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20S proteasome

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
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
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
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
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
Anna Maria Santoro, Irene Monaco, Francesco Attanasio, Valeria Lanza, Giuseppe Pappalardo, Marianna Flora Tomasello, Alessandra Cunsolo, Enrico Rizzarelli, Ada De Luigi, Mario Salmona, Danilo Milardi
Due to their altered metabolism cancer cells are more sensitive to proteasome inhibition or changes of copper levels than normal cells. Thus, the development of copper complexes endowed with proteasome inhibition features has emerged as a promising anticancer strategy. However, limited information is available about the exact mechanism by which copper inhibits proteasome. Here we show that Cu(II) ions simultaneously inhibit the three peptidase activities of isolated 20S proteasomes with potencies (IC50) in the micromolar range...
2016: Scientific Reports
Hongjun Xie, Jie Wu
Silica nanoparticles (SiO2-NPs) are widely applied in diagnosis, imaging, and drug delivery of central nervous diseases. Previously, we found that SiO2-NPs enter the brain and, more specifically, the dopaminergic neurons in the striatum. Whether SiO2-NPs have neurotoxicity and contribute to development of Parkinson's disease (PD) remains unclear. In this study, we investigated the effect of SiO2-NPs on PC12 cells, a dopaminergic neuron-like cell line. We showed that SiO2-NPs up-regulated α-synuclein expression, and N-acetyl cysteine reduced α-synuclein...
October 25, 2016: Chemico-biological Interactions
R A Ferreira, C Roma-Rodrigues, L C Davies, I Sá-Correia, S Martins-Dias
Phragmites sp. is present worldwide in treatment wetlands though the mechanisms involved in the phytoremediation remain unclear. In this study a quantitative proteomic approach was used to study the prompt response and adaptation of Phragmites to the textile dyeing pollutant, Acid Orange 7 (AO7). Previously, it was demonstrated that AO7 could be successfully removed from wastewater and mineralized in a constructed wetland planted with Phragmites sp. This azo dye is readily taken up by roots and transported to the plant aerial part by the xylem...
September 1, 2016: Science of the Total Environment
Joseph D Racca, Yen-Shan Chen, Yanwu Yang, Nelson B Phillips, Michael A Weiss
A general problem is posed by analysis of transcriptional thresholds governing cell fate decisions in metazoan development. A model is provided by testis determination in therian mammals. Its key step, Sertoli cell differentiation in the embryonic gonadal ridge, is initiated by SRY, a Y-encoded architectural transcription factor. Mutations in human SRY cause gonadal dysgenesis leading to XY female development (Swyer syndrome). Here, we have characterized an inherited mutation compatible with either male or female somatic phenotypes as observed in an XY father and XY daughter, respectively...
October 14, 2016: Journal of Biological Chemistry
Alexey V Morozov, Alexandra A Kulikova, Tatiana M Astakhova, Vladimir A Mitkevich, Ksenia M Burnysheva, Alexei A Adzhubei, Pavel A Erokhov, Michail B Evgen'ev, Natalia P Sharova, Vadim L Karpov, Alexander A Makarov
Accumulation of amyloid-β (Aβ) in neurons accompanies Alzheimer's disease progression. In the cytoplasm Aβ influences activity of proteasomes, the multisubunit protein complexes that hydrolyze the majority of intracellular proteins. However, the manner in which Aβ affects the proteolytic activity of proteasomes has not been established. In this study the effect of Aβ42 and Aβ42 with isomerized Asp7 on activity of different forms of proteasomes has been analyzed. It has been shown that Aβ peptides efficiently reduce activity of the 20S proteasomes, but increase activity of the 20S proteasomes capped with the 19S and/or 11S regulators...
September 6, 2016: Journal of Alzheimer's Disease: JAD
A Mehdad, G Brumana, A A Souza, Jarg Barbosa, M M Ventura, S M de Freitas
Proteasome inhibitors are emerging as a new class of chemopreventive agents and have gained huge importance as potential pharmacological tools in breast cancer treatment. Improved understanding of the role played by proteases and their specific inhibitors in humans offers novel and challenging opportunities for preventive and therapeutic intervention. In this study, we demonstrated that the Bowman-Birk protease inhibitor from Vigna unguiculata seeds, named black-eyed pea trypsin/chymotrypsin Inhibitor (BTCI), potently suppresses human breast adenocarcinoma cell viability by inhibiting the activity of proteasome 20S...
2016: Cell Death Discovery
Maria Vaiou, Evanthia Pangou, Panagiotis Liakos, Nikos Sakellaridis, George Vassilopoulos, Konstantinos Dimas, Christos Papandreou
PURPOSE: Bortezomib (BTZ) is used for the treatment of multiple myeloma (MM). However, a significant proportion of patients may be refractory to the drug. This study aimed to investigate whether the endothelin (ET-1) axis may act as an escape mechanism to treatment with bortezomib in MM cells. METHODS: NCI-H929 and RPMI-8226 (human MM cell lines) were cultured with or without ET-1, BTZ, and inhibitors of the endothelin receptors. ET-1 levels were determined by ELISA, while the protein levels of its receptors and of the PI3K and MAPK pathways' components by western blot...
