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Deubiquitinase

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https://www.readbyqxmd.com/read/28431405/usp5-functions-as-an-oncogene-for-stimulating-tumorigenesis-in-hepatocellular-carcinoma
#1
Yi Liu, Wei-Mao Wang, Ying-Fei Lu, Lu Feng, Li Li, Ming-Zhu Pan, Yu Sun, Chun-Wai Suen, Wei Guo, Jian-Xin Pang, Jin-Fang Zhang, Wei-Ming Fu
As deubiquitinases, several ubiquitin specific protease members have been reported to mediate tumorigenesis. Although ubiquitin specific protease 5 (Usp5) was previously demonstrated to suppress p53 transcriptional activity and DNA repair, its role in carcinogenesis remains elusive. In this study, we sought to define a novel role of Usp5 in tumorigenesis. It was found that Usp5 was significantly upregulated in hepatocellular carcinoma (HCC) cells and most clinical specimens. Further functional investigation also showed that Usp5 knockdown suppressed cell proliferation, migration, drug resistance and induced apoptosis; on the other hand, Usp5 overexpression promoted colony formation, migration, drug resistance and tumorigenesis...
April 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28425671/activity-based-probes-for-hect-e3-ubiquitin-ligases
#2
Robert Byrne, Thomas Mund, Julien Licchesi
Activity-Based Probes (ABPs) have been used to dissect the biochemical/structural properties and cellular functions of deubiquitinases. However, their utility in studying cysteine-based E3 ubiquitin ligases has so far been limited. In this study, we evaluate the use of Ubiquitin-ABPs (Ub-VME and Ub-PA) and a novel set of E2~Ub-ABPs, on a panel of HECT E3 ubiquitin ligases. Our in vitro data show that ubiquitin-ABPs can label HECT domains and we also provide the first evidence that, in addition to the RBR E3 ubiquitin ligase Parkin, E2~Ub-ABPs can also label the catalytic HECT domain of NEDD4, UBE3C and HECTD1...
April 20, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28423502/acute-lymphoblastic-leukemia-cells-are-sensitive-to-disturbances-in-protein-homeostasis-induced-by-proteasome-deubiquitinase-inhibition
#3
Magdalena Mazurkiewicz, Ellin-Kristina Hillert, Xin Wang, Paola Pellegrini, Maria Hägg Olofsson, Karthik Selvaraju, Padraig D'Arcy, Stig Linder
The non-genotoxic nature of proteasome inhibition makes it an attractive therapeutic option for the treatment of pediatric malignancies. We recently described the small molecule VLX1570 as an inhibitor of proteasome deubiquitinase (DUB) activity that induces proteotoxic stress and apoptosis in cancer cells. Here we show that acute lymphoblastic leukemia (ALL) cells are highly sensitive to treatment with VLX1570, resulting in the accumulation of polyubiquitinated proteasome substrates and loss of cell viability...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416749/acute-lymphoblastic-leukemia-cells-are-sensitive-to-disturbances-in-protein-homeostasis-induced-by-proteasome-deubiquitinase-inhibition
#4
Magdalena Mazurkiewicz, Ellin-Kristina Hillert, Xin Wang, Paola Pellegrini, Maria Hägg Olofsson, Karthik Selvaraju, Padraig D'Arcy, Stig Linder
The non-genotoxic nature of proteasome inhibition makes it an attractive therapeutic option for the treatment of pediatric malignancies. We recently described the small molecule VLX1570 as an inhibitor of proteasome deubiquitinase (DUB) activity that induces proteotoxic stress and apoptosis in cancer cells. Here we show that acute lymphoblastic leukemia (ALL) cells are highly sensitive to treatment with VLX1570, resulting in the accumulation of polyubiquitinated proteasome substrates and loss of cell viability...
February 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416659/deubiquitinase-yod1-potentiates-yap-taz-activities-through-enhancing-itch-stability
#5
Youngeun Kim, Wantae Kim, Yonghee Song, Jeong-Rae Kim, Kyungjoo Cho, Hyuk Moon, Simon Weonsang Ro, Eunjeong Seo, Yeon-Mi Ryu, Seung-Jae Myung, Eek-Hoon Jho
Hippo signaling controls the expression of genes regulating cell proliferation and survival and organ size. The regulation of core components in the Hippo pathway by phosphorylation has been extensively investigated, but the roles of ubiquitination-deubiquitination processes are largely unknown. To identify deubiquitinase(s) that regulates Hippo signaling, we performed unbiased siRNA screening and found that YOD1 controls biological responses mediated by YAP/TAZ. Mechanistically, YOD1 deubiquitinates ITCH, an E3 ligase of LATS, and enhances the stability of ITCH, which leads to reduced levels of LATS and a subsequent increase in the YAP/TAZ level...
