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https://www.readbyqxmd.com/read/29233834/the-arabidopsis-alf4-protein-is-a-regulator-of-scf-e3-ligases
#1
Rammyani Bagchi, Charles W Melnyk, Gideon Christ, Martin Winkler, Kerstin Kirchsteiner, Mohammad Salehin, Julia Mergner, Michael Niemeyer, Claus Schwechheimer, Luz Irina A Calderón Villalobos, Mark Estelle
The cullin-RING E3 ligases (CRLs) regulate diverse cellular processes in all eukaryotes. CRL activity is controlled by several proteins or protein complexes, including NEDD8, CAND1, and the CSN Recently, a mammalian protein called Glomulin (GLMN) was shown to inhibit CRLs by binding to the RING BOX (RBX1) subunit and preventing binding to the ubiquitin-conjugating enzyme. Here, we show that Arabidopsis ABERRANT LATERAL ROOT FORMATION4 (ALF4) is an ortholog of GLMN The alf4 mutant exhibits a phenotype that suggests defects in plant hormone response...
December 12, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29232579/structure-based-identification-of-a-nedd8-activating-enzyme-inhibitor-via-drug-repurposing
#2
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/29228602/fbxw8-dependent-degradation-of-mrfap1-in-anaphase-controls-mitotic-cell-death
#3
Duan-Zhuo Li, Shun-Fang Liu, Lan Zhu, Yu-Xing Wang, Yi-Xiang Chen, Jie Liu, Gang Hu, Xin Yu, Jian Li, Jin Zhang, Zhi-Xiang Wu, Han Lu, Wei Liu, Bin Liu
Mof4 family associated protein 1 (MRFAP1) is a 14 kDa nuclear protein, which involves in maintaining normal histone modification levels by negatively regulating recruitment of the NuA4 (nucleosome acetyltransferase of H4) histone acetyltransferase complex to chromatin. MRFAP1 has been identified as one of the most up-regulated proteins after NEDD8 (neural precursor cell expressed developmentally down-regulated 8) inhibition in multiple human cell lines. However, the biological function of MRFAP1 and the E3 ligase that targets MRFAP1 for destruction remain mysterious...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29157102/chk1-inhibitor-sch-900776-enhances-the-antitumor-activity-of-mln4924-on-pancreatic-cancer
#4
Jian-Ang Li, Chao Song, Yefei Rong, Tiantao Kuang, Dansong Wang, Xuefeng Xu, Jian Yuan, Kuntian Luo, Bo Qin, Somaira Nowsheen, Zhenkun Lou, Wenhui Lou
MLN4924 inhibits the cullin-RING ligases mediated ubiquitin-proteasome system, and has showed antitumor activities in preclinical studies, but its effects and mechanisms on pancreatic cancer (PC) remains elusive. We found that MLN4924 inhibited the proliferation and clonogenicity of PC cells, caused DNA damage, particularly double-strand breaks, and leaded to Chk1 activation and cell-cycle arrest. Chk1 inhibitor SCH 900776 alone exhibited minimal cytotoxicity, and caused no DNA damage on PC cells. But in the combination therapy, SCH 900776 enhanced the cytotoxicity and DNA damage caused by MLN4924, likely by abrogating G2/M arrest and promoting DNA re-replication...
November 20, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29103612/composition-and-regulation-of-the-cellular-repertoire-of-scf-ubiquitin-ligases
#5
Justin M Reitsma, Xing Liu, Kurt M Reichermeier, Annie Moradian, Michael J Sweredoski, Sonja Hess, Raymond J Deshaies
SCF (Skp1-Cullin-F-box) ubiquitin ligases comprise several dozen modular enzymes that have diverse roles in biological regulation. SCF enzymes share a common catalytic core containing Cul1⋅Rbx1, which is directed toward different substrates by a variable substrate receptor (SR) module comprising 1 of 69 F-box proteins bound to Skp1. Despite the broad cellular impact of SCF enzymes, important questions remain about the architecture and regulation of the SCF repertoire, including whether SRs compete for Cul1 and, if so, how this competition is managed...
October 26, 2017: Cell
https://www.readbyqxmd.com/read/29091922/characterization-of-the-deubiquitination-activity-and-substrate-specificity-of-the-chicken-ubiquitin-specific-protease-1-usp-associated-factor-1-complex
#6
Hainan Zheng, Mengyun Wang, Chengcheng Zhao, Shanli Wu, Peifeng Yu, Yan Lü, Tiedong Wang, Yongxing Ai
Deubiquitinases (DUBs) are essential regulators of intracellular processes involving ubiquitin (Ub) modification. The human DUB ubiquitin-specific protease 1 (hUSP1) interacts with human USP-associated factor 1 (hUAF1), and helps to regulate processes such as DNA damage repair. Previously, we identified a chicken USP1 homologue (chUSP1) during an investigation into the properties of Marek's disease virus (MDV). However, chUSP1's deubiquitination activity, interaction with chUAF1, and substrate specificity remained unknown...
2017: PloS One
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/29032425/heterologous-expression-of-wheat-tarub1-gene-enhances-disease-resistance-in-arabidopsis-thaliana
#8
Yanlin Yang, Wenqiang Wang, Tian Xu, Na Liu, Honggang Wang, Deshun Feng
Expression of TaRUB1 gene in Arabidopsis thaliana elevates the level of disease-related genes in response to pathogen invasion through the accumulation of callose, necrotic cells, and the outbreak of ROS. Ubiquitin (Ub) and ubiquitin-like proteins are highly conserved in sequence and can covalently bind and modify many intracellular proteins which can be recognized and degraded by 26S proteasome. Post-translational modification of proteins has become a hot research spot today. In the previous study, a cDNA of related-to-ubiquitin protein belonged to ubiquitin-like proteins, whose spatial structure comprised Ub and NEDD8, was obtained from wheat SN6306 by suppression-subtractive hybridization and was named TaRUB1...
