scholarly journals USP47 Promotes Tumorigenesis by Negative Regulation of p53 through Deubiquitinating Ribosomal Protein S2

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1137 ◽  
Author(s):  
Jinhong Cho ◽  
Jinyoung Park ◽  
Sang Chul Shin ◽  
Mihue Jang ◽  
Jae-Hong Kim ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Xenograft Model ◽  
Deubiquitinating Enzymes ◽  
Potential Therapeutic Target ◽  
Mouse Xenograft Model ◽  
Specific Protease ◽  
Important Regulator ◽  
Ubiquitin Specific Protease ◽  
Cellular Stresses ◽  
Ribosomal Stress

p53 is activated in response to cellular stresses such as DNA damage, oxidative stress, and especially ribosomal stress. Although the regulations of p53 by E3 ligase and deubiquitinating enzymes (DUBs) have been described, the cellular roles of DUB associated with ribosomal stress have not been well studied. In this study, we report that Ubiquitin Specific Protease 47 (USP47) functions as an important regulator of p53. We show that ubiquitinated ribosomal protein S2 (RPS2) by Mouse double minute 2 homolog (MDM2) is deubiquitinated by USP47. USP47 inhibits the interaction between RPS2 and MDM2 thereby alleviating RPS2-mediated suppression of MDM2 under normal conditions. However, dissociation of USP47 leads to RPS2 binding to MDM2, which is required for the suppression of MDM2, consequently inducing up-regulation of the p53 level under ribosomal stress. Finally, we show that depletion of USP47 induces p53 and therefore inhibits cell proliferation, colony formation, and tumor progression in cancer cell lines and a mouse xenograft model. These findings suggest that USP47 could be a potential therapeutic target for cancer.

USP48 Sustains Chemoresistance and Metastasis in Ovarian Cancer

2020 ◽  
Vol 20 (9) ◽  
pp. 689-699
Author(s):  
Xuemeng Lei ◽  
Xukun Li ◽  
Hongyan Chen ◽  
Zhihua Liu
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Migration And Invasion ◽  
Clinical Samples ◽  
Deubiquitinating Enzymes ◽  
Potential Therapeutic Target ◽  
Kaplan Meier ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

Background: Ubiquitin specific protease 48 (USP48) is a member of the deubiquitinating enzymes (DUBs) family. However, the function of USP48 in ovarian cancer remains unclear. Objective: The present study reveals that USP48 knockdown could significantly inhibit cell migration and invasion in ES2, 3AO and A2780 cells, without affecting cell proliferation. Methods: After carboplatin (CBP) treatment, the USP48 ablation increases the apoptosis rate, and the cleaved PARP and cleaved caspase 3 expression levels in ES2, 3AO and A2780 cells. The subcutaneous tumor and intraperitoneally injected experiments demonstrated that the USP48 knockdown significantly increases responsiveness to CBP, and alleviates the metastasis in vivo. Meanwhile, USP48 deficiency results in the improved survival of mice. Results: Finally, the analysis of clinical samples and the TCGA and Kaplan-Meier Plot database revealed that the high expression of USP48 in ovarian cancer patients is associated with poor survival and resistance to CBP therapy. Conclusion: In summary, USP48 may be a potential therapeutic target for ovarian cancer patients.

scholarly journals USP19 is a ubiquitin-specific protease regulated in rat skeletal muscle during catabolic states

2005 ◽  
Vol 288 (4) ◽  
pp. E693-E700 ◽  
Author(s):  
Lydie Combaret ◽  
Olasunkanmi A. J. Adegoke ◽  
Nathalie Bedard ◽  
Vickie Baracos ◽  
Didier Attaix ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
De Novo ◽  
Deubiquitinating Enzyme ◽  
Mrna Levels ◽  
Deubiquitinating Enzymes ◽  
Rat Skeletal Muscle ◽  
Ubiquitin System ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

Ubiquitin-dependent proteolysis is activated in skeletal muscle atrophying in response to various catabolic stimuli. Previous studies have demonstrated activation of ubiquitin conjugation. Because ubiquitination can also be regulated by deubiquitinating enzymes, we used degenerate oligonucleotides derived from conserved sequences in the ubiquitin-specific protease (UBP) family of deubiquitinating enzymes in RT-PCR with skeletal muscle RNA to amplify putative deubiquitinating enzymes. We identified USP19, a 150-kDa deubiquitinating enzyme that is widely expressed in various tissues including skeletal muscle. Expression of USP19 mRNA increased by ∼30–200% in rat skeletal muscle atrophying in response to fasting, streptozotocin-induced diabetes, dexamethasone treatment, and cancer. Increased mRNA levels during fasting returned to normal with refeeding, but 1 day later than the normalization of rates of proteolysis and coincided instead with recovery of muscle mass. Indