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https://www.readbyqxmd.com/read/30054382/new-ubiquitin-dependent-mechanisms-regulating-the-aurora-b-protein-phosphatase-1-balance-in-saccharomyces-cerevisiae
#1
Rini Ravindran, Paula Polk, Lucy C Robinson, Kelly Tatchell
Protein ubiquitylation regulates many cellular processes, including cell division. We report here a novel mutation altering the S. cerevisiae E1 ubiquitin activating enzyme ( uba1-W928R) that suppresses the temperature sensitivity and chromosome loss phenotype of a well-characterized Aurora B mutant ( ip1-2 ). The uba1-W928R mutation increases Histone H3-S10 phosphorylation in the ipl1-2 strain, indicating that uba1-W928R acts by increasing Ipl1 activity and/or reducing the opposing PP1 (Glc7 in S. cerevisiae ) phosphatase activity...
July 27, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29802913/effects-of-acute-and-chronic-methamphetamine-administration-on-cynomolgus-monkey-hippocampus-structure-and-cellular-transcriptome
#2
Mi Ran Choi, Ji-Won Chun, Su Min Kwak, Sol Hee Bang, Yeung-Bae Jin, Youngjeon Lee, Han-Na Kim, Kyu-Tae Chang, Young Gyu Chai, Sang-Rae Lee, Dai-Jin Kim
Methamphetamine (MA), a psychostimulant abused worldwide, gives rise to neurotoxicity in the hippocampus, resulting in cognitive impairments and hippocampal volume reduction. The cellular and molecular mechanisms associated with hippocampal impairments due to MA remain unknown. The aim of this study was to investigate the effects of MA on structural alterations and gene expressions in the hippocampus. We analyzed the pattern of volumetric changes in the hippocampus using magnetic resonance imaging (MRI) after acute and chronic administration of MA to cynomolgus macaques...
May 23, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29755650/preclinical-comparison-of-proteasome-and-ubiquitin-e1-enzyme-inhibitors-in-cutaneous-squamous-cell-carcinoma-the-identification-of-mechanisms-of-differential-sensitivity
#3
Angela McHugh, Kenneth Fernandes, Andrew P South, Jemima E Mellerio, Julio C Salas-Alanís, Charlotte M Proby, Irene M Leigh, Mark K Saville
Proteasome inhibitors have distinct properties and the biochemical consequences of suppressing ubiquitin E1 enzymes and the proteasome differ. We compared the effects of the proteasome inhibitors bortezomib, ixazomib and carfilzomib and the ubiquitin E1 enzyme inhibitor MLN7243/TAK-243 on cell viability and cell death in normal keratinocytes and cutaneous squamous cell carcinoma (cSCC) cell lines. The effects of both a pulse of treatment and more extended incubation were investigated. This is relevant to directly-delivered therapy (topical treatment/intratumoral injection) where the time of exposure can be controlled and a short exposure may better reflect systemically-delivered inhibitor pharmacokinetics...
April 17, 2018: Oncotarget
https://www.readbyqxmd.com/read/29721631/multiple-chemo-genetic-interactions-between-a-toxic-metabolite-and-the-ubiquitin-pathway-in-yeast
#4
Delphine Albrecht, Hans C Hürlimann, Johanna Ceschin, Christelle Saint-Marc, Benoît Pinson, Bertrand Daignan-Fornier
AICAR is the precursor of ZMP, a metabolite with antiproliferative properties in yeast and human. We aim at understanding how AICAR (and its active form ZMP) affects essential cellular processes. In this work, we found that ZMP accumulation is synthetic lethal with a hypomorphic allele of the ubiquitin-activating enzyme Uba1. A search for gene-dosage suppressors revealed that ubiquitin overexpression was sufficient to restore growth of the uba1 mutant upon AICAR treatment, suggesting that the ubiquitin pool is critical for cells to cope with AICAR...
May 2, 2018: Current Genetics
https://www.readbyqxmd.com/read/29667327/novel-west-syndrome-candidate-genes-in-a-chinese-cohort
#5
Jing Peng, Ying Wang, Fang He, Chen Chen, Li-Wen Wu, Li-Fen Yang, Yu-Ping Ma, Wen Zhang, Zi-Qing Shi, Chao Chen, Kun Xia, Hui Guo, Fei Yin, Nan Pang
AIMS: West syndrome (WS) is a classic form of early infantile epileptic encephalopathy (EIEE) characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on electroencephalography. Genetic defects play a critical role in the pathology of WS, and 54 EIEE genes have been identified till date. This study was designed to uncover new candidate genes for West syndrome. METHODS: In this study, we recruited 56 Chinese families with WS of unknown etiology...
