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https://www.readbyqxmd.com/read/29464016/inhibition-of-the-nedd8-conjugation-pathway-induces-calcium-dependent-compensatory-activation-of-the-pro-survival-mek-erk-pathway-in-acute-lymphoblastic-leukemia
#1
Shuhua Zheng, Gilles M Leclerc, Bin Li, Ronan T Swords, Julio C Barredo
De novo and acquired drug resistance and subsequent relapse remain major challenges in acute lymphoblastic leukemia (ALL). We previously identified that pevonedistat (TAK-924, MLN4924), a first-in-class inhibitor of NEDD8 activating enzyme (NAE), elicits ER stress and has potent in vitro and in vivo efficacy against ALL. However, in pevonedistat-treated ALL cell lines, we found consistent activation of the pro-survival MEK/ERK pathway, which has been associated with relapse and poor outcome in ALL. We uncovered that inhibition of the MEK/ERK pathway in vitro and in vivo sensitized ALL cells to pevonedistat...
January 19, 2018: Oncotarget
https://www.readbyqxmd.com/read/29438612/high-affinity-peptidomimetic-inhibitors-of-the-dcn1-ubc12-protein-protein-interaction
#2
Hai-Bin ZHou, Weihua Zhou, Bing Zhou, Liu Liu, Ting-Rong Chern, Krishnapriya Chinnaswamy, Jianfeng Lu, Denzil Bernard, Chaoyie Yang, Shasha Li, Mi Wang, Jeanne A Stuckey, Yi Sun, Shaomeng Wang
The Cullin-RING ligases (CRLs) regulate the turnover of approximately 20% of the proteins in mammalian cells and are emerging therapeutic targets in human diseases. The activation of CRLs requires the neddylation of their cullin subunit, which is controlled by an activation complex consisting of Cullin-RBX1-UBC12-NEDD8-DCN1. Herein, we describe the design, synthesis and evaluation of peptidomimetics targeting the DCN1-UBC12 protein-protein interaction. Starting from a 12-residue UBC12 peptide, we have successfully obtained a series of peptidomimetic compounds that bind to DCN1 protein with KD values of <10 nM...
February 13, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29436659/cholangiocarcinoma%C3%A2-associated-genes-identified-by-integrative-analysis-of-gene-expression-data
#3
Wei Zhong, Lianzhi Dai, Jing Liu, Song Zhou
Cholangiocarcinoma (CCA) is characterized by delayed diagnosis and poor survival rate. Research efforts have focused on novel diagnostic technologies for this type of cancer. Transcriptomic microarray technology is a useful research strategy for investigating the molecular properties of CCA. The objective of the present study was to identify candidate biomarkers with high potential for clinical application in CCA using a meta‑analysis‑based approach. Gene expression profiles of CCA were downloaded from the Gene Expression Omnibus database for integrated analysis...
February 12, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29434977/neddylation-inhibitor-mln4924-induces-g2-cell-cycle-arrest-dna-damage-and-sensitizes-esophageal-squamous-cell-carcinoma-cells-to-cisplatin
#4
Shan Lin, Zhaoyang Shang, Shuo Li, Peng Gao, Yi Zhang, Shuaiheng Hou, Peng Qin, Ziming Dong, Tao Hu, Ping Chen
Inhibiting the protein neddylation pathway using the NEDD8-activating enzyme inhibitor MLN4924 represents an attractive anticancer strategy having been demonstrated to exhibit promising anticancer efficacy and with tolerable levels of toxicity; however, the mechanism by which MLN4924 inhibits cell proliferation in human esophageal squamous cell carcinoma (ESCC) cells requires further investigation. The present study revealed that MLN4924 treatment led to G2 cell cycle arrest and enhanced the protein stability of Wee1-like protein kinase and cyclin dependent protein kinase inhibitor 1A and B and p27...
February 2018: Oncology Letters
https://www.readbyqxmd.com/read/29387232/mln4924-neddylation-inhibitor-promotes-cell-death-in-paclitaxel-resistant-human-lung-adenocarcinoma-cells
#5
Qiang Xu, Guibin Lin, Huizhe Xu, Lulu Hu, Yupeng Wang, Sha Du, Wuguo Deng, Wenxian Hu, Wei Cheng, Ke Jiang
Acquired resistance to first-line chemotherapeutics, including paclitaxel (PTX), is a primary factor contributing to chemotherapy failure in non-small cell lung cancer (NSCLC) patients. Previous studies have identified that targeting NEDD8-activating enzyme (NAE) with MLN4924 effectively overcomes platinum resistance in preclinical models of ovarian cancer. However, the underlying mechanisms are yet to be fully elucidated. The present study demonstrates that the inhibition of the neddylation pathway with MLN4924 an NAE inhibitor inhibited protein neddylation, inactivated cullin-RING E3 ligase and exhibited a potent antiproliferative effect on PTX-resistant A549 and H460 cells (A549/PTX and H460/PTX)...
