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https://www.readbyqxmd.com/read/28388520/discovery-of-benzothiazole-derivatives-as-novel-non-sulfamide-nedd8-activating-enzyme-inhibitors-by-target-based-virtual-screening
#1
Hao Ma, Chunlin Zhuang, Xiguo Xu, Jiao Li, Juan Wang, Xiao Min, Wannian Zhang, Huojun Zhang, Zhenyuan Miao
NEDD8 activating enzyme (NAE) plays a critical role in various cellular functions in cancers. In this study, a target-based virtual screening was applied to discover benzothiazoles to be potent non-covalent NAE inhibitors. Further two round optimizations concluded a preliminary structure-activity relationship (SAR) of their derivatives. Three compounds (6k, 7b, ZM223) exhibited antitumor activities in nanomolar range. ZM223 showed excellent anticancer activity against HCT116 colon cancer cells with an IC50 value of 100 nM...
March 31, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28388044/disclosing-the-interaction-of-carbonic-anhydrase-ix-with-cullin-associated-nedd8-dissociated-protein-1-by-molecular-modeling-and-integrated-binding-measurements
#2
Martina Buonanno, Emma Langella, Nicola Zambrano, Mariangela Succoio, Emanuele Sasso, Vincenzo Alterio, Anna Di Fiore, Annamaria Sandomenico, Claudiu T Supuran, Andrea Scaloni, Simona Maria Monti, Giuseppina De Simone
Human Carbonic Anhydrase (hCA) IX is a membrane-associated member of the CA enzyme family, involved in solid tumor acidification. This enzyme is a marker of tumor hypoxia and a prognostic factor for several human cancers. In a recent paper, we showed that CA IX interacts with cullin-associated NEDD8-dissociated protein 1 (CAND1), a nuclear protein involved in gene transcription and assembly of SCF ubiquitin ligase complexes. A functional role for this interaction was also identified, since lower CA IX levels were observed in cells with decreased CAND1 expression via shRNA-mediated interference...
April 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28376221/efficacy-of-nedd8-pathway-inhibition-in-preclinical-models-of-poorly-differentiated-clinically-aggressive-colorectal-cancer
#3
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 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28330952/effects-of-insulin-and-the-glucagon-like-peptide-1-receptor-agonist-liraglutide-on-the-kidney-proteome-in-db-db-mice
#4
Leena Liljedahl, Jenny Norlin, James N McGuire, Peter James
Diabetes mellitus (DM) is a worldwide disease that affects 9% of the adult world population and type 2 DM accounts for 90% of those. A common consequence of DM is kidney complications, which could lead to kidney failure. We studied the potential effects of treatment with insulin and the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide on the diabetic kidney proteome through the use of the db/db mouse model system and mass spectrometry (MS). Multivariate analyses revealed distinct effects of insulin and liraglutide on the db/db kidney proteome, which was seen on the protein levels of, for example, pterin-4 α-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor-1α (PCBD1), neural precursor cell expressed developmentally down-regulated-8 (NEDD8), transcription elongation factor-B polypeptide-1 (ELOC) and hepcidin (HEPC)...
March 2017: Physiological Reports
https://www.readbyqxmd.com/read/28297583/assessment-of-drug-sensitivity-in-hematopoietic-stem-and-progenitor-cells-from-acute-myelogenous-leukemia-and-myelodysplastic-syndrome-ex-vivo
#5
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...
March 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28292897/inhibition-of-atherogenesis-by-the-cop9-signalosome-subunit-5-in-vivo
#6
Yaw Asare, Miriam Ommer, Florence A Azombo, Setareh Alampour-Rajabi, Marieke Sternkopf, Maryam Sanati, Marion J Gijbels, Corinna Schmitz, Dzmitry Sinitski, Pathricia V Tilstam, Hongqi Lue, André Gessner, Denise Lange, Johannes A Schmid, Christian Weber, Martin Dichgans, Joachim Jankowski, Ruggero Pardi, Menno P J de Winther, Heidi Noels, Jürgen Bernhagen
Constitutive photomorphogenesis 9 (COP9) signalosome 5 (CSN5), an isopeptidase that removes neural precursor cell-expressed, developmentally down-regulated 8 (NEDD8) moieties from cullins (thus termed "deNEDDylase") and a subunit of the cullin-RING E3 ligase-regulating COP9 signalosome complex, attenuates proinflammatory NF-κB signaling. We previously showed that CSN5 is up-regulated in human atherosclerotic arteries. Here, we investigated the role of CSN5 in atherogenesis in vivo by using mice with myeloid-specific Csn5 deletion...
March 28, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28252002/neddylation-of-pb2-reduces-its-stability-and-blocks-the-replication-of-influenza-a-virus
#7
Tinghong Zhang, Zhen Ye, Xiaohai Yang, Yujie Qin, Yi Hu, Xiaomei Tong, Wenbin Lai, Xin Ye
Post-translational modifications of viral proteins play important roles in regulating viral replication. Here we demonstrated that the PB2 of influenza A virus (IAV) can be modified by NEDD8. We revealed that E3 ligase HDM2 can promote PB2 NEDDylation. Overexpression of either NEDD8 or HDM2 can inhibit IAV replication, while knockdown of HDM2 has the opposite effect. Then we identified residue K699 in PB2 as the major NEDDylation site. We found that NEDDylation deficient PB2 mutant (PB2 K699R) has a longer half-life than wild-type PB2, indicating that NEDDylation of PB2 reduces its stability...
March 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28241406/interferon-stimulated-gene-15-in-the-control-of-cellular-responses-to-genotoxic-stress
#8
REVIEW
Young Joo Jeon, Jong Ho Park, Chin Ha Chung
Error-free replication and repair of DNA are pivotal to organisms for faithful transmission of their genetic information. Cells orchestrate complex signaling networks that sense and resolve DNA damage. Post-translational protein modifications by ubiquitin and ubiquitin-like proteins, including SUMO and NEDD8, are critically involved in DNA damage response (DDR) and DNA damage tolerance (DDT). The expression of interferon-stimulated gene 15 (ISG15), the first identified ubiquitin-like protein, has recently been shown to be induced under various DNA damage conditions, such as exposure to UV, camptothecin, and doxorubicin...
February 2017: Molecules and Cells
https://www.readbyqxmd.com/read/28238764/cullin-e3-ligase-activity-is-required-for-myoblast-differentiation
#9
Jordan Blondelle, Paige Shapiro, Andrea A Domenighetti, Stephan Lange
The role of cullin E3-ubiquitin ligases for muscle homeostasis is best known during muscle atrophy, as the cullin-1 substrate adaptor atrogin-1 is among the most well-characterized muscle atrogins. We investigated whether cullin activity was also crucial during terminal myoblast differentiation and aggregation of acetylcholine receptors for the establishment of neuromuscular junctions in vitro. The activity of cullin E3-ligases is modulated through post-translational modification with the small ubiquitin-like modifier nedd8...
April 7, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28216678/the-cul3-spop-daxx-axis-is-a-novel-regulator-of-vegfr2-expression-in-vascular-endothelial-cells
#10
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
#11
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
#12
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...
March 28, 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
#13
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
#14
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
#15
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
#16
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
#17
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-protein-counters-automodification-of-neddylating-enzymes-to-maintain-nedd8-protein-homeostasis-in-arabidopsis
#18
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...
March 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28035772/deregulated-neddylation-in-liver-fibrosis
#19
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. Importantly, neddylation inhibition, by using the pharmacological inhibitor, MLN4924, reduced liver injury, apoptosis, inflammation, and fibrosis by targeting different hepatic cell types...
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
#20
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
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