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20S proteasome

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https://www.readbyqxmd.com/read/28719185/small-molecule-enhancement-of-20s-proteasome-activity-targets-intrinsically-disordered-proteins
#1
Corey L Jones, Evert Njomen, Benita Sjogren, Thomas S Dexheimer, Jetze J Tepe
The 20S proteasome is the main protease for degradation of oxidatively damaged and intrinsically disordered proteins. When accumulation of disordered or oxidatively damaged proteins exceed proper clearance in neurons, imbalanced pathway signaling or aggregation occurs, which have been implicated in the pathogenesis of several neurological disor-ders. Screening of the NIH Clinical Collection and Prestwick libraries identified the neuroleptic agent chlorpromazine as a lead agent capable of enhancing 20S proteasome activity...
July 18, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28710470/deviation-of-the-typical-aaa-substrate-threading-pore-prevents-fatal-protein-degradation-in-yeast-cdc48
#2
Masatoshi Esaki, Md Tanvir Islam, Naoki Tani, Teru Ogura
Yeast Cdc48 is a well-conserved, essential chaperone of ATPases associated with diverse cellular activity (AAA) proteins, which recognizes substrate proteins and modulates their conformations to carry out many cellular processes. However, the fundamental mechanisms underlying the diverse pivotal roles of Cdc48 remain unknown. Almost all AAA proteins form a ring-shaped structure with a conserved aromatic amino acid residue that is essential for proper function. The threading mechanism hypothesis suggests that this residue guides the intrusion of substrate proteins into a narrow pore of the AAA ring, thereby becoming unfolded...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28698635/inhibitory-effects-of-local-anesthetics-on-the-proteasome-and-their-biological-actions
#3
Udin Bahrudin, Masaki Unno, Kazuya Nishio, Akiko Kita, Peili Li, Masaru Kato, Masashi Inoue, Shunichi Tsujitani, Takuto Murakami, Rina Sugiyama, Yasushi Saeki, Yuji Obara, Keiji Tanaka, Hiroshi Yamaguchi, Isao Sakane, Yasushi Kawata, Toshiyuki Itoh, Haruaki Ninomiya, Ichiro Hisatome, Yukio Morimoto
Local anesthetics (LAs) inhibit endoplasmic reticulum-associated protein degradation, however the mechanisms remain elusive. Here, we show that the clinically used LAs pilsicainide and lidocaine bind directly to the 20S proteasome and inhibit its activity. Molecular dynamic calculation indicated that these LAs were bound to the β5 subunit of the 20S proteasome, and not to the other active subunits, β1 and β2. Consistently, pilsicainide inhibited only chymotrypsin-like activity, whereas it did not inhibit the caspase-like and trypsin-like activities...
July 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28694661/relevance-of-proteolysis-and-proteasome-activation-in-fatty-liver-graft-preservation-an-institut-georges-lopez-1-vs-university-of-wisconsin-appraisal
#4
Mohamed Amine Zaouali, Arnau Panisello-Roselló, Alexandre Lopez, Carlos Castro Benítez, Emma Folch-Puy, Agustín García-Gil, Teresa Carbonell, René Adam, Joan Roselló-Catafau
AIM: To compare liver proteolysis and proteasome activation in steatotic liver grafts conserved in University of Wisconsin (UW) and Institut Georges Lopez-1 (IGL-1) solutions. METHODS: Fatty liver grafts from male obese Zücker rats were conserved in UW and IGL-1 solutions for 24 h at 4 °Cand subjected to "ex vivo" normo-thermic perfusion (2 h; 37 °C). Liver proteolysis in tissue specimens and perfusate was measured by reverse-phase high performance liquid chromatography...
June 21, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28656878/proteasome-beta-4-subunit-contributes-to-the-development-of-melanoma-and-is-regulated-by-mir-148b
#5
Xiaodong Zhang, Di Lin, Yueqin Lin, Hongqing Chen, Minghua Zou, Shan Zhong, Xuefeng Yi, Siqi Han
The proteasome beta-4 subunit is required for the assembly of 20S proteasome complex, forming a pivotal component for the ubiquitin-proteasome system. Emerging evidence indicates that proteasome beta-4 subunit may be involved in underlying progression and mechanisms of malignancies. However, the role of proteasome beta-4 subunit in melanoma is currently unknown. Here, we reported that proteasome beta-4 subunit was markedly upregulated in human melanoma tissues and cells, compared with normal skin samples. High proteasome beta-4 subunit levels were significantly associated with poor overall survival in patients with melanoma...
