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Deubiquitination

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https://www.readbyqxmd.com/read/28933784/inhibition-of-the-deubiquitinase-usp5-leads-to-c-maf-protein-degradation-and-myeloma-cell-apoptosis
#1
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/28930533/53bp1-a-guardian-for-centrosomal-integrity
#2
Haeyoung Kim, Hyungshin Yim
53BP1 is known as a mediator in DNA damage response and a regulator of DNA double-stranded breaks (DSBs) repair. 53BP1 was recently reported to be a centrosomal protein and a binding partner of mitotic polo-like kinase 1 (Plk1). The stability of 53BP1, in response to DSBs, is regulated by its phosphorylation, deubiquitination, and ubiquitination. During mitosis, 53BP1 is stabilized by phosphorylation at S380, a putative binding region with polo-box domain of Plk1, and deubiquitination by ubiquitin-specific protease 7 (USP7)...
January 1, 2018: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/28929193/immune-regulation-by-ubiquitin-tagging-as-checkpoint-code
#3
Peng Zeng, Jieyu Ma, Runqing Yang, Yun-Cai Liu
The immune system is equipped with effective machinery to mobilize its activation to defend invading microorganisms, and at the same time, to refrain from attacking its own tissues to maintain immune tolerance. The balance of activation and tolerance is tightly controlled by diverse mechanisms, since breakdown of tolerance could result in disastrous consequences such as the development of autoimmune diseases. One of the mechanisms is by the means of protein ubiquitination, which involves the process of tagging a small peptide ubiquitin to protein substrates...
September 20, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28923280/the-roles-of-ubiquitin-modifying-enzymes-in-neoplastic-disease
#4
REVIEW
Nishi Kumari, Patrick William Jaynes, Azad Saei, Prasanna Vasudevan Iyengar, John Lalith Charles Richard, Pieter Johan Adam Eichhorn
The initial experiments performed by Rose, Hershko, and Ciechanover describing the identification of a specific degradation signal in short-lived proteins paved the way to the discovery of the ubiquitin mediated regulation of numerous physiological functions required for cellular homeostasis. Since their discovery of ubiquitin and ubiquitin function over 30years ago it has become wholly apparent that ubiquitin and their respective ubiquitin modifying enzymes are key players in tumorigenesis. The human genome encodes approximately 600 putative E3 ligases and 80 deubiquitinating enzymes and in the majority of cases these enzymes exhibit specificity in sustaining either pro-tumorigenic or tumour repressive responses...
September 15, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28923245/a20-inhibits-both-the-degradation-and-limited-processing-of-the-nf-%C3%AE%C2%BAb-p105-precursor-a-novel-additional-layer-to-its-regulator-role
#5
Dana Lapid, Shirly Lahav-Baratz, Shai Cohen
p105 plays dual roles in NF-κB signaling: it generates the active subunit p50 and in its precursor form inhibits NF-κB activation. p105 processing occurs under basal conditions and increases following signaling. IκB kinase β (IKKβ) mediates phosphorylation at the C-terminal domain of p105, leads to accelerated processing and degradation of the precursor. A20 is a dual function deubiquitinating and ubiquitin ligating enzyme, involving in turning-off the NF-κB signaling pathway. Here we show that A20 suppresses TNFα-induced proteolysis of p105...
September 15, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28919039/a-linear-diubiquitin-based-probe-for-efficient-and-selective-detection-of-the-deubiquitinating-enzyme-otulin
#6
Aurelia Weber, Paul R Elliott, Adan Pinto-Fernandez, Sarah Bonham, Benedikt M Kessler, David Komander, Farid El Oualid, Daniel Krappmann
The methionine 1 (M1)-specific deubiquitinase (DUB) OTULIN acts as a negative regulator of nuclear factor κB signaling and immune homeostasis. By replacing Gly76 in distal ubiquitin (Ub) by dehydroalanine we designed the diubiquitin (diUb) activity-based probe UbG76Dha-Ub (OTULIN activity-based probe [ABP]) that couples to the catalytic site of OTULIN and thereby captures OTULIN in its active conformation. The OTULIN ABP displays high selectivity for OTULIN and does not label other M1-cleaving DUBs, including CYLD...
August 28, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28911816/lead-discovery-and-chemical-biology-approaches-targeting-the-ubiquitin-proteasome-system
#7
REVIEW
Favour A Akinjiyan, Seth Carbonneau, Nathan T Ross
Protein degradation is critical for proteostasis, and the addition of polyubiquitin chains to a substrate is necessary for its recognition by the 26S proteasome. Therapeutic intervention in the ubiquitin proteasome system has implications ranging from cancer to neurodegeneration. Novel screening methods and chemical biology tools for targeting E1-activating, E2-conjugating and deubiquitinating enzymes will be discussed in this review. Approaches for targeting E3 ligase-substrate interactions as well as the proteasome will also be covered, with a focus on recently described approaches...
August 30, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28900035/prion-protein-is-required-for-tumor-necrosis-factor-alpha-tnf%C3%AE-triggered-nuclear-factor-kappa-b-nf-%C3%AE%C2%BAb-signaling-and-cytokine-production
#8
Gui-Ru Wu, Tian-Chen Mu, Zhen-Xing Gao, Jun Wang, Man-Sun Sy, Chao-yang Li
The expression of normal cellular prion protein (PrP) is required for the pathogenesis of prion diseases. However, the physiological functions of PrP remain ambiguous. Here, we identified PrP as being critical for tumor necrosis factor (TNF)α-triggered signaling in a human melanoma cell line, M2, and a pancreatic ductal cell adenocarcinoma cell line, BxPC-3. In M2 cells, TNFα upregulates the expression of p-I-kappa-B-kinase α/β (p-IKKα/β), p-p65, and p-JNK, but downregulates the IκBα protein, all of which are downstream signaling intermediates in the TNF receptor signaling cascade...
September 12, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28887042/hinokitiol-copper-complex-inhibits-proteasomal-deubiquitination-and-induces-paraptosis-like-cell-death-in-human-cancer-cells
#9
Xin Chen, Xiaolan Zhang, Jinghong Chen, Qianqian Yang, Li Yang, Dacai Xu, Peiquan Zhang, Xuejun Wang, Jinbao Liu
The ubiquitin-proteasome system (UPS) plays a central role in the regulation of proteins that control cell growth and apoptosis and has therefore become an important target for anticancer therapy. Several constitutive subunits of the 19S proteasome display deubiquitinase (DUB) activity, suggesting that ubiquitin modification of proteins is dynamically regulated. Our study and others have shown that metal complexes, such as copper complexes, can induce cancer cell apoptosis through inhibiting 19S proteasome-associated DUBs and/or 20S proteasome activity...
September 5, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28885059/viral-deubiquitinases-role-in-evasion-of-anti-viral-innate-immunity
#10
Puja Kumari, Himanshu Kumar
Host anti-viral innate-immune signalling pathways are regulated by a variety of post-translation modifications including ubiquitination, which is critical to regulate various signalling pathways for synthesis of anti-viral molecules. A homeostasis of host immune responses, induced due to viral infection and further ubiquitination, is maintained by the action of deubiquitinases (DUB). Infecting viruses utilize the process of deubiquitination for tricking host immune system wherein viral DUBs compete with host DUBs for inhibition of innate-immune anti-viral signalling pathways, which instead of maintaining an immune homeostasis bring about virus-mediated pathogenesis...
September 8, 2017: Critical Reviews in Microbiology
https://www.readbyqxmd.com/read/28882872/mechanical-activation-of-hypoxia-inducible-factor-1%C3%AE-drives-endothelial-dysfunction-at-atheroprone-sites
#11
Shuang Feng, Neil Bowden, Maria Fragiadaki, Celine Souilhol, Sarah Hsiao, Marwa Mahmoud, Scott Allen, Daniela Pirri, Blanca Tardajos Ayllon, Shamima Akhtar, A A Roger Thompson, Hanjoong Jo, Christian Weber, Victoria Ridger, Andreas Schober, Paul C Evans
OBJECTIVE: Atherosclerosis develops near branches and bends of arteries that are exposed to low shear stress (mechanical drag). These sites are characterized by excessive endothelial cell (EC) proliferation and inflammation that promote lesion initiation. The transcription factor HIF1α (hypoxia-inducible factor 1α) is canonically activated by hypoxia and has a role in plaque neovascularization. We studied the influence of shear stress on HIF1α activation and the contribution of this noncanonical pathway to lesion initiation...
