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https://www.readbyqxmd.com/read/29049989/the-usp7-inhibitor-p5091-induces-cell-death-in-ovarian-cancers-with-different-p53-status
#1
Mengying Wang, Yayun Zhang, Taishu Wang, Jinrui Zhang, Zhu Zhou, Yan Sun, Shanshan Wang, Yulin Shi, Xuelin Luan, Yingqiu Zhang, Yifei Wang, Yang Wang, Zhongwen Zou, Lan Kang, Han Liu
BACKGROUND/AIMS: Ovarian cancer is often diagnosed at later stages with poor prognosis. Recent studies have associated the expression of deubiquitylase USP7 with the survival of ovarian cancers. Being a cysteine protease, USP7 could become a target for pharmacological intervention. Therefore, in this study, we assessed the influence of its inhibitor P5091 on ovarian cancer cells. METHODS: Ovarian cancer cells were treated with P5091, and cell proliferation was measured with MTT assay; cell morphology was inspected under a phase-contrast microscope; cell cycle and cell death were examined by flow cytometry...
October 19, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29045831/usp7-is-a-tumor-specific-wnt-activator-for-apc-mutated-colorectal-cancer-by-mediating-%C3%AE-catenin-deubiquitination
#2
Laura Novellasdemunt, Valentina Foglizzo, Laura Cuadrado, Pedro Antas, Anna Kucharska, Vesela Encheva, Ambrosius P Snijders, Vivian S W Li
The tumor suppressor gene adenomatous polyposis coli (APC) is mutated in most colorectal cancers (CRCs), resulting in constitutive Wnt activation. To understand the Wnt-activating mechanism of the APC mutation, we applied CRISPR/Cas9 technology to engineer various APC-truncated isogenic lines. We find that the β-catenin inhibitory domain (CID) in APC represents the threshold for pathological levels of Wnt activation and tumor transformation. Mechanistically, CID-deleted APC truncation promotes β-catenin deubiquitination through reverse binding of β-TrCP and USP7 to the destruction complex...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045389/molecular-basis-of-usp7-inhibition-by-selective-small-molecule-inhibitors
#3
Andrew P Turnbull, Stephanos Ioannidis, Wojciech W Krajewski, Adan Pinto-Fernandez, Claire Heride, Agnes C L Martin, Louise M Tonkin, Elizabeth C Townsend, Shane M Buker, David R Lancia, Justin A Caravella, Angela V Toms, Thomas M Charlton, Johanna Lahdenranta, Erik Wilker, Bruce C Follows, Nicola J Evans, Lucy Stead, Cristina Alli, Vladislav V Zarayskiy, Adam C Talbot, Alexandre J Buckmelter, Minghua Wang, Crystal L McKinnon, Fabienne Saab, Joanna F McGouran, Hannah Century, Malte Gersch, Marc S Pittman, C Gary Marshall, Tony M Raynham, Mary Simcox, Lorna M D Stewart, Sheila B McLoughlin, Jaime A Escobedo, Kenneth W Bair, Christopher J Dinsmore, Tim R Hammonds, Sunkyu Kim, Sylvie Urbé, Michael J Clague, Benedikt M Kessler, David Komander
Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells...
October 18, 2017: Nature
https://www.readbyqxmd.com/read/29045385/usp7-small-molecule-inhibitors-interfere-with-ubiquitin-binding
#4
Lorna Kategaya, Paola Di Lello, Lionel Rougé, Richard Pastor, Kevin R Clark, Jason Drummond, Tracy Kleinheinz, Eva Lin, John-Paul Upton, Sumit Prakash, Johanna Heideker, Mark McCleland, Maria Stella Ritorto, Dario R Alessi, Matthias Trost, Travis W Bainbridge, Michael C M Kwok, Taylur P Ma, Zachary Stiffler, Bradley Brasher, Yinyan Tang, Priyadarshini Jaishankar, Brian R Hearn, Adam R Renslo, Michelle R Arkin, Frederick Cohen, Kebing Yu, Frank Peale, Florian Gnad, Matthew T Chang, Christiaan Klijn, Elizabeth Blackwood, Scott E Martin, William F Forrest, James A Ernst, Chudi Ndubaku, Xiaojing Wang, Maureen H Beresini, Vickie Tsui, Carsten Schwerdtfeger, Robert A Blake, Jeremy Murray, Till Maurer, Ingrid E Wertz
The ubiquitin system regulates essential cellular processes in eukaryotes. Ubiquitin is ligated to substrate proteins as monomers or chains and the topology of ubiquitin modifications regulates substrate interactions with specific proteins. Thus ubiquitination directs a variety of substrate fates including proteasomal degradation. Deubiquitinase enzymes cleave ubiquitin from substrates and are implicated in disease; for example, ubiquitin-specific protease-7 (USP7) regulates stability of the p53 tumour suppressor and other proteins critical for tumour cell survival...
