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https://www.readbyqxmd.com/read/29242641/ubiquitin-ligases-in-oncogenic-transformation-and-cancer-therapy
#1
REVIEW
Daniela Senft, Jianfei Qi, Ze'ev A Ronai
The cellular response to external stress signals and DNA damage depends on the activity of ubiquitin ligases (E3s), which regulate numerous cellular processes, including homeostasis, metabolism and cell cycle progression. E3s recognize, interact with and ubiquitylate protein substrates in a temporally and spatially regulated manner. The topology of the ubiquitin chains dictates the fate of the substrates, marking them for recognition and degradation by the proteasome or altering their subcellular localization or assembly into functional complexes...
December 15, 2017: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/29242538/nuclear-rnf2-inhibits-interferon-function-by-promoting-k33-linked-stat1-disassociation-from-dna
#2
Shuo Liu, Minghong Jiang, Wendie Wang, Wei Liu, Xiaoqi Song, Zhongfei Ma, Shikun Zhang, Lun Liu, Yin Liu, Xuetao Cao
Prolonged activation of interferon-STAT1 signaling is closely related to inflammatory autoimmune disorders, and therefore the identification of negative regulators of these pathways is important. Through high-content screening of 115 mouse RING-domain E3 ligases, we identified the E3 ubiquitin ligase RNF2 as a potent inhibitor of interferon-dependent antiviral responses. RNF2 deficiency substantially enhanced interferon-stimulated gene (ISG) expression and antiviral responses. Mechanistically, nuclear RNF2 directly bound to STAT1 after interferon stimulation and increased K33-linked polyubiquitination of the DNA-binding domain of STAT1 at position K379, in addition to promoting the disassociation of STAT1/STAT2 from DNA and consequently suppressing ISG transcription...
January 2018: Nature Immunology
https://www.readbyqxmd.com/read/29242247/chip-regulates-aquaporin-2-quality-control-and-body-water-homeostasis
#3
Qi Wu, Hanne B Moeller, Donté A Stevens, Rebekah Sanchez-Hodge, Gabrielle Childers, Marleen L A Kortenoeven, Lei Cheng, Lena L Rosenbaek, Carrie Rubel, Cam Patterson, Trairak Pisitkun, Jonathan C Schisler, Robert A Fenton
The importance of the kidney distal convoluted tubule (DCT) and cortical collecting duct (CCD) is highlighted by various water and electrolyte disorders that arise when the unique transport properties of these segments are disturbed. Despite this critical role, little is known about which proteins have a regulatory role in these cells and how these cells can be regulated by individual physiologic stimuli. By combining proteomics, bioinformatics, and cell biology approaches, we found that the E3 ubiquitin ligase CHIP is highly expressed throughout the collecting duct; is modulated in abundance by vasopressin; interacts with aquaporin-2 (AQP2), Hsp70, and Hsc70; and can directly ubiquitylate the water channel AQP2 in vitro shRNA knockdown of CHIP in CCD cells increased AQP2 protein t1/2 and reduced AQP2 ubiquitylation, resulting in greater levels of AQP2 and phosphorylated AQP2...
December 14, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/29242192/the-ubiquitin-e3-ligase-chip-promotes-proteasomal-degradation-of-the-serine-threonine-protein-kinase-pink1-during-staurosporine-induced-cell-death
#4
Lang Yoo, Kwang Chul Chung
Mutations in the gene for the serine/threonine protein kinase PTEN-induced putative kinase 1 (PINK1) are the second most frequent cause of autosomal recessive Parkinson disease (PD). Via its kinase activity, PINK1 regulates neuronal cell survival and mitochondrial quality control. Numerous reports have revealed that PINK1 has diverse and physiologically significant functions, and, therefore, its activity should be tightly regulated. However, the molecular mechanisms regulating PINK1 stability and the modulator(s) involved have not been elucidated...
December 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29241538/an-elongin-cullin-socs-box-complex-regulates-stress-induced-serotonergic-neuromodulation
#5
Xicotencatl Gracida, Michael F Dion, Gareth Harris, Yun Zhang, John A Calarco
Neuromodulatory cells transduce environmental information into long-lasting behavioral responses. However, the mechanisms governing how neuronal cells influence behavioral plasticity are difficult to characterize. Here, we adapted the translating ribosome affinity purification (TRAP) approach in C. elegans to profile ribosome-associated mRNAs from three major tissues and the neuromodulatory dopaminergic and serotonergic cells. We identified elc-2, an Elongin C ortholog, specifically expressed in stress-sensing amphid neuron dual ciliated sensory ending (ADF) serotonergic sensory neurons, and we found that it plays a role in mediating a long-lasting change in serotonin-dependent feeding behavior induced by heat stress...
December 12, 2017: Cell Reports
https://www.readbyqxmd.com/read/29237971/expression-of-ww-domain-containing-protein-2-is-correlated-with-pathological-grade-and-recurrence-of-glioma
#6
Jun Liang, Wei-Feng Qi, Shao Xie, Wei-Feng Wang, Xian-Li Zhang, Xiu-Ping Zhou, Jin-Xia Hu, Ru-Tong Yu
OBJECTIVE: WW domain-containing protein 2 (WWP2) is an E3 ubiquitin ligase, which belongs to the NEDD4-like protein family. Recently, it is reported to play a key role in tumorigenesis and development of tumors such as prostate and lung cancer. However, there has been not related report on glioma until now. The aim of this study is to detect the expression of WWP2 and analyze its correlation to the pathological grade and tumor recurrence in patients with glioma. MATERIALS AND METHODS: Western blot and immunohistochemistry were separately used to detect the expression of WWP2 protein in 31 brain glioma tissue samples and 80 brain glioma paraffin specimens...
October 2017: Journal of Cancer Research and Therapeutics
https://www.readbyqxmd.com/read/29237723/the-e3-ligase-drought-hypersensitive-negatively-regulates-cuticular-wax-biosynthesis-by-promoting-the-degradation-of-transcription-factor-roc4-in-rice
#7
Zhenyu Wang, Xiaojie Tian, Qingzhen Zhao, Zhiqi Liu, Xiufeng Li, Yuekun Ren, Jiaqi Tang, Jun Fang, Qijiang Xu, Qingyun Bu
Cuticular wax plays crucial roles in protecting plants from environmental stresses, particularly drought stress. Many enzyme-encoding genes and transcription factors involved in wax biosynthesis have been identified, but the underlying posttranslational regulatory mechanisms are poorly understood. Here, we demonstrate that DROUGHT HYPERSENSITIVE (DHS), encoding a Really Interesting New Gene (RING)-type protein, is a critical regulator of wax biosynthesis in rice (Oryza sativa). The cuticular wax contents were significantly reduced in DHS overexpression plants but increased in dhs mutants compared to the wild type, which resulted in a response opposite that of drought stress...
December 13, 2017: Plant Cell
https://www.readbyqxmd.com/read/29237719/ift20-modulates-ciliary-pdgfr%C3%AE-signaling-by-regulating-the-stability-of-cbl-e3-ubiquitin-ligases
#8
Fabian Marc Schmid, Kenneth Bødtker Schou, Martin Juel Vilhelm, Maria Schrøder Holm, Loretta Breslin, Pietro Farinelli, Lars Allan Larsen, Jens Skorstengaard Andersen, Lotte Bang Pedersen, Søren Tvorup Christensen
Primary cilia have pivotal roles as organizers of many different signaling pathways, including platelet-derived growth factor receptor α (PDGFRα) signaling, which, when aberrantly regulated, is associated with developmental disorders, tumorigenesis, and cancer. PDGFRα is up-regulated during ciliogenesis, and ciliary localization of the receptor is required for its appropriate ligand-mediated activation by PDGF-AA. However, the mechanisms regulating sorting of PDGFRα and feedback inhibition of PDGFRα signaling at the cilium are unknown...
December 13, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29237114/emerging-paradigm-of-crosstalk-between-autophagy-and-the-ubiquitin-proteasome-system
#9
Taewook Nam, Jong Hyun Han, Sushil Devkota, Han-Woong Lee
Cellular protein homeostasis is maintained by two major degradation pathways, namely the ubiquitin-proteasome system (UPS) and autophagy. Until recently, the UPS and autophagy were considered to be largely independent systems targeting proteins for degradation in the proteasome and lysosome, respectively. However, the identification of crucial roles of molecular players such as ubiquitin and p62 in both of these pathways as well as the observation that blocking the UPS affects autophagy flux and vice versa has generated interest in studying crosstalk between these pathways...
December 12, 2017: Molecules and Cells
https://www.readbyqxmd.com/read/29237060/news-from-the-pub-plant-u-box-type-e3-ubiquitin-ligases
#10
Marco Trujillo
Plant U-box type E3 ubiquitin ligases (PUBs) are well known for their functions in a variety of stress responses, including immune responses and the adaptation to abiotic stresses. First linked to pollen self-incompatibility, their repertoire of roles has grown to encompass also the regulation of developmental processes. Notably, new studies provide clues to their mode of action, underline the existence of conserved PUB-kinase modules, and suggest new links to G-protein signalling, placing PUBs at the crossroads of major signalling hubs...
