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20S proteasome

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https://www.readbyqxmd.com/read/27921229/an-extracellular-proteasome-releases-endostatin-from-human-collagen-xviii
#1
Maria L V Reiss-Pistilli, Detlef Schuppan, Madalena M S Barroso, Iranaia Assunção-Miranda, Shirley Farias, Letícia Lery, Michael Bauer, Luiz Juliano, Maria A Juliano, Tatiana Coelho-Sampaio
Endostatin is a potent anti-angiogenic and anti-tumor protein capable of regressing tumors without inducing acquired resistance. Since it is a fragment of the parental molecule, collagen XVIII, its endogenous production depends on the activity of a specific proteolytic enzyme. While such an enzyme has been described in mice, a human counterpart has not been identified so far. Here, we searched for this enzyme by using a fluorescence resonance energy transfer peptide containing the cleavage site of human collagen XVIII...
December 5, 2016: Angiogenesis
https://www.readbyqxmd.com/read/27917682/the-preclinical-discovery-and-development-of-bortezomib-for-the-treatment-of-mantle-cell-lymphoma
#2
Richard Arkwright, Tri Minh Pham, Jeffrey A Zonder, Q Ping Dou
Introduction- Mantle cell lymphoma (MCL) is an incurable, often aggressive B-cell malignancy. Bortezomib (BTZ), the 20S proteasome inhibitor was originally developed and approved for treatment of relapsed refractory multiple myeloma, and subsequently approved for treatment of MCL. BTZ's single-agent activity induces clinical responses in approximately one-third of relapsed MCL patients. BTZ-containing combination therapies have further improved the quality and duration of clinical responses compared to standard chemotherapies in previously untreated MCL patients...
December 3, 2016: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/27916088/-hyperoxia-induces-aecii-apoptosis-of-premature-rats-by-reducing-the-activity-of-20s-proteasome
#3
Yanyu Zhang, Hongyan Lu, Huimin Ju, Ming Chang, Qiuxia Wang, Qiang Zhang
Objective To establish a hyperoxia-exposed cell damage model of primary cultured premature rat alveolar type II epithelial cells (AECIIs) and investigate the effect of hyperoxia on ubiquitinated protein degradation and apoptosis of AECIIs. Methods Primary cultured premature rat AECIIs in vitro were divided into air group and hyperoxia group, which were exposed to air and 950 mL/L O2, respectively. After 24-, 48- and 72-hour exposure, isothiocyanate-labeled annexinV/propidium iodide (annexinV-FITC/PI) double staining combined with flow cytometry was utilized to detect the apoptosis of AECIIs...
December 2016: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/27889629/terminal-functionalized-thiourea-containing-dipeptides-as-multidrug-resistance-reversers-that-target-20s-proteasome-and-cell-proliferation
#4
Jian-Mei Qin, Ri-Zhen Huang, Gui-Yang Yao, Zhi-Xin Liao, Ying-Ming Pan, Heng-Shan Wang
A series of inhibitors of 20S proteasome based on terminal functionalized dipeptide derivatives containing the thiourea moiety were synthesized and evaluated for inhibition of 20S proteasome and the effects of multidrug-resistance reversers. These compounds exhibited significant selectivity to the β5-subunit of the human 20S proteasome with IC50 values at submicromolar concentrations. A docking study of the most active compound 6i revealed key interactions between 6i and the active site of the 20S proteasome in which the thiourea moiety and a nitro group were important for improving activity...
November 11, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27884201/nickel-pyrithione-induces-apoptosis-in-chronic-myeloid-leukemia-cells-resistant-to-imatinib-via-both-bcr-abl-dependent-and-bcr-abl-independent-mechanisms
#5
Xiaoying Lan, Chong Zhao, Xin Chen, Peiquan Zhang, Dan Zang, Jinjie Wu, Jinghong Chen, Huidan Long, Li Yang, Hongbiao Huang, Bing Z Carter, Xuejun Wang, Xianping Shi, Jinbao Liu
BACKGROUND: Acquired imatinib (IM) resistance is frequently characterized by Bcr-Abl mutations that affect IM binding and kinase inhibition in patients with chronic myelogenous leukemia (CML). Bcr-Abl-T315I mutation is the predominant mechanism of the acquired resistance to IM. Therefore, it is urgent to search for additional approaches and targeting strategies to overcome IM resistance. We recently reported that nickel pyrithione (NiPT) potently inhibits the ubiquitin proteasome system via targeting the 19S proteasome-associated deubiquitinases (UCHL5 and USP14), without effecting on the 20S proteasome...