June 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28646424/proteasome-properties-of-hemocytes-differ-between-the-whiteleg-shrimp-penaeus-vannamei-and-the-brown-shrimp-crangon-crangon-crustacea-decapoda
#6
Sandra Götze, Reinhard Saborowski, Oliviert Martínez-Cruz, Adriana Muhlia-Almazán, Arturo Sánchez-Paz
Crustaceans are intensively farmed in aquaculture facilities where they are vulnerable to parasites, bacteria, or viruses, often severely compromising the rearing success. The ubiquitin-proteasome system (UPS) is crucial for the maintenance of cellular integrity. Analogous to higher vertebrates, the UPS of crustaceans may also play an important role in stress resistance and pathogen defense. We studied the general properties of the proteasome system in the hemocytes of the whiteleg shrimp, Penaeus vannamei, and the European brown shrimp Crangon crangon...
June 23, 2017: Cell Stress & Chaperones
https://www.readbyqxmd.com/read/28634643/acute-high-caffeine-exposure-increases-autophagic-flux-and-reduces-protein-synthesis-in-c2c12-skeletal-myotubes
#7
M A Hughes, R M Downs, G W Webb, C L Crocker, S T Kinsey, Bradley L Baumgarner
Caffeine is a highly catabolic dietary stimulant. High caffeine concentrations (1-10 mM) have previously been shown to inhibit protein synthesis and increase protein degradation in various mammalian cell lines. The purpose of this study was to examine the effect of short-term caffeine exposure on cell signaling pathways that regulate protein metabolism in mammalian skeletal muscle cells. Fully differentiated C2C12 skeletal myotubes either received vehicle (DMSO) or 5 mM caffeine for 6 h. Our analysis revealed that caffeine promoted a 40% increase in autolysosome formation and a 25% increase in autophagic flux...
June 20, 2017: Journal of Muscle Research and Cell Motility
https://www.readbyqxmd.com/read/28617443/bilirubin-neurotoxicity-is-associated-with-proteasome-inhibition
#8
Hongbiao Huang, Mingxing Guo, Ningning Liu, Chong Zhao, Haoyu Chen, Xiaoli Wang, Siyan Liao, Ping Zhou, Yuning Liao, Xin Chen, Xiaoying Lan, Jinghong Chen, Dacai Xu, Xiaofen Li, Xianping Shi, Li Yu, Yuqiang Nie, Xuejun Wang, Chang-E Zhang, Jinbao Liu
The molecular mechanism underlying bilirubin neurotoxicity remains obscure. Ubiquitin-proteasome system-mediated proteolysis is pivotal to virtually all cellular processes and cell survival. Here we report for the first time that bilirubin at a clinically relevant elevated level impairs proteasomal function via inhibiting both the 19S proteasome-associated deubiquitinases (USP14 and UCHL5) and the chymotrypsin-like (CT-like) peptidase activity of 20S proteasomes, thereby contributing to bilirubin neurotoxicity...
June 15, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28583440/proteasome-structure-and-assembly
#9
REVIEW
Lauren Budenholzer, Chin Leng Cheng, Yanjie Li, Mark Hochstrasser
The eukaryotic 26S proteasome is a large multi-subunit complex that degrades the majority of proteins in the cell under normal conditions. The 26S proteasome can be divided into two subcomplexes: the 19S regulatory particle (RP) and the 20S core particle (CP). Most substrates are first covalently modified by ubiquitin, which then directs them to the proteasome. The function of the RP is to recognize, unfold, deubiquitylate and translocate substrates into the CP, which contains the proteolytic sites of the proteasome...
June 2, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28581522/blockade-of-deubiquitylating-enzyme-rpn11-triggers-apoptosis-in-multiple-myeloma-cells-and-overcomes-bortezomib-resistance
#10
Y Song, S Li, A Ray, D S Das, J Qi, M K Samur, Y-T Tai, N Munshi, R D Carrasco, D Chauhan, K C Anderson
Proteasome inhibition is an effective therapy for multiple myeloma (MM) patients; however, the emergence of drug resistance is common. Novel therapeutic strategies to overcome proteasome inhibitor resistance are needed. In this study, we examined whether targeting deubiquitylating (DUB) enzymes upstream of 20S proteasome overcomes proteasome inhibitor resistance. Gene expression analysis, immunohistochemical studies of MM patient bone marrow, reverse transcription-PCR and protein analysis show that Rpn11/POH1, a DUB enzyme upstream of 20S proteasome, is more highly expressed in patient MM cells than in normal plasma cells...
