5 to inhibit cellular growth is affected by its posttranslational modifications and its localization to the nucleus. Since the mechanism of VACM-1/CUL5 translocation to the nucleus is not clear, the goal of this project was to determine the role that the putative nuclear localization signal (NLS) we identified in the VACM-1/CUL5 ((640)PKLKRQ(646)) plays in the cellular localization of VACM-1/CUL5 and its effect on cellular growth...
November 11, 2016: Cell and Tissue Research
https://www.readbyqxmd.com/read/27833851/overexpression-of-cop9-signalosome-subunits-csn7a-and-csn7b-exerts-different-effects-on-adipogenic-differentiation
#5
Xiaohua Huang, Jürgen Ordemann, Johann Pratschke, Wolfgang Dubiel
The COP9 signalosome (CSN) is an essential regulator of cullin-RING-ubiquitin (Ub) ligases (CRLs), which ubiquitinate important cellular regulators and target them for degradation by the Ub proteasome system (UPS). The CSN exhibits deneddylating activity localized on subunit CSN5, which removes the ubiquitin-like protein Nedd8 from the cullins of CRLs. CSN-mediated deneddylation is an important step in the process of CRL remodeling, in which new substrate recognition units are incorporated into Ub ligases to meet changed requirements for proteolysis in cells...
November 2016: FEBS Open Bio
https://www.readbyqxmd.com/read/27821554/assessment-of-drug-sensitivity-in-hematopoietic-stem-and-progenitor-cells-from-acute-myelogenous-leukemia-and-myelodysplastic-syndrome-ex-vivo
#6
Katherine L B Knorr, Laura E Finn, B Douglas Smith, Allan D Hess, James M Foran, Judith E Karp, Scott H Kaufmann
: : Current understanding suggests that malignant stem and progenitor cells must be reduced or eliminated for prolonged remissions in myeloid neoplasms such as acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Multicolor flow cytometry has been widely used to distinguish stem and myeloid progenitor cells from other populations in normal and malignant bone marrow. In this study, we present a method for assessing drug sensitivity in MDS and AML patient hematopoietic stem and myeloid progenitor cell populations ex vivo using the investigational Nedd8-activating enzyme inhibitor MLN4924 and standard-of-care agent cytarabine as examples...
November 7, 2016: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/27815049/therapeutic-effects-of-a-nedd8-activating-enzyme-inhibitor-pevonedistat-on-sclerodermatous-graft-versus-host-disease-in-mice
#7
Chien-Chun Steven Pai, Lam T Khuat, Mingyi Chen, William J Murphy, Mehrdad Abedi
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the ultimate treatment for highly malignant hematologic disease; however, the major complication-graft-versus-host disease (GVHD)-still hinders its clinical application. In addition, chronic GVHD remains the major cause of long-term morbidity and mortality after allo-HSCT. Previously we showed that bortezomib, a proteasome inhibitor, can ameliorate the sclerodermatous GVHD response while maintaining graft-versus-tumor (GVT) effects. Here we report that pevonedistat (MLN4924), an inhibitor of the Nedd8-activating enzyme, which functions upstream of the proteasome in the ubiquitin-proteasome pathway, can also show similar protective effects...
November 1, 2016: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/27814385/from-proteomic-analysis-to-potential-therapeutic-targets-functional-profile-of-two-lung-cancer-cell-lines-a549-and-sw900-widely-studied-in-pre-clinical-research
#8
Luís Korrodi-Gregório, Vanessa Soto-Cerrato, Rui Vitorino, Margarida Fardilha, Ricardo Pérez-Tomás
Lung cancer is a serious health problem and the leading cause of cancer death worldwide. The standard use of cell lines as in vitro pre-clinical models to study the molecular mechanisms that drive tumorigenesis and access drug sensitivity/effectiveness is of undisputable importance. Label-free mass spectrometry and bioinformatics were employed to study the proteomic profiles of two representative lung cancer cell lines and to unravel the specific biological processes. Adenocarcinoma A549 cells were enriched in proteins related to cellular respiration, ubiquitination, apoptosis and response to drug/hypoxia/oxidative stress...
2016: PloS One
https://www.readbyqxmd.com/read/27783255/targeting-the-protein-ubiquitination-machinery-in-melanoma-by-the-nedd8-activating-enzyme-inhibitor-pevonedistat-mln4924
#9
Kit Man Wong, Lindsey N Micel, Heather M Selby, Aik Choon Tan, Todd M Pitts, Stacey M Bagby, Anna Spreafico, Peter J Klauck, Stephen J Blakemore, Peter F Smith, Alice McDonald, Allison Berger, John J Tentler, S Gail Eckhardt
Background The neddylation pathway conjugates NEDD8 to cullin-RING ligases and controls the proteasomal degradation of specific proteins involved in essential cell processes. Pevonedistat (MLN4924) is a selective small molecule targeting the NEDD8-activating enzyme (NAE) and inhibits an early step in neddylation, resulting in DNA re-replication, cell cycle arrest and death. We investigated the anti-tumor potential of pevonedistat in preclinical models of melanoma. Methods Melanoma cell lines and patient-derived tumor xenografts (PDTX) treated with pevonedistat were assessed for viability/apoptosis and tumor growth, respectively, to identify sensitive/resistant models...
October 25, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27774986/targeted-inhibition-of-the-cop9-signalosome-for-treatment-of-cancer
#10
Anita Schlierf, Eva Altmann, Jean Quancard, Anne B Jefferson, René Assenberg, Martin Renatus, Matthew Jones, Ulrich Hassiepen, Michael Schaefer, Michael Kiffe, Andreas Weiss, Christian Wiesmann, Richard Sedrani, Jörg Eder, Bruno Martoglio
The COP9 signalosome (CSN) is a central component of the activation and remodelling cycle of cullin-RING E3 ubiquitin ligases (CRLs), the largest enzyme family of the ubiquitin-proteasome system in humans. CRLs are implicated in the regulation of numerous cellular processes, including cell cycle progression and apoptosis, and aberrant CRL activity is frequently associated with cancer. Remodelling of CRLs is initiated by CSN-catalysed cleavage of the ubiquitin-like activator NEDD8 from CRLs. Here we describe CSN5i-3, a potent, selective and orally available inhibitor of CSN5, the proteolytic subunit of CSN...
October 24, 2016: Nature Communications
https://www.readbyqxmd.com/read/27771897/profiling-of-signaling-proteins-in-penumbra-after-focal-photothrombotic-infarct-in-the-rat-brain-cortex
#11
Svetlana Demyanenko, Anatoly Uzdensky
In ischemic stroke, cell damage propagates from infarct core to surrounding tissue. To reveal proteins involved in neurodegeneration and neuroprotection, we explored the protein profile in penumbra surrounding the photothrombotic infarct core induced in rat cerebral cortex by local laser irradiation after Bengal Rose administration. Using antibody microarrays, we studied changes in expression of 224 signaling proteins 1, 4, or 24 h after photothrombotic infarct compared with untreated contralateral cortex...
October 22, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27771609/efficacy-of-nedd8-pathway-inhibition-in-preclinical-models-of-poorly-differentiated-clinically-aggressive-colorectal-cancer
#12
Gabriele Picco, Consalvo Petti, Francesco Sassi, Katia Grillone, Giorgia Migliardi, Teresa Rossi, Claudio Isella, Federica Di Nicolantonio, Ivana Sarotto, Anna Sapino, Alberto Bardelli, Livio Trusolino, Andrea Bertotti, Enzo Medico
BACKGROUND: The NEDD8 conjugation pathway modulates the ubiquitination and activity of a wide range of intracellular proteins, and its blockade by pevonedistat is emerging as a promising therapeutic approach in various cancer settings. However, systematic characterization of pevonedistat efficacy in specific tumor types and definition of response predictors are still missing. METHODS: We investigated in vitro sensitivity to pevonedistat in 122 colorectal cancer (CRC) cell lines by an ATP-based proliferation assay and evaluated apoptosis and DNA content by flow cytometry...