October 18, 2017: Nature
https://www.readbyqxmd.com/read/28930533/53bp1-a-guardian-for-centrosomal-integrity
#5
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/28900000/correction-for-lecona-et-al-usp7-cooperates-with-scml2-to-regulate-the-activity-of-prc1
#6
Emilio Lecona, Varun Narendra, Danny Reinberg
No abstract text is available yet for this article.
October 1, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28807012/protein-deubiquitinase-usp7-is-required-for-osteogenic-differentiation-of-human-adipose-derived-stem-cells
#7
Yiman Tang, Longwei Lv, Wenyue Li, Xiao Zhang, Yong Jiang, Wenshu Ge, Yongsheng Zhou
BACKGROUND: Human adipose-derived stem cells (hASCs) are multipotent progenitor cells with self-renewal capabilities and multilineage differentiation potential, including osteogenesis. Although protein deubiquitinases have been linked to stem cell fate determination, whether protein deubiquitination contributes to lineage commitment during osteogenic differentiation of hASCs remains to be investigated. The objective of this study was to evaluate the effects of the ubiquitin specific protease 7 (USP7) on osteogenic differentiation of hASCs...
August 14, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28805676/inhibitors-of-deubiquitinating-enzymes-block-hiv-1-replication-and-augment-the-presentation-of-gag-derived-mhc-i-epitopes
#8
Christian Setz, Melanie Friedrich, Pia Rauch, Kirsten Fraedrich, Alina Matthaei, Maximilian Traxdorf, Ulrich Schubert
In recent years it has been well established that two major constituent parts of the ubiquitin proteasome system (UPS)-the proteasome holoenzymes and a number of ubiquitin ligases-play a crucial role, not only in virus replication but also in the regulation of the immunogenicity of human immunodeficiency virus type 1 (HIV-1). However, the role in HIV-1 replication of the third major component, the deubiquitinating enzymes (DUBs), has remained largely unknown. In this study, we show that the DUB-inhibitors (DIs) P22077 and PR-619, specific for the DUBs USP7 and USP47, impair Gag processing and thereby reduce the infectivity of released virions without affecting viral protease activity...
August 12, 2017: Viruses
https://www.readbyqxmd.com/read/28768102/chemical-approaches-to-intervening-in-ubiquitin-specific-protease-7-usp7-function-for-oncology-and-immune-oncology-therapies
#9
Jian Wu, Suresh Kumar, Feng Wang, Hui Wang, Lijia Chen, Patrick Arsenault, Michael Mattern, Joseph Weinstock
USP7, the most widely studied among the nearly 100 deubiquitinating enzymes, supports cancer by positively affecting tumor growth and negatively affecting the patient's immune response to tumors. Great interest exists, therefore, in developing USP7 inhibitors for clinical evaluation. While the proteasome inhibitor field has enjoyed clinical success, very few clinically appropriate effectors of deubiquitinating (protease) or ubiquitinating (ligase) enzymes have appeared. The ubiquitin protease/ligase field is moving from the initial discovery of potent, selective modulators with cell proof of concept and/or in vivo activity to the optimization of these molecules to impart drug-like properties or the discovery of new inhibitor scaffolds by improved screening or rational design...
August 2, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28767131/a-prognostic-mutation-panel-for-predicting-cancer-recurrence-in-stages-ii-and-iii-colorectal-cancer
#10
Shonan Sho, Colin M Court, Paul Winograd, Marcia M Russell, James S Tomlinson
BACKGROUND AND OBJECTIVES: Approximately 20-40% of stage II/III colorectal cancer (CRC) patients develop relapse. Clinicopathological factors alone are limited in detecting these patients, resulting in potential under/over-treatment. We sought to identify a prognostic tumor mutational profile that could predict CRC recurrence. METHODS: Whole-exome sequencing data were obtained for 207 patients with stage II/III CRC from The Cancer Genome Atlas. Mutational landscape in relapse-free versus relapsed cohort was compared using Fisher's exact test, followed by multivariate Cox regression to identify genes associated with cancer recurrence...
