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Kit Man Wong, Lindsey N Micel, Heather M Selby, Aik Choon Tan, Todd M Pitts, Stacey M Bagby, Anna Spreafico, Peter J Klauck, Stephen J Blakemore, Peter F Smith, Alice McDonald, Allison Berger, John J Tentler, S Gail Eckhardt
Background The neddylation pathway conjugates NEDD8 to cullin-RING ligases and controls the proteasomal degradation of specific proteins involved in essential cell processes. Pevonedistat (MLN4924) is a selective small molecule targeting the NEDD8-activating enzyme (NAE) and inhibits an early step in neddylation, resulting in DNA re-replication, cell cycle arrest and death. We investigated the anti-tumor potential of pevonedistat in preclinical models of melanoma. Methods Melanoma cell lines and patient-derived tumor xenografts (PDTX) treated with pevonedistat were assessed for viability/apoptosis and tumor growth, respectively, to identify sensitive/resistant models...
October 25, 2016: Investigational New Drugs
Fei Wu, Xiangpeng Dai, Wenjian Gan, Lixin Wan, Min Li, Nicholas Mitsiades, Wenyi Wei, Qiang Ding, Jinfang Zhang
Recent studies revealed that mutations in SPOP (Speckle-type POZ protein) occur in up to 15% of patients with prostate cancer. However, the physiological role of SPOP in regulating prostate tumorigenesis remains elusive. Here, we identified the Cdc20 oncoprotein as a novel ubiquitin substrate of SPOP. As such, pharmacological inhibition of Cullin-based E3 ligases by MLN4924 could stabilize endogenous Cdc20 in cells. Furthermore, we found that Cullin 3, and, to a less extent, Cullin 1, specifically interacted with Cdc20...
October 22, 2016: Cancer Letters
Anita Schlierf, Eva Altmann, Jean Quancard, Anne B Jefferson, René Assenberg, Martin Renatus, Matthew Jones, Ulrich Hassiepen, Michael Schaefer, Michael Kiffe, Andreas Weiss, Christian Wiesmann, Richard Sedrani, Jörg Eder, Bruno Martoglio
The COP9 signalosome (CSN) is a central component of the activation and remodelling cycle of cullin-RING E3 ubiquitin ligases (CRLs), the largest enzyme family of the ubiquitin-proteasome system in humans. CRLs are implicated in the regulation of numerous cellular processes, including cell cycle progression and apoptosis, and aberrant CRL activity is frequently associated with cancer. Remodelling of CRLs is initiated by CSN-catalysed cleavage of the ubiquitin-like activator NEDD8 from CRLs. Here we describe CSN5i-3, a potent, selective and orally available inhibitor of CSN5, the proteolytic subunit of CSN...
October 24, 2016: Nature Communications
Manuela Antonioli, Martina Di Rienzo, Mauro Piacentini, Gian Maria Fimia
Autophagy is a major degradative process activated in a rapid and transient manner to cope with stress conditions. Whether autophagy is beneficial or detrimental depends upon the rate of induction and the appropriateness of the duration. Alterations in both autophagy initiation and termination predispose the cell to death, and affect the execution of other inducible processes such as inflammation. In this review we discuss how stress signaling pathways dynamically control the activity of the autophagy machinery by mediating post-translational modifications and regulatory protein interactions...
October 17, 2016: Trends in Biochemical Sciences
Yusuke Matsui, Keisuke Shindo, Kayoko Nagata, Noriyoshi Yoshinaga, Kotaro Shirakawa, Masayuki Kobayashi, Akifumi Takaori-Kondo
HIV type 1 overcomes the host restriction factor apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) proteins by organizing an E3 ubiquitin ligase complex together with viral infectivity factor (Vif) and a host transcription cofactor core binding factor β (CBFβ ). CBFβ is essential for Vif to counteract APOBEC3 by enabling the recruitment of cullin 5 to the complex and increasing steady-state level of Vif protein, however, the mechanisms by which CBFβ up-regulates Vif protein remains unclear...
October 7, 2016: Journal of Biological Chemistry
Yuya Yamagishi, Marc Tessier-Lavigne
Axon degeneration is a tightly regulated, self-destructive program that is a critical feature of many neurodegenerative diseases, but the molecular mechanisms regulating this program remain poorly understood. Here, we identify S-phase kinase-associated protein 1A (Skp1a), a core component of a Skp/Cullin/F-box (SCF)-type E3 ubiquitin ligase complex, as a critical regulator of axon degeneration after injury in mammalian neurons. Depletion of Skp1a prolongs survival of injured axons in vitro and in the optic nerve in vivo...
October 11, 2016: Cell Reports
Maryam Ataeian, Justus Tegha-Dunghu, Donna G Curtis, Ellen M E Sykes, Ashkan Nozohourmehrabad, Megha Bajaj, Karen Cheung, Martin Srayko
In most animals, female meiosis completes only after fertilization. Sperm entry has been implicated in providing a signal for the initiation of the final meiotic processes, however, a maternal component required for this process has not been previously identified. We report the characterization of a novel family of three highly similar paralogs (memi-1, memi-2, memi-3) that encode oocyte-specific proteins. A hypermorphic mutation memi-1(sb41) results in failure to exit female meiosis II properly, however, loss of all three paralogs results in a "skipped meiosis II" phenotype...
October 11, 2016: Genetics
Zhao Zhang, Emre Turer, Xiaohong Li, Xiaoming Zhan, Mihwa Choi, Miao Tang, Amanda Press, Steven R Smith, Adeline Divoux, Eva Marie Y Moresco, Bruce Beutler
We describe a metabolic disorder characterized by lipodystrophy, hepatic steatosis, insulin resistance, severe diabetes, and growth retardation observed in mice carrying N-ethyl-N-nitrosourea (ENU)-induced mutations. The disorder was ascribed to a mutation of kelch repeat and BTB (POZ) domain containing 2 (Kbtbd2) and was mimicked by a CRISPR/Cas9-targeted null allele of the same gene. Kbtbd2 encodes a BTB-Kelch family substrate recognition subunit of the Cullin-3-based E3 ubiquitin ligase. KBTBD2 targeted p85α, the regulatory subunit of the phosphoinositol-3-kinase (PI3K) heterodimer, causing p85α ubiquitination and proteasome-mediated degradation...
October 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
Siyuan Ding, Nancie Mooney, Bin Li, Marcus R Kelly, Ningguo Feng, Alexander V Loktev, Adrish Sen, John T Patton, Peter K Jackson, Harry B Greenberg
Rotaviruses (RVs) are the leading cause of severe gastroenteritis in young children, accounting for half a million deaths annually worldwide. RV encodes non-structural protein 1 (NSP1), a well-characterized interferon (IFN) antagonist, which facilitates virus replication by mediating the degradation of host antiviral factors including IRF3 and β-TrCP. Here, we utilized six human and animal RV NSP1s as baits and performed tandem-affinity purification coupled with high-resolution mass spectrometry to comprehensively characterize NSP1-host protein interaction network...
October 2016: PLoS Pathogens
Keiji Uematsu, Fumihiko Okumura, Syunsuke Tonogai, Akiko Joo-Okumura, Dawit Hailu Alemayehu, Akihiko Nishikimi, Yoshinori Fukui, Kunio Nakatsukasa, Takumi Kamura
Proper dynamic regulation of the spindle is essential for successful cell division. However, the molecular mechanisms that regulate spindle dynamics in mitosis are not fully understood. In this study, we show that Cullin 5-interacting suppressor of cytokine signaling box protein ASB7 ubiquitinates DDA3, a regulator of spindle dynamics, thereby targeting it for proteasomal degradation. The presence of microtubules (MTs) prevented the ASB7-DDA3 interaction, thus stabilizing DDA3. Knockdown of ASB7 decreased MT polymerization and increased the proportion of cells with unaligned chromosomes, and this phenotype was rescued by deletion of DDA3...
October 10, 2016: Journal of Cell Biology
Risa Mukai, Takayuki Ohshima
Human T-cell leukemia virus type1 (HTLV-1) is an oncogenic retrovirus that is the etiological agent of adult T-cell leukemia (ATL). The HTLV-1 basic leucine-zipper factor (HBZ), which is encoded by the minus strand of the provirus, is constitutively expressed in all ATL patient cells and likely contributes to the development and maintenance of ATL. Furthermore, the overexpression of myeloid cell leukemia-1 (MCL1) is frequently observed in hematological cancers as well as several other types of cancers. Here, we found that the expression of HBZ in cells stabilized MCL1 protein expression and suppressed MCL-mediated release of cytochrome c from the mitochondria...
October 3, 2016: Molecular and Cellular Biology
Tatsuro Iso, Takafumi Suzuki, Liam Baird, Masayuki Yamamoto
The transcription factor Nrf2 (NF-E2-related-factor-2) is essential for the oxidative and electrophilic stress responses. Keap1 (Kelch-like-ECH-associated-protein-1), an adaptor for a Cullin-3 (Cul3)-based ubiquitin ligase, regulates Nrf2 activity through proteasomal degradation, and acts as a sensor for oxidative and electrophilic stresses. The Keap1-Cul3 complex is a critical regulator of the cellular Nrf2 level, yet quantitative information regarding their endogenous intracellular concentrations in homeostatic conditions and during stress responses is unknown...