February 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/27771247/an-inhibitor-of-apoptosis-protein-antagonist-t-3256336-potentiates-the-antitumor-efficacy-of-the-nedd8-activating-enzyme-inhibitor-pevonedistat-tak-924-mln4924
#13
Hiroyuki Sumi, Masakazu Inazuka, Megumi Morimoto, Ryosuke Hibino, Kentaro Hashimoto, Tomoyasu Ishikawa, Keisuke Kuida, Peter G Smith, Sei Yoshida, Masato Yabuki
Inhibitors of apoptosis proteins (IAPs) are antiapoptotic regulators that block cell death, and are frequently overexpressed in several human cancers, where they facilitate evasion of apoptosis and promote cell survival. IAP antagonists are also known as second mitochondria-derived activator of caspase (SMAC)-mimetics, and have recently been considered as novel therapeutic agents for inducing apoptosis, alone and in combination with other anticancer drugs. In this study, we showed that T-3256336, the orally available IAP antagonist has synergistically enhances the antiproliferative effects of the NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924), and these effects were attenuated by a TNFα-neutralizing antibody...
October 19, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27756846/syvn1-nedd8-and-fbxo2-regulate-%C3%AE-f508-cftr-ubiquitin-mediated-proteasomal-degradation
#14
Shyam Ramachandran, Samantha R Osterhaus, Kalpaj R Parekh, Ashley M Jacobi, Mark A Behlke, Paul B McCray
We previously reported that delivery of a microRNA (miR)-138 mimic or siRNA against SIN3A to cultured cystic fibrosis (CF) (ΔF508/ΔF508) airway epithelia partially restored ΔF508-CFTR mediated cAMP-stimulated Cl-conductance. We hypothesized that dissecting this miR-138/SIN3A regulated gene network would identify individual proteins contributing to the rescue of ΔF508-CFTR function. Among the genes in the network, we rigorously validated candidates using functional CFTR maturation and electrolyte transport assays in polarized airway epithelia...
October 18, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27682585/perturbation-of-neddylation-dependent-nf-%C3%AE%C2%BAb-responses-in-the-intestinal-epithelium-drives-apoptosis-and-inhibits-resolution-of-mucosal-inflammation
#15
Stefan F Ehrentraut, Valerie F Curtis, Ruth X Wang, Bejan J Saeedi, Heidi Ehrentraut, Joseph C Onyiah, Caleb J Kelly, Eric L Campbell, Louise E Glover, Douglas J Kominsky, Sean P Colgan
Recent work has revealed a central role for neddylation (the conjugation of a Nedd8-moiety to Cullin proteins) in the fine tuning of the NF-κB response (via Cullin-1). In the present study, we investigated the contribution of Cullin-1 neddylation and NF-κB signaling to mucosal inflammatory responses in vitro and in vivo. Initial in vitro studies using cultured intestinal epithelial cells revealed that the neddylation inhibitor MLN4924 prominently induces the deneddylation of Cullin-1. Parallel western blot, luciferase reporter and gene target assays identified MLN4924 as a potent inhibitor of intestinal epithelial NF-κB...
September 28, 2016: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27626304/direct-proximity-tagging-of-small-molecule-protein-targets-using-an-engineered-nedd8-ligase
#16
Zachary B Hill, Samuel B Pollock, Min Zhuang, James A Wells
Identifying the protein targets of bioactive small molecules remains a major problem in the discovery of new chemical probes and therapeutics. While activity-based probes and photo-cross-linkers have had success in identifying protein targets of small molecules, each technique has limitations. Here we describe a method for direct proximity tagging of proteins that bind small molecules. We engineered a promiscuous ligase based on the NEDD8 conjugating enzyme, Ubc12, which can be covalently linked to a small molecule of interest...