December 10, 2017: Journal of Experimental Botany
https://www.readbyqxmd.com/read/29236296/rna-decay-factor-upf1-promotes-protein-decay-a-hidden-talent
#11
REVIEW
Terra-Dawn M Plank, Miles F Wilkinson
The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay (NMD) pathway. Feng et al. now report a new function for UPF1-it is an E3 ubiquitin ligase that specifically promotes the decay of a key pro-muscle transcription factor: MYOD. UPF1 achieves this through its RING-like domain, which confers ubiquitin E3 ligase activity. Feng et al. provide evidence that the ability of UPF1 to destabilize MYOD represses myogenesis. In the future, it will be important to define other protein substrates of UPF1-driven ubiquitination and to determine whether this biochemical activity is responsible for some of UPF1's previously defined biological functions, including in development and stress responses...
December 13, 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/29235573/constitutively-elevated-levels-of-socs1-suppress-innate-responses-in-df-1-immortalised-chicken-fibroblast-cells
#12
E S Giotis, C S Ross, R C Robey, A Nohturfft, S Goodbourn, M A Skinner
The spontaneously immortalised DF-1 cell line is rapidly replacing its progenitor primary chicken embryo fibroblasts (CEFs) for studies on avian viruses such as avian influenza but no comprehensive study has as yet been reported comparing their innate immunity phenotypes. We conducted microarray analyses of DF-1 and CEFs, under both normal and stimulated conditions using chicken interferon-α (chIFN-α) and the attenuated infectious bursal disease virus vaccine strain PBG98. We found that DF-1 have an attenuated innate response compared to CEFs...
December 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29234478/fructose-ingestion-impairs-expression-of-genes-involved-in-skeletal-muscle-s-adaptive-response-to-aerobic-exercise
#13
Natalia Gomes Gonçalves, Stephanie Heffer Cavaletti, Carlos Augusto Pasqualucci, Milton Arruda Martins, Chin Jia Lin
Background: The inverse relationship between exercise capacity and its variation over time and both cardiovascular and all-cause mortality suggests the existence of an etiological nexus between cardiometabolic diseases and the molecular regulators of exercise capacity. Coordinated adaptive responses elicited by physical training enhance exercise performance and metabolic efficiency and possibly mediate the health benefits of physical exercise. In contrast, impaired expression of genes involved in mitochondrial biogenesis or protein turnover in skeletal muscle-key biological processes involved in adaptation to physical training-leads to insulin resistance and obesity...
2017: Genes & Nutrition
https://www.readbyqxmd.com/read/29234018/dynamics-of-rif1-sumoylation-is-regulated-by-pias4-in-the-maintenance-of-genomic-stability
#14
Ramesh Kumar, Cheok Chit Fang
RIF1 plays a key role in inhibiting DNA end resection and promoting NHEJ mediated DNA double stand break repair in G1. However, whether SUMOlyation may regulate RIF1 functions is still largely unknown. Here, we report that RIF1 is SUMOlyated in response to DNA damage. We identified PIAS4 as the primary SUMO E3 ligase required for the SUMOylation of RIF1 protein. Mammalian cells compromised of PIAS4 expression, show impaired RIF1 SUMOylation and defective for the disassembly of DNA damage responsive RIF1 foci...
December 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29233968/hrd1-prevents-apoptosis-in-renal-tubular-epithelial-cells-by-mediating-eif2%C3%AE-ubiquitylation-and-degradation
#15
Yujie Huang, Yifei Sun, Yizhi Cao, Hui Sun, Min Li, Hui You, Dongming Su, Yanjiao Li, Xiubin Liang
Apoptosis of renal tubular epithelial cells is a key feature of the pathogenicity associated with tubulointerstitial fibrosis and other kidney diseases. One factor that regulates important cellular processes like apoptosis and cell proliferation is HRD1, an E3 ubiquitin ligase that acts by promoting ubiquitylation and degradation of its target protein. However, the detailed mechanisms by which HRD1 acts as a regulator of apoptosis in renal tubular epithelial cells have not been established. In our previous liquid chromatography-tandem mass spectrometry (LC-MS/MS) study (Mol Endocrinol...