October 3, 2016: Molecular and Cellular Biology
Marta Delgado-Camprubi, Noemi Esteras, Marc Pm Soutar, Helene Plun-Favreau, Andrey Y Abramov
The Parkinson's disease (PD)-related protein F-box only protein 7 (Fbxo7) is the substrate-recognition component of the Skp1-Cullin-F-box protein E3 ubiquitin ligase complex. We have recently shown that PD-associated mutations in Fbxo7 disrupt mitochondrial autophagy (mitophagy), suggesting a role for Fbxo7 in modulating mitochondrial homeostasis. Here we report that Fbxo7 deficiency is associated with reduced cellular NAD(+) levels, which results in increased mitochondrial NADH redox index and impaired activity of complex I in the electron transport chain...
September 30, 2016: Cell Death and Differentiation
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
E Malek, M A Y Abdel-Malek, S Jagannathan, N Vad, R Karns, A G Jegga, A Broyl, M van Duin, P Sonneveld, F Cottini, K C Anderson, J J Driscoll
While clinical benefit of the proteasome inhibitor (PI) bortezomib for multiple myeloma (MM) patients remains unchallenged, dose-limiting toxicities and drug resistance limit the long-term utility. The E3 ubiquitin (Ub) ligase Skp1-Cullin-1-Skp2 (SCF(Skp2)) promotes proteasomal degradation of the cell cycle inhibitor p27 to enhance tumor growth. Increased SKP2 expression and reduced p27 levels are frequent in human cancers and are associated with therapeutic resistance. SCF(Skp2) activity is increased by the Cullin-1-binding protein Commd1 and the Skp2-binding protein Cks1B...
September 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Yan Li, Leonidas N Carayannopoulos, Michael Thomas, Maria Palmisano, Simon Zhou
CC-122 hydrochloride is a novel pleiotropic pathway modifier compound that binds cereblon, a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex. CC-122 has multiple activities including modulation of immune cells, antiproliferative activity of multiple myeloma and lymphoma cells, and antiangiogenic activity. CC-122 is being developed as an oncology treatment for hematologic malignancies and advanced solid tumors. Cardiovascular and vital sign assessments of CC-122 have been conducted in hERG assays in vitro and in a 28-day good laboratory practice monkey study with negative signals...
2016: Clinical Pharmacology: Advances and Applications
Eduardo Henrique Goulin, Daiani Cristina Savi, Desirrê Alexia Lourenço Petters, Vanessa Kava, Lygia Galli-Terasawa, Geraldo José Silva, Chirlei Glienke
Phyllosticta citricarpa is the epidemiological agent of Citrus Black Spot (CBS) disease, which is responsible for large economic losses worldwide. CBS is characterized by the presence of spores (pycnidiospores) in dark lesions of fruit, which are also responsible for short distance dispersal of the disease. The identification of genes involved in asexual reproduction of P. citricarpa can be an alternative for directional disease control. We analyzed a library of mutants obtained through Agrobacterium tumefaciens transformation system, looking for alterations in growth and reproductive structure formation...
November 2016: Microbiological Research
Giada Zurlo, Jianping Guo, Mamoru Takada, Wenyi Wei, Qing Zhang
Protein hydroxylation is a post-translational modification catalyzed by 2-oxoglutarate-dependent dioxygenases. The hydroxylation modification can take place on various amino acids, including but not limited to proline, lysine, asparagine, aspartate and histidine. A classical example of this modification is hypoxia inducible factor alpha (HIF-α) prolyl hydroxylation, which affects HIF-α protein stability via the Von-Hippel Lindau (VHL) tumor suppressor pathway, a Cullin 2-based E3 ligase adaptor protein frequently mutated in kidney cancer...
September 20, 2016: Biochimica et Biophysica Acta
Gilles M Leclerc, Shuhua Zheng, Guy J Leclerc, Joanna DeSalvo, Ronan T Swords, Julio C Barredo
Acute lymphoblastic leukemia (ALL) is the leading cause of cancer-related death in children, and cure rates for adults remain dismal. Further, effective treatment strategies for relapsed/refractory ALL remain elusive. We previously uncovered that ALL cells are prone to apoptosis via endoplasmic reticulum (ER) stress/unfolded protein response (UPR)-mediated mechanisms. We investigated the antineoplastic activity of pevonedistat(®), a novel NEDD8-activating enzyme inhibitor that targets E3 cullin-RING ligases (CRLs) dependent proteasomal protein degradation, in ALL...
September 5, 2016: Leukemia Research
Amnon Golan, Ning Wei, Elah Pick
The COP9 signalosome (CSN) is an evolutionary conserved complex that is found in all eukaryotes, and implicated in regulating the activity of Cullin-RING ubiquitin Ligases (CRLs). Activity of CRLs is highly regulated; complexes are active when the cullin subunit is covalently attached to the ubiquitin like modifier, Nedd8. Neddylation/deneddylation cycles are required for proper CRLs activity, and deneddylation is performed by the CSN complex.We describe here a method utilizing resin-coupled antibodies to deplete the CSN from human cell extracts, and to obtain endogenous CSN complexes by immunopurification...
2016: Methods in Molecular Biology
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