November 25, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27881056/recent-patents-on-proteasome-inhibitors-of-natural-origin
#6
Daniela Correia da Silva, Paula B Andrade, Vera Ribeiro, Patrícia Valentão, David Pereira
BACKGROUND: The proteasome is the major proteolytic site on the eukaryotic cell, degrading most of its short-lived or misfolded polypeptides. The ubiquitin-proteasome pathway has been found to play a fundamental role in the development of several pathologies, from cancer to neurodegenerative diseases, or even retroviral infections. Nature remains a powerful source for the discovery of bioactive compounds. Recently, a number of molecules of natural origin, as well as natural product derivatives, have been described as proteasome inhibitors...
November 23, 2016: Recent Patents on Anti-cancer Drug Discovery
https://www.readbyqxmd.com/read/27872216/the-effect-of-temperature-adaptation-on-the-ubiquitin-proteasome-pathway-in-notothenioid-fishes
#7
Anne E Todgham, Timothy A Crombie, Gretchen E Hofmann
There is an accumulating body of evidence suggesting that the sub-zero Antarctic marine environment places physiological constraints on protein homeostasis. Levels of ubiquitin (Ub)-conjugated proteins, 20S proteasome activity and mRNA expression of many proteins involved in both the ubiquitin (Ub) tagging of damaged proteins as well as the different complexes of the 26S proteasome were measured to examine whether there is thermal compensation of the Ub-proteasome pathway in Antarctic fishes to better understand the efficiency of the protein degradation machinery in polar species...
November 21, 2016: Journal of Experimental Biology
https://www.readbyqxmd.com/read/27834734/nano-liquid-chromatography-orbitrap-ms-based-quantitative-proteomics-reveals-differences-between-the-mechanisms-of-action-of-carnosic-acid-and-carnosol-in-colon-cancer-cells
#8
Alberto Valdés, Virginia García-Cañas, Konstantin A Artemenko, Carolina Simó, Jonas Bergquist, Alejandro Cifuentes
Carnosic acid (CA) and carnosol (CS) are two structurally related diterpenes present in rosemary herb (Rosmarinus officinalis). Although several studies have demonstrated that both diterpenes can scavenge free radicals and interfere in cellular processes such as cell proliferation, they may not necessarily exert the same effects at the molecular level. In this work, a shotgun proteomics study based on stable isotope dimethyl labeling (DML) and nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) has been performed to identify the relative changes in proteins and to gain some light on the specific molecular targets and mechanisms of action of CA and CS in HT-29 colon cancer cells...
November 10, 2016: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/27833849/rrp15-affects-cell-cycle-proliferation-and-apoptosis-in-nih3t3-cells
#9
Tao Wu, Mei-Xia Ren, Guo-Ping Chen, Zheng-Ming Jin, Gang Wang
Riken 2810430M08 (hereinafter referred to as Rrp15) is a newly identified and reported gene from the mouse genome. In our previous work, we found that the gene had a relationship with the proliferation and activation of T cells. Rrp15 protein is highly homologous with RRP15 (budding yeast), which has an important role in ribosomal RNA processing. We explored the potential function of Rrp15 in apoptosis, cell proliferation, and its involvement with RNA in the nucleus. We constructed a knockdown of the Rrp15 gene in NIH3T3 cells and then performed real-time PCR, western blotting, flow cytometry, and immunofluorescence to determine the function of the Rrp15 gene...
November 2016: FEBS Open Bio
https://www.readbyqxmd.com/read/27833096/immunoproteasome-induction-is-suppressed-in-hepatitis-c-virus-infected-cells-in-a-protein-kinase-r-dependent-manner
#10
In Soo Oh, Kathrin Textoris-Taube, Pil Soo Sung, Wonseok Kang, Xenia Gorny, Thilo Kähne, Seon-Hui Hong, Young Joon Choi, Clemens Cammann, Michael Naumann, Jong Hoon Kim, Su-Hyung Park, Ook Joon Yoo, Peter M Kloetzel, Ulrike Seifert, Eui-Cheol Shin
By changing the relative abundance of generated antigenic peptides through alterations in the proteolytic activity, interferon (IFN)-γ-induced immunoproteasomes influence the outcome of CD8(+) cytotoxic T lymphocyte responses. In the present study, we investigated the effects of hepatitis C virus (HCV) infection on IFN-γ-induced immunoproteasome expression using a HCV infection cell culture system. We found that, although IFN-γ induced the transcriptional expression of mRNAs encoding the β1i/LMP2, β2i/MECL-1 and β5i/LMP7 immunoproteasome subunits, the formation of immunoproteasomes was significantly suppressed in HCV-infected cells...