September 7, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28874458/the-deubiquitinating-enzyme-usp48-stabilizes-traf2-and-reduces-e-cadherin-mediated-adherens-junctions
#12
Shuang Li, Dan Wang, Jing Zhao, Nathaniel M Weathington, Dong Shang, Yutong Zhao
The tumor necrosis factor receptor-associated factor 2 (TRAF2) is a second messenger adaptor protein that plays an essential role in propagating TNF-α-mediated signaling pathways. Modulation of TRAF2 activity by ubiquitination is well studied; however, the deubiquitinating enzyme (DUB), which regulates TRAF2 stability, has not been identified. Here we reveal USP48 as the first identified DUB to deubiquitinate and stabilize TRAF2 in epithelial cells. Down-regulation of USP48 increases K48-linked polyubiquitination of TRAF2 and reduces TRAF2 protein levels...
September 5, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28852924/usp10-inhibits-lung-cancer-cell-growth-and-invasion-by-upregulating-pten
#13
Jia Sun, Tianxiang Li, Yinying Zhao, Lirong Huang, Hua Sun, Hui Wu, Xiufeng Jiang
To determine the potential tumor suppressor functions of ubiquitin-specific protease 10 (USP10) in lung cancer and elucidate underlying molecular mechanism. The relative expression of USP10 was determined by real-time PCR and immunoblotting. The inhibitory effect of USP10 on tumor growth was demonstrated on allograft mice with Lewis carcinoma cell inoculation. The relative cell proliferation was measured with Cell Counting Kit-8 (CCK-8). The invasive capacity was evaluated by transwell assay. The interaction between USP10 and Phosphatase And Tensin Homolog (PTEN) was examined by co-immunoprecipitation...
August 29, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28851806/the-deubiquitinase-usp10-regulates-integrin-beta1-and-beta5-and-fibrotic-wound-healing
#14
Stephanie R Gillespie, Liana J Tedesco, Lingyan Wang, Audrey M Bernstein
Scarring and fibrotic disease result from the persistence of myofibroblasts characterized by high surface expression of αv integrins and subsequent activation of TGFβ, however the mechanism controlling their surface abundance is unknown. Genetic screening revealed that human primary stromal corneal myofibroblasts overexpress a subset of deubiquitinating enzymes (DUBs), which remove ubiquitin from proteins, preventing degradation. Silencing of the DUB USP10 induces a buildup of ubiquitin on integrins β1 and β5 in cell lysates whereas recombinant USP10 removes ubiquitin from these integrin subunits...
August 29, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28844860/an-aaa-motor-driven-mechanical-switch-in-rpn11-controls-deubiquitination-at-the-26s-proteasome
#15
Evan J Worden, Ken C Dong, Andreas Martin
Poly-ubiquitin chains direct protein substrates to the 26S proteasome, where they are removed by the deubiquitinase Rpn11 during ATP-dependent substrate degradation. Rapid deubiquitination is required for efficient degradation but must be restricted to committed substrates that are engaged with the ATPase motor to prevent premature ubiquitin chain removal and substrate escape. Here we reveal the ubiquitin-bound structure of Rpn11 from S. cerevisiae and the mechanisms for mechanochemical coupling of substrate degradation and deubiquitination...
September 7, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28841265/release-of-enzymatically-active-deubiquitinating-enzymes-upon-reversible-capture-by-disulfide-ubiquitin-reagents
#16
Annemieke de Jong, Katharina Witting, Raymond Kooij, Dennis Flierman, Huib Ovaa
Deubiquitinating enzymes (DUBs) catalyze the cleavage of ubiquitin from target proteins. Ubiquitin is post-translationally attached to proteins and serves as an important regulatory signal for key cellular processes. In this study, novel activity-based probes to study DUBs were synthesized that comprise of a ubiquitin moiety and a novel disulfide warhead at the C-terminus. These reagents can bind DUBs covalently by forming a disulfide bridge between the active site cysteine residue and the ubiquitin-based probe...