April 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28416112/flexibility-and-design-conformational-heterogeneity-along-the-evolutionary-trajectory-of-a-redesigned-ubiquitin
#6
Justin T Biel, Michael C Thompson, Christian N Cunningham, Jacob E Corn, James S Fraser
Although protein design has been used to introduce new functions, designed variants generally only function as well as natural proteins after rounds of laboratory evolution. One possibility for this pattern is that designed mutants frequently sample nonfunctional conformations. To test this idea, we exploited advances in multiconformer modeling of room-temperature X-ray data collection on redesigned ubiquitin variants selected for increasing binding affinity to the deubiquitinase USP7. Initial core mutations disrupt natural packing and lead to increased flexibility...
April 12, 2017: Structure
https://www.readbyqxmd.com/read/28400515/saga-complex-mediates-the-transcriptional-up-regulation-of-antiviral-rna-silencing
#7
Ida Bagus Andika, Atif Jamal, Hideki Kondo, Nobuhiro Suzuki
Pathogen recognition and transcriptional activation of defense-related genes are crucial steps in cellular defense responses. RNA silencing (RNAi) functions as an antiviral defense in eukaryotic organisms. Several RNAi-related genes are known to be transcriptionally up-regulated upon virus infection in some host organisms, but little is known about their induction mechanism. A phytopathogenic ascomycete, Cryphonectria parasitica (chestnut blight fungus), provides a particularly advantageous system to study RNAi activation, because its infection by certain RNA viruses induces the transcription of dicer-like 2 (dcl2) and argonaute-like 2 (agl2), two major RNAi players...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28395284/indole-3-carbinol-induces-apoptosis-of-hepatic-stellate-cells-through-k63-de-ubiquitination-of-rip1-in-rats
#8
Bin Li, Meng Cong, Yanan Zhu, Ying Xiong, Wenyi Jin, Yang Wan, Yunjiao Zhou, Ying Ao, Hui Wang
BACKGROUND/AIMS: The apoptosis of activated hepatic stellate cells (HSCs) is the central event in the reversal of liver fibrosis. K63 de-ubiquitinated receptor-interacting protein (RIP)1 promotes apoptosis in tumor necrosis factor (TNF)-α signaling pathway. In the previous study, we have proved that indole-3-carbinol (I3C) could reverse different models of liver fibrosis in rats, but the mechanism is still unclear. Thus, the present research aimed to demonstrate the induction of I3C on apoptosis of HSCs and the underlying molecular mechanism...
March 24, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28374134/the-p38-cyld-pathway-is-involved-in-necroptosis-induced-by-oxygen-glucose-deprivation-combined-with-zvad-in-primary-cortical-neurons
#9
Tao Feng, WeiWei Chen, CaiYi Zhang, Jie Xiang, HongMei Ding, LianLian Wu, DeQin Geng
Recently, necroptosis, a form of programmed necrosis, has been widely studied. It has previously been shown that knockout of lysine 63 deubiquitinase CYLD significantly inhibits necroptosis in other cell lines, and serum response factor (SRF) could regulate CYLD gene expression through p38 mitogen-activated protein kinase (p38 MAPK). In the following study, we show oxygen-glucose deprivation (OGD) combined with a caspase inhibitor, ZVAD (OGD/ZVAD), induced CYLD protein expression in a time-dependent manner...
April 4, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28372990/neurotoxic-mechanisms-by-which-the-usp14-inhibitor-iu1-depletes-ubiquitinated-proteins-and-tau-in-rat-cerebral-cortical-neurons-relevance-to-alzheimer-s-disease
#10
Magdalena J Kiprowska, Anna Stepanova, Dustin R Todaro, Alexander Galkin, Arthur Haas, Scott M Wilson, Maria E Figueiredo-Pereira
In Alzheimer's disease proteasome activity is reportedly downregulated, thus increasing it could be therapeutically beneficial. The proteasome-associated deubiquitinase USP14 disassembles polyubiquitin-chains, potentially delaying proteasome-dependent protein degradation. We assessed the protective efficacy of inhibiting or downregulating USP14 in rat and mouse (Usp14(axJ)) neuronal cultures treated with prostaglandin J2 (PGJ2). IU1 concentrations (HIU1>25μM) reported by others to inhibit USP14 and be protective in non-neuronal cells, reduced PGJ2-induced Ub-protein accumulation in neurons...
