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Hiroyuki Sumi, Masakazu Inazuka, Megumi Morimoto, Ryosuke Hibino, Kentaro Hashimoto, Tomoyasu Ishikawa, Keisuke Kuida, Peter G Smith, Sei Yoshida, Masato Yabuki
Inhibitors of apoptosis proteins (IAPs) are antiapoptotic regulators that block cell death, and are frequently overexpressed in several human cancers, where they facilitate evasion of apoptosis and promote cell survival. IAP antagonists are also known as second mitochondria-derived activator of caspase (SMAC)-mimetics, and have recently been considered as novel therapeutic agents for inducing apoptosis, alone and in combination with other anticancer drugs. In this study, we showed that T-3256336, the orally available IAP antagonist has synergistically enhances the antiproliferative effects of the NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924), and these effects were attenuated by a TNFα-neutralizing antibody...
October 19, 2016: Biochemical and Biophysical Research Communications
Stefan F Ehrentraut, Valerie F Curtis, Ruth X Wang, Bejan J Saeedi, Heidi Ehrentraut, Joseph C Onyiah, Caleb J Kelly, Eric L Campbell, Louise E Glover, Douglas J Kominsky, Sean P Colgan
Recent work has revealed a central role for neddylation (the conjugation of a Nedd8-moiety to Cullin proteins) in the fine tuning of the NF-κB response (via Cullin-1). In the present study, we investigated the contribution of Cullin-1 neddylation and NF-κB signaling to mucosal inflammatory responses in vitro and in vivo. Initial in vitro studies using cultured intestinal epithelial cells revealed that the neddylation inhibitor MLN4924 prominently induces the deneddylation of Cullin-1. Parallel western blot, luciferase reporter and gene target assays identified MLN4924 as a potent inhibitor of intestinal epithelial NF-κB...
September 28, 2016: Molecular Biology of the Cell
Shuju Zhang, Jiaming Zhang, Zhiyuan Deng, Huadie Liu, Wei Mao, Fang Jiang, Zanxian Xia, Jia-Da Li
The anticancer small molecule MLN4924, a Nedd8-activating enzyme (NAE) inhibitor, triggers cell-cycle arrest, apoptosis, and senescence in cancer cells. In this study, we demonstrate that MLN4924 suppresses osteosarcoma cell proliferation by inducing G2/M cell cycle arrest and apoptosis. Our results indicate that MLN4924 stabilizes the retinoid orphan nuclear receptor alpha (RORα) by decreasing its ubiquitination. RNA interference of RORα attenuates the anti-proliferative effect of MLN4924 in U2OS osteosarcoma cells...
September 1, 2016: Oncotarget
Xueying Zhang, Zhenjie Ye, Yujun Pei, Guihua Qiu, Qingyang Wang, Yunlu Xu, Beifen Shen, Jiyan Zhang
Type I interferons such as interferon-beta (IFN-β) play essential roles in the host innate immune response to herpes simplex virus type I (HSV-1) infection. The transcription of type I interferon genes is controlled by nuclear factor-κB (NF-κB) and interferon regulatory factor (IRF) family members including IRF3. NF-κB activation depends on the phosphorylation of inhibitor of κB (IκB), which triggers its ubiqitination and degradation. It has been reported that neddylation inhibition by a pharmacological agent MLN4924 potently suppresses lipopolysaccharide (LPS)-induced proinflammatory cytokine production with the accumulation of phosphorylated IκBα...
September 2016: Cellular & Molecular Immunology
Nathan D Mathewson, Hideaki Fujiwara, Shin-Rong Wu, Tomomi Toubai, Katherine Oravecz-Wilson, Yaping Sun, Corinne Rossi, Cynthia Zajac, Yi Sun, Pavan Reddy
Neddylation is a crucial post-translational modification that depends on the E3 cullin ring ligase (CRL). The E2-adapter component of the CRL, sensitive to apoptosis gene (SAG), is critical for the function of CRL-mediated ubiquitination; thus, the deletion of SAG regulates neddylation. We examined the role of SAG-dependent neddylation in T-cell-mediated immunity using multiple approaches: a novel T-cell-specific, SAG genetic knockout (KO) and chemical inhibition with small-molecule MLN4924. The KO animals were viable and showed phenotypically normal mature T-cell development...
October 2016: American Journal of Pathology
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No abstract text is available yet for this article.
August 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Yanling Yan, Fang Huang, Ting Yuan, Binlian Sun, Rongge Yang
Coinfection of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) occurs at a high frequency, in which HIV shows a promotion of HCV-derived liver diseases. However, the mechanism of how this occurs is not well understood. Our previous work has demonstrated that the HIV-1 accessory protein Vpr enhances HCV RNA replication in cell culture. Because Vpr performs most of its functions through host protein VprBP (DCAF1), the role of VprBP in the regulation of HCV by Vpr was investigated in this study...
