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https://www.readbyqxmd.com/read/28522566/nedd8-modification-of-cullin-5-regulates-lipopolysaccharide-induced-acute-lung-injury
#1
Ziyan Zhu, Lei Sun, Rui Hao, Hongchao Jiang, Feng Qian, Richard D Ye
Lung infections are major causes of acute lung injury (ALI), with limited effective treatment available. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an essential adaptor regulating Toll-like receptors (TLRs). We recently identified Cullin-5 (Cul-5) as a prominent component in the regulation of TRAF6 polyubiquitination, but its physiological significance in acute lung injury has not been explored. In this study, we investigated the potential role of Cul-5 in regulating ALI using mice receiving intratracheal instillation of LPS...
May 18, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28516844/clues-for-two-step-virion-infectivity-factor-regulation-by-core-binding-factor-beta
#2
Youwei Ai, Jianzhang Ma, Xiaojun Wang
Lentiviruses threaten human and animal health. Virion infectivity factor (Vif) is essential for the infectivity of most lentiviruses, except for the equine infectious anaemia virus (EIAV). Vif promotes viral infectivity by recruiting a Cullin-based E3 ligase to induce the degradation of a class of host restriction factors, named APOBEC3. Core binding factor beta (CBF-β) is necessary for several primate lentiviral Vif functions, including HIV-1 Vif. Although much progress has been made in understanding the contribution of CBF-β to Vif function, the precise mechanism has not yet been fully elucidated...
May 18, 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28499918/cul3-neddylation-is-crucial-for-gradual-lipid-droplet-formation-during-adipogenesis
#3
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...
May 9, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28494021/rice-black-streaked-dwarf-virus-p7-2-forms-a-scf-complex-through-binding-to-oryza-sativa-skp1-like-proteins-and-interacts-with-gid2-involved-in-the-gibberellin-pathway
#4
Tao Tao, Cui-Ji Zhou, Qian Wang, Xiang-Ru Chen, Qian Sun, Tian-Yu Zhao, Jian-Chun Ye, Ying Wang, Zong-Ying Zhang, Yong-Liang Zhang, Ze-Jian Guo, Xian-Bing Wang, Da-Wei Li, Jia-Lin Yu, Cheng-Gui Han
As a core subunit of the SCF complex that promotes protein degradation through the 26S proteasome, S-phase kinase-associated protein 1 (SKP1) plays important roles in multiple cellular processes in eukaryotes, including gibberellin (GA), jasmonate, ethylene, auxin and light responses. P7-2 encoded by Rice black streaked dwarf virus (RBSDV), a devastating viral pathogen that causes severe symptoms in infected plants, interacts with SKP1 from different plants. However, whether RBSDV P7-2 forms a SCF complex and targets host proteins is poorly understood...
2017: PloS One
https://www.readbyqxmd.com/read/28483055/the-improvement-of-salt-tolerance-in-transgenic-tobacco-by-overexpression-of-wheat-f-box-gene-tafba1
#5
Zhongxian Zhao, Guangqiang Zhang, Shumei Zhou, Yuanqing Ren, Wei Wang
F-box protein is a major subunit of the Skp1-Cullin-F-box (SCF) complex. We previously isolated an F-box gene from wheat, TaFBA1, and here we show that overexpression of TaFBA1 in transgenic plants under salt stress increases germination rate, root elongation, and biomass accumulation compared with WT plants. Improvements in the photosynthetic rate and its corresponding parameters were also found in the transgenic plants. These results suggest that overexpression of TaFBA1 improves salt stress tolerance in transgenic tobacco...
June 2017: Plant Science: An International Journal of Experimental Plant Biology
https://www.readbyqxmd.com/read/28481879/cytoplasmic-e3-ubiquitin-ligase-cul9-controls-cell-proliferation-senescence-apoptosis-and-genome-integrity-through-p53
#6
Z Li, Y Xiong
CUL9 is a member of the cullin family of E3 ubiquitin ligases, and it localizes predominantly in the cytoplasm. Deletion of Cul9 in mice results in increased DNA damage, widespread aneuploidy, spontaneous tumor development, accelerated Eμ-Myc-induced lymphomagenesis and susceptibility to carcinogenesis. CUL9 binds to p53 and causes cell apoptosis when ectopically expressed. Whether the function of CUL9 in maintaining genomic integrity and suppressing tumorigenesis is linked to p53 has not been genetically tested...
