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Neddylation

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https://www.readbyqxmd.com/read/29232579/structure-based-identification-of-a-nedd8-activating-enzyme-inhibitor-via-drug-repurposing
#1
Ke-Jia Wu, Hai-Jing Zhong, Guodong Li, Chenfu Liu, Hui-Min David Wang, Dik-Lung Ma, Chung-Hang Leung
NEDD8-activating enzyme (NAE) is an essential player of the NEDD8 conjugation pathway that regulates protein degradation. Meanwhile, drug repurposing is a cost-efficient strategy to identify new therapeutic uses for existing scaffolds. In this report, mitoxantrone (1) was repurposed as an inhibitor of NAE by virtual screening of an FDA-approved drug database. Compound 1 inhibited NAE activity in cell-free and cell-based systems with high selectivity and was competitive with ATP. Furthermore, compound 1 induced apoptosis of colorectal adenocarcinoma cancer cells through inhibiting the degradation of the neddylation substrate p53...
December 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29176748/roles-of-neddylation-against-viral-infections
#2
Kun Han, Jiyan Zhang
No abstract text is available yet for this article.
November 27, 2017: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/29112949/integrative-analysis-of-genome-wide-gene-copy-number-changes-and-gene-expression-in-non-small-cell-lung-cancer
#3
Verena Jabs, Karolina Edlund, Helena König, Marianna Grinberg, Katrin Madjar, Jörg Rahnenführer, Simon Ekman, Michael Bergkvist, Lars Holmberg, Katja Ickstadt, Johan Botling, Jan G Hengstler, Patrick Micke
Non-small cell lung cancer (NSCLC) represents a genomically unstable cancer type with extensive copy number aberrations. The relationship of gene copy number alterations and subsequent mRNA levels has only fragmentarily been described. The aim of this study was to conduct a genome-wide analysis of gene copy number gains and corresponding gene expression levels in a clinically well annotated NSCLC patient cohort (n = 190) and their association with survival. While more than half of all analyzed gene copy number-gene expression pairs showed statistically significant correlations (10,296 of 18,756 genes), high correlations, with a correlation coefficient >0...
2017: PloS One
https://www.readbyqxmd.com/read/29077169/clinical-significance-of-sccro-dcun1d1-in-prostate-cancer-and-its-proliferation-inhibiting-effect-on-lncap-cells
#4
Z-H Zhang, J Li, F Luo, Y-S Wang
OBJECTIVE:   SCCRO/DCUN1D1/DCN1 (squamous cell carcinoma-related oncogene/defective in cullin neddylation 1 domain containing 1/defective in cullin neddylation) is considered as an oncogene, but its role in the prostate cancer (PC) is still not clear. The current study aims to investigate the expression of SCCRO in PC tumor tissues, further its clinical significance, and proliferation inhibiting effect on PC cells in vitro. PATIENTS AND METHODS: RT-PCR was used to detect the expression of SCCRO in PC tissue and corresponding adjacent normal tissues from 160 cases, and its relationship with clinical pathological characteristics was analyzed...
October 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/29074978/a-potent-small-molecule-inhibitor-of-the-dcn1-ubc12-interaction-that-selectively-blocks-cullin-3-neddylation
#5
Haibin Zhou, Jianfeng Lu, Liu Liu, Denzil Bernard, Chao-Yie Yang, Ester Fernandez-Salas, Krishnapriya Chinnaswamy, Stephanie Layton, Jeanne Stuckey, Qing Yu, Weihua Zhou, Zhenqiang Pan, Yi Sun, Shaomeng Wang
The Cullin-RING E3 ubiquitin ligases (CRLs) regulate homeostasis of ~20% of cellular proteins and their activation require neddylation of their cullin subunit. Cullin neddylation is modulated by a scaffolding DCN protein through interactions with both the cullin protein and an E2 enzyme such as UBC12. Here we report the development of DI-591 as a high-affinity, cell-permeable small-molecule inhibitor of the DCN1-UBC12 interaction. DI-591 binds to purified recombinant human DCN1 and DCN2 proteins with K i values of 10-12 nM, and disrupts the DCN1-UBC12 interaction in cells...
October 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/29046292/identification-of-ut-a1-and-aqp2-interacting-proteins-in-rat-inner-medullary-collecting-duct
#6
Chung-Lin Chou, Gloria Hwang, Daniel J Hageman, Lichy Han, Prashasti Agrawal, Trairak Pisitkun, Mark A Knepper
The urea channel UT-A1 and the water channel aquaporin-2 (AQP2) mediate vasopressin-regulated transport in the renal inner medullary collecting duct (IMCD). To identify the proteins that interact with UT-A1 and AQP2 in native rat IMCD cells, we carried out chemical cross-linking followed by detergent solubilization, immunoprecipitation, and LC-MS/MS analysis of the immunoprecipitated material. The analyses revealed 133 UT-A1-interacting proteins and 139 AQP2-interacting proteins, each identified in multiple replicates...