September 2, 2016: Virus Research
A C Andérica-Romero, J Hernández-Damián, G I Vázquez-Cervantes, I Torres, Irma Gabriela González-Herrera, J Pedraza-Chaverri
No abstract text is available yet for this article.
July 4, 2016: Redox Biology
Mouadh Benamar, Fadila Guessous, Kangping Du, Patrick Corbett, Joseph Obeid, Daniel Gioeli, Craig L Slingluff, Tarek Abbas
UNLABELLED: The cullin-based CRL4-CDT2 ubiquitin ligase is emerging as a master regulator of cell proliferation. CRL4-CDT2 prevents re-initiation of DNA replication during the same cell cycle "rereplication" through targeted degradation of CDT1, SET8 and p21 during S-phase of the cell cycle. We show that CDT2 is overexpressed in cutaneous melanoma and predicts poor overall and disease-free survival. CDT2 ablation inhibited a panel of melanoma cell lines through the induction of SET8- and p21-dependent DNA rereplication and senescence...
August 2016: EBioMedicine
Xiaofang Wang, Wenjuan Zhang, Zi Yan, Yupei Liang, Lihui Li, Xiaoli Yu, Yan Feng, Shen Fu, Yanmei Zhang, Hu Zhao, Jinha Yu, Lak Shin Jeong, Xiaomao Guo, Lijun Jia
Salvage radiotherapy (SRT) is the first-line treatment for prostate cancer patients with biochemical recurrence following radical prostatectomy, and new specific radiosensitizers are in urgent need to enhance SRT effect. MLN4924 (also known as Pevonedistat), a specific inhibitor of NEDD8-activating enzyme, has recently entered phase I/II clinical trials in several malignancies. By inhibiting cullin neddylation, MLN4924 inactivates Cullin-RING ligases (CRL), which have been validated as an attractive radiosensitizing target...
May 20, 2016: Oncotarget
Yi Zhang, Cheng-Cheng Shi, Hua-Peng Zhang, Gong-Quan Li, Shan-Shan Li
Neddylation is a post-translational protein modification process associated with carcinogenesis and cancer development. MLN4924, a pharmaceutical neddylation inhibitor, induces potent anti-cancer effects in multiple types of cancers. In this study, we investigated the effects of MLN4924 on human osteosarcoma (OS). Levels of both NEDD8 activating enzyme E1 (NAE1) and ubiquitin-conjugating enzyme E2M (Ube2M), two critical components of the neddylation pathway, were much higher in OS tissues and cells than in normal osseous tissues and cells...
May 19, 2016: Oncotarget
Xiaochen Zhou, Mingjia Tan, Mukesh K Nyati, Yongchao Zhao, Gongxian Wang, Yi Sun
MLN4924, also known as pevonedistat, is the first-in-class inhibitor of NEDD8-activating enzyme, which blocks the entire neddylation modification of proteins. Previous preclinical studies and current clinical trials have been exclusively focused on its anticancer property. Unexpectedly, we show here, to our knowledge for the first time, that MLN4924, when applied at nanomolar concentrations, significantly stimulates in vitro tumor sphere formation and in vivo tumorigenesis and differentiation of human cancer cells and mouse embryonic stem cells...
May 24, 2016: Proceedings of the National Academy of Sciences of the United States of America
Huiyin Lan, Zaiming Tang, Hongchuan Jin, Yi Sun
MLN4924 is a recently discovered small molecule inhibitor of NEDD8-Activating Enzyme (NAE). Because cullin RING ligase (CRL), the largest family of E3 ubiquitin ligase, requires cullin neddylation for its activity, MLN4924, therefore, acts as an indirect inhibitor of CRL by blocking cullin neddylation. Given that CRLs components are up-regulated, whereas neddylation modification is over-activated in a number of human cancers, MLN4924 was found to be effective in growth suppression of cancer cells. Whether MLN4924 is effective against gastric cancer cells, however, remains elusive...
2016: Scientific Reports
Shailender Bhatia, Anna C Pavlick, Peter Boasberg, John A Thompson, George Mulligan, Michael D Pickard, Hélène Faessel, Bruce J Dezube, Omid Hamid
Purpose The therapeutic index of proteasome inhibitors may be improved through selective inhibition of a sub-component of the ubiquitin-proteasome system, such as the NEDD8-conjugation pathway. This multicenter, phase I, dose-escalation study assessed safety and the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of pevonedistat, an investigational NEDD8-activating enzyme (NAE) inhibitor, in patients with metastatic melanoma. Methods Patients received intravenous pevonedistat on Days 1, 4, 8, 11 (schedule A) or 1, 8, 15 (schedule B) of 21-day cycles...
