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https://www.readbyqxmd.com/read/28216678/the-cul3-spop-daxx-axis-is-a-novel-regulator-of-vegfr2-expression-in-vascular-endothelial-cells
#1
Tomohisa Sakaue, Iori Sakakibara, Takahiro Uesugi, Ayako Fujisaki, Koh-Ichi Nakashiro, Hiroyuki Hamakawa, Eiji Kubota, Takashi Joh, Yu-Ki Imai, Hironori Izutani, Shigeki Higashiyama
Vascular endothelial cell growth factor receptor 2 (VEGFR2) is an essential receptor for the homeostasis of endothelial cells. In this study, we showed that NEDD8-conjugated Cullin3 (CUL3)-based ubiquitin E3 (UbE3) ligase plays a crucial role in VEGFR2 mRNA expression. Human umbilical vein endothelial cells treated with MLN4924, an inhibitor of NEDD8-activating enzyme, or with CUL3 siRNA drastically lost their response to VEGF due to the intense decrease in VEGFR2 expression. Moreover, speckle-type POZ protein (SPOP) and death-domain associated protein (DAXX) were involved in the CUL3 UbE3 ligase complex as a substrate adaptor and a substrate, respectively...
February 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28178525/single-cell-analysis-of-smn-reveals-its-broader-role-in-neuromuscular-disease
#2
Natalia Rodriguez-Muela, Nadia K Litterman, Erika M Norabuena, Jesse L Mull, Maria José Galazo, Chicheng Sun, Shi-Yan Ng, Nina R Makhortova, Andrew White, Maureen M Lynes, Wendy K Chung, Lance S Davidow, Jeffrey D Macklis, Lee L Rubin
The mechanism underlying selective motor neuron (MN) death remains an essential question in the MN disease field. The MN disease spinal muscular atrophy (SMA) is attributable to reduced levels of the ubiquitous protein SMN. Here, we report that SMN levels are widely variable in MNs within a single genetic background and that this heterogeneity is seen not only in SMA MNs but also in MNs derived from controls and amyotrophic lateral sclerosis (ALS) patients. Furthermore, cells with low SMN are more susceptible to cell death...
February 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/28177892/pevonedistat-a-nedd8-activating-enzyme-inhibitor-sensitizes-neoplastic-b-cells-to-death-receptor-mediated-apoptosis
#3
Cody Paiva, J Claire Godbersen, Taylor Rowland, Olga V Danilova, Christopher Danes, Allison Berger, Alexey V Danilov
While death receptor ligands (Fas and TRAIL) kill chemoresistant tumor cell lines, related therapies have limited clinical efficacy as single agents. Death receptor signaling is modulated by nuclear factor-κB (NFκB), a family of transcription factors which are constitutively active in B-cell malignancies. We and others have shown that pevonedistat, an investigational inhibitor of the NEDD8-activating enzyme, abrogates NFκB activity in B-cell neoplasia. Here we demonstrate that diffuse large B-cell lymphoma, particularly activated B-cell type, and primary chronic lymphocytic leukemia cells are re-sensitized to extrinsic apoptosis by pevonedistat...
February 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28169289/the-nedd8-non-covalent-binding-region-in-the-smurf-hect-domain-is-critical-to-its-ubiquitn-ligase-function
#4
Shan He, Yu Cao, Ping Xie, Guanglong Dong, Lingqiang Zhang
Nedd8 is a ubiquitin-like protein that controls vital biological events through conjugation to target proteins. We previously identified the HECT-type ubiquitin ligase Smurf1 which controls diverse cellular processes is activated by Nedd8 through covalent neddylation. However, the effect of non-covalent binding to Nedd8 remains unknown. In this study, we demonstrate that both Smurf1 and its homologue Smurf2 carry a non-covalent Nedd8-binding site within its catalytic HECT domain. Structural analysis reveals that Smurf2 has Nedd8-binding sites within the small sub-domain of N-lobe and the C-lobe of HECT domain...
February 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28166272/activation-of-mapk-erk-signaling-by-burkholderia-pseudomallei-cycle-inhibiting-factor-cif
#5
Mei Ying Ng, Mei Wang, Patrick J Casey, Yunn-Hwen Gan, Thilo Hagen
Cycle inhibiting factors (Cifs) are virulence proteins secreted by the type III secretion system of some Gram-negative pathogenic bacteria including Burkholderia pseudomallei. Cif is known to function to deamidate Nedd8, leading to inhibition of Cullin E3 ubiquitin ligases (CRL) and consequently induction of cell cycle arrest. Here we show that Cif can function as a potent activator of MAPK/ERK signaling without significant activation of other signaling pathways downstream of receptor tyrosine kinases. Importantly, we found that the ability of Cif to activate ERK is dependent on its deamidase activity, but independent of Cullin E3 ligase inhibition...
2017: PloS One
https://www.readbyqxmd.com/read/28157218/expanded-safety-analysis-of-pevonedistat-a-first-in-class-nedd8-activating-enzyme-inhibitor-in-patients-with-acute-myeloid-leukemia-and-myelodysplastic-syndromes
#6
R T Swords, J Watts, H P Erba, J K Altman, M Maris, F Anwer, Z Hua, H Stein, H Faessel, F Sedarati, B J Dezube, F J Giles, B C Medeiros, D J DeAngelo
No abstract text is available yet for this article.
February 3, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28101194/inhibition-of-nedd8-and-fat10-ligase-activities-through-the-degrading-enzyme-nedd8-ultimate-buster-1-a-potential-anticancer-approach
#7
Ka-Liong Tan, Francesco Pezzella
The capabilities of tumour cells to survive through deregulated cell cycles and evade apoptosis are hallmarks of cancer. The ubiquitin-like proteins (UBL) proteasome system is important in regulating cell cycles via signaling proteins. Deregulation of the proteasomal system can lead to uncontrolled cell proliferation. The Skp, Cullin, F-box containing complex (SCF complex) is the predominant E3 ubiquitin ligase, and has diverse substrates. The ubiquitin ligase activity of the SCF complexes requires the conjugation of neural precursor cell expressed, developmentally down-regulated 8 (NEDD8) to cullin proteins...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28099510/regulation-of-nub1-activity-through-non-proteolytic-mdm2-mediated-ubiquitination
#8
Thomas Bonacci, Stéphane Audebert, Luc Camoin, Emilie Baudelet, Juan-Lucio Iovanna, Philippe Soubeyran
NUB1 (Nedd8 ultimate buster 1) is an adaptor protein which negatively regulates the ubiquitin-like protein Nedd8 as well as neddylated proteins levels through proteasomal degradation. However, molecular mechanisms underlying this function are not completely understood. Here, we report that the oncogenic E3 ubiquitin ligase Mdm2 is a new NUB1 interacting protein which induces its ubiquitination. Interestingly, we found that Mdm2-mediated ubiquitination of NUB1 is not a proteolytic signal. Instead of promoting the conjugation of polyubiquitin chains and the subsequent proteasomal degradation of NUB1, Mdm2 rather induces its di-ubiquitination on lysine 159...
2017: PloS One
https://www.readbyqxmd.com/read/28096463/deneddylase1-counters-automodification-of-neddylating-enzymes-to-maintain-nedd8-homeostasis-in-arabidopsis
#9
Julia Mergner, Bernhard Kuster, Claus Schwechheimer
In eukaryotes, the conjugation of the ubiquitin-like protein NEDD8 onto protein targets is an important post-translational modification. The best understood neddylation targets are the cullins, scaffold subunits of E3 ubiquitin ligases, where neddylation as well as deneddylation, facilitated by the protease activity of the CSN (COP9 signalosome), are required to control ubiquitin ligase assembly, function and ultimately substrate degradation. Little is known about the role of other deneddylating enzymes besides CSN and the role of neddylation and deneddylation of their substrates...
January 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28035772/deregulated-neddylation-in-liver-fibrosis
#10
Imanol Zubiete-Franco, Pablo Fernández-Tussy, Lucía Barbier-Torres, Jorge Simon, David Fernández-Ramos, Fernando Lopitz-Otsoa, Virginia Gutiérrez-de Juan, Sergio López de Davalillo, Antonio Martín Duce, Paula Iruzubieta, Daniel Taibo, Javier Crespo, Juan Caballeria, Erica Villa, Igor Aurrekoetxea, Patricia Aspichueta, Marta Varela-Rey, Shelly C Lu, José M Mato, Naiara Beraza, Teresa C Delgado, María L Martínez-Chantar
: Hepatic fibrosis is a global health problem currently without effective therapeutic approaches. Even though the ubiquitin-like posttranslational modification of neddylation, that conjugates Nedd8 (neural precursor cell expressed developmentally downregulated) to specific targets, is aberrant in many pathologies, its relevance in liver fibrosis (LF) remained unexplored. Our results show deregulated neddylation in clinical fibrosis and both in mouse bileductligation- and CCl4 -induced fibrosis...
