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https://www.readbyqxmd.com/read/27906959/pcna-dependent-cleavage-and-degradation-of-sde2-regulates-response-to-replication-stress
#1
Ukhyun Jo, Winson Cai, Jingming Wang, Yoojin Kwon, Alan D D'Andrea, Hyungjin Kim
Maintaining genomic integrity during DNA replication is essential for cellular survival and for preventing tumorigenesis. Proliferating cell nuclear antigen (PCNA) functions as a processivity factor for DNA replication, and posttranslational modification of PCNA plays a key role in coordinating DNA repair against replication-blocking lesions by providing a platform to recruit factors required for DNA repair and cell cycle control. Here, we identify human SDE2 as a new genome surveillance factor regulated by PCNA interaction...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27906774/lessons-from-characterization-and-treatment-of-the-autoinflammatory-syndromes
#2
Ivona Aksentijevich, Michael F McDermott
PURPOSE OF REVIEW: The list of genes associated with systemic inflammatory diseases has been steadily growing because of the explosion of new genomic technologies. Significant advances in the past year have deepened our understanding of the molecular mechanisms linked to inflammation and elucidated insights on the efficacy of specific therapies for these and related conditions. We review the molecular pathogenesis of four recently characterized monogenic autoinflammatory diseases: haploinsufficiency of A20, otulipenia, a severe form of pyrin-associated disease, and a monogenic form of systemic juvenile idiopathic arthritis...
November 30, 2016: Current Opinion in Rheumatology
https://www.readbyqxmd.com/read/27893708/tgf-%C3%AE-upregulates-the-translation-of-usp15-via-the-pi3k-akt-pathway-to-promote-p53-stability
#3
W-T Liu, K-Y Huang, M-C Lu, H-L Huang, C-Y Chen, Y-L Cheng, H-C Yu, S-Q Liu, N-S Lai, H-B Huang
Crosstalk between transforming growth factor beta (TGF-β) signaling and p53 has a critical role in cancer progression. TGF-β signals via Smad and non-Smad pathways. Under normal conditions, wild-type p53 forms a complex with Smad2/3 and co-activates transcription of a variety of tumor suppressor genes, resulting in tumor suppressive effects. Thus, p53 stability is essential in progression of tumor suppressive responses mediated by TGF-β signaling. However, it remains unknown whether p53 stability is regulated by TGF-β...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27892457/amplification-of-usp13-drives-ovarian-cancer-metabolism
#4
Cecil Han, Lifeng Yang, Hyun Ho Choi, Joelle Baddour, Abhinav Achreja, Yunhua Liu, Yujing Li, Jiada Li, Guohui Wan, Cheng Huang, Guang Ji, Xinna Zhang, Deepak Nagrath, Xiongbin Lu
Dysregulated energetic metabolism has been recently identified as a hallmark of cancer. Although mutations in metabolic enzymes hardwire metabolism to tumourigenesis, they are relatively infrequent in ovarian cancer. More often, cancer metabolism is re-engineered by altered abundance and activity of the metabolic enzymes. Here we identify ubiquitin-specific peptidase 13 (USP13) as a master regulator that drives ovarian cancer metabolism. USP13 specifically deubiquitinates and thus upregulates ATP citrate lyase and oxoglutarate dehydrogenase, two key enzymes that determine mitochondrial respiration, glutaminolysis and fatty acid synthesis...
November 28, 2016: Nature Communications
https://www.readbyqxmd.com/read/27886188/the-deubiquitinase-usp21-maintains-the-stemness-of-mouse-embryonic-stem-cells-via-stabilization-of-nanog
#5
Jiali Jin, Jian Liu, Cong Chen, Zhenping Liu, Cong Jiang, Hongshang Chu, Weijuan Pan, Xinbo Wang, Lingqiang Zhang, Bin Li, Cizhong Jiang, Xin Ge, Xin Xie, Ping Wang
Nanog is a master pluripotency factor of embryonic stem cells (ESCs). Stable expression of Nanog is essential to maintain the stemness of ESCs. However, Nanog is a short-lived protein and quickly degraded by the ubiquitin-dependent proteasome system. Here we report that the deubiquitinase USP21 interacts with, deubiquitinates and stabilizes Nanog, and therefore maintains the protein level of Nanog in mouse ESCs (mESCs). Loss of USP21 results in Nanog degradation, mESCs differentiation and reduces somatic cell reprogramming efficiency...
November 25, 2016: Nature Communications
https://www.readbyqxmd.com/read/27883090/sphingosine-1-phosphate-lyase-ablation-disrupts-presynaptic-architecture-and-function-via-an-ubiquitin-proteasome-mediated-mechanism
#6
Daniel N Mitroi, André U Deutschmann, Maren Raucamp, Indulekha Karunakaran, Konstantine Glebov, Michael Hans, Jochen Walter, Julie Saba, Markus Gräler, Dan Ehninger, Elena Sopova, Oleg Shupliakov, Dieter Swandulla, Gerhild van Echten-Deckert
The bioactive lipid sphingosine 1-phosphate (S1P) is a degradation product of sphingolipids that are particularly abundant in neurons. We have shown previously that neuronal S1P accumulation is toxic leading to ER-stress and an increase in intracellular calcium. To clarify the neuronal function of S1P, we generated brain-specific knockout mouse models in which S1P-lyase (SPL), the enzyme responsible for irreversible S1P cleavage was inactivated. Constitutive ablation of SPL in the brain (SPL(fl/fl/Nes)) but not postnatal neuronal forebrain-restricted SPL deletion (SPL(fl/fl/CaMK)) caused marked accumulation of S1P...
November 24, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27880911/usp44-is-an-integral-component-of-n-cor-that-contributes-to-gene-repression-by-deubiquitinating-histone-h2b
#7
Xianjiang Lan, Boyko S Atanassov, Wenqian Li, Ying Zhang, Laurence Florens, Ryan D Mohan, Paul J Galardy, Michael P Washburn, Jerry L Workman, Sharon Y R Dent
Decreased expression of the USP44 deubiquitinase has been associated with global increases in H2Bub1 levels during mouse embryonic stem cell (mESC) differentiation. However, whether USP44 directly deubiquitinates histone H2B or how its activity is targeted to chromatin is not known. We identified USP44 as an integral subunit of the nuclear receptor co-repressor (N-CoR) complex. USP44 within N-CoR deubiquitinates H2B in vitro and in vivo, and ablation of USP44 impairs the repressive activity of the N-CoR complex...
November 22, 2016: Cell Reports
https://www.readbyqxmd.com/read/27878624/the-creb-deubiquitinating-enzyme-does-not-directly-target-the-crea-repressor-protein-in-aspergillus-nidulans
#8
Md Ashiqul Alam, Niyom Kamlangdee, Joan M Kelly
Ubiquitination/deubiquitination pathways are now recognized as key components of gene regulatory mechanisms in eukaryotes. The major transcriptional repressor for carbon catabolite repression in Aspergillus nidulans is CreA, and mutational analysis led to the suggestion that a regulatory ubiquitination/deubiquitination pathway is involved. A key unanswered question is if and how this pathway, comprising CreB (deubiquitinating enzyme) and HulA (ubiquitin ligase) and other proteins, is involved in the regulatory mechanism...
November 23, 2016: Current Genetics
https://www.readbyqxmd.com/read/27866850/deubiquitination-and-stabilization-of-pd-l1-by-csn5
#9
Seung-Oe Lim, Chia-Wei Li, Weiya Xia, Jong-Ho Cha, Li-Chuan Chan, Yun Wu, Shih-Shin Chang, Wan-Chi Lin, Jung-Mao Hsu, Yi-Hsin Hsu, Taewan Kim, Wei-Chao Chang, Jennifer L Hsu, Hirohito Yamaguchi, Qingqing Ding, Yan Wang, Yi Yang, Chung-Hsuan Chen, Aysegul A Sahin, Dihua Yu, Gabriel N Hortobagyi, Mien-Chie Hung
Pro-inflammatory cytokines produced in the tumor microenvironment lead to eradication of anti-tumor immunity and enhanced tumor cell survival. In the current study, we identified tumor necrosis factor alpha (TNF-α) as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1). We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNF-α-mediated PD-L1 stabilization in cancer cells. CSN5 inhibits the ubiquitination and degradation of PD-L1...
November 14, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27857073/usp21-prevents-the-generation-of-t-helper-1-like-treg-cells
#10
Yangyang Li, Yue Lu, Shuaiwei Wang, Zhijun Han, Fuxiang Zhu, Yingmeng Ni, Rui Liang, Yan Zhang, Qibin Leng, Gang Wei, Guochao Shi, Ruihong Zhu, Dan Li, Haikun Wang, Song Guo Zheng, Hongxi Xu, Andy Tsun, Bin Li
FOXP3(+) Regulatory T (Treg) cells play a key role in the maintenance of immune homeostasis and tolerance. Disruption of Foxp3 expression results in the generation of instable Treg cells and acquisition of effector T-cell-like function. Here we report that the E3 deubiquitinase USP21 prevents the depletion of FOXP3 at the protein level and restricts the generation of T-helper-1-like Treg cells. Mice depleted of Usp21 specifically in Treg cells display immune disorders characterized by spontaneous T-cell activation and excessive T-helper type 1 (Th1) skewing of Treg cells into Th1-like Treg cells...
November 18, 2016: Nature Communications
https://www.readbyqxmd.com/read/27852225/a-functional-endosomal-pathway-is-necessary-for-lysosome-biogenesis-in-drosophila
#11
Anne-Claire Jacomin, Marie-Odile Fauvarque, Emmanuel Taillebourg
BACKGROUND: Lysosomes are the major catabolic compartment within eukaryotic cells, and their biogenesis requires the integration of the biosynthetic and endosomal pathways. Endocytosis and autophagy are the primary inputs of the lysosomal degradation pathway. Endocytosis is specifically needed for the degradation of membrane proteins whereas autophagy is responsible for the degradation of cytoplasmic components. We previously identified the deubiquitinating enzyme UBPY/USP8 as being necessary for lysosomal biogenesis and productive autophagy in Drosophila...
November 16, 2016: BMC Cell Biology
https://www.readbyqxmd.com/read/27851749/the-machado-joseph-disease-deubiquitinase-ataxin-3-regulates-the-stability-and-apoptotic-function-of-p53
#12
Hongmei Liu, Xiaoling Li, Guozhu Ning, Shu Zhu, Xiaolu Ma, Xiuli Liu, Chunying Liu, Min Huang, Ina Schmitt, Ullrich Wüllner, Yamei Niu, Caixia Guo, Qiang Wang, Tie-Shan Tang
As a deubiquitinating enzyme (DUB), the physiological substrates of ataxin-3 (ATX-3) remain elusive, which limits our understanding of its normal cellular function and that of pathogenic mechanism of spinocerebellar ataxia type 3 (SCA3). Here, we identify p53 to be a novel substrate of ATX-3. ATX-3 binds to native and polyubiquitinated p53 and deubiquitinates and stabilizes p53 by repressing its degradation through the ubiquitin (Ub)-proteasome pathway. ATX-3 deletion destabilizes p53, resulting in deficiency of p53 activity and functions, whereas ectopic expression of ATX-3 induces selective transcription/expression of p53 target genes and promotes p53-dependent apoptosis in both mammalian cells and the central nervous system of zebrafish...
November 2016: PLoS Biology
https://www.readbyqxmd.com/read/27848959/carbene-footprinting-accurately-maps-binding-sites-in-protein-ligand-and-protein-protein-interactions
#13
Lucio Manzi, Andrew S Barrow, Daniel Scott, Robert Layfield, Timothy G Wright, John E Moses, Neil J Oldham
Specific interactions between proteins and their binding partners are fundamental to life processes. The ability to detect protein complexes, and map their sites of binding, is crucial to understanding basic biology at the molecular level. Methods that employ sensitive analytical techniques such as mass spectrometry have the potential to provide valuable insights with very little material and on short time scales. Here we present a differential protein footprinting technique employing an efficient photo-activated probe for use with mass spectrometry...
November 16, 2016: Nature Communications
https://www.readbyqxmd.com/read/27844253/the-role-of-deubiquitinases-in-breast-cancer
#14
Zhenna Xiao, Peijing Zhang, Li Ma
Although growing numbers of oncoproteins and pro-metastatic proteins have been extensively characterized, many of these tumor-promoting proteins are not good drug targets, which represent a major barrier to curing breast cancer and other cancers. There is a need, therefore, for alternative therapeutic approaches to destroying cancer-promoting proteins. The human genome encodes approximately 100 deubiquitinating enzymes (DUBs, also called deubiquitinases), which are amenable to pharmacologic inhibition by small molecules...
November 14, 2016: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/27835898/prognostic-significance-of-usp33-in-advanced-colorectal-cancer-patients-new-insights-into-%C3%AE-arrestin-dependent-erk-signaling
#15
Hongda Liu, Qun Zhang, Kangshuai Li, Zheng Gong, Zhaochen Liu, Yunfei Xu, Mary Hannah Swaney, Kunhong Xiao, Yuxin Chen
Patients with liver metastases of colorectal cancer (CRCLM) have a poorer prognosis compared to colorectal cancer (CRC) patients in local stage. Evaluating the recurrence and overall survival of advanced patients is critical in improving disease treatment and clinical outcome. Here we investigated the expression pattern of USP33, a deubiquitinating enzyme, in both primary CRC tissues and liver metastases tissues. Univariate and multivariate analyses identified that low expression of USP33 in CRCLM tissues indicated high recurrence risk and poor overall prognosis...
