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Yuyong Tan, Deliang Liu, Jian Gong, Jia Liu, Jirong Huo
F-box only protein 31 (FBXO31), initially identified in 2005, is a novel subunit of the S-phase kinase associated protein 1-Cullin 1-F-box ubiquitin ligase. As with other F-box proteins, FBXO31 may interact with several proteins to promote their ubquitination and subsequent degradation in an F-box-dependent manner. It has been revealed that FBXO31 serves a crucial role in DNA damage response and tumorigenesis. However, the expression and function of FBXO31 varies in different types of human cancer. To the best of our knowledge, the present review is the first to summarize the role of FBXO31 in different types of human cancer and determine its underlying mechanisms, thereby paving the road for the design of FBXO31-targeted anticancer therapies...
April 2018: Oncology Letters
Hironao Nakayama, Tomohisa Sakaue, Masashi Maekawa, Ayako Fujisaki, Shigeki Higashiyama
A disintegrin and metalloproteinase (ADAM) family are crucial enzymes for ectodomain shedding of multiple substrates and are involved in diverse biologic and pathologic processes. However, the molecular mechanism underlying substrate selectivity of ADAMs is poorly understood. In this study, we observed that disruption of actin polymerization by pharmacological inhibitors, latrunculin A (LatA) and cytochalasin D (CyD), induced ectodomain shedding of epidermal growth factor (EGF) family ligands. Induced shedding activity by LatA or CyD was suppressed by a metalloprotease inhibitor KB-R7785, indicating that ADAMs-mediated shedding is tightly controlled by actin cytoskeleton...
March 14, 2018: Biochemical and Biophysical Research Communications
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
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
Yanping Chen, Yingjun Chi, Qingchang Meng, Xiaolin Wang, Deyue Yu
In plants, various proteins are regulated by the ubiquitin-mediated system in response to different environmental stresses, such as drought, cold and heat. The Skp1-Cullin-F-box (SCF) complex, one of the multisubunit E3 ligases, has been shown to be involved in abiotic response pathways. In this study, Glycine max SKP1-like 1 (GmSK1), which had the typical characteristics of an SKP1 protein, with an alpha/beta structure, targeted to the cytoplasm and nucleus, was isolated from soybean [Glycine max (L.)]. GmSK1 was constitutively expressed in all the tested tissues, especially in the roots...
March 7, 2018: Plant Physiology and Biochemistry: PPB
Alex Pines, Madelon Dijk, Matthew Makowski, Elisabeth M Meulenbroek, Mischa G Vrouwe, Yana van der Weegen, Marijke Baltissen, Pim J French, Martin E van Royen, Martijn S Luijsterburg, Leon H Mullenders, Michiel Vermeulen, Wim Vermeulen, Navraj S Pannu, Haico van Attikum
Transcription-blocking DNA lesions are removed by transcription-coupled nucleotide excision repair (TC-NER) to preserve cell viability. TC-NER is triggered by the stalling of RNA polymerase II at DNA lesions, leading to the recruitment of TC-NER-specific factors such as the CSA-DDB1-CUL4A-RBX1 cullin-RING ubiquitin ligase complex (CRLCSA ). Despite its vital role in TC-NER, little is known about the regulation of the CRLCSA complex during TC-NER. Using conventional and cross-linking immunoprecipitations coupled to mass spectrometry, we uncover a stable interaction between CSA and the TRiC chaperonin...
March 12, 2018: Nature Communications
Jianxin Wei, Su Dong, Kangning Yao, Maria Francesca Ysabelle M Martinez, Paine R Fleisher, Yutong Zhao, Haichun Ma, Jing Zhao
Ubiquitin E3 ligases mediate ubiquitination and degradation of intracellular proteins. We have shown that a relatively new Skp, Cullin, F-box (SCF) protein E3 ligase, SCF FBXL19, has an anti-inflammatory effect and controls actin cytoskeleton dynamics via targeting cell membrane receptor and small GTPases for their ubiquitination and degradation, but the molecular regulation of its subunit FBXL19 stability remains unclear. Here we show that FBXL19 degradation is controlled by the balance between its ubiquitination and acetylation...