August 2, 2017: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28756477/p53-signaling-pathway-polymorphisms-cancer-risk-and-tumor-phenotype-in-tp53-r337h-mutation-carriers
#11
Gabriel S Macedo, Igor Araujo Vieira, Fernanda Salles Luiz Vianna, Barbara Alemar, Juliana Giacomazzi, Ana Paula Carneiro Brandalize, Maira Caleffi, Sahlua Miguel Volc, Henrique de Campos Reis Galvão, Edenir Inez Palmero, Maria Isabel Achatz, Patricia Ashton-Prolla
Li-Fraumeni and Li-Fraumeni-like syndrome (LFS/LFL) are clinically heterogeneous cancer predisposition syndromes characterized by diagnosis of early-onset and often multiple cancers with variable tumor patterns and incomplete penetrance. To date, the genetic modifiers described in LFS/LFL have been shown to map to either TP53 or its main negative regulator, MDM2. Additionally, all studies were focused on families with different TP53 germline mutations. Hence, in this study we explored the effect of the most studied polymorphisms of p53 pathway genes on clinical manifestations of individuals carrying the founder TP53 mutation R337H (n = 136) and controls (n = 186)...
July 29, 2017: Familial Cancer
https://www.readbyqxmd.com/read/28656291/usp7-is-associated-with-greater-disease-activity-in-systemic-lupus-erythematosus-via-stabilization-of-the-ifn%C3%AE-receptor
#12
Ying Yu, Zhaoliang Su, Zhejiong Wang, Huaxi Xu
An improved understanding of the mechanism of interferon (IFN)α activation in systemic lupus erythematosus (SLE) is likely to aid the identification of effective therapeutic targets. Increasing evidence has indicated that the activity of IFNα is mediated by the interplay of ubiquitylation/deubiquitylation enzyme regulators. The present study identified the deubiquitylation enzyme ubiquitin‑specific‑processing protease 7 (USP7) as a critical regulator of the human IFNα‑2 receptor (IFNAR1) protein levels...
August 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28655758/ubiquitin-specific-peptidase-7-usp7-mediated-deubiquitination-of-the-histone-deacetylase-sirt7-regulates-gluconeogenesis
#13
Lu Jiang, Jiannan Xiong, Junsi Zhan, Fengjie Yuan, Ming Tang, Chaohua Zhang, Ziyang Cao, Yongcan Chen, Xiaopeng Lu, Yinglu Li, Hui Wang, Lina Wang, Jiadong Wang, Wei-Guo Zhu, Haiying Wang
Sirtuin 7 (SIRT7), a member of the NAD(+)-dependent class III histone deacetylases, is involved in the regulation of various cellular processes and in resisting various stresses, such as hypoxia, low glucose levels, and DNA damage. Interestingly, SIRT7 is linked to the control of glycolysis, suggesting a role in glucose metabolism. Given the important roles of SIRT7, it is critical to clarify how SIRT7 activity is potentially regulated. It has been reported that some transcriptional and post-transcriptional regulatory mechanisms are involved...
August 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28650472/dub3-and-usp7-de-ubiquitinating-enzymes-control-replication-inhibitor-geminin-molecular-characterization-and-associations-with-breast-cancer
#14
S Hernández-Pérez, E Cabrera, E Salido, M Lim, L Reid, S R Lakhani, K K Khanna, J M Saunus, R Freire
This corrects the article DOI: 10.1038/onc.2017.21.
August 17, 2017: Oncogene
https://www.readbyqxmd.com/read/28646551/prospero-related-homeobox-1-drives-angiogenesis-of-hepatocellular-carcinoma-through-selectively-activating-il-8-expression
#15
Yanfeng Liu, Yonglong Zhang, Shenghao Wang, Qiong-Zhu Dong, Zhongliang Shen, Wei Wang, Shuai Tao, Chenjian Gu, Jing Liu, Youhua Xie, Lun-Xiu Qin
Angiogenesis has been proven to play an important role in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanism underlying HCC angiogenesis is not well understood. In this study, Prospero-related homeobox 1 (PROX1) was identified as a novel pro-angiogenic factor in HCC cell lines and tissues. A strong positive correlation was found between the levels of PROX1 and microvessel density in HCC tissues. Knockdown of PROX1 expression in HCC cells significantly inhibited the in vitro capillary tube formation by human vascular endothelial cells and in vivo angiogenesis of HCC, while overexpression of PROX1 in HCC cells induced the opposite effects...