August 2016: Investigational New Drugs
Kun Han, Qingyang Wang, Huanling Cao, Guihua Qiu, Junxia Cao, Xin Li, Jing Wang, Beifen Shen, Jiyan Zhang
The first-in-class compound MLN4924 is a small molecule inhibitor that selectively inactivates NEDD8-activating enzyme (NAE). The anticancer effects of MLN4924 have been attributed to impaired neddylation of Cullin proteins. Here, we show that treatment of T-cell acute lymphoblastic leukemia (T-ALL) cells with MLN4924 potently suppressed the neddylation of Cullins and the oncogenic growth of T-ALL cells in-vitro. Moreover, MLN4924 induced disease regression in an in vivo xenograft model. MLN4924 also induced cell cycle arrest at G2 phase and apoptosis in T-ALL cells...
April 26, 2016: Oncotarget
H-S Park, U-I Ju, J-W Park, J Y Song, D H Shin, K-H Lee, L S Jeong, J Yu, H W Lee, J Y Cho, S Y Kim, S W Kim, J B Kim, K S Park, Y-S Chun
The preadipocyte-to-adipocyte differentiation (adipogenesis) is a key process in fat mass increase and thus it is regarded as a compelling target for preventing or treating obesity. Of adipogenic hormone receptors, peroxisome proliferator-activated receptor gamma (PPARγ) has crucial roles in adipogenesis and lipid accumulation within adipocytes. Here we demonstrate that the NEDD8 (neuronal precursor cell expressed, developmentally downregulated 8)-based post-translation modification (neddylation) of PPARγ is essential for adipogenesis...
August 2016: Cell Death and Differentiation
Ping Chen, Tao Hu, Yupei Liang, Pei Li, Xiaoyu Chen, Jingyang Zhang, Yangcheng Ma, Qianyun Hao, Jinwu Wang, Ping Zhang, Yanmei Zhang, Hu Zhao, Shengli Yang, Jinha Yu, Lak Shin Jeong, Hui Qi, Meng Yang, Robert M Hoffman, Ziming Dong, Lijun Jia
PURPOSE: Targeting the protein neddylation pathway has become an attractive anticancer strategy; however, the role of death receptor-mediated extrinsic apoptosis during treatment remained to be determined. EXPERIMENTAL DESIGN: The activation of extrinsic apoptosis and its role in MLN4924 treatment of human esophageal squamous cell carcinoma (ESCC) were evaluated both in vitro and in vivo The expression of the components of extrinsic apoptotic pathway was determined by immunoblotting analysis and downregulated by siRNA silencing for mechanistic studies...
August 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Paul C Scherer, Yan Ding, Zhiqing Liu, Jing Xu, Haibin Mao, James C Barrow, Ning Wei, Ning Zheng, Solomon H Snyder, Feng Rao
The family of cullin-RING E3 Ligases (CRLs) and the constitutive photomorphogenesis 9 (COP9) signalosome (CSN) form dynamic complexes that mediate ubiquitylation of 20% of the proteome, yet regulation of their assembly/disassembly remains poorly understood. Inositol polyphosphates are highly conserved signaling molecules implicated in diverse cellular processes. We now report that inositol hexakisphosphate (IP6) is a major physiologic determinant of the CRL-CSN interface, which includes a hitherto unidentified electrostatic interaction between the N-terminal acidic tail of CSN subunit 2 (CSN2) and a conserved basic canyon on cullins...
March 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
Ana Cristina Andérica-Romero, Jacqueline Hernández-Damián, Gustavo Ignacio Vázquez-Cervantes, Ismael Torres, José Pedraza-Chaverri
It was explored the cytoprotective and antioxidant effect of MLN4924, a specific inhibitor of Nedd8-activating enzyme (NAE), against hydrogen peroxide (H2O2)-induced damage in cerebellar granule neurons (CGNs). Primary cultures of CGNs were exposed to H2O2 after preincubation with MLN4924. The compounds were removed, and CGNs were incubated in culture medium for 24h in order to determine cell viability by 3-[4,5-dimethylthiazol-2-yl)]-2,5-diphenyl-tetrazolium bromide (MTT) and fluorescein diacetate (FDA) assays...
August 2016: Redox Biology
Hui Song, Wanwan Huai, Zhongxia Yu, Wenwen Wang, Jing Zhao, Lining Zhang, Wei Zhao
Neddylation is a posttranslational protein modification that conjugates ubiquitin-like protein neural precursor cell-expressed developmentally downregulated protein 8 (NEDD8) to target proteins and regulates diverse cellular processes. MLN4924, a novel NEDD8 activating enzyme inhibitor, which has emerged as a promising anticancer drug, has a multifaceted function by inhibiting the process of neddylation. However, the potential roles of MLN4924 and neddylation in IFN-β production remain unknown. In this study, we show that MLN4924 inhibits TLR3/4- and retinoic acid-inducible gene-I-induced IFN-β expression in different cells, whereas NEDD8 knockdown had no effects on IFN-β expression...
April 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
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