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https://www.readbyqxmd.com/read/28536428/the-molecular-determinants-for-distinguishing-between-ubiquitin-and-nedd8-by-usp2
#1
Yung-Cheng Shin, Jou-Han Chen, Shih-Chung Chang
Ubiquitin (Ub) shares the highest sequence identity with neuronal-precursor-cell-expressed developmentally downregulated protein-8 (NEDD8) in the Ub-like protein family. However, different enzyme systems are precisely employed for targeting Ub and NEDD8 to specific substrates. The molecular determinants for distinguishing between Ub and NEDD8 by Ub-specific peptidases (USPs) remain poorly characterized. By replacing the non-conserved residues of Ub with their NEDD8 equivalents by mutagenesis, and vice versa, we observed that the Ub(4K), Ub(12E), and Ub(14E) mutants partially and the Ub(4K/12E/14E/72A) mutant completely prevented their hydrolysis by USP2...
May 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28535453/inhibition-of-neddylation-modification-sensitizes-pancreatic-cancer-cells-to-gemcitabine
#2
Hua Li, Weihua Zhou, Lihui Li, Jianfu Wu, Xiaoli Liu, Lili Zhao, Lijun Jia, Yi Sun
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA with a 5-year survival rate less than 3% to 5%. Gemcitabine remains as a standard care for PDAC patients. Although protein neddylation is abnormally activated in many human cancers, whether neddylation dysregulation is involved in PDAC and whether targeting neddylation would sensitize pancreatic cancer cells to gemcitabine remain elusive. Here we report that high expression of neddylation components, NEDD8 and NAE1, are associated with poor survival of PDAC patients...
May 20, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28522566/nedd8-modification-of-cullin-5-regulates-lipopolysaccharide-induced-acute-lung-injury
#3
Ziyan Zhu, Lei Sun, Rui Hao, Hongchao Jiang, Feng Qian, Richard D Ye
Lung infections are major causes of acute lung injury (ALI), with limited effective treatment available. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an essential adaptor regulating Toll-like receptors (TLRs). We recently identified Cullin-5 (Cul-5) as a prominent component in the regulation of TRAF6 polyubiquitination, but its physiological significance in acute lung injury has not been explored. In this study, we investigated the potential role of Cul-5 in regulating ALI using mice receiving intratracheal instillation of LPS...
May 18, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28498721/mechanisms-of-deubiquitinase-specificity-and-regulation
#4
Tycho E T Mevissen, David Komander
Protein ubiquitination is one of the most powerful posttranslational modifications of proteins, as it regulates a plethora of cellular processes in distinct manners. Simple monoubiquitination events coexist with more complex forms of polyubiquitination, the latter featuring many different chain architectures. Ubiquitin can be subjected to further posttranslational modifications (e.g., phosphorylation and acetylation) and can also be part of mixed polymers with ubiquitin-like modifiers such as SUMO (small ubiquitinrelated modifier) or NEDD8 (neural precursor cell expressed, developmentally downregulated 8)...
May 12, 2017: Annual Review of Biochemistry
https://www.readbyqxmd.com/read/28475037/senp8-limits-aberrant-neddylation-of-nedd8-pathway-components-to-promote-cullin-ring-ubiquitin-ligase-function
#5
Kate E Coleman, Miklós Békés, Jessica R Chapman, Sarah B Crist, Mathew Jk Jones, Beatrix M Ueberheide, Tony T Huang
NEDD8 is a ubiquitin-like modifier most well-studied for its role in activating the largest family of ubiquitin E3 ligases, the cullin-RING ligases (CRLs). While many non-cullin neddylation substrates have been proposed over the years, validation of true NEDD8 targets has been challenging, as overexpression of exogenous NEDD8 can trigger NEDD8 conjugation through the ubiquitylation machinery. Here, we developed a deconjugation-resistant form of NEDD8 to stabilize the neddylated form of cullins and other non-cullin substrates...