April 17, 2018: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/29411616/new-in-depth-analytical-approach-of-the-porcine-seminal-plasma-proteome-reveals-potential-fertility-biomarkers
#6
Cristina Pérez-Patiño, Inmaculada Parrilla, Isabel Barranco, María Vergara-Barberán, Ernesto F Simó-Alfonso, José M Herrero-Martínez, Heriberto Rodriguez-Martínez, Emilio A Martínez, Jordi Roca
A complete characterization of the proteome of seminal plasma (SP) is an essential step to understand how SP influences sperm function and fertility after artificial insemination (AI). The purpose of this study was to identify which among characterized proteins in boar SP were differently expressed among AI boars with significantly different fertility outcomes. A total of 872 SP proteins, 390 of them belonging specifically to Sus Scrofa taxonomy, were identified (Experiment 1) by using a novel proteomic approach that combined size exclusion chromatography and solid-phase extraction as prefractionation steps prior to Nano LC-ESI-MS/MS analysis...
March 2, 2018: Journal of Proteome Research
https://www.readbyqxmd.com/read/29152096/the-non-canonical-ubiquitin-activating-enzyme-uba6-suppresses-epithelial-mesenchymal-transition-of-mammary-epithelial-cells
#7
Xianpeng Liu, Limin Sun, Demirkan B Gursel, Chonghui Cheng, Sui Huang, Alfred W Rademaker, Seema A Khan, Jun Yin, Hiroaki Kiyokawa
Ubiquitination plays critical roles in the regulation of oncoproteins and tumor suppressors during carcinogenesis. The two ubiquitin activating enzymes (E1) in human genome, UBA1 and UBA6, initiate ubiquitination by ATP-dependent activation of ubiquitin. Recent evidence suggests that UBA1 and UBA6 play partially overlapped yet distinct roles in controlling the proteome. Here we demonstrate that ubiquitination pathways initiated specifically by UBA6 set a suppressive barrier against critical steps of mammary carcinogenesis such as loss of polarity, anoikis resistance and epithelial-mesenchymal transition (EMT)...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29046292/identification-of-ut-a1-and-aqp2-interacting-proteins-in-rat-inner-medullary-collecting-duct
#8
Chung-Lin Chou, Gloria Hwang, Daniel J Hageman, Lichy Han, Prashasti Agrawal, Trairak Pisitkun, Mark A Knepper
The urea channel UT-A1 and the water channel aquaporin-2 (AQP2) mediate vasopressin-regulated transport in the renal inner medullary collecting duct (IMCD). To identify the proteins that interact with UT-A1 and AQP2 in native rat IMCD cells, we carried out chemical cross-linking followed by detergent solubilization, immunoprecipitation, and LC-MS/MS analysis of the immunoprecipitated material. The analyses revealed 133 UT-A1-interacting proteins and 139 AQP2-interacting proteins, each identified in multiple replicates...
January 1, 2018: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29034082/functional-characterizations-of-rare-uba1-variants-in-x-linked-spinal-muscular-atrophy
#9
Chris D Balak, Jesse M Hunter, Mary E Ahearn, David Wiley, Gennaro D'urso, Lisa Baumbach-Reardon
Background: X-linked spinal muscular atrophy (XL-SMA) results from mutations in the Ubiquitin-Like Modifier Activating Enzyme 1 ( UBA1 ). Previously, four novel closely clustered mutations have been shown to cause this fatal infantile disorder affecting only males. These mutations, three missense and one synonymous, all lie within Exon15 of the UBA1 gene, which contains the active adenylation domain (AAD). Methods: In this study, our group characterized the three known missense variants in vitro . Using a novel Uba1 assay and other methods, we investigated Uba1 adenylation, thioester, and transthioesterification reactions in vitro to determine possible biochemical effects of the missense variants...
2017: F1000Research
https://www.readbyqxmd.com/read/28933784/inhibition-of-the-deubiquitinase-usp5-leads-to-c-maf-protein-degradation-and-myeloma-cell-apoptosis
#10
Siyu Wang, Jiaxiang Juan, Zubin Zhang, Yanyun Du, Yujia Xu, Jiefei Tong, Biyin Cao, Michael F Moran, Yuanying Zeng, Xinliang Mao
The deubiquitinase USP5 stabilizes c-Maf, a key transcription factor in multiple myeloma (MM), but the mechanisms and significance are unclear. In the present study, USP5 was found to interact with c-Maf and prevented it from degradation by decreasing its polyubiquitination level. Specifically, the 308th and 347th lysine residues in c-Maf were critical for USP5-mediated deubiquitination and stability. There are five key domains in the USP5 protein and subsequent studies revealed that the cryptic ZnF domain and the C-box domain interacted with c-Maf but the UBA1/UBA2 domain partly increased its stability...