August 25, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28840581/dishevelled-proteins-and-cyld-reciprocally-regulate-each-other-in-cml-cell-lines
#17
Ceyda Çalışkan, Melek Pehlivan, Zeynep Yüce, Ogun Sercan
Dishevelled (Dvl) proteins are activated by Wnt pathway stimulation and have crucial roles in the regulation of β-catenin destruction complex. CYLD is a tumor suppressor and a deubiquitination enzyme. CYLD negatively regulates the Wnt/β-catenin signaling pathway by deubiquitinating Dvl proteins. Loss of function and mutations of CYLD were linked to different types of solid tumors. Loss of function in CYLD is associated with Dvl hyper ubiquitination, resulting in the transmission of Wnt signaling to downstream effectors...
August 24, 2017: Molecular Biology Reports
https://www.readbyqxmd.com/read/28836754/cell-lysate-based-alphalisa-deubiquitinase-assay-platform-for-identification-of-small-molecule-inhibitors
#18
Christine A Ott, Bolormaa Baljinnyam, Alexey V Zakharov, Ajit Jadhav, Anton Simeonov, Zhihao Zhuang
The deubiquitinases, or DUBs, are associated with various human diseases, including neurological disorders, cancer, and viral infection, making them excellent candidates for pharmacological intervention. Drug discovery campaigns against DUBs require enzymatic deubiquitination assays amenable for high-throughput screening (HTS). Although several DUB substrates and assays have been developed in recent years, they are largely limited to recombinantly purified DUBs. Many DUBs are large multidomain proteins that are difficult to obtain recombinantly in sufficient quantities for HTS...
August 24, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28817177/the-n-terminal-ubiquitin-associated-domain-of-cezanne-is-crucial-for-its-function-to-suppress-nf-%C3%AE%C2%BAb-pathway
#19
Yanxi Ji, Liu Cao, Lanyi Zeng, Zhen Zhang, Qiaoqiao Xiao, Penglin Guan, Shiyou Chen, Yu Chen, Min Wang, Deyin Guo
Cezanne, a deubiquitinating cysteine protease (DUB) belonging to A20 subgroup of ovarian tumor (OTU) protein superfamily, functions as a negative regulator of NF-κB to attenuate NF-κB activation and to restrain pro-inflammatory transcription in response to TNF receptor (TNFR) signaling. It is the first documented OTU DUB that preferably disassembles Lys11-linked polyubiquitin chains and has been shown to regulate multiple cellular events including immune signaling, cell survival and tumor progression. Previous studies showed that in response to TNF stimulation, Cezanne is recruited to the activated TNFR complex to suppress the build-up of polyubiquitinated RIP1 signal by removing Lys63 polyubiquitin from RIP1...
August 17, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28811325/ppar%C3%AE-ligand-induced-annexin-a1-expression-determines-chemotherapy-response-via-deubiquitination-of-death-domain-kinase-rip-in-triple-negative-breast-cancers
#20
Luxi Chen, Yi Yuan, Shreya Kar, Madhu M Kanchi, Suruchi Arora, Ji E Kim, Pei F Koh, Einas Yousef, Ramar P Samy, Muthu K Shanmugam, Tuan Z Tan, Sung W Shin, Frank Arfuso, Han M Shen, Henry Yang, Boon C Goh, Joo I Park, Louis Gaboury, Peter E Lobie, Gautam Sethi, Lina Hk Lim, Alan P Kumar
Metastatic breast cancer is still remain incurable so far, new specifically targeted and more effective therapies for triple negative breast cancer (TNBC) are required in the clinic. In this study, our clinical data has established that basal and claudin-low subtypes of breast cancer (TNBC types) express significantly higher levels of Annexin A1 (ANXA1) with poor survival outcomes. Using human cancer cell lines which model the TNBC subtype, we observed a strong positive correlation between expression of ANXA1 and Peroxisome Proliferator-Activated Receptor gamma (PPARγ)...
August 15, 2017: Molecular Cancer Therapeutics
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