March 31, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28364380/ubiquitin-specific-protease-14-regulates-lps-induced-inflammation-by-increasing-erk1-2-phosphorylation-and-nf-%C3%AE%C2%BAb-activation
#11
Ningning Liu, Tianyu Kong, Xiaohua Chen, Huan Hu, Hongjiao Gu, Shiming Liu, Xiaohui Chen, Qilin Yang, Aiqun Li, Xuming Xiong, Zhenhui Zhang
Persistent activation of nuclear factor B (NF-κB) is very important in the modulation of macrophages cellular response to microbial infections. The deubiquitinase USP14, which is critical for ubiquitin-mediated proteasomal degradation of proteins, is known to be involved in cancer, neurological diseases, and aging. However, the mechanism by which USP14 regulates inflammation remains unclear. Here, we demonstrated that decreasing the deubiquitinase activity of USP14 resulted in reduced lipopolysaccharides (LPS)-mediated tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 release in THP-1 and RAW264...
March 31, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28363942/usp49-negatively-regulates-tumorigenesis-and-chemoresistance-through-fkbp51-akt-signaling
#12
Kuntian Luo, Yunhui Li, Yujiao Yin, Lei Li, Chenming Wu, Yuping Chen, Somaira Nowsheen, Qi Hu, Lizhi Zhang, Zhenkun Lou, Jian Yuan
The AKT pathway is a fundamental signaling pathway that mediates multiple cellular processes, such as cell proliferation and survival, angiogenesis, and glucose metabolism. We recently reported that the immunophilin FKBP51 is a scaffolding protein that can enhance PHLPP-AKT interaction and facilitate PHLPP-mediated dephosphorylation of AKT at Ser473, negatively regulating AKT activation. However, the regulation of FKBP51-PHLPP-AKT pathway remains unclear. Here we report that a deubiquitinase, USP49, is a new regulator of the AKT pathway...
March 31, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28363724/hidden-targets-of-ubiquitin-proteasome-system-to-prevent-diabetic-nephropathy
#13
REVIEW
Santosh Kumar Goru, Almesh Kadakol, Anil Bhanudas Gaikwad
Diabetic nephropathy (DN) is the major cause of end stage renal failure. Although, several therapeutic targets have emerged to prevent the progression of DN, the number of people with DN still continues to rise worldwide, suggesting an urgent need of novel targets to prevent DN completely. Currently, the role of ubiquitin proteasome system (UPS) has been highlighted in the pathogenesis and progression of various diseases like obesity, insulin resistance, atherosclerosis, cancers, neurodegerative disorders and including secondary complications of diabetes...
March 29, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28362430/cyld-a20-and-otulin-deubiquitinases-in-nf-%C3%AE%C2%BAb-signaling-and-cell-death-so-similar-yet-so-different
#14
REVIEW
Marie Lork, Kelly Verhelst, Rudi Beyaert
Polyubiquitination of proteins has a pivotal role in the regulation of numerous cellular functions such as protein degradation, DNA repair and cell signaling. As deregulation of these processes can result in pathological conditions such as inflammatory diseases, neurodegeneration or cancer, tight regulation of the ubiquitin system is of tremendous importance. Ubiquitination by E3 ubiquitin ligases can be counteracted by the activity of several deubiquitinating enzymes (DUBs). CYLD, A20 and OTULIN have been implicated as key DUBs in the negative regulation of NF-κB transcription factor-mediated gene expression upon stimulation of cytokine receptors, antigen receptors and pattern recognition receptors, by removing distinct types of polyubiquitin chains from specific NF-κB signaling proteins...
March 31, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28361952/usp9x-regulates-centrosome-duplication-and-promotes-breast-carcinogenesis
#15
Xin Li, Nan Song, Ling Liu, Xinhua Liu, Xiang Ding, Xin Song, Shangda Yang, Lin Shan, Xing Zhou, Dongxue Su, Yue Wang, Qi Zhang, Cheng Cao, Shuai Ma, Na Yu, Fuquan Yang, Yan Wang, Zhi Yao, Yongfeng Shang, Lei Shi
Defective centrosome duplication is implicated in microcephaly and primordial dwarfism as well as various ciliopathies and cancers. Yet, how the centrosome biogenesis is regulated remains poorly understood. Here we report that the X-linked deubiquitinase USP9X is physically associated with centriolar satellite protein CEP131, thereby stabilizing CEP131 through its deubiquitinase activity. We demonstrate that USP9X is an integral component of centrosome and is required for centrosome biogenesis. Loss-of-function of USP9X impairs centrosome duplication and gain-of-function of USP9X promotes centrosome amplification and chromosome instability...