December 2017: Plant Cell 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
#9
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
#10
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/28926941/why-ubiquitin-has-not-evolved
#11
Douglas C Allan, James C Phillips
Ubiquitin, discovered less than 50 years ago, tags thousands of diseased proteins for destruction. It is small (only 76 amino acids), and is found unchanged in mammals, birds, fish, and even worms, indicating that ubiquitin is perfect. Key features of its functionality are identified here using critical point thermodynamic scaling theory. These include synchronized pivots and hinges, a stabilizing central pivot, and Fano interference between first- and second-order elements of correlated long-range (allosteric) globular surface shape transitions...
September 16, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28923850/increasing-the-unneddylated-cullin1-portion-rescues-the-csn-phenotypes-by-stabilizing-adaptor-modules-to-drive-scf-assembly
#12
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/28898250/effects-of-proteasome-inhibitor-mg-132-on-the-parasite-schistosoma-mansoni
#13
Enyara R Morais, Katia C Oliveira, Renato G de Paula, Alice M M Ornelas, Érika B C Moreira, Fernanda Rafacho Badoco, Lizandra G Magalhães, Sergio Verjovski-Almeida, Vanderlei Rodrigues
Proteasome is a proteolytic complex responsible for intracellular protein turnover in eukaryotes, archaea and in some actinobacteria species. Previous work has demonstrated that in Schistosoma mansoni parasites, the proteasome inhibitor MG-132 affects parasite development. However, the molecular targets affected by MG-132 in S. mansoni are not entirely known. Here, we used expression microarrays to measure the genome-wide changes in gene expression of S. mansoni adult worms exposed in vitro to MG-132, followed by in silico functional analyses of the affected genes using Ingenuity Pathway Analysis (IPA)...
2017: PloS One
https://www.readbyqxmd.com/read/28892104/synergistic-anti-aml-effects-of-the-lsd1-inhibitor-t-3775440-and-the-nedd8-activating-enzyme-inhibitor-pevonedistat-via-transdifferentiation-and-dna-rereplication
#14
Y Ishikawa, K Nakayama, M Morimoto, A Mizutani, A Nakayama, K Toyoshima, A Hayashi, S Takagi, R Dairiki, H Miyashita, S Matsumoto, K Gamo, T Nomura, K Nakamura
Lysine-specific demethylase 1A (LSD1, KDM1A) specifically demethylates di- and monomethylated histones H3K4 and K9, resulting in context-dependent transcriptional repression or activation. We previously identified an irreversible LSD1 inhibitor T-3775440, which exerts antileukemic activities in a subset of acute myeloid leukemia (AML) cell lines by inducing cell transdifferentiation. The NEDD8-activating enzyme inhibitor pevonedistat (MLN4924, TAK-924) is an investigational drug with antiproliferative activities in AML, and is also reported to induce cell differentiation...
September 11, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28871425/mir-33a-inhibits-cell-proliferation-and-invasion-by-targeting-cand1-in-lung-cancer
#15
M Kang, Y Li, Y Zhao, S He, J Shi
BACKGROUND: Lung cancer continues to be one of the top five causes of cancer-related mortality. This study aims to identify down- and upregulated miRNAs and mRNA which can be used as potential biomarkers and/or therapeutic targets for lung cancer. METHODS: Integrated analysis of differential expression profiles of miRNA and mRNA in lung cancer was performed by searching Gene Expression Omnibus datasets. Based on miRNA expression profiles, direct mRNA targets of miRNAs with experimental support were identified through miRTarBase...
September 4, 2017: Clinical & Translational Oncology
https://www.readbyqxmd.com/read/28838998/the-neddylation-inhibitor-pevonedistat-mln4924-suppresses-and-radiosensitizes-head-and-neck-squamous-carcinoma-cells-and-tumors
#16
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
#17
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/28734548/ubiquitin-like-modifications-in-the-dna-damage-response
#18
REVIEW
Zhifeng Wang, Wei-Guo Zhu, Xingzhi Xu
Genomic DNA is damaged at an extremely high frequency by both endogenous and environmental factors. An improper response to DNA damage can lead to genome instability, accelerate the aging process and ultimately cause various human diseases, including cancers and neurodegenerative disorders. The mechanisms that underlie the cellular DNA damage response (DDR) are complex and are regulated at many levels, including at the level of post-translational modification (PTM). Since the discovery of ubiquitin in 1975 and ubiquitylation as a form of PTM in the early 1980s, a number of ubiquitin-like modifiers (UBLs) have been identified, including small ubiquitin-like modifiers (SUMOs), neural precursor cell expressed, developmentally down-regulated 8 (NEDD8), interferon-stimulated gene 15 (ISG15), human leukocyte antigen (HLA)-F adjacent transcript 10 (FAT10), ubiquitin-fold modifier 1 (UFRM1), URM1 ubiquitin-related modifier-1 (URM1), autophagy-related protein 12 (ATG12), autophagy-related protein 8 (ATG8), fan ubiquitin-like protein 1 (FUB1) and histone mono-ubiquitylation 1 (HUB1)...
October 2017: Mutation Research
https://www.readbyqxmd.com/read/28717191/mln4924-pevonedistat-a-protein-neddylation-inhibitor-suppresses-proliferation-and-migration-of-human-clear-cell-renal-cell-carcinoma
#19
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
#20
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
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