March 9, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Christine C Lee, Bing Li, Hongtao Yu, Michael J Matunis
The Anaphase Promoting Complex/Cyclosome (APC/C) is a ubiquitin E3 ligase that functions as the gatekeeper to mitotic exit. APC/C activity is controlled by an interplay of multiple pathways during mitosis, including the spindle assembly checkpoint (SAC), that are not yet fully understood. Here, we show that sumoylation of the APC4 subunit of the APC/C peaks during mitosis and is critical for timely APC/C activation and anaphase onset. We have also identified a functionally important SUMO interacting motif in the cullin-homology domain of APC2 located near the APC4 sumoylation sites and APC/C catalytic core...
March 8, 2018: ELife
Rufen Yu, Limei Cai, Yingui Chi, Xiangcui Ding, Xueqing Wu
The incidence and recurrence rates of ovarian cancer are still high, and once the disease metastasizes, it is nearly always fatal. Cullin 4A (CUL4A) serves a significant role in tumourigenesis and tumour progression; however, the effect and mechanisms underlying CUL4A overexpression are still unknown. The role of microRNAs (miRs) in the regulation of metastatic capability in ovarian cancer cell lines was investigated. The interaction between miR‑377 and CUL4A was investigated using bioinformatics analyses and dual‑luciferase reporter assays...
March 7, 2018: International Journal of Molecular Medicine
Leping Shao, Li Cui, Jingru Lu, Yanhua Lang, Irene Bottillo, Xiangzhong Zhao
Pseudohypoaldosteronism type II (PHAII) is a rare renal tubular disease that is inherited in an autosomal dominant manner. Mutations in four genes ( WNK1 , WNK4 , CUL3, and KLHL3 ) have been identified to be responsible for this disease. Cullin 3 (CUL3) and KLHL3 are subunits of Cullin-RING E3 ubiquitin ligase complexes, and the serine-threonine kinases WNK1 and WNK4 are substrates of this ubiquitin ligase. For CUL3 , all mutations associated with PHAII exclusively lead to exon 9 skipping. In this study, we identified a Chinese PHAII kindred caused by a novel synonymous mutation (c...
March 2018: FEBS Open Bio
Varun Jayeshkumar Shah, Subbareddy Maddika
Cullin-RING E3 ligases (CRLs) control broad range of biological processes by ubiquitinating numerous cellular substrates. However, role of CRL E3 ligases in chromatid cohesion is unknown. In this study, we identified a new CRL type E3 ligase (designated as CRL7SMU1 complex) that has an essential role in maintenance of chromatid cohesion. We demonstrate that SMU1, DDB1, CUL7 and RNF40 as integral components of this complex. SMU1 by acting as a substrate recognition module, binds to H2B and mediates monoubiquitination at K120 site through CRL7SMU1 E3 ligase complex...
March 5, 2018: Journal of Cell Science
Zhi Chen, Wei Zhang, Kaibiao Jiang, Bin Chen, Kun Wang, Lifeng Lao, Canglong Hou, Fei Wang, Caiguo Zhang, Hongxing Shen
Cullins, critical members of the cullin-RING ubiquitin ligases (CRLs), are often aberrantly expressed in different cancers. However, the underlying mechanisms regarding aberrant expression of these cullins and the specific substrates of CRLs in different cancers are mostly unknown. Here, we demonstrate that overexpressed CUL4B in human osteosarcoma cells forms an E3 complex with DNA damage binding protein 1 (DDB1) and DDB1- and CUL4-associated factor 13 (DCAF13). In vitro and in vivo analyses indicated that the CRL4BDCAF13 E3 ligase specifically recognized the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) for degradation, and disruption of this E3 ligase resulted in PTEN accumulation...
March 2, 2018: Molecular Therapy. Nucleic Acids
Yanpeng Ci, Xiaoning Li, Maorong Chen, Jiateng Zhong, Brian J North, Hiroyuki Inuzuka, Xi He, Yu Li, Jianping Guo, Xiangpeng Dai
Wnt signaling has emerged as a major regulator of tissue development by governing the self-renewal and maintenance of stem cells in most tissue types. As a key upstream regulator of the Wnt pathway, the transmembrane E3 ligase ZNRF3 has recently been established to play a role in negative regulation of Wnt signaling by targeting Frizzled (FZD) receptor for ubiquitination and degradation. However, the upstream regulation of ZNRF3, in particular the turnover of ZNRF3, is still unclear. Here we report that ZNRF3 is accumulated in the presence of proteasome inhibitor treatment independent of its E3-ubiquitin ligase activity...