June 5, 2017: Oncogene
https://www.readbyqxmd.com/read/28580914/high-resolution-cryo-em-proteasome-structures-in-drug-development
#11
Edward P Morris, Paula C A da Fonseca
With the recent advances in biological structural electron microscopy (EM), protein structures can now be obtained by cryo-EM and single-particle analysis at resolutions that used to be achievable only by crystallographic or NMR methods. We have explored their application to study protein-ligand interactions using the human 20S proteasome, a well established target for cancer therapy that is also being investigated as a target for an increasing range of other medical conditions. The map of a ligand-bound human 20S proteasome served as a proof of principle that cryo-EM is emerging as a realistic approach for more general structural studies of protein-ligand interactions, with the potential benefits of extending such studies to complexes that are unfavourable to other methods and allowing structure determination under conditions that are closer to physiological, preserving ligand specificity towards closely related binding sites...
June 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28566998/relative-contribution-of-prolyl-hydroxylase-dependent-and-independent-degradation-of-hif-1alpha-by-proteasomal-pathways-in-cerebral-ischemia
#12
Yomna Badawi, Honglian Shi
Hypoxia inducible factor-1 (HIF-1) is a key regulator in hypoxia and can determine the fate of brain cells during ischemia. However, the mechanism of HIF-1 regulation is still not fully understood in ischemic brains. We tested a hypothesis that both the 26S and the 20S proteasomal pathways were involved in HIF-1α degradation under ischemic conditions. Using in vitro ischemic model (oxygen and glucose deprivation) and a mouse model of middle cerebral artery occlusion, we tested effects of inhibitors of proteasomes and prolyl hydroxylase (PHD) on HIF-1α stability and brain injury in cerebral ischemia...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28560424/secretomic-profiling-of-cells-from-hollow-fiber-bioreactor-reveals-psma3-as-a-potential-cholangiocarcinoma-biomarker
#13
Chris Verathamjamras, Churat Weeraphan, Daranee Chokchaichamnankit, Kamolwan Watcharatanyatip, Pantipa Subhasitanont, Penchatr Diskul-Na-Ayudthaya, Kanokwan Mingkwan, Virat Luevisadpaibul, Somchai Chutipongtanate, Voraratt Champattanachai, Jisnuson Svasti, Chantragan Srisomsap
Cholangiocarcinoma (CCA), derived from the bile duct, occurs with a relatively high incidence in Northeast Thailand. Early diagnosis is still hampered by the lack of sufficient biomarkers. In recent years, biomarker discovery using secretomes has provided interesting results, including our studies on CCA secretomes, especially with three-dimensional cell cultures. Thus, cells cultured using the hollow fiber bioreactor (HFB) with 20 kDa molecular weight cut-off (MWCO) yielded higher quality and quantity of secretomes than those from conditioned media of the monolayer culture (MNC) system...
May 29, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28541292/long-range-allosteric-regulation-of-the-human-26s-proteasome-by-20s-proteasome-targeting-cancer-drugs
#14
David Haselbach, Jil Schrader, Felix Lambrecht, Fabian Henneberg, Ashwin Chari, Holger Stark
The proteasome holoenzyme is the major non-lysosomal protease; its proteolytic activity is essential for cellular homeostasis. Thus, it is an attractive target for the development of chemotherapeutics. While the structural basis of core particle (CP) inhibitors is largely understood, their structural impact on the proteasome holoenzyme remains entirely elusive. Here, we determined the structure of the 26S proteasome with and without the inhibitor Oprozomib. Drug binding modifies the energy landscape of conformational motion in the proteasome regulatory particle (RP)...
May 25, 2017: Nature Communications
https://www.readbyqxmd.com/read/28539385/phosphatase-ublcp1-controls-proteasome-assembly
#15
Shuangwu Sun, Sisi Liu, Zhengmao Zhang, Wang Zeng, Chuang Sun, Tao Tao, Xia Lin, Xin-Hua Feng
Ubiquitin-like domain-containing C-terminal domain phosphatase 1 (UBLCP1), an FCP/SCP phosphatase family member, was identified as the first proteasome phosphatase. UBLCP1 binds to proteasome subunit Rpn1 and dephosphorylates the proteasome in vitro However, it is still unclear which proteasome subunit(s) are the bona fide substrate(s) of UBLCP1 and the precise mechanism for proteasome regulation remains elusive. Here, we show that UBLCP1 selectively binds to the 19S regulatory particle (RP) through its interaction with Rpn1, but not the 20S core particle (CP) or the 26S proteasome holoenzyme...