November 11, 2016: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/27833017/assembly-of-proteasome-subunits-into-non-canonical-complexes-in%C3%A2-vivo
#11
Lindsay J Hammack, Andrew R Kusmierczyk
Proteasomes exist in all domains of life. In general, they are comprised of a compartmentalized protease whose activity is modulated by one or more regulatory complexes with which it interacts. The quaternary structure of this compartmentalized protease, called the 20S proteasome, is absolutely conserved and consists of four heptameric rings stacked coaxially. The rings are made of structurally related α and β subunits. In eukaryotes, assembly factors chaperone the α and β subunits during 20S biogenesis...
November 8, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27830089/proteasome-activators-pa28%C3%AE-and-pa28%C3%AE-govern-development-of-microvascular-injury-in-diabetic-nephropathy-and-retinopathy
#12
Saeed Yadranji Aghdam, Ali Mahmoudpour
Diabetic nephropathy (DN) and diabetic retinopathy (DR) are major complications of type 1 and type 2 diabetes. DN and DR are mainly caused by injury to the perivascular supporting cells, the mesangial cells within the glomerulus, and the pericytes in the retina. The genes and molecular mechanisms predisposing retinal and glomerular pericytes to diabetic injury are poorly characterized. In this study, the genetic deletion of proteasome activator genes, PA28α and PA28β genes, protected the diabetic mice in the experimental STZ-induced diabetes model against renal injury and retinal microvascular injury and prolonged their survival compared with wild type STZ diabetic mice...
2016: International Journal of Nephrology
https://www.readbyqxmd.com/read/27795417/the-potyviral-silencing-suppressor-protein-vpg-mediates-degradation-of-sgs3-via-ubiquitination-and-autophagy-pathways
#13
Xiaofei Cheng, Aiming Wang
: RNA silencing is an innate antiviral immunity of plants and animals. To counteract this host immune response, viruses have evolved an effective strategy to protect themselves by expression of viral suppressors of RNA silencing (VSRs). Most potyviruses encode two VSRs, the helper component-proteinase (HC-Pro) and the viral genome-linked protein (VPg). The molecular biology of the former has been well characterized, whereas how VPg exerts its function in RNA silencing suppression is yet to be understood...
October 19, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27795298/fabp4-ap2-regulates-macrophage-redox-signaling-and-inflammasome-activation-via-control-of-ucp2
#14
Kaylee A Steen, Hongliang Xu, David A Bernlohr
Obesity-linked metabolic disease is mechanistically associated with the accumulation of proinflammatory macrophages in adipose tissue leading to increased reactive oxygen species (ROS) production and low-grade, chronic inflammation. Previous work has demonstrated that deletion of the adipocyte fatty acid-binding protein (FABP4/aP2) uncouples obesity from inflammation via up-regulation of the uncoupling protein 2 (UCP2). Herein we demonstrate that ablation of FABP4/aP2 regulates systemic redox capacity, reduces cellular protein sulfhydryl oxidation and in particular, oxidation of mitochondrial protein cysteine residues...
October 17, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27769033/urea-containing-peptide-boronic-acids-as-potent-proteasome-inhibitors
#15
Li-Qiang Han, Xia Yuan, Xing-Yu Wu, Ri-Dong Li, Bo Xu, Qing Cheng, Zhen-Ming Liu, Tian-Yan Zhou, Hao-Yun An, Xin Wang, Tie-Ming Cheng, Ze-Mei Ge, Jing-Rong Cui, Run-Tao Li
A novel class of urea-containing peptide boronic acids as proteasome inhibitors was designed by introducing a urea scaffold to replace an amido bond. Compounds were synthesized and their antitumor activities were evaluated. After two rounds of optimizations, the compound I-14 was found to be a potent proteasome inhibitor. Compared with Bortezomib, I-14 showed higher potency against the chymotrypsin-like activity of human 20S proteasome (IC50 < 1 pM), similar potency against four different cancer cell lines (IC50 < 10 nM), and better pharmacokinetic profile...