November 8, 2016: Oncotarget
https://www.readbyqxmd.com/read/27827840/usp19-mediated-deubiquitination-facilitates-the-stabilization-of-hrd1-ubiquitin-ligase
#16
Kumi Harada, Masako Kato, Nobuhiro Nakamura
In the endoplasmic reticulum (ER), misfolded and unfolded proteins are eliminated by a process called ER-associated protein degradation (ERAD) in order to maintain cell homeostasis. In the ERAD pathway, several ER-localized E3 ubiquitin ligases target ERAD substrate proteins for ubiquitination and subsequent proteasomal degradation. However, little is known about how the functions of the ERAD ubiquitin ligases are regulated. Recently, USP19, an ER-anchored deubiquitinating enzyme (DUB), has been suggested to be involved in the regulation of ERAD...
November 2, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27825468/novel-therapeutic-targets-in-waldenstrom-macroglobulinemia
#17
REVIEW
Aneel Paulus, Sikander Ailawadhi, Asher Chanan-Khan
Understanding of molecular mechanisms that drive Waldenstrom macroglobulinemia (WM) cell survival are rapidly evolving. This review briefly highlights emerging "WM-relevant" targets; for which therapeutic strategies are currently being investigated in preclinical and clinical studies. With the discovery of MYD88L265P signaling and remarkable activity of ibrutinib in WM, other targets within the B-cell receptor pathway are now being focused on for therapeutic intervention. Additional targets which play a role in WM cell survival include TLR7, 8 and 9, proteasome-associated deubiquitinating enzymes (USP14 and UCHL5), XPO1/CRM1 and AURKA...
June 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27813535/coinhibition-of-the-deubiquitinating-enzymes-usp14-and-uchl5-with-vlx1570-is-lethal-to-ibrutinib-or-bortezomib-resistant-waldenstrom-macroglobulinemia-tumor-cells
#18
A Paulus, S Akhtar, T R Caulfield, K Samuel, H Yousaf, Y Bashir, S M Paulus, D Tran, R Hudec, D Cogen, J Jiang, B Edenfield, A Novak, S M Ansell, T Witzig, P Martin, M Coleman, V Roy, S Ailawadhi, K Chitta, S Linder, A Chanan-Khan
The survival of Waldenstrom macroglobulinemia (WM) tumor cells hinges on aberrant B-cell receptor (BCR) and MYD88 signaling. WM cells upregulate the proteasome function to sustain the BCR-driven growth while maintaining homeostasis. Clinically, two treatment strategies are used to disrupt these complementary yet mutually exclusive WM survival pathways via ibrutinib (targets BTK/MYD88 node) and bortezomib (targets 20 S proteasome). Despite the success of both agents, WM patients eventually become refractory to treatment, highlighting the adaptive plasticity of WM cells and underscoring the need for development of new therapeutics...
November 4, 2016: Blood Cancer Journal
https://www.readbyqxmd.com/read/27810359/the-testis-specific-usp26-is-a-deubiquitinating-enzyme-of-the-ubiquitin-ligase-mdm2
#19
Shirly Lahav-Baratz, Yelena Kravtsova-Ivantsiv, Shai Golan, Aaron Ciechanover
Murine double minute-2 (Mdm2) is one of the E3-ligases of the androgen receptor besides being the major regulator of the p53 tumor suppressor. The testis-specific USP26 was demonstrated to regulate the androgen receptor. In the present study we examined possible association between the deubiquitinating enzyme - ubiquitin specific protease 26 (USP26), and the oncoprotein E3 ligase - (Mdm-2). We analyzed the half-life time of USP26 in HEK293 cells. In a cell-free system we asked whether USP26 can be ubiquitinated by HeLa extract...
October 31, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27807830/targeting-deubiquitinating-enzymes-and-autophagy-in-cancer
#20
Ashley Mooneyham, Martina Bazzaro
Maintenance of proper cellular homeostasis requires constant surveillance and precise regulation of intracellular protein content. Protein monitoring and degradation is performed by two distinct pathways in a cell: the autophage-lysosome pathway and the ubiquitin-proteasome pathway. Protein degradation pathways are frequently dysregulated in multiple cancer types and can be both tumor suppressive and tumor promoting. This knowledge has presented the ubiquitin proteasome system (UPS) and autophagy as attractive cancer therapeutic targets...
2017: Methods in Molecular Biology
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