September 21, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28798148/ubiquitination-of-basal-vegfr2-regulates-signal-transduction-and-endothelial-function
#11
Gina A Smith, Gareth W Fearnley, Izma Abdul-Zani, Stephen B Wheatcroft, Darren C Tomlinson, Michael A Harrison, Sreenivasan Ponnambalam
Cell surface receptors can undergo recycling or proteolysis but the cellular decision-making events that sort between these pathways remain poorly defined. Vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2) regulate signal transduction and angiogenesis, but how signaling and proteolysis is regulated is not well understood. Here, we provide evidence that a pathway requiring the E1 ubiquitin-activating enzyme UBA1 controls basal VEGFR2 levels, hence metering plasma membrane receptor availability for the VEGF-A-regulated endothelial cell response...
October 15, 2017: Biology Open
https://www.readbyqxmd.com/read/28635376/advances-in-understanding-the-role-of-disease-associated-proteins-in-spinal-muscular-atrophy
#12
REVIEW
Seyyedmohsen Hosseinibarkooie, Svenja Schneider, Brunhilde Wirth
Spinal muscular atrophy (SMA) is a neurodegenerative disorder characterized by alpha motor neuron loss in the spinal cord due to reduced survival motor neuron (SMN) protein level. While the genetic basis of SMA is well described, the specific molecular pathway underlying SMA is still not fully understood. Areas covered: This review discusses the recent advancements in understanding the molecular pathways in SMA using different omics approaches and genetic modifiers identified in both vertebrate and invertebrate systems...
July 2017: Expert Review of Proteomics
https://www.readbyqxmd.com/read/28578874/dissecting-the-specificity-of-adenosyl-sulfamate-inhibitors-targeting-the-ubiquitin-activating-enzyme
#13
Mohit Misra, Maximilian Kuhn, Mark Löbel, Heeseon An, Alexander V Statsyuk, Christoph Sotriffer, Hermann Schindelin
Targeting the activating enzymes (E1) of ubiquitin (Ub) and ubiquitin-like modifiers (Ubls) has emerged as a promising anti-cancer strategy, possibly overcoming the ineffectiveness of proteasome inhibitors against solid tumors. Here, we report crystal structures of the yeast ubiquitin E1 (Uba1) with three adenosyl sulfamate inhibitors exhibiting different E1 specificities, which are all covalently linked to ubiquitin. The structures illustrate how the chemically diverse inhibitors are accommodated within the adenylation active site...
July 5, 2017: Structure
https://www.readbyqxmd.com/read/28572513/domain-alternation-and-active-site-remodeling-are-conserved-structural-features-of-ubiquitin-e1
#14
COMPARATIVE STUDY
Zongyang Lv, Lingmin Yuan, James H Atkison, Grace Aldana-Masangkay, Yuan Chen, Shaun K Olsen
E1 enzymes for ubiquitin (Ub) and Ub-like modifiers (Ubls) harbor two catalytic activities that are required for Ub/Ubl activation: adenylation and thioester bond formation. Structural studies of the E1 for the Ubl <u>s</u>mall <u>u</u>biquitin-like <u>mo</u>difier (SUMO) revealed a single active site that is transformed by a conformational switch that toggles its competency for catalysis of these two distinct chemical reactions. Although the mechanisms of adenylation and thioester bond formation revealed by SUMO E1 structures are thought to be conserved in Ub E1, there is currently a lack of structural data supporting this hypothesis...
July 21, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28422048/sak-hv-decreases-the-self-ubiquitination-of-mekk1-to-promote-macrophage-proliferation-via-mapk-erk-and-jnk-pathways
#15
Chao Zhang, Yao Chen, Xiangdong Gan, Zhiguang Huang, Minji Zou, Wenliang Fu, Weiwei Xing, Donggang Xu
SAK-HV is an anti-atherosclerosis recombinant fusion protein developed by our lab. Our study determined that SAK-HV promoted macrophage proliferation, of which the mechanism was explored by both RAW264.7 cells and primary macrophages. Mass spectrometric analysis and co-immunoprecipitation were combined to screen the SAK-HV-interacting proteins in RAW264.7 cells. Confocal microscopy was adopted to detect the localization of SAK-HV in cells. The results indicated that SAK-HV triggered macrophage proliferation via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinases (JNK) pathways by its SAK-mutant functional domain...