January 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27704767/boc3arg-linked-ligands-induce-degradation-by-localizing-target-proteins-to-the-20s-proteasome
#16
Yuntao Shi, Marcus J C Long, Masha M Rosenberg, Shican Li, Aimee Kobjack, Philip Lessans, Rory T Coffey, Lizbeth Hedstrom
Targeted protein degradation is a promising strategy for drug design and functional assessment. Several small molecule approaches have been developed that localize target proteins to ubiquitin ligases, inducing ubiquitination and subsequent degradation by the 26S proteasome. We discovered that the degradation of a target protein can also be induced by a recognition ligand linked to tert-butyl carbamate (Boc3)-protected arginine (B3A). Here we show that this process requires the proteasome, but does not involve ubiquitination of the target protein...
October 5, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27697639/effect-of-notch1-2-3-genes-silicing-on-nf-%C3%AE%C2%BAb-signaling-pathway-of-macrophages-in-patients-with-atherosclerosis
#17
Zhong-Bao Ruan, Xing-Li Fu, Wei Li, Jun Ye, Ru-Zhu Wang, Li Zhu
BACKGROUND: Notch and NF-κB signaling pathways both play important roles in the regulation of atherosclerosis (AS). However, the mechanisms of notch and NF-κB signaling pathways on AS are still unclear. In this study, we aimed to investigate the effects of notch1,2,3 genes silicing by siRNA on notch and NF-κB signaling pathways of macrophages in patients with atherosclerosis (AS), so as to seek the treatment of AS from genetic perspective. METHODS: Peripheral blood mononuclears of 31 patients with AS were isolated by density gradient centrifugation and transformed by PMA to macrophages...
September 30, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/27687480/enzymatic-activities-of-circulating-plasma-proteasomes-in-newly-diagnosed-multiple-myeloma-patients-treated-with-carfilzomib-lenalidomide-and-dexamethasone
#18
Elisabet E Manasanch, Carlos Fernández de Larrea, Adriana Zingone, Seth M Steinberg, Mary Kwok, Nishant Tageja, Manisha Bhutani, Dickran Kazandjian, Mark Roschewski, Peter Wu, George Carter, Diamond Zuchlinski, Marcia Mulquin, Liz Lamping, Rene Costello, Deborah Burton, Lindsey Gil, William D Figg, Irina Maric, Katherine R Calvo, Constance Yuan, Maryalice Stetler-Stevenson, Neha Korde, Ola Landgren
The proteasome inhibitor carfilzomib is highly effective in the treatment of multiple myeloma. It irreversibly binds the chymotrypsin-like active site in the β5 subunit of the 20S proteasome. Despite impressive response rates when carfilzomib is used in combination with immunomodulatory agents in newly diagnosed multiple myeloma patients; no biomarker exists to accurately predict response and clinical outcomes. We prospectively assessed the activity in peripheral blood of the chymotrypsin-like (CHYM), caspase-like (CASP) and trypsin-like (TRYP) proteolytic sites in 45 newly diagnosed multiple myeloma patients treated with eight cycles of carfilzomib, lenalidomide and dexamethasone (CRd) (NCT01402284)...
August 9, 2016: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/27648923/human-telomerase-reverse-transcriptase-htert-positively-regulates-26s-proteasome-activity
#19
Eunju Im, Jong Bok Yoon, Han-Woong Lee, Kwang Chul Chung
Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase, an RNA-dependent DNA polymerase that elongates telomeric DNA. hTERT displays several extra-telomeric functions that are independent of its telomere-regulatory function, including tumor progression and neuronal cell death regulation. In this study, we evaluated these additional hTERT non-telomeric functions. We determined that hTERT interacts with several 19S and 20S proteasome subunits. The 19S regulatory particle and 20S core particle are part of 26S proteasome complex, which plays a central role in ubiquitin-dependent proteolysis...
September 20, 2016: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/27647735/four-domains-of-ada1-form-a-heterochromatin-boundary-through-different-mechanisms
#20
Kazuma Kamata, Kaori Shinmyozu, Jun-Ichi Nakayama, Masanori Hatashita, Hiroyuki Uchida, Masaya Oki
In eukaryotic cells, there are two chromatin states, silenced and active, and the formation of a so-called boundary plays a critical role in demarcating these regions; however, the mechanisms underlying boundary formation are not well understood. In this study, we focused on S. cerevisiae ADA1, a gene previously shown to encode a protein with a robust boundary function. Ada1 is a component of the histone modification complex Spt-Ada-Gcn5-acetyltransferase (SAGA) and the SAGA-like (SLIK) complex, and it helps to maintain the integrity of these complexes...
October 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
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