June 23, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28626083/cellular-and-disease-functions-of-the-prader-willi-syndrome-gene-magel2
#16
REVIEW
Klementina Fon Tacer, Patrick Ryan Potts
Melanoma antigen L2 (MAGEL2 or MAGE-L2) is a member of the MAGE family of ubiquitin ligase regulators. It is maternally imprinted and often paternally deleted or mutated in the related neurodevelopmental syndromes, Prader-Willi Syndrome (PWS) and Schaaf-Yang Syndrome (SHFYNG). MAGEL2 is highly expressed in the hypothalamus and plays an important role in a fundamental cellular process that recycles membrane proteins from endosomes through the retromer sorting pathway. MAGEL2 is part of a multi-subunit protein complex consisting of MAGEL2, the TRIM27 E3 ubiquitin ligase, and the USP7 deubiquitinating enzyme...
June 16, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28621941/sulawesins-a-c-furanosesterterpene-tetronic-acids-that-inhibit-usp7-from-a-psammocinia-sp-marine-sponge
#17
Ahmed H Afifi, Ippei Kagiyama, Ahmed H El-Desoky, Hikaru Kato, Remy E P Mangindaan, Nicole J de Voogd, Nagwa M Ammar, Mohammed S Hifnawy, Sachiko Tsukamoto
Three new furanosesterterpene tetronic acids, sulawesins A-C (1-3), were isolated from a Psammocinia sp. marine sponge, along with the known compounds ircinins-1 (4) and -2 (5). Although ircinins-1 and -2 were previously isolated as (+)- or (-)-enantiomers from marine sponges, we isolated them as enantiomeric mixtures. Sulawesins A and B possess a new carbon skeleton with a 5-(furan-3-yl)-4-hydroxycyclopent-2-enone moiety and were also found to be diastereomeric mixtures of four isomers by an HPLC analysis with a chiral-phase column...
July 28, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/28591556/regulation-of-usp7-a-high-incidence-of-e3-complexes
#18
REVIEW
Robbert Q Kim, Titia K Sixma
Ubiquitin conjugation is a critical signalling process in eukaryotic cells. The precise regulation of deubiquitination is an important component of this signalling cascade. Here we discuss how USP7 (or HAUSP), one of the most abundant deubiquitinating enzymes (DUBs) is regulated by complex formation with regulatory proteins and targets. Full activity of USP7 requires that its C-terminal ubiquitin-like domains fold back onto the catalytic domain, to allow remodelling of the active site to a catalytically competent state by the very C-terminal peptide...
June 4, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28587923/generation-and-validation-of-intracellular-ubiquitin-variant-inhibitors-for-usp7-and-usp10
#19
Wei Zhang, Maria A Sartori, Taras Makhnevych, Kelly E Federowicz, Xiaohui Dong, Li Liu, Satra Nim, Aiping Dong, Jingsong Yang, Yanjun Li, Dania Haddad, Andreas Ernst, Dirk Heerding, Yufeng Tong, Jason Moffat, Sachdev S Sidhu
Post-translational modification of the p53 signaling pathway plays an important role in cell cycle progression and stress-induced apoptosis. Indeed, a large body of work has shown that dysregulation of p53 and its E3 ligase MDM2 by the ubiquitin-proteasome system (UPS) promotes carcinogenesis and malignant transformation. Thus, drug discovery efforts have focused on the restoration of wild-type p53 activity or inactivation of oncogenic mutant p53 by targeted inhibition of UPS components, particularly key deubiquitinases (DUBs) of the ubiquitin-specific protease (USP) class...
June 3, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28495793/usp7-inhibition-alters-homologous-recombination-repair-and-targets-cll-cells-independently-of-atm-p53-functional-status
#20
Angelo Agathanggelou, Edward Smith, Nicholas J Davies, Marwan Kwok, Anastasia Zlatanou, Ceri E Oldreive, Jingwen Mao, David Da Costa, Sina Yadollahi, Tracey Perry, Pamela Kearns, Anna Skowronska, Elliot Yates, Helen Parry, Peter Hillmen, Celine Reverdy, Remi Delansorne, Shankara Paneesha, Guy Pratt, Paul Moss, A Malcolm R Taylor, Grant S Stewart, Tatjana Stankovic
The role of deubiquitylase ubiquitin-specific protease 7 (USP7) in the regulation of the p53-dependent DNA damage response (DDR) pathway is well established. Whereas previous studies have mostly focused on the mechanisms underlying how USP7 directly controls p53 stability, we recently showed that USP7 modulates the stability of the DNA damage responsive E3 ubiquitin ligase RAD18. This suggests that targeting USP7 may have therapeutic potential even in tumors with defective p53 or ibrutinib resistance. To test this hypothesis, we studied the effect of USP7 inhibition in chronic lymphocytic leukemia (CLL) where the ataxia telangiectasia mutated (ATM)-p53 pathway is inactivated with relatively high frequency, leading to treatment resistance and poor clinical outcome...
July 13, 2017: Blood
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