January 2018: Oncology Letters
https://www.readbyqxmd.com/read/29367474/cullin-associated-nedd8-dissociated-protein-1-a-novel-interactor-of-rabphilin-3a-deubiquitylates-rabphilin-3a-and-regulates-arginine-vasopressin-secretion-in-pc12-cells
#6
Kohtaro Nakashima, Seiji Takeuchi, Shintaro Iwama, Atsushi Kiyota, Yoshinori Yasuda, Naoko Iwata, Atsushi Enomoto, Hiroshi Arima, Yoshihisa Sugimura
The molecular mechanism involved in the exocytosis of arginine vasopressin (AVP) is not fully known. Rabphilin-3A has been suggested as a novel autoantigen in infundibulo-neurohypophysitis (LINH), which leads to central diabetes insipidus through insufficient secretion of AVP. However, the role of rabphilin-3A in the pathogenesis of LINH remains unclear. Thus, the aim of the present study was to identify proteins binding rabphilin-3A in the posterior pituitary. Using glutathione S-transferase (GST)-pulldown assays and proteomic analyses, cullin-associated NEDD8-dissociated protein 1 (CAND1) was identified as a rabphilin-3A-binding protein in the posterior pituitary...
January 23, 2018: Endocrine Journal
https://www.readbyqxmd.com/read/29357390/herpesvirus-deconjugases-inhibit-the-ifn-response-by-promoting-trim25-autoubiquitination-and-functional-inactivation-of-the-rig-i-signalosome
#7
Soham Gupta, Päivi Ylä-Anttila, Simone Callegari, Ming-Han Tsai, Henri-Jacques Delecluse, Maria G Masucci
The N-terminal domains of the herpesvirus large tegument proteins encode a conserved cysteine protease with ubiquitin- and NEDD8-specific deconjugase activity. The proteins are expressed during the productive virus cycle and are incorporated into infectious virus particles, being delivered to the target cells upon primary infection. Members of this viral enzyme family were shown to regulate different aspects of the virus life cycle and the innate anti-viral response. However, only few substrates have been identified and the mechanisms of these effects remain largely unknown...
January 22, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29355077/the-cop9-signalosome-inhibits-cullin-ring-e3-ubiquitin-ligases-independently-of-its-deneddylase-activity
#8
Annabelle Suisse, Miklós Békés, Tony T Huang, Jessica E Treisman
The COP9 signalosome inhibits the activity of Cullin-RING E3 ubiquitin ligases by removing Nedd8 modifications from their Cullin subunits. Neddylation renders these complexes catalytically active, but deneddylation is also necessary for them to exchange adaptor subunits and avoid auto-ubiquitination. Although deneddylation is thought to be the primary function of the COP9 signalosome, additional activities have been ascribed to some of its subunits. We recently showed that COP9 subunits protect the transcriptional repressor and tumor suppressor Capicua from two distinct modes of degradation...
January 22, 2018: Fly
https://www.readbyqxmd.com/read/29348128/pevonedistat-a-first-in-class-nedd8-activating-enzyme-nae-inhibitor-combined-with-azacitidine-in-patients-with-aml
#9
Ronan T Swords, Steven Coutre, Michael B Maris, Joshua F Zeidner, James M Foran, Jose Cruz, Harry P Erba, Jesus G Berdeja, Wayne Tam, Saran Vardhanabhuti, Iwona Pawlikowska-Dobler, Hélène M Faessel, Ajeeta B Dash, Farhad Sedarati, Bruce J Dezube, Douglas V Faller, Michael R Savona
Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study (NCT01814826) of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naïve AML, unfit for standard induction therapy, received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5, combined with fixed-dose AZA (75 mg/m2 IV/SC) on days 1-5, 8, and 9, every 28 days...
January 18, 2018: Blood
https://www.readbyqxmd.com/read/29345925/catalytic-mechanism-of-the-ubiquitin-like-nedd8-transfer-in-ring-e3-e2-nedd8-target-complex-from-qm-mm-free-energy-simulations
#10
Yufei Yue, Yue Ma, Ping Qian, Hong Guo
Ubiquitin-like (UBL) protein modifications play a key role in regulating protein function. In contrast to the ubiquitin (UB) and small ubiquitin-like modifier (SUMO) which are ligated to a massive segment of proteome, the UBL NEDD8 is highly selective for modifying a lysine residue on closely related cullin proteins (CULs). In this study, the X-ray structure of a trapped E3-E2~NEDD8-target intermediate (RBX1-UBC1~NEDD8-CUL1-DCN1) is used to build computer models, and combined quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) and free energy (potential of mean force) simulations are performed to investigate the catalytic mechanism of the NEDD8 transfer from E2 to the lysine residue (K720) on the substrate in the complex...