March 31, 2017: Nature Communications
https://www.readbyqxmd.com/read/28355105/josd1-negatively-regulates-type-i-interferon-antiviral-activity-by-deubiquitinating-and-stabilizing-socs1
#16
Xiaofang Wang, Liting Zhang, Yunli Zhang, Peng Zhao, Liping Qian, Yukang Yuan, Jin Liu, Qiao Cheng, Wenqian Xu, Yibo Zuo, Tingting Guo, Zhengyuan Yu, Hui Zheng
The Josephin domain-containing (JOSD) protein 1 (JOSD1) is recognized as one member of deubiquitinases (DUBs) due to its catalytic "Josephin" domain. However, the in vivo deubiquitinating activity of JOSD1 remains unidentified, and the biological functions of JOSD1 are largely unknown. In this study, we report that JOSD1 plays an important role in regulating type-I interferon (IFN-I)-mediated antiviral activity. JOSD1 physically interacts with SOCS1, which is an essential negative regulator of many cytokines signaling, and enhances SOCS1 stability by deubiquitinating K48-linked polyubiquitination of SOCS1...
March 29, 2017: Viral Immunology
https://www.readbyqxmd.com/read/28348081/the-herpes-simplex-virus-1-ul36usp-deubiquitinase-suppresses-dna-repair-in-host-cells-via-deubiquitination-of-proliferating-cell-nuclear-antigen
#17
Xiaodong Dong, Junhong Guan, Chunfu Zheng, Xiaofeng Zheng
Herpes simplex virus 1 (HSV-1) infection manipulates distinct host DNA damage responses (DDR) to facilitate virus proliferation, but the molecular mechanisms remain to be elucidated. One possible HSV-1 target might be DNA damage-tolerance mechanisms, such as the translesion synthesis (TLS) pathway. In TLS, proliferating cell nuclear antigen (PCNA) is monoubiquitinated in response to DNA damage-caused replication fork stalling. Ubiquitinated PCNA then facilitates the error-prone DNA polymerase eta (pol eta)-mediated TLS, allowing the fork to bypass damaged sites...
March 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28347402/chlamydia-trachomatis-containing-vacuole-serves-as-deubiquitination-platform-to-stabilize-mcl-1-and-to-interfere-with-host-defense
#18
Annette Fischer, Kelly S Harrison, Yesid Ramirez, Daniela Auer, Suvagata Roy Chowdhury, Bhupesh K Prusty, Florian Sauer, Zoe Dimond, Caroline Kisker, P Scott Hefty, Thomas Rudel
Obligate intracellular Chlamydia trachomatis replicate in a membrane-bound vacuole called inclusion, which serves as a signaling interface with the host cell. Here, we show that the chlamydial deubiquitinating enzyme (Cdu) 1 localizes in the inclusion membrane and faces the cytosol with the active deubiquitinating enzyme domain. The structure of this domain revealed high similarity to mammalian deubiquitinases with a unique α-helix close to the substrate-binding pocket. We identified the apoptosis regulator Mcl-1 as a target that interacts with Cdu1 and is stabilized by deubiquitination at the chlamydial inclusion...
March 28, 2017: ELife
https://www.readbyqxmd.com/read/28343940/lithocholic-acid-hydroxyamide-destabilizes-cyclin-d1-and-induces-g0-g1-arrest-by-inhibiting-deubiquitinase-usp2a
#19
Katarzyna Magiera, Marcin Tomala, Katarzyna Kubica, Virginia De Cesare, Matthias Trost, Bartosz J Zieba, Neli Kachamakova-Trojanowska, Marcin Les, Grzegorz Dubin, Tad A Holak, Lukasz Skalniak
USP2a is a deubiquitinase responsible for stabilization of cyclin D1, a crucial regulator of cell-cycle progression and a proto-oncoprotein overexpressed in numerous cancer types. Here we report that lithocholic acid (LCA) derivatives are inhibitors of USP proteins, including USP2a. The most potent LCA derivative, LCA hydroxyamide (LCAHA), inhibits USP2a, leading to a significant Akt/GSK3β-independent destabilization of cyclin D1, but does not change the expression of p27. This leads to the defects in cell-cycle progression...
April 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28338014/entropic-stabilization-of-a-deubiquitinase-provides-conformational-plasticity-and-slow-unfolding-kinetics-beneficial-for-functioning-on-the-proteasome
#20
Yun-Tzai Cloud Lee, Chia-Yun Chang, Szu-Yu Chen, Yun-Ru Pan, Meng-Ru Ho, Shang-Te Danny Hsu
Human ubiquitin C-terminal hydrolyase UCH-L5 is a topologically knotted deubiquitinase that is activated upon binding to the proteasome subunit Rpn13. The length of its intrinsically disordered cross-over loop is essential for substrate recognition. Here, we showed that the catalytic domain of UCH-L5 exhibits higher equilibrium folding stability with an unfolding rate on the scale of 10(-8) s(-1), over four orders of magnitudes slower than its paralogs, namely UCH-L1 and -L3, which have shorter cross-over loops...
March 24, 2017: Scientific Reports
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