May 2017: Open Biology
https://www.readbyqxmd.com/read/28536293/peroxisome-proliferator-activated-receptor-%C3%AE-agonism-attenuates-endotoxaemia-induced-muscle-protein-loss-and-lactate-accumulation-in%C3%A2-rats
#16
Hannah Crossland, Dumitru Constantin-Teodosiu, Sheila Gardiner, Paul Greenhaff
The peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (Rosi) appears to provide protection against organ dysfunction during endotoxaemia. We examined the potential benefits of Rosi on skeletal muscle protein maintenance and carbohydrate metabolism during lipopolysaccharide (LPS)-induced endotoxaemia. Sprague-Dawley rats were fed either standard chow (control) or standard chow containing Rosi (8.5±0.1 mg(.)kg(-1.)day(-1)) for two weeks before and during 24 h continuous intravenous infusion of LPS (15 μg(...
May 23, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/28508171/over-expression-of-tobacco-ubc1-encoding-a-ubiquitin-conjugating-enzyme-increases-cadmium-tolerance-by-activating-the-20s-26s-proteasome-and-by-decreasing-cd-accumulation-and-oxidative-stress-in-tobacco-nicotiana-tabacum
#17
Ramin Bahmani, DongGwan Kim, Byoung Doo Lee, Seongbin Hwang
Ubiquitin (Ub)-conjugating enzyme (UBC, E2) receives Ub from Ub-activating enzyme (E1) and transfers it to target proteins, thereby playing a key role in Ub/26S proteasome-dependent proteolysis. UBC has been reported to be involved in tolerating abiotic stress in plants, including drought, salt, osmotic and water stresses. To isolate the genes involved in Cd tolerance, we transformed WT (wild-type) yeast Y800 with a tobacco cDNA expression library and isolated a tobacco cDNA, NtUBC1 (Ub-conjugating enzyme), that enhances cadmium tolerance...
July 2017: Plant Molecular Biology
https://www.readbyqxmd.com/read/28502636/diabetogenic-agent-alloxan-is-a-proteasome-inhibitor
#18
Wenjuan Zhou, Lingling Wei, Ting Xiao, Chunyou Lai, Min Peng, Lingli Xu, Xiangwei Luo, Shaoping Deng, Fengxue Zhang
Alloxan has been used as a diabetogenic agent to induce diabetes. It selectively induces pancreatic β-cell death. The specific toxicity, however, is not fully understood. In this study, we observed the effect of alloxan on proteasome function. We found that alloxan caused the accumulation of ubiquitinated proteins in NRK cells through the inhibition of the proteolytic activities of the proteasome. Biochemistry experiments with purified 26S and 20S proteasomes revealed that alloxan directly acts on the chymotrypsin- and trypsin-like peptidase activities...
May 11, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28494385/l-leucine-dietary-supplementation-modulates-muscle-protein-degradation-and-increases-pro-inflammatory-cytokines-in-tumour-bearing-rats
#19
Bread Cruz, André Oliveira, Maria Cristina Cintra Gomes-Marcondes
Cancer cachexia is characterised by involuntary weight loss associated with systemic inflammation and metabolic changes. Studies aimed at maintaining lean body mass in cachectic tumour-bearing hosts have made important contributions reducing the number of deaths and improving the quality of life. In recent years, leucine has demonstrated effective action in maintaining lean body mass by decreasing muscle protein degradation. Currently, there is a growing need to understand how leucine stimulates protein synthesis and acts protectively in a cachectic organism...
May 8, 2017: Cytokine
https://www.readbyqxmd.com/read/28491076/a-proteomic-approach-suggests-unbalanced-proteasome-functioning-induced-by-the-growth-promoting-bacterium-kosakonia-radicincitans-in-arabidopsis
#20
Katja Witzel, Suayib Üstün, Monika Schreiner, Rita Grosch, Frederik Börnke, Silke Ruppel
Endophytic plant growth-promoting bacteria have significant impact on the plant physiology and understanding this interaction at the molecular level is of particular interest to support crop productivity and sustainable production systems. We used a proteomics approach to investigate the molecular mechanisms underlying plant growth promotion in the interaction of Kosakonia radicincitans DSM 16656 with Arabidopsis thaliana. Four weeks after the inoculation, the proteome of roots from inoculated and control plants was compared using two-dimensional gel electrophoresis and differentially abundant protein spots were identified by liquid chromatography tandem mass spectrometry...
2017: Frontiers in Plant Science
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