October 2016: Journal of Cancer Research and Clinical Oncology
Gina Sanchez, Daniela Berrios, Ivonne Olmedo, Javier Pezoa, Jaime A Riquelme, Luis Montecinos, Zully Pedrozo, Paulina Donoso
Inhibitors of the ubiquitin-proteasome system improve hemodynamic parameters and decrease the infarct size after ischemia reperfusion. The molecular basis of this protection is not fully understood since most available data report inhibition of the 26 proteasome after ischemia reperfusion. The decrease in cellular ATP levels during ischemia leads to the dissociation of the 26S proteasome into the 19S regulatory complex and the 20S catalytic core, which results in protein degradation independently of ubiquitination...
2016: PloS One
(no author information available yet)
Crystal structures of the 20S proteasome bound to inhibitors elucidate the mechanisms of inhibition.
October 2016: Cancer Discovery
Krystyna Oracz, Marlena Stawska
Each step of the seed-to-seed cycle of plant development including seed germination is characterized by a specific set of proteins. The continual renewal and/or replacement of these biomolecules are crucial for optimal plant adaptation. As proteins are the main effectors inside the cells, their levels need to be tightly regulated. This is partially achieved by specific proteolytic pathways via multicatalytic protease complexes defined as 20S and 26S proteasomes. In plants, the 20S proteasome is responsible for degradation of carbonylated proteins, while the 26S being a part of ubiquitin-proteasome pathway is known to be involved in proteolysis of phytohormone signaling regulators...
2016: Frontiers in Plant Science
Sandra Reeg, Tobias Jung, José P Castro, Kelvin J A Davies, Andrea Henze, Tilman Grune
One hallmark of aging is the accumulation of protein aggregates, promoted by the unfolding of oxidized proteins. Unraveling the mechanism by which oxidized proteins are degraded may provide a basis to delay the early onset of features, such as protein aggregate formation, that contribute to the aging phenotype. In order to prevent aggregation of oxidized proteins, cells recur to the 20S proteasome, an efficient turnover proteolysis complex. It has previously been shown that upon oxidative stress the 26S proteasome, another form, dissociates into the 20S form...
August 3, 2016: Free Radical Biology & Medicine
Rex Shun Chiu, Shiyue Pan, Rongmin Zhao, Sonia Gazzarrini
During germination, endogenous and environmental factors trigger changes in the transcriptome, translatome and proteome to break dormancy. In Arabidopsis thaliana, the ubiquitin proteasome system (UPS) degrades proteins that promote dormancy to allow germination. While research on the UPS has focused on the identification of proteasomal substrates, little information is known about the regulation of its activity. Here we characterized the activity of the UPS during dormancy release and maintenance by monitoring protein ubiquitination and degradation of two proteasomal substrates: Suc-LLVY-AMC, a well characterized synthetic substrate, and FUSCA3 (FUS3), a dormancy-promoting transcription factor degraded by the 26S proteasome...
August 6, 2016: Plant Journal: for Cell and Molecular Biology
Jil Schrader, Fabian Henneberg, Ricardo A Mata, Kai Tittmann, Thomas R Schneider, Holger Stark, Gleb Bourenkov, Ashwin Chari
The proteasome is a validated target for anticancer therapy, and proteasome inhibition is employed in the clinic for the treatment of tumors and hematological malignancies. Here, we describe crystal structures of the native human 20S proteasome and its complexes with inhibitors, which either are drugs approved for cancer treatment or are in clinical trials. The structure of the native human 20S proteasome was determined at an unprecedented resolution of 1.8 angstroms. Additionally, six inhibitor-proteasome complex structures were elucidated at resolutions between 1...
August 5, 2016: Science
Yoshiro Saito, Yoko Akazawa-Ogawa, Akihiro Matsumura, Kazumasa Saigoh, Sayoko Itoh, Kenta Sutou, Mayuka Kobayashi, Yuichiro Mita, Mototada Shichiri, Shin Hisahara, Yasuo Hara, Harutoshi Fujimura, Hiroyuki Takamatsu, Yoshihisa Hagihara, Yasukazu Yoshida, Takao Hamakubo, Susumu Kusunoki, Shun Shimohama, Noriko Noguchi
Parkinson's disease (PD) is a progressive, age-related, neurodegenerative disorder, and oxidative stress is an important mediator in its pathogenesis. DJ-1, the product of the causative gene of a familial form of PD, plays a significant role in anti-oxidative defence to protect cells from oxidative stress. DJ-1 undergoes preferential oxidation at the cysteine residue at position 106 (Cys-106) under oxidative stress. Here, using specific antibodies against Cys-106-oxidized DJ-1 (oxDJ-1), it was found that the levels of oxDJ-1 in the erythrocytes of unmedicated PD patients (n = 88) were higher than in those of medicated PD patients (n = 62) and healthy control subjects (n = 33)...
2016: Scientific Reports
Ewa Matuszczak, Marzena Tylicka, Adam Hermanowicz, Wojciech Debek, Anna Sankiewicz, Ewa Gorodkiewicz
BACKGROUND: Determination of proteasome concentration in blood plasma in children with burns, with the Surface Plasmon Resonance Imaging biosensor. MATERIAL AND METHODS: 35 children scalded by hot water, with burns in 4-20% TBSA were included into the study (age 9 months up to 14 years, mean age 2,5+1 years). Blood plasma 20S proteasome concentration was assessed in 2-6h, 12-16h, 3d, 5d, and 7d after injury using Surface Plasmon Resonance Imaging biosensor. RESULTS: Statistically significant elevation of circulating 20S proteasome concentration was noted in all groups 12-16 hours after the injury; however, differences were more evident in children with the more severe burns...
July 2016: Annals of Clinical and Laboratory Science
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