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Neddylation

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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/29667067/a-first-in-class-inhibitor-mln4924-pevonedistat-induces-cell-cycle-arrest-senescence-and-apoptosis-in-human-renal-cell-carcinoma-by-suppressing-ube2m-dependent-neddylation-modification
#2
Bo Xu, Yuyou Deng, Ran Bi, Haoran Guo, Chang Shu, Neelam Kumari Shah, Junliang Chang, Guanchen Liu, Yujun Du, Wei Wei, Chunxi Wang
PURPOSE: MLN4924 is a second-generation inhibitor that targets ubiquitin-proteasome system by inhibiting neddylation activation enzyme (NAE), and subsequently blocking the neddylation-dependent activation of Cullin-RING E3 ligases (CRLs), which leads to the accumulation of CRLs substrates and hence, suppressing diverse tumor development. In this study, we investigated the potential application of this first-in-class inhibitor MLN4924 in the treatment of human renal cell carcinoma both in vitro and in vivo...
April 17, 2018: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29610291/the-need-for-neddylation-a-key-to-achieving-ned-in-uveal-melanoma
#3
Jessica Yang, Omid Hamid, Richard D Carvajal
The ability of uveal melanoma cells to enter and exit dormancy plays a fundamental role in the development of metastatic disease.  Neddylation blockade is a promising strategy to prolong tumor dormancy via impaired angiogenesis and prevent the establishment of metastases via elimination of cancer stem-like cells.
April 2, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29547696/piperidinyl-ureas-chemically-control-defective-in-cullin-neddylation-1-dcn1-mediated-cullin-neddylation
#4
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
#5
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/29541423/role-of-novel-histone-modifications-in-cancer
#6
REVIEW
Muthu K Shanmugam, Frank Arfuso, Surendar Arumugam, Arunachalam Chinnathambi, Bian Jinsong, Sudha Warrier, Ling Zhi Wang, Alan Prem Kumar, Kwang Seok Ahn, Gautam Sethi, Manikandan Lakshmanan
Oncogenesis is a multistep process mediated by a variety of factors including epigenetic modifications. Global epigenetic post-translational modifications have been detected in almost all cancers types. Epigenetic changes appear briefly and do not involve permanent changes to the primary DNA sequence. These epigenetic modifications occur in key oncogenes, tumor suppressor genes, and transcription factors, leading to cancer initiation and progression. The most commonly observed epigenetic changes include DNA methylation, histone lysine methylation and demethylation, histone lysine acetylation and deacetylation...
February 16, 2018: Oncotarget
https://www.readbyqxmd.com/read/29450620/targeting-the-neddylation-pathway-in-cells-as-a-potential-therapeutic-approach-for-diseases
#7
REVIEW
Jie Ying, Miaomiao Zhang, Xiaoyan Qiu, Yu Lu
The ubiquitin-proteasome system (UPS) is an important system that regulates the balance of intracellular proteins, and it is involved in the regulation of multiple vital biological processes. The approval of bortezomib for relapsed and refractory multiple myeloma has proven that agents targeting the UPS have the potential to be effective treatment strategies for diseases. Among of all of the components of the UPS, cullin-RING ligases (CRLs) are the focus of research. CRLs are the largest family of ubiquitin E3 ligases and they play a critical role in substrate binding...
February 15, 2018: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29438612/high-affinity-peptidomimetic-inhibitors-of-the-dcn1-ubc12-protein-protein-interaction
#8
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/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/29375125/inhibition-of-neddylation-ameliorates-dss-induced-colitis
#11
Ping Wan, Xiao-Dan Zhu, Xiao-Peng Liu, Tao Yu, Run-Wei Yan, Yuan Guo, Ai-Ping Bai
No abstract text is available yet for this article.
January 29, 2018: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/29355077/the-cop9-signalosome-inhibits-cullin-ring-e3-ubiquitin-ligases-independently-of-its-deneddylase-activity
#12
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/29331584/protein-neddylation-and-its-alterations-in-human-cancers-for-targeted-therapy
#13
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/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 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
#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...
January 15, 2018: Virology
https://www.readbyqxmd.com/read/29233905/neddylation-blockade-diminishes-hepatic-metastasis-by-dampening-cancer-stem-like-cells-and-angiogenesis-in-uveal-melanoma
#17
Yanli Jin, Ping Zhang, Yun Wang, Bei Jin, Jingfeng Zhou, Jing Zhang, Jingxuan Pan
PURPOSE: Liver metastasis is the major and direct cause of death in patients with uveal melanoma (UM). There is no effective therapy for patients with metastatic UM. Improved treatments of hepatic metastatic patients with UM were urgently needed. Inspired by readily detectable key components in neddylation pathway in UM cells, we aimed at exploring whether neddylation pathway was a therapeutic target for liver metastatic UM. EXPERIMENTAL DESIGN: Expression of key proteins in neddylation pathway in UM was detected by Western blotting, real-time quantitative RT-PCR (qRT-PCR), and immunohistochemical staining...
December 12, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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...
January 1, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29176748/roles-of-neddylation-against-viral-infections
#19
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
#20
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
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