October 18, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29039560/20-hydroxyeicosatetraenoic-acid-regulates-the-expression-of-nedd4%C3%A2-2-in-kidney-and-liver-through-a-neddylation-modification-pathway
#7
Jianzhu Zhao, Bijun Zhang, Guangrui Lai, Runhong Xu, Guoming Chu, Yanyan Zhao
The present study aimed to test whether 20-hydroxyeicosatetraenoic acid (20‑HETE) affected neddylation modification of E3‑ligase Nedd4‑2 (neural precursor cell expressed, developmentally down‑regulated 4‑like, E3 ubiquitin protein ligase). A cytochrome P450 family 4 subfamily F member 2 (CYP4F2) transgenic mouse model that overproduces 20‑HETE in the kidney and the liver was used in the present study. Transgenic mice with high salt intake exhibited increased activation of Nedd4‑2‑mediated ubiquitin‑proteasome pathway...
December 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29027989/inhibition-of-neddylation-by-mln4924-improves-neointimal-hyperplasia-and-promotes-apoptosis-of-vascular-smooth-muscle-cells-through-p53-and-p62
#8
Tang-Jun Ai, Jian-Yong Sun, Lin-Juan Du, Chaoji Shi, Chao Li, Xue-Nan Sun, Yan Liu, Lihui Li, Zhixiong Xia, Lijun Jia, Jianmiao Liu, Sheng-Zhong Duan
Targeting apoptosis of vascular smooth muscle cells (VSMCs) represents an attractive approach to diminish the occurrence of restenosis. Neddylation is a highly conserved post-translational modification process and inhibition of neddylation has been shown to regulate apoptosis of other cells. However, the impacts of neddylation inhibition on VSMCs and neointimal hyperplasia have not been studied. In our present study, we have shown that MLN4924, a selective inhibitor of NEDD8-activating enzyme (NAE), markedly inhibited neointimal hyperplasia and accumulation of VSMCs, whereas increased apoptosis in the vascular wall...
October 13, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28964913/functions-and-substrates-of-neddylation-during-cell-cycle-in-the-silkworm-bombyx-mori
#9
Zhiqing Li, Qixin Cui, Xiaoyan Wang, Bingqian Li, Dongchao Zhao, Qingyou Xia, Ping Zhao
NEDDylation, a post-translational modification mediated by the conjugation of the ubiquitin-like protein Nedd8 to specific substrates, is an essential biological process that regulates cell cycle progression in eukaryotes. Here, we report the conservation of NEDDylation machinery and NEDDylated proteins in the silkworm, Bombyx mori. We have identified all the components necessary for reversible NEDDylation in the silkworm including Nedd8, E1, E2, E3, and deNEDDylation enzymes. By the approach of RNAi-mediated gene silencing, it was shown that knockdown of BmNedd8 and the conjugating enzymes decreased the global level of NEDDylation, while knockdown of deNEDDylation enzymes increased the prevalence of this modification in cultured silkworm cells...
November 2017: Insect Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28923850/increasing-the-unneddylated-cullin1-portion-rescues-the-csn-phenotypes-by-stabilizing-adaptor-modules-to-drive-scf-assembly
#10
Qingqing Liu, Yike Zhou, Ruiqi Tang, Xuehong Wang, Qiwen Hu, Ying Wang, Qun He
The dynamic SCF (Skp1-cullin1-F-box protein) assembly is controlled by cycles of cullin neddylation/deneddylation based on the deneddylation activity of the COP9 signalosome (CSN) and global sequestration of cullins by CAND1. However, acceptance of this prediction was hampered by the results of recent studies, and the regulatory mechanism and key players remain to be identified. We found that maintaining a proper Cul1(Nedd8)/Cul1 ratio is crucial to ensure SCF functions. Reducing the high Cul1(Nedd8)/Cul1 ratios in csn mutants through ectopic expression of the nonneddylatable Cul1(K722R) proteins or introducing the endogenous cul1(K722R) point mutation significantly rescues their defective phenotypes...