December 11, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29233925/a20-regulates-the-dna-damage-response-and-mediates-tumor-cell-resistance-to-dna-damaging-therapy
#16
Chuanzhen Yang, Weicheng Zang, Zefang Tang, Yapeng Ji, Ruidan Xu, Yongfeng Yang, Aiping Luo, Bin Hu, Zemin Zhang, Zhihua Liu, Xiaofeng Zheng
A competent DNA damage response (DDR) helps prevent cancer, but once cancer has arisen DDR can blunt the efficacy of chemotherapy and radiotherapy which cause lethal DNA breakage in cancer cells. Thus, blocking DDR may improve the efficacy of these modalities. Here we report a new DDR mechanism that interfaces with inflammatory signaling and might be blocked to improve anticancer outcomes. Specifically, we report that the ubiquitin-editing enzyme A20 binds and inhibits the E3 ubiquitin ligase RNF168, which is responsible for regulating histone H2A turnover critical for proper DNA repair...
December 12, 2017: Cancer Research
https://www.readbyqxmd.com/read/29233834/the-arabidopsis-alf4-protein-is-a-regulator-of-scf-e3-ligases
#17
Rammyani Bagchi, Charles W Melnyk, Gideon Christ, Martin Winkler, Kerstin Kirchsteiner, Mohammad Salehin, Julia Mergner, Michael Niemeyer, Claus Schwechheimer, Luz Irina A Calderón Villalobos, Mark Estelle
The cullin-RING E3 ligases (CRLs) regulate diverse cellular processes in all eukaryotes. CRL activity is controlled by several proteins or protein complexes, including NEDD8, CAND1, and the CSN Recently, a mammalian protein called Glomulin (GLMN) was shown to inhibit CRLs by binding to the RING BOX (RBX1) subunit and preventing binding to the ubiquitin-conjugating enzyme. Here, we show that Arabidopsis ABERRANT LATERAL ROOT FORMATION4 (ALF4) is an ortholog of GLMN The alf4 mutant exhibits a phenotype that suggests defects in plant hormone response...
December 12, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29230038/the-lps-inducible-lncrna-mirt2-is-a-negative-regulator-of-inflammation
#18
Meng Du, Lin Yuan, Xin Tan, Dandan Huang, Xiaojing Wang, Zhe Zheng, Xiaoxiang Mao, Xiangrao Li, Liu Yang, Kun Huang, Fengxiao Zhang, Yan Wang, Xi Luo, Dan Huang, Kai Huang
Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRR) with a crucial function in innate immune responses. Activation of TLR4 signaling at the plasma membrane by lipopolysaccharide (LPS) stimulates proinflammatory signaling pathways dependent on the E3 ubiquitin ligase TRAF6. Here we show the LPS-induced long non-coding RNA (lncRNA) Mirt2 functions as a checkpoint to prevent aberrant activation of inflammation, and is a potential regulator of macrophage polarization. Mirt2 associates with, and attenuates Lys63 (K63)-linked ubiquitination of, TRAF6, thus inhibiting activation of NF-κB and MAPK pathways and limiting production of proinflammatory cytokines...
December 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/29229926/cell-cycle-dependent-phosphorylation-regulates-recql4-pathway-choice-and-ubiquitination-in-dna-double-strand-break-repair
#19
Huiming Lu, Raghavendra A Shamanna, Jessica K de Freitas, Mustafa Okur, Prabhat Khadka, Tomasz Kulikowicz, Priscella P Holland, Jane Tian, Deborah L Croteau, Anthony J Davis, Vilhelm A Bohr
Pathway choice within DNA double-strand break (DSB) repair is a tightly regulated process to maintain genome integrity. RECQL4, deficient in Rothmund-Thomson Syndrome, promotes the two major DSB repair pathways, non-homologous end joining (NHEJ) and homologous recombination (HR). Here we report that RECQL4 promotes and coordinates NHEJ and HR in different cell cycle phases. RECQL4 interacts with Ku70 to promote NHEJ in G1 when overall cyclin-dependent kinase (CDK) activity is low. During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs...
December 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/29228602/fbxw8-dependent-degradation-of-mrfap1-in-anaphase-controls-mitotic-cell-death
#20
Duan-Zhuo Li, Shun-Fang Liu, Lan Zhu, Yu-Xing Wang, Yi-Xiang Chen, Jie Liu, Gang Hu, Xin Yu, Jian Li, Jin Zhang, Zhi-Xiang Wu, Han Lu, Wei Liu, Bin Liu
Mof4 family associated protein 1 (MRFAP1) is a 14 kDa nuclear protein, which involves in maintaining normal histone modification levels by negatively regulating recruitment of the NuA4 (nucleosome acetyltransferase of H4) histone acetyltransferase complex to chromatin. MRFAP1 has been identified as one of the most up-regulated proteins after NEDD8 (neural precursor cell expressed developmentally down-regulated 8) inhibition in multiple human cell lines. However, the biological function of MRFAP1 and the E3 ligase that targets MRFAP1 for destruction remain mysterious...
November 14, 2017: Oncotarget
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