February 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28034751/mln4924-suppresses-the-brca1-complex-and-synergizes-with-parp-inhibition-in-nsclc-cells
#11
Zong-Pei Guo, Ying-Chun Hu, Yu Xie, Feng Jin, Zhi-Quan Song, Xiao-Dan Liu, Teng Ma, Ping-Kun Zhou
Like ubiquitination, several studies have demonstrated that neddylation is implicated to be involved in the double strand break repair. BRCA1 is one of the key repair factors in the homologous recombination repair and may play a downstream role of the neddylation. BRCA1 is also a frequently mutated gene in cancers, which serve as the targets for PARP inhibitors. Here we further investigated the correlation between neddylation and BRCA1 complex using neddylation inhibitor MLN4924. MLN4924 efficiently inhibited the recruitment of components of BRCA1 complex to DNA damage sites...
January 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27987332/neddylated-cullin-3-is-required-for-vascular-endothelial-cadherin-mediated-endothelial-barrier-function
#12
Tomohisa Sakaue, Ayako Fujisaki, Hironao Nakayama, Masashi Maekawa, Hiromi Hiyoshi, Eiji Kubota, Takashi Joh, Hironori Izutani, Shigeki Higashiyama
Vascular endothelial-cadherin, a major endothelial adhesion molecule, regulates vascular permeability, and increased vascular permeability has been observed in several cancers. The aim of this study was to elucidate the role of the NEDD8-Cullin E3 ligase, in maintaining barrier permeability. To this end, we investigated the effects of the inhibition of Cullin E3 ligases, by using inhibitors and knockdown techniques in human umbilical vein endothelial cells. Further, we analyzed the mRNA and protein levels of the ligases by quantitative reverse transcription-polymerase chain reaction and western blotting, respectively...
December 17, 2016: Cancer Science
https://www.readbyqxmd.com/read/27981705/azaindoles-as-zinc-binding-small-molecule-inhibitors-of-the-jamm-protease-csn5
#13
Eva Altmann, Paul Erbel, Martin Renatus, Michael Schaefer, Anita Schlierf, Adelaide Druet, Laurence Kieffer, Mickael Sorge, Keith Pfister, Ulrich Hassiepen, Matthew Jones, Simon Ruedisser, Daniela Ostermeier, Bruno Martoglio, Anne B Jefferson, Jean Quancard
CSN5 is the zinc metalloprotease subunit of the COP9 signalosome (CSN), which is an important regulator of cullin-RING E3 ubiquitin ligases (CRLs). CSN5 is responsible for the cleavage of NEDD8 from CRLs, and blocking deconjugation of NEDD8 traps the CRLs in a hyperactive state, thereby leading to auto-ubiquitination and ultimately degradation of the substrate recognition subunits. Herein, we describe the discovery of azaindoles as a new class of CSN5 inhibitors, which interact with the active-site zinc ion of CSN5 through an unprecedented binding mode...
December 16, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/27976900/a-rhodium-iii-complex-as-an-inhibitor-of-neural-precursor-cell-expressed-developmentally-down-regulated-8-activating-enzyme-with-in-vivo-activity-against-inflammatory-bowel-disease
#14
Hai-Jing Zhong, Wanhe Wang, Tian-Shu Kang, Hui Yan, Yali Yang, Lipeng Xu, Yuqiang Wang, Dik-Lung Ma, Chung-Hang Leung
We report herein the identification of the rhodium(III) complex [Rh(phq)2(MOPIP)](+) (1) as a potent and selective ATP-competitive neural precursor cell expressed, developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) inhibitor. Structure-activity relationship analysis indicated that the overall organometallic design of complex 1 was important for anti-inflammatory activity. Complex 1 showed promising anti-inflammatory activity in vivo for the potential treatment of inflammatory bowel disease.
December 23, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27956554/the-protein-neddylation-pathway-in-trypanosoma-brucei-functional-characterization-and-substrate-identification
#15
Shanhui Liao, Huiqing Hu, Tao Wang, Xiaoming Tu, Ziyin Li
Protein posttranslational modifications such as neddylation play crucial roles in regulating protein function. Only a few neddylated substrates have been validated to date, and the role of neddylation remains poorly understood. Here, using Trypanosoma brucei as the model organism, we investigated the function and substrates of TbNedd8. TbNedd8 is distributed throughout the cytosol but enriched in the nucleus and the flagellum. Depletion of TbNedd8 by RNAi abolished global protein ubiquitination, caused DNA re-replication in postmitotic cells, impaired spindle assembly, and compromised the flagellum attachment zone filament, leading to flagellum detachment...
January 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27906189/distinct-outcomes-of-crl-nedd8-pathway-inhibition-reveal-cancer-cell-plasticity
#16
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
#17
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
#18
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...
January 22, 2017: 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
#19
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
#20
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
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