May 5, 2017: ELife
https://www.readbyqxmd.com/read/28469786/mln4924-protects-against-bleomycin-induced-pulmonary-fibrosis-by-inhibiting-the-early-inflammatory-process
#6
Qi Deng, Jiaojiao Zhang, Yaqun Gao, Xiaofei She, Yunchao Wang, Yilin Wang, Xin Ge
Pulmonary fibrosis is a complex pathological process characterized by massive destruction of the structure of lung tissues and aggravated pulmonary function impairment. The underlying mechanisms of pulmonary fibrosis are incompletely understood and therefore limited treatment options are available currently. Here, we report that MLN4924, an NEDD8 activation enzyme (NAE) activity-inhibiting molecule, blocks the maintenance and progression of established pulmonary fibrosis. We found that MLN4924 acts against bleomycin-induced pulmonary fibrosis mainly at the early inflammatory stage...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28468780/combined-inhibition-of-nedd8-activating-enzyme-and-mtor-suppresses-nf2-loss-driven-tumorigenesis
#7
Jonathan Cooper, Qingwen Xu, Lu Zhou, Milica Pavlovic, Virginia Ojeda, Kamalika Moulick, Elisa de Stanchina, J T Poirier, Marjorie Zauderer, Charles M Rudin, Matthias A Karajannis, C Oliver Hanemann, Filippo G Giancotti
Inactivation of NF2/Merlin causes the autosomal dominant cancer predisposition syndrome Familial Neurofibromatosis Type 2 (NF2) and contributes to the development of malignant pleural mesothelioma (MPM). In order to develop a targeted therapy for NF2-mutant tumors, we have exploited the recent realization that Merlin loss drives tumorigenesis by activating the E3 ubiquitin ligase CRL4(DCAF1) - thereby inhibiting the Hippo pathway component Lats. Here, we show that MLN4924 - a NEDD8 activating enzyme (NAE) inhibitor - suppresses CRL4(DCAF1) and attenuates activation of YAP in NF2-mutant tumor cells...
May 3, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28450112/nedd8-activating-enzyme-inhibitor-mln4924-pevonedistat-induces-noxa-dependent-apoptosis-through-up-regulation-of-atf-4
#8
Xiaojun Liu, Yanan Jiang, Jianfu Wu, Wenjuan Zhang, Yupei Liang, Lijun Jia, Jinha Yu, L S Jeong, Lihui Li
It has been reported that MLN4924 can inhibit cell growth and metastasis in various kinds of cancer. We have reported that MLN4924 is able to inhibit angiogenesis through the induction of cell apoptosis both in vitro and in vivo models. Moreover, Neddylation inhibition using MLN4924 triggered the accumulation of pro-apoptotic protein NOXA in Human umbilical vein endothelial cells (HUVECs). However, the mechanism of MLN4924-induced NOXA up-regulation has not been addressed in HUVECs yet. In this study, we investigated how MLN4924 induced NOXA expression and cellular apoptosis in HUVECs treated with MLN4924 at indicated concentrations...
June 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28447739/neural-precursor-cell-expressed-developmentally-downregulated-8%C3%A2-activating-enzyme-inhibitor-mln4924-sensitizes-colorectal-cancer-cells-to-oxaliplatin-by-inducing-dna-damage-g2-cell-cycle-arrest-and-apoptosis
#9
Wanwei Zheng, Zhongguang Luo, Jun Zhang, Pei Min, Wenshuai Li, Diannan Xu, Ziqiang Zhang, Panpan Xiong, Hong Liang, Jie Liu
Oxaliplatin-based chemotherapy is a primary treatment for patients with metastatic colorectal cancer (CRC); however, its efficacy is limited. Therefore, novel therapeutic agents are urgently required. MLN4924 is a first‑in‑class inhibitor of neural precursor cell expressed, developmentally downregulated 8 (NEDD8)‑activating enzyme E1, and has entered various phase‑I/II clinical trials for cancer therapy due to its significant anticancer efficacy. The aim of the present study was to examine the synergistic effect and underlying mechanisms of MLN4924 and oxaliplatin combined treatment for CRC...
May 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28388520/discovery-of-benzothiazole-derivatives-as-novel-non-sulfamide-nedd8-activating-enzyme-inhibitors-by-target-based-virtual-screening
#10
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
#11
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
#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 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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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