January 18, 2018: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29334660/global-proteomic-analysis-of-water-buffalo-bubalus-bubalis-saliva-at-different-stages-of-estrous-cycle-using-high-throughput-mass-spectrometry
#11
N G Shashikumar, R K Baithalu, S Bathla, S A Ali, P Rawat, A Kumaresan, S Kumar, B R Maharana, G Singh, D S Puneeth Kumar, S K Singh, S S Lathwal, L Jaiswal, T K Mohanty, A K Mohanty
Accurate and efficient detection of estrus is one of the major constraints for exploitation of the production potential of buffalo owing to its poor manifestation of estrus signs, seasonal differences in expression and higher incidences of silent estrus (29%). The current study focused on identification of estrus specific candidate proteins in saliva of buffaloes. Estrus was detected based on behavioral signs in response to the teaser and changes in reproductive organs and confirmed by per-rectal examination, trans-rectal USG of reproductive organs, cervico-vaginal mucus characteristics and blood serum progesterone estimation...
January 9, 2018: Theriogenology
https://www.readbyqxmd.com/read/29331584/protein-neddylation-and-its-alterations-in-human-cancers-for-targeted-therapy
#12
REVIEW
Lisha Zhou, Wenjuan Zhang, Yi Sun, Lijun Jia
Neddylation, a post-translational modification that conjugates an ubiquitin-like protein NEDD8 to substrate proteins, is an important biochemical process that regulates protein function. The best-characterized substrates of neddylation are the cullin subunits of Cullin-RING ligases (CRLs), which, as the largest family of E3 ubiquitin ligases, control many important biological processes, including tumorigenesis, through promoting ubiquitylation and subsequent degradation of a variety of key regulatory proteins...
January 10, 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29327103/1h-13c-and-15n-resonance-assignments-of-nedd8-from-trypanosoma-brucei
#13
Rui Wang, Jiahai Zhang, Shanhui Liao, Xiaoming Tu
Neural precursor cell-expressed, developmently downregulated 8 (NEDD8) is a small ubiquitin-like modifier, which plays important roles in many cellular processes. Although it has been well studied in many eukaryotes, NEDD8 is still uncharacterized in some unicellular parasites, such as Trypanosoma brucei (T. brucei). Here we report the resonance assignments of NEDD8 from T. brucei.
January 11, 2018: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/29321163/antitumor-effects-of-blocking-protein-neddylation-in-t315i-bcr-abl-leukemia-cells-and-leukemia-stem-cells
#14
Chang Liu, Danian Nie, Juan Li, Xin Du, Yuhong Lu, Yangqiu Li, Jingfeng Zhou, Yanli Jin, Jingxuan Pan
Imatinib (IM) revolutionized the treatment of chronic myeloid leukemia (CML) but drug resistance and disease recurrence remain a challenge. In this study, we suggest a novel strategy based on blocking protein neddylation to address BCR-ABL point mutations and leukemia stem cells (LSCs) that lie at the root of IM-resistant recurrences. Based on the finding that the NEDD8-activating enzyme subunit NAE1 is overexpressed in CML cells, we hypothesized that the function of certain neddylation-dependent protein substrates might be targeted to therapeutic ends in IM-resistant CML cells and LSCs...
January 10, 2018: Cancer Research
https://www.readbyqxmd.com/read/29301501/inhibition-of-neddylation-facilitates-cell-migration-through-enhanced-phosphorylation-of-caveolin-1-in-pc3-and-u373mg-cells
#15
Sung Yeon Park, Jong-Wan Park, Gun-Woo Lee, Lan Li, Yang-Sook Chun
BACKGROUND: Protein neddylation is a post-translational modification by a covalent conjugation with the neural precursor cell expressed, developmentally downregulated 8 (NEDD8). Although this process has been reported to participate in diverse cellular signaling, little is known about its role in cancer cell migration. Given a recent proteomics report showing that NEDD8 is downregulated in prostate cancer tissues versus normal prostate tissues, we tested the possibility that neddylation plays a role in cancer evolution, and then tried to identify target proteins of the neddylation...
January 5, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29248752/inhibition-of-neddylation-pathway-represses-influenza-virus-replication-and-pro-inflammatory-responses
#16
Haiwei Sun, Wei Yao, Kai Wang, Yingjuan Qian, Hongjun Chen, Yong-Sam Jung
The neddylation pathway belongs post-translational modifications and plays important roles in regulating viral infection and replication. To address the relationship of influenza A virus with the neddylation modification pathway, we demonstrate that IAV infection in A549 cells can activate the neddylation modification pathway to increase virus growth and enhance the expression of pro-inflammatory cytokines to increase pathogenicity. The pre-treatment of Nedd8-activating enzyme subunit 1 (NAE1)-specific inhibitor, MLN4924, interferes with Nedd8 conjugation and NF-κB activity...
December 14, 2017: Virology
https://www.readbyqxmd.com/read/29233834/the-arabidopsis-alf4-protein-is-a-regulator-of-scf-e3-ligases
#17
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
#18
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
#19
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
#20
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
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