December 1, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28891468/epidermal-growth-factor-receptor-neddylation-is-regulated-by-a-desmosomal-cop9-constitutive-photomorphogenesis-9-signalosome-complex
#11
Nicole Ann Najor, Gillian Nicole Fitz, Jennifer Leigh Koetsier, Lisa Marie Godsel, Lauren Veronica Albrecht, Robert Harmon, Kathleen Janee Green
Cell junctions are scaffolds that integrate mechanical and chemical signaling. We previously showed that a desmosomal cadherin promotes keratinocyte differentiation in an adhesion-independent manner by dampening Epidermal Growth Factor Receptor (EGFR) activity. Here we identify a potential mechanism by which desmosomes assist the de-neddylating COP9 signalosome (CSN) in attenuating EGFR through an association between the Cops3 subunit of the CSN and desmosomal components, Desmoglein1 (Dsg1) and Desmoplakin (Dp), to promote epidermal differentiation...
September 11, 2017: ELife
https://www.readbyqxmd.com/read/28878074/cooperation-of-the-ebola-virus-proteins-vp40-and-gp1-2-with-bst2-to-activate-nf-%C3%AE%C2%BAb-independently-of-virus-like-particle-trapping
#12
Maryan G Rizk, Christopher F Basler, John Guatelli
BST2 is a host protein with dual functions in response to viral infections: it traps newly assembled enveloped virions at the plasma membrane in infected cells, and it induces NF-κB activity, especially in the context of retroviral assembly. In this study, we examined whether Ebola virus proteins affect BST2-mediated induction of NF-κB. We found that the Ebola virus matrix protein, VP40, and envelope glycoprotein, GP, each cooperate with BST2 to induce NF-κB activity, with maximal activity when all three proteins are expressed...
November 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28838998/the-neddylation-inhibitor-pevonedistat-mln4924-suppresses-and-radiosensitizes-head-and-neck-squamous-carcinoma-cells-and-tumors
#13
Vanessa Vanderdys, Amir Allak, Fadila Guessous, Mouadh Benamar, Paul W Read, Mark J Jameson, Tarek Abbas
The cullin RING E3 ubiquitin ligase 4 (CRL4) with its substrate receptor CDT2 (CRL4-CDT2) is emerging as a critical regulator of DNA replication through targeting CDT1, SET8 and p21 for ubiquitin-dependent proteolysis. The aberrant increased stability of these proteins in cells with inactivated CRL4-CDT2 results in DNA rereplication, which is deleterious to cells due to the accumulation of replication intermediates and stalled replication forks. Here, we demonstrate that CDT2 is overexpressed in head and neck squamous cell carcinoma (HNSCC) and its depletion by siRNA inhibits the proliferation of human papilloma virus negative (HPV-ve) HNSCC cells primarily through the induction of rereplication...
August 24, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28831681/neddylation-antagonizes-ubiquitination-of-proliferating-cell-nuclear-antigen-and-regulates-the-recruitment-of-polymerase-%C3%AE-in-response-to-oxidative-dna-damage
#14
Junhong Guan, Shuyu Yu, Xiaofeng Zheng
NEDDylation has been shown to participate in the DNA damage pathway, but the substrates of neural precursor cell expressed developmentally downregulated 8 (NEDD8) and the roles of NEDDylation involved in the DNA damage response (DDR) are largely unknown. Translesion synthesis (TLS) is a damage-tolerance mechanism, in which RAD18/RAD6-mediated monoubiquitinated proliferating cell nuclear antigen (PCNA) promotes recruitment of polymerase η (polη) to bypass lesions. Here we identify PCNA as a substrate of NEDD8, and show that E3 ligase RAD18-catalyzed PCNA NEDDylation antagonizes its ubiquitination...
August 22, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28717191/mln4924-pevonedistat-a-protein-neddylation-inhibitor-suppresses-proliferation-and-migration-of-human-clear-cell-renal-cell-carcinoma
#15
Shuai Tong, Yang Si, Hefen Yu, Lingqiang Zhang, Ping Xie, Wenguo Jiang
Neddylation is a post-translational protein modification associated with cancer development. MLN4924 is a neddylation inhibitor currently under investigation in multiple phase I studies on various malignancies, and its clincal name is Pevonedistat. It has been documented that MLN4924 blocks Cullins neddylation and inactivates CRLs and, in turn, triggers cell-cycle arrest, apoptosis, senescence and autophagy in many cancer cells. In this study, we investigated the anti-tumor effect of MLN4924 in human clear cell renal carcinoma (ccRCC)...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28701396/effects-of-the-nedd8-activating-enzyme-inhibitor-mln4924-on-lytic-reactivation-of-kaposi-s-sarcoma-associated-herpesvirus
#16
Pey-Jium Chang, Lee-Wen Chen, Li-Yu Chen, Chien-Hui Hung, Ying-Ju Shih, Shie-Shan Wang
The switch of Kaposi's sarcoma-associated herpesvirus (KSHV) from latency to lytic replication is a key event for viral dissemination and pathogenesis. MLN4924, a novel neddylation inhibitor, reportedly causes the onset of KSHV reactivation but impairs later phases of the viral lytic program in infected cells. Thus far, the molecular mechanism involved in the modulation of the KSHV lytic cycle by MLN4924 is not yet fully understood. Here, we confirmed that treatment of different KSHV-infected primary effusion lymphoma (PEL) cell lines with MLN4924 substantially induces viral lytic protein expression...