March 1, 2018: Protein & Cell
Edyta Kisielnicka, Ryuji Minasaki, Christian R Eckmann
RNA-binding proteins (RBPs) are important regulators of gene expression programs, especially during gametogenesis. How the abundance of particular RBPs is restricted to defined stages of meiosis remains largely elusive. Here, we report a molecular pathway that subjects two nonrelated but broadly evolutionarily conserved translational regulators (CPB-3/CPEB and GLD-1/STAR) to proteosomal degradation in Caenorhabditis elegans germ cells at the transition from pachytene to diplotene of meiotic prophase. Both RBPs are recognized by the same ubiquitin ligase complex, containing the molecular scaffold Cullin-1 and the tumor suppressor SEL-10/FBXW7 as its substrate recognition subunit...
March 1, 2018: Proceedings of the National Academy of Sciences of the United States of America
Othon Michail, Demetrios Moris, Stamatios Theocharis, John Griniatsos
BACKGROUND/AIM: The cullin (CUL) family of proteins is involved in the ubiquitin/mediated degradation of proteins, regulating cell proliferation, cell-cycle control, migration, invasion and metastasis in the process of tumor progression. The aim of the present study was to examine if there is any correlation between the immunohistochemical (IHC) expression of Cullin-1 and -2 proteins in colorectal cancer tissue specimens with several clinicopathological variables. MATERIALS AND METHODS: Between January 2012 and December 2014, 96 consecutive adenocarcinoma patients were submitted to oncological colectomy, as the first therapeutic option, with a curative intent...
March 2018: In Vivo
Kouhei Shimizu, Naoe Taira Nihira, Hiroyuki Inuzuka, Wenyi Wei
FBW7 is one of the most well characterized F-box proteins that serve as substrate recognition subunits of SCF (Skp1-Cullin 1-F-box proteins) E3 ubiquitin ligase complexes. SCFFBW7 plays key roles in regulating cell cycle progression, differentiation, and stem cell maintenance largely through targeting a broad range of oncogenic substrates for proteasome-dependent degradation. The identification of an increasing number of FBW7 substrates for ubiquitination, and intensive in vitro and in vivo studies have revealed a network of signaling components controlled by FBW7 that contributes to metabolic regulation as well as its tumor suppressor role...
February 20, 2018: Cellular Signalling
Susan Patalano, José Rodríguez-Nieves, Cory Colaneri, Justin Cotellessa, Diego Almanza, Alisa Zhilin-Roth, Todd Riley, Jill Macoska
Tissue fibrosis is mediated by the actions of multiple pro-fibrotic proteins that can induce myofibroblast phenoconversion through diverse signaling pathways coupled predominantly to Smads or MEK/Erk proteins. The TGFβ/TGFβR and CXCL12/CXCR4 axes induce myofibroblast phenoconversion independently through Smads and MEK/Erk proteins, respectively. To investigate these mechanisms at the genetic level, we have now elucidated the TGFβ/TGFβR and CXCL12/CXCR4 transcriptomes in human fibroblasts. These transcriptomes are largely convergent, and up-regulate transcripts encoding proteins known to promote myofibroblast phenoconversion...
February 22, 2018: Scientific Reports
Marieke Dubois, Katia Selden, Alexis Bediée, Gaëlle Rolland, Nicolas Baumberger, Sandra Noir, Lien Bach, Geneviève Lamy, Christine Granier, Pascal Genschik
The plant cell cycle is tightly regulated by factors that integrate endogenous cues and environmental signals to adapt plant growth to changing conditions. Under drought, cell division in young leaves is blocked by an active mechanism, reducing the evaporative surface and conserving energy resources. The molecular function of cyclin-dependent kinase-inhibitory proteins (CKIs) in regulating the cell cycle has already been well studied, but little is known about their involvement in cell cycle regulation under adverse growth conditions...
February 22, 2018: Plant Physiology
Dan Jin, Ming Wu, Bosheng Li, Birte Bücker, Philipp Keil, Shaoman Zhang, Jigang Li, Dingming Kang, Jie Liu, Jie Dong, Xing Wang Deng, Vivian Irish, Ning Wei
The control of seed germination and seed dormancy are critical for the successful propagation of plant species, and are important agricultural traits. Seed germination is tightly controlled by the balance of gibberellin (GA) and abscisic acid (ABA), and is influenced by environmental factors. The COP9 Signalosome (CSN) is a conserved multi-subunit protein complex that is best known as a regulator of the Cullin-RING family of ubiquitin E3 ligases (CRLs). Multiple viable mutants of the CSN showed poor germination, except for csn5b-1...
February 20, 2018: PLoS Genetics
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
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