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https://www.readbyqxmd.com/read/29670864/mechanism-of-apoptosis-induction-by-mycoplasmal-nuclease-mga_0676-in-chicken-embryo-fibroblasts
#1
Peng Li, Jian Xu, Hong-Mei Rao, Xia Li, Yun-Ke Zhang, Fei Jiang, Wen-Xue Wu
MGA_0676 has been characterized as a Mycoplasma gallisepticum nuclease that can induce apoptosis of chicken cells. However, the mechanism by which MGA_0676 induces apoptosis has remained unclear. In this study, we evaluated MGA_0676-induced apoptosis and internalization in immortalized chicken embryo fibroblasts (DF-1) and cancer cell lines. The internalization of MGA_0676 was proven through caveolin-mediated endocytosis by blocking the endocytosis with specific inhibitors or with siRNA. We identified the Thif domain of NEDD8-activating enzyme E1 regulatory subunit (NAE) in DF-1 as the target region interacting with the SNC domain of MGA_0676...
2018: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/29547696/piperidinyl-ureas-chemically-control-defective-in-cullin-neddylation-1-dcn1-mediated-cullin-neddylation
#2
Jared T Hammill, Daniel C Scott, Jaeki Min, Michele C Connelly, Gloria Holbrook, Fangyi Zhu, Amy Matheny, Lei Yang, Bhuvanesh Singh, Brenda A Schulman, R Kiplin Guy
We previously discovered and validated a class of piperidinyl ureas that regulate defective in cullin neddylation 1 (DCN1)-dependent neddylation of cullins. Here, we report preliminary structure-activity relationship studies aimed at advancing our high-throughput screen hit into a tractable tool compound for dissecting the effects of acute DCN1-UBE2M inhibition on the NEDD8/cullin pathway. Structure-enabled optimization led to a 100-fold increase in biochemical potency and modestly increased solubility and permeability as compared to our initial hit...
March 16, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29547693/discovery-of-an-orally-bioavailable-inhibitor-of-defective-in-cullin-neddylation-1-dcn1-mediated-cullin-neddylation
#3
Jared T Hammill, Deepak Bhasin, Daniel C Scott, Jaeki Min, Yizhe Chen, Yan Lu, Lei Yang, Ho Shin Kim, Michele C Connelly, Courtney Hammill, Gloria Holbrook, Cynthia Jeffries, Bhuvanesh Singh, Brenda A Schulman, R Kiplin Guy
We previously reported the discovery, validation, and structure-activity relationships of a series of piperidinyl ureas that potently inhibit the DCN1-UBE2M interaction. We demonstrated that compound 7 inhibits both the DCN1-UBE2M protein-protein interaction and DCN1-mediated cullin neddylation in biochemical assays and reduces levels of steady-state cullin neddylation in a squamous carcinoma cell line harboring DCN1 amplification. Although compound 7 exhibits good solubility and permeability, it is rapidly metabolized in microsomal models (CLint = 170 mL/min/kg)...
March 16, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29513006/top-down-analysis-of-branched-proteins-using-mass-spectrometry
#4
Dapeng Chen, Fabio Gomes, Dulith Abeykoon, Betsegaw Lemma, Yan Wang, David Fushman, Catherine Fenselau
Post-translational modifications by the covalent attachment of Rub1 (NEDD8), ubiquitin, SUMO, and other small signaling proteins have profound impacts on the functions and fates of cellular proteins. Investigations of the relationship of these bioactive structures and their functions are limited by analytical methods that are scarce and tedious. A novel strategy is reported here for the analysis of branched proteins by top-down mass spectrometry and illustrated by application to four recombinant proteins and one synthetic peptide modified by covalent bonds with ubiquitin or Rub1...
March 7, 2018: Analytical Chemistry
https://www.readbyqxmd.com/read/29499133/cand1-mediated-adaptive-exchange-mechanism-enables-variation-in-f-box-protein-expression
#5
Xing Liu, Justin M Reitsma, Jennifer L Mamrosh, Yaru Zhang, Ronny Straube, Raymond J Deshaies
Skp1⋅Cul1⋅F-box (SCF) ubiquitin ligase assembly is regulated by the interplay of substrate binding, reversible Nedd8 conjugation on Cul1, and the F-box protein (FBP) exchange factors Cand1 and Cand2. Detailed investigations into SCF assembly and function in reconstituted systems and Cand1/2 knockout cells informed the development of a mathematical model for how dynamical assembly of SCF complexes is controlled and how this cycle is coupled to degradation of an SCF substrate. Simulations predicted an unanticipated hypersensitivity of Cand1/2-deficient cells to FBP expression levels, which was experimentally validated...
March 1, 2018: Molecular Cell
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29355077/the-cop9-signalosome-inhibits-cullin-ring-e3-ubiquitin-ligases-independently-of-its-deneddylase-activity
#13
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-inhibitor-combined-with-azacitidine-in-patients-with-aml
#14
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 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-naive 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/subcutaneously) on days 1 to 5, 8, and 9, every 28 days...
March 29, 2018: Blood
https://www.readbyqxmd.com/read/29345925/catalytic-mechanism-of-the-ubiquitin-like-nedd8-transfer-in-ring-e3-e2%C3%A2-nedd8-target-complex-from-qm-mm-free-energy-simulations
#15
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...
February 26, 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
#16
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...
April 1, 2018: Theriogenology
https://www.readbyqxmd.com/read/29331584/protein-neddylation-and-its-alterations-in-human-cancers-for-targeted-therapy
#17
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...
April 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29327103/-1-h-13-c-and-15-n-resonance-assignments-of-nedd8-from-trypanosoma-brucei
#18
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.
April 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
#19
Chang Liu, Danian Nie, Juan Li, Xin Du, Yuhong Lu, Yangqiu Li, Jingfeng Zhou, Yanli Jin, Jingxuan Pan
Imatinib 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 (LSC) that lie at the root of imatinib-resistant recurrences. On the basis of 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 imatinib-resistant CML cells and LSCs...
March 15, 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
#20
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
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