October 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28669728/targeting-neddylation-pathway-with-mln4924-pevonedistat-induces-noxa-dependent-apoptosis-in-renal-cell-carcinoma
#17
Jiyou Wang, Shiwen Wang, Wenjuan Zhang, Xiaofang Wang, Xiaojun Liu, Liang Liu, Lihui Li, Yupei Liang, Jinha Yu, Lak Shin Jeong, Lijun Jia, Hu Zhao, Yanmei Zhang
Inhibition of protein neddylation pathway has emerged an attractive anticancer strategy in preclinical studies by using Nedd8-activating enzyme (NAE) inhibitor MLN4924 (Pevonedistat). Previous studies have reported the antitumor activity of MLN4924 mediated by its efficacy on apoptosis, autophagy and senescence. However, whether MLN4924 has any effect on renal carcinoma cells (RCC) remains unexplored. Here we reported that MLN4924 specifically inhibited protein neddylation pathway, leading to statistically significantly suppress the proliferation, survival and migration of RCC cells by inducing G2 cell-cycle arrest, followed by apoptosis in a MLN4924 dose-dependent manner...
September 2, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28663057/inhibition-of-mcl-1-enhances-pevonedistat-triggered-apoptosis-in-osteosarcoma-cells
#18
Yi Zhang, Chengcheng Shi, Li Yin, Wei Zhou, Haitao Wang, Jingjing Seng, Wencai Li
Neddylation inhibitor Pevonedistat (MLN4924) is a novel anticancer drug and has demonstrated broad-spectrum anticancer activity. Nevertheless, we found that Pevonedistat had only a modest apoptotic effect in osteosarcoma (OS) cells. Moreover, we noted that inhibition of neddylation by Pevonedistat led to accumulation of Mcl-1 protein in OS cells. Because Mcl-1 is an important anti-apoptotic protein and also because apoptosis has been shown to be a major cell death pathway, we hypothesized that Mcl-1 accumulation negatively impacted Pevonedistat-mediated anticancer activity in OS cells...
September 15, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28620047/squamous-cell-carcinoma-related-oncogene-sccro-neddylates-cul3-protein-to-selectively-promote-midbody-localization-and-activity-of-cul3-klhl21-protein-complex-during-abscission
#19
Guochang Huang, Andrew J Kaufman, Ke Xu, Katia Manova, Bhuvanesh Singh
Squamous cell carcinoma-related oncogene (SCCRO)/DCUN1D1, a component of the neddylation E3 complex, regulates the activity of the cullin-RING-ligase type of ubiquitination E3s by promoting neddylation of cullin family members. Studies have shown that SCCRO regulates proliferation in vitro and in vivo Here we show that inactivation of SCCRO results in prolonged mitotic time because of delayed and/or failed abscission. The effects of SCCRO on abscission involve its role in neddylation and localization of Cul3 to the midbody...
September 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28617871/hypoxia-inducible-factor-1%C3%AE-plays-roles-in-epstein-barr-virus-s-natural-life-cycle-and-tumorigenesis-by-inducing-lytic-infection-through-direct-binding-to-the-immediate-early-bzlf1-gene-promoter
#20
Richard J Kraus, Xianming Yu, Blue-Leaf A Cordes, Saraniya Sathiamoorthi, Tawin Iempridee, Dhananjay M Nawandar, Shidong Ma, James C Romero-Masters, Kyle G McChesney, Zhen Lin, Kathleen R Makielski, Denis L Lee, Paul F Lambert, Eric C Johannsen, Shannon C Kenney, Janet E Mertz
When confronted with poor oxygenation, cells adapt by activating survival signaling pathways, including the oxygen-sensitive transcriptional regulators called hypoxia-inducible factor alphas (HIF-αs). We report here that HIF-1α also regulates the life cycle of Epstein-Barr virus (EBV). Incubation of EBV-positive gastric carcinoma AGS-Akata and SNU-719 and Burkitt lymphoma Sal and KemIII cell lines with a prolyl hydroxylase inhibitor, L-mimosine or deferoxamine, or the NEDDylation inhibitor MLN4924 promoted rapid and sustained accumulation of both HIF-1α and lytic EBV antigens...
June 2017: PLoS Pathogens
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