May 8, 2017: Oncogene
https://www.readbyqxmd.com/read/28475037/senp8-limits-aberrant-neddylation-of-nedd8-pathway-components-to-promote-cullin-ring-ubiquitin-ligase-function
#7
Kate E Coleman, Miklós Békés, Jessica R Chapman, Sarah B Crist, Mathew Jk Jones, Beatrix M Ueberheide, Tony T Huang
NEDD8 is a ubiquitin-like modifier most well-studied for its role in activating the largest family of ubiquitin E3 ligases, the cullin-RING ligases (CRLs). While many non-cullin neddylation substrates have been proposed over the years, validation of true NEDD8 targets has been challenging, as overexpression of exogenous NEDD8 can trigger NEDD8 conjugation through the ubiquitylation machinery. Here, we developed a deconjugation-resistant form of NEDD8 to stabilize the neddylated form of cullins and other non-cullin substrates...
May 5, 2017: ELife
https://www.readbyqxmd.com/read/28470146/microrna-520b-functions-as-a-tumor-suppressor-in-colorectal-cancer-by-inhibiting-dcun1d1
#8
Jing Xiao, Guang Li, Jingyu Zhou, Shalong Wang, Dongcai Liu, Guoshun Shu, Jianping Zhou, Feng Ren
MicroRNAs (miRs), a class of small non-coding RNAs, are important regulators for gene expression through directly binding to the 3'untranslated region (UTR) of their target mRNA. Recently, downregulation of miR-520b has been observed in several common human cancers. However, the exact role of miR-520b in colorectal cancer (CRC) has not previously been studied. In this study, our data showed that miR-520b was significantly downregulated in CRC and cell lines, when compared with adjacent normal tissues and normal intestinal epithelial cell line, respectively...
May 4, 2017: Oncology Research
https://www.readbyqxmd.com/read/28469786/mln4924-protects-against-bleomycin-induced-pulmonary-fibrosis-by-inhibiting-the-early-inflammatory-process
#9
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
#10
Jonathan Cooper, Qingwen Xu, Lu Zhou, Milica Pavlovic, Virginia Ojeda, Kamalika Moulick, Elisa de Stanchina, J 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). In order 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...
May 3, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28465351/an-hnf4%C3%AE-microrna-194-192-signaling-axis-maintains-hepatic-cell-function
#11
Aoi Morimoto, Mana Kannari, Yuichi Tsuchida, Shota Sasaki, Chinatsu Saito, Tsuyoshi Matsuta, Tsukasa Maeda, Megumi Akiyama, Takahiro Nakamura, Masakiyo Sakaguchi, Nobukazu Nameki, Frank J Gonzalez, Yusuke Inoue
HNF4α controls the expression of liver-specific protein-coding genes. However, some microRNAs (miRNAs) are also modulated by HNF4α, and it is not known whether they are direct targets of HNF4α, and whether they influence the hepatic function. In this study, we found that HNF4α regulates miRNAs, indicated by marked down-regulation of miR-194 and miR-192 (miR-194/192) in liver-specific Hnf4a-null (Hnf4a(ΔH)) mice. Transactivation of the shared miR-194/192 promoter was dependent on HNF4α expression, indicating that miR194/192 is a target gene of HNF4α...
May 2, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28461484/protein-mediated-viral-latency-is-a-novel-mechanism-for-merkel-cell-polyomavirus-persistence
#12
Hyun Jin Kwun, Yuan Chang, Patrick S Moore
Viral latency, in which a virus genome does not replicate independently of the host cell genome and produces no infectious particles, is required for long-term virus persistence. There is no known latency mechanism for chronic small DNA virus infections. Merkel cell polyomavirus (MCV) causes an aggressive skin cancer after prolonged infection and requires an active large T (LT) phosphoprotein helicase to replicate. We show that evolutionarily conserved MCV LT phosphorylation sites are constitutively recognized by cellular Fbw7, βTrCP, and Skp2 Skp-F-box-cullin (SCF) E3 ubiquitin ligases, which degrade and suppress steady-state LT protein levels...
May 1, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28455357/fission-yeast-neddylation-ligase-dcn1-facilitates-cohesin-cleavage-and-chromosome-segregation-at-anaphase
#13
Lan Lin, Li Chen, Phong T Tran
Posttranslational protein modification such as phosphorylation and ubiquitination are critical during mitosis to ensure proper timing and progression of chromosome segregation. It has been recently recognized that another type of protein modification - neddylation - may also regulate mitosis and chromosome segregation. The conserved protein DCN1 (defective cullin neddylation 1) has been shown, when knock-downed by RNAi, to result in multinucleated cells and/or blockage of cell proliferation. However, how DCN1 functions in mitosis and chromosome segregation is not known...