October 12, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/27626202/the-nedd8-activating-enzyme-inhibitor-pevonedistat-activates-the-eif2%C3%AE-and-mtor-pathways-inducing-upr-mediated-cell-death-in-acute-lymphoblastic-leukemia
#17
Gilles M Leclerc, Shuhua Zheng, Guy J Leclerc, Joanna DeSalvo, Ronan T Swords, Julio C Barredo
Acute lymphoblastic leukemia (ALL) is the leading cause of cancer-related death in children, and cure rates for adults remain dismal. Further, effective treatment strategies for relapsed/refractory ALL remain elusive. We previously uncovered that ALL cells are prone to apoptosis via endoplasmic reticulum (ER) stress/unfolded protein response (UPR)-mediated mechanisms. We investigated the antineoplastic activity of pevonedistat(®), a novel NEDD8-activating enzyme inhibitor that targets E3 cullin-RING ligases (CRLs) dependent proteasomal protein degradation, in ALL...
September 5, 2016: Leukemia Research
https://www.readbyqxmd.com/read/27613030/immunodepletion-and-immunopurification-as-approaches-for-csn-research
#18
Amnon Golan, Ning Wei, Elah Pick
The COP9 signalosome (CSN) is an evolutionary conserved complex that is found in all eukaryotes, and implicated in regulating the activity of Cullin-RING ubiquitin Ligases (CRLs). Activity of CRLs is highly regulated; complexes are active when the cullin subunit is covalently attached to the ubiquitin like modifier, Nedd8. Neddylation/deneddylation cycles are required for proper CRLs activity, and deneddylation is performed by the CSN complex.We describe here a method utilizing resin-coupled antibodies to deplete the CSN from human cell extracts, and to obtain endogenous CSN complexes by immunopurification...
2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27602774/circadian-clock-components-ror%C3%AE-and-bmal1-mediate-the-anti-proliferative-effect-of-mln4924-in-osteosarcoma-cells
#19
Shuju Zhang, Jiaming Zhang, Zhiyuan Deng, Huadie Liu, Wei Mao, Fang Jiang, Zanxian Xia, Jia-Da Li
The anticancer small molecule MLN4924, a Nedd8-activating enzyme (NAE) inhibitor, triggers cell-cycle arrest, apoptosis, and senescence in cancer cells. In this study, we demonstrate that MLN4924 suppresses osteosarcoma cell proliferation by inducing G2/M cell cycle arrest and apoptosis. Our results indicate that MLN4924 stabilizes the retinoid orphan nuclear receptor alpha (RORα) by decreasing its ubiquitination. RNA interference of RORα attenuates the anti-proliferative effect of MLN4924 in U2OS osteosarcoma cells...
September 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27565346/two-distinct-types-of-e3-ligases-work-in-unison-to-regulate-substrate-ubiquitylation
#20
Daniel C Scott, David Y Rhee, David M Duda, Ian R Kelsall, Jennifer L Olszewski, Joao A Paulo, Annemieke de Jong, Huib Ovaa, Arno F Alpi, J Wade Harper, Brenda A Schulman
Hundreds of human cullin-RING E3 ligases (CRLs) modify thousands of proteins with ubiquitin (UB) to achieve vast regulation. Current dogma posits that CRLs first catalyze UB transfer from an E2 to their client substrates and subsequent polyubiquitylation from various linkage-specific E2s. We report an alternative E3-E3 tagging cascade: many cellular NEDD8-modified CRLs associate with a mechanistically distinct thioester-forming RBR-type E3, ARIH1, and rely on ARIH1 to directly add the first UB and, in some cases, multiple additional individual monoubiquitin modifications onto CRL client substrates...
August 25, 2016: Cell
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