April 19, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28162934/s-pombe-uba1-ubc15-structure-reveals-a-novel-regulatory-mechanism-of-ubiquitin-e2-activity
#16
Zongyang Lv, Kimberly A Rickman, Lingmin Yuan, Katelyn Williams, Shanmugam Panneer Selvam, Alec N Woosley, Philip H Howe, Besim Ogretmen, Agata Smogorzewska, Shaun K Olsen
Ubiquitin (Ub) E1 initiates the Ub conjugation cascade by activating and transferring Ub to tens of different E2s. How Ub E1 cooperates with E2s that differ substantially in their predicted E1-interacting residues is unknown. Here, we report the structure of S. pombe Uba1 in complex with Ubc15, a Ub E2 with intrinsically low E1-E2 Ub thioester transfer activity. The structure reveals a distinct Ubc15 binding mode that substantially alters the network of interactions at the E1-E2 interface compared to the only other available Ub E1-E2 structure...
February 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28134249/orthogonal-ubiquitin-transfer-identifies-ubiquitination-substrates-under-differential-control-by-the-two-ubiquitin-activating-enzymes
#17
Xianpeng Liu, Bo Zhao, Limin Sun, Karan Bhuripanyo, Yiyang Wang, Yingtao Bi, Ramana V Davuluri, Duc M Duong, Dhaval Nanavati, Jun Yin, Hiroaki Kiyokawa
Protein ubiquitination is mediated sequentially by ubiquitin activating enzyme E1, ubiquitin conjugating enzyme E2 and ubiquitin ligase E3. Uba1 was thought to be the only E1 until the recent identification of Uba6. To differentiate the biological functions of Uba1 and Uba6, we applied an orthogonal ubiquitin transfer (OUT) technology to profile their ubiquitination targets in mammalian cells. By expressing pairs of an engineered ubiquitin and engineered Uba1 or Uba6 that were generated for exclusive interactions, we identified 697 potential Uba6 targets and 527 potential Uba1 targets with 258 overlaps...
January 30, 2017: Nature Communications
https://www.readbyqxmd.com/read/27935244/different-enzymatic-processing-of-%C3%AE-phosphoramidate-and-%C3%AE-phosphoester-modified-atp-analogues
#18
Susanne Ermert, Stephan M Hacker, Alexander Buntru, Martin Scheffner, Christof R Hauck, Andreas Marx
Monitoring the activity of ATP-consuming enzymes provides the basis for elucidating their modes of action and regulation. Although a number of ATP analogues have been developed for this, their scope is restricted because of the limited acceptance by respective enzymes. In order to clarify which kind of phosphate-modified ATP analogues are accepted by the α-β-phosphoanhydride-cleaving ubiquitin-activating enzyme 1 (UBA1) and the β-γ-phosphoanhydride-cleaving focal adhesion kinase (FAK), we tested phosphoramidate- and phosphoester-modified ATP analogues...
February 16, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/27699224/systemic-restoration-of-uba1-ameliorates-disease-in-spinal-muscular-atrophy
#19
Rachael A Powis, Evangelia Karyka, Penelope Boyd, Julien Côme, Ross A Jones, Yinan Zheng, Eva Szunyogova, Ewout J N Groen, Gillian Hunter, Derek Thomson, Thomas M Wishart, Catherina G Becker, Simon H Parson, Cécile Martinat, Mimoun Azzouz, Thomas H Gillingwater
The autosomal recessive neuromuscular disease spinal muscular atrophy (SMA) is caused by loss of survival motor neuron (SMN) protein. Molecular pathways that are disrupted downstream of SMN therefore represent potentially attractive therapeutic targets for SMA. Here, we demonstrate that therapeutic targeting of ubiquitin pathways disrupted as a consequence of SMN depletion, by increasing levels of one key ubiquitination enzyme (ubiquitin-like modifier activating enzyme 1 [UBA1]), represents a viable approach for treating SMA...
July 21, 2016: JCI Insight
https://www.readbyqxmd.com/read/27626685/pathological-complete-response-after-cisplatin-neoadjuvant-therapy-is-associated-with-the-downregulation-of-dna-repair-genes-in-brca1-associated-triple-negative-breast-cancers
#20
Pawel Domagala, Jolanta Hybiak, Janusz Rys, Tomasz Byrski, Cezary Cybulski, Jan Lubinski
Pathologic complete response (pCR) after neoadjuvant chemotherapy is considered a suitable surrogate marker of treatment efficacy in patients with triple-negative breast cancers (TNBCs). However, the molecular mechanisms underlying pCR as a result of such treatment remain obscure. Using real-time PCR arrays we compared the expression levels of 120 genes involved in the main mechanisms of DNA repair in 43 pretreatment biopsies of BRCA1-associated TNBCs exhibiting pCR and no pathological complete response (non-pCR) after neoadjuvant chemotherapy with cisplatin...
October 18, 2016: Oncotarget
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