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MLN4924

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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
#1
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
#2
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/28986259/inhibition-of-constitutive-nf-%C3%AE%C2%BAb-activity-induces-platelet-apoptosis-via-er-stress
#3
Manoj Paul, Kempaiah Kemparaju, Kesturu S Girish
Platelets are anucleate cells, known for their pivotal roles in hemostasis, inflammation, immunity, and disease progression. Being anuclear, platelets are known to express several transcriptional factors which exert nongenomic functions, including the positive and negative regulation of platelet activation. NF-κB is one such transcriptional factor involved in the regulation of genes for survival, proliferation, inflammation and immunity. Although, the role NF-κB in platelet activation and aggregation is partially known, its function in management of platelet survival and apoptosis remain unexplored...
December 2, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28939057/the-cks1-cks2-axis-fine-tunes-mll1-expression-and-is-crucial-for-mll-rearranged-leukaemia-cell-viability
#4
William Grey, Adam Ivey, Thomas A Milne, Torsten Haferlach, David Grimwade, Frank Uhlmann, Edwige Voisset, Veronica Yu
The Cdc28 protein kinase subunits, Cks1 and Cks2, play dual roles in Cdk-substrate specificity and Cdk-independent protein degradation, in concert with the E3 ubiquitin ligase complexes SCF(Skp2) and APC(Cdc20). Notable targets controlled by Cks include p27 and Cyclin A. Here, we demonstrate that Cks1 and Cks2 proteins interact with both the Mll(N) and Mll(C) subunits of Mll1 (Mixed-lineage leukaemia 1), and together, the Cks proteins define Mll1 levels throughout the cell cycle. Overexpression of CKS1B and CKS2 is observed in multiple human cancers, including various MLL-rearranged (MLLr) AML subtypes...
September 20, 2017: Biochimica et Biophysica Acta
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
#5
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/28838998/the-neddylation-inhibitor-pevonedistat-mln4924-suppresses-and-radiosensitizes-head-and-neck-squamous-carcinoma-cells-and-tumors
#6
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/28717191/mln4924-pevonedistat-a-protein-neddylation-inhibitor-suppresses-proliferation-and-migration-of-human-clear-cell-renal-cell-carcinoma
#7
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
#8
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
#9
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
#10
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/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
#11
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
https://www.readbyqxmd.com/read/28599312/cullin-3spop-ubiquitin-e3-ligase-promotes-the-poly-ubiquitination-and-degradation-of-hdac6
#12
Yuyong Tan, Yanpeng Ci, Xiangpeng Dai, Fei Wu, Jianping Guo, Deliang Liu, Brian J North, Jirong Huo, Jinfang Zhang
The histone deacetylase 6 (HDAC6) plays critical roles in human tumorigenesis and metastasis. As such, HDAC6-selective inhibitors have entered clinical trials for cancer therapy. However, the upstream regulator(s), especially ubiquitin E3 ligase(s), responsible for controlling the protein stability of HDAC6 remains largely undefined. Here, we report that Cullin 3SPOP earmarks HDAC6 for poly-ubiquitination and degradation. We found that the proteasome inhibitor MG132, or the Cullin-based E3 ligases inhibitor MLN4924, but not the autophagosome-lysosome inhibitor bafilomycin A1, stabilized endogenous HDAC6 protein in multiple cancer cell lines...
July 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28569775/promoting-tumorigenesis-in-nasopharyngeal-carcinoma-nedd8-serves-as-a-potential-theranostic-target
#13
Ping Xie, Jun-Ping Yang, Yun Cao, Li-Xia Peng, Li-Sheng Zheng, Rui Sun, Dong-Fang Meng, Meng-Yao Wang, Yan Mei, Yuan-Yuan Qiang, Li Cao, Yan-Qun Xiang, Dong-Hua Luo, Jing-Ping Yun, Bi-Jun Huang, Li-Jun Jia, Chao-Nan Qian
Nasopharyngeal carcinoma (NPC), is one of the most common human malignancies in south China, it has the highest recurrence rate and treatment resistance. The underlying molecular mechanisms of NPC relapse and treatment tolerance are not fully understood. In this study, the effects of NEDD8 and NEDD8-activating enzyme inhibitor (MLN4924) on NPC were studied both in vitro and in vivo. Immunohistochemical staining of 197 NPC tissues revealed an elevated NEDD8 expression as an unfavorable independent factor in overall survival and disease-free survival rates...
June 1, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28535453/inhibition-of-neddylation-modification-sensitizes-pancreatic-cancer-cells-to-gemcitabine
#14
Hua Li, Weihua Zhou, Lihui Li, Jianfu Wu, Xiaoli Liu, Lili Zhao, Lijun Jia, Yi Sun
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA with a 5-year survival rate less than 3% to 5%. Gemcitabine remains as a standard care for PDAC patients. Although protein neddylation is abnormally activated in many human cancers, whether neddylation dysregulation is involved in PDAC and whether targeting neddylation would sensitize pancreatic cancer cells to gemcitabine remain elusive. Here we report that high expression of neddylation components, NEDD8 and NAE1, are associated with poor survival of PDAC patients...
June 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28499918/cul3-neddylation-is-crucial-for-gradual-lipid-droplet-formation-during-adipogenesis
#15
Dawadschargal Dubiel, Willem Bintig, Thilo Kähne, Wolfgang Dubiel, Michael Naumann
Cullin 3 (Cul3) belongs to the family of cullins (Cul1-7) providing the scaffold for cullin-RING ubiquitin (Ub) ligases (CRLs), which are activated by neddylation and represent essential E3 ligases of the Ub proteasome system. During adipogenic differentiation neddylated Cul3 accumulates in LiSa-2 preadipocytes. Downregulation of Cul3 and inhibition of neddylation by MLN4924 blocks the formation of lipid droplets (LDs), the lipid storage organelles and markers of adipogenesis. Neddylation of Cul3 coincides with an increase of Rab18, a GTPase associated with LDs...
August 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28469786/mln4924-protects-against-bleomycin-induced-pulmonary-fibrosis-by-inhibiting-the-early-inflammatory-process
#16
Qi Deng, Jiaojiao Zhang, Yaqun Gao, Xiaofei She, Yunchao Wang, Yilin Wang, Xin Ge
Pulmonary fibrosis is a complex pathological process characterized by massive destruction of the structure of lung tissues and aggravated pulmonary function impairment. The underlying mechanisms of pulmonary fibrosis are incompletely understood and therefore limited treatment options are available currently. Here, we report that MLN4924, an NEDD8 activation enzyme (NAE) activity-inhibiting molecule, blocks the maintenance and progression of established pulmonary fibrosis. We found that MLN4924 acts against bleomycin-induced pulmonary fibrosis mainly at the early inflammatory stage...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28468780/combined-inhibition-of-nedd8-activating-enzyme-and-mtor-suppresses-nf2-loss-driven-tumorigenesis
#17
Jonathan Cooper, Qingwen Xu, Lu Zhou, Milica Pavlovic, Virginia Ojeda, Kamalika Moulick, Elisa de Stanchina, John T Poirier, Marjorie Zauderer, Charles M Rudin, Matthias A Karajannis, C Oliver Hanemann, Filippo G Giancotti
Inactivation of NF2/Merlin causes the autosomal-dominant cancer predisposition syndrome familial neurofibromatosis type 2 (NF2) and contributes to the development of malignant pleural mesothelioma (MPM). To develop a targeted therapy for NF2-mutant tumors, we have exploited the recent realization that Merlin loss drives tumorigenesis by activating the E3 ubiquitin ligase CRL4(DCAF1), thereby inhibiting the Hippo pathway component Lats. Here, we show that MLN4924, a NEDD8-activating enzyme (NAE) inhibitor, suppresses CRL4(DCAF1) and attenuates activation of YAP in NF2-mutant tumor cells...
August 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28450112/nedd8-activating-enzyme-inhibitor-mln4924-pevonedistat-induces-noxa-dependent-apoptosis-through-up-regulation-of-atf-4
#18
Xiaojun Liu, Yanan Jiang, Jianfu Wu, Wenjuan Zhang, Yupei Liang, Lijun Jia, Jinha Yu, L S Jeong, Lihui Li
It has been reported that MLN4924 can inhibit cell growth and metastasis in various kinds of cancer. We have reported that MLN4924 is able to inhibit angiogenesis through the induction of cell apoptosis both in vitro and in vivo models. Moreover, Neddylation inhibition using MLN4924 triggered the accumulation of pro-apoptotic protein NOXA in Human umbilical vein endothelial cells (HUVECs). However, the mechanism of MLN4924-induced NOXA up-regulation has not been addressed in HUVECs yet. In this study, we investigated how MLN4924 induced NOXA expression and cellular apoptosis in HUVECs treated with MLN4924 at indicated concentrations...
June 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28447739/neural-precursor-cell-expressed-developmentally-downregulated-8%C3%A2-activating-enzyme-inhibitor-mln4924-sensitizes-colorectal-cancer-cells-to-oxaliplatin-by-inducing-dna-damage-g2-cell-cycle-arrest-and-apoptosis
#19
Wanwei Zheng, Zhongguang Luo, Jun Zhang, Pei Min, Wenshuai Li, Diannan Xu, Ziqiang Zhang, Panpan Xiong, Hong Liang, Jie Liu
Oxaliplatin-based chemotherapy is a primary treatment for patients with metastatic colorectal cancer (CRC); however, its efficacy is limited. Therefore, novel therapeutic agents are urgently required. MLN4924 is a first‑in‑class inhibitor of neural precursor cell expressed, developmentally downregulated 8 (NEDD8)‑activating enzyme E1, and has entered various phase‑I/II clinical trials for cancer therapy due to its significant anticancer efficacy. The aim of the present study was to examine the synergistic effect and underlying mechanisms of MLN4924 and oxaliplatin combined treatment for CRC...
May 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28297583/assessment-of-drug-sensitivity-in-hematopoietic-stem-and-progenitor-cells-from-acute-myelogenous-leukemia-and-myelodysplastic-syndrome-ex-vivo
#20
Katherine L B Knorr, Laura E Finn, B Douglas Smith, Allan D Hess, James M Foran, Judith E Karp, Scott H Kaufmann
Current understanding suggests that malignant stem and progenitor cells must be reduced or eliminated for prolonged remissions in myeloid neoplasms such as acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Multicolor flow cytometry has been widely used to distinguish stem and myeloid progenitor cells from other populations in normal and malignant bone marrow. In this study, we present a method for assessing drug sensitivity in MDS and AML patient hematopoietic stem and myeloid progenitor cell populations ex vivo using the investigational Nedd8-activating enzyme inhibitor MLN4924 and standard-of-care agent cytarabine as examples...
March 2017: Stem Cells Translational Medicine
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