April 28, 2017: Biology Open
https://www.readbyqxmd.com/read/28450112/nedd8-activating-enzyme-inhibitor-mln4924-pevonedistat-induces-noxa-dependent-apoptosis-through-up-regulation-of-atf-4
#14
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
#15
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/28446751/crl4b-dcaf11-e3-ligase-targets-p21-for-degradation-to-control-cell-cycle-progression-in-human-osteosarcoma-cells
#16
Zhi Chen, Kun Wang, Canglong Hou, Kaibiao Jiang, Bin Chen, Jianwei Chen, Lifeng Lao, Lie Qian, Guibin Zhong, Zude Liu, Caiguo Zhang, Hongxing Shen
Cell cycle progression in mammals is strictly controlled by a number of cyclin-dependent kinases (CDKs) and CDK inhibitors (CKIs), the expression of which is often dysregulated in cancer cells. Our previous work revealed that Cullin 4B (CUL4B), a critical component of the Cullin4B-RING E3 ligase complex (CRL4B), is overexpressed in human osteosarcoma cells through an unknown mechanism. Here, we demonstrated that CUL4B forms an E3 ligase with RBX1 (RING-box 1), DDB1 (DNA damage binding protein 1), and DCAF11 (DDB1 and CUL4 associated factor 11) in human osteosarcoma cells...
April 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28442889/cul4a-promotes-cell-invasion-in-gastric-cancer-by-activating-the-nf-%C3%AE%C2%BAb-signaling-pathway
#17
Yu Gong, Xiao-Jun Xiang, Miao Feng, Jun Chen, Zi-Ling Fang, Jian-Ping Xiong
Cullin 4A (CUL4A) overexpression has been reported to be involved in the carcinogenesis and progression of many malignant tumors. However, the role of CUL4A in the progression of gastric cancer (GC) remains unclear. In this study, we explored whether and how CUL4A regulates proinflammatory signaling to promote GC cell invasion. Our results showed that knockdown of CUL4A inhibited GC cell migration and invasion induced by lipopolysaccharide (LPS) stimulation. We also found that both CUL4A and nuclear factor-kappa B (NF-κB) protein expressions were enhanced by LPS stimulation in HGC27 GC cell lines...
2017: Biologics: Targets & Therapy
https://www.readbyqxmd.com/read/28437394/selective-degradation-of-splicing-factor-caper%C3%AE-by-anticancer-sulfonamides
#18
Taisuke Uehara, Yukinori Minoshima, Koji Sagane, Naoko Hata Sugi, Kaoru Ogawa Mitsuhashi, Noboru Yamamoto, Hiroshi Kamiyama, Kentaro Takahashi, Yoshihiko Kotake, Mai Uesugi, Akira Yokoi, Atsushi Inoue, Taku Yoshida, Miyuki Mabuchi, Akito Tanaka, Takashi Owa
Target-protein degradation is an emerging field in drug discovery and development. In particular, the substrate-receptor proteins of the cullin-ubiquitin ligase system play a key role in selective protein degradation, which is an essential component of the anti-myeloma activity of immunomodulatory drugs (IMiDs), such as lenalidomide. Here, we demonstrate that a series of anticancer sulfonamides NSC 719239 (E7820), indisulam, and NSC 339004 (chloroquinoxaline sulfonamide, CQS) induce proteasomal degradation of the U2AF-related splicing factor coactivator of activating protein-1 and estrogen receptors (CAPERα) via CRL4(DCAF15) mediated ubiquitination in human cancer cell lines...
June 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28429677/increased-expression-of-cullin-3-in-nasopharyngeal-carcinoma-and-knockdown-inhibits-proliferation-and-invasion
#19
Ruifang Zeng, Guolin Tan, Wei Li, Yanhong Ma
This study aimed to investigate the clinical significance of Cullin 3 expression in nasopharyngeal carcinoma (NPC), aswell as explore the regulatory mechanism of Cullin 3 underlying the growth and metastasis of NPC cells. Our findings showed that the expression levels of Cullin 3 expression were significantly increased in both NPC tissues and cell lines. A strong positive correlation was found between the Cullin 3 expression and Ki67-based proliferation index in NPC tissues. Moreover, Cullin 3 overexpression was correlated with the local relapse and distant metastasis in NPC patients...
April 18, 2017: Oncology Research
https://www.readbyqxmd.com/read/28428711/cullin-4a-is-associated-with-epithelial-to-mesenchymal-transition-and-poor-prognosis-in-perihilar-cholangiocarcinoma
#20
Tong-Jun Zhang, Dong Xue, Cheng-De Zhang, Ze-Dong Zhang, Qing-Ran Liu, Jian-Qiang Wang
AIM: To explore the functional role of cullin 4A (CUL4A), a core subunit of E3 ubiquitin ligase, in perihilar cholangiocarcinoma (PHCC). METHODS: The expression of CUL4A in PHCC cell lines was evaluated by Western blot and quantitative reverse transcription-polymerase chain reaction. Immunohistochemistry (IHC) was adopted to investigate the relationship between CUL4A expression and clinicopathological characteristics of PHCC. Univariate analysis and multivariate regression analysis were performed to analyze the risk factors related to overall survival (OS) and progression-free survival (PFS) of PHCC patients...
April 7, 2017: World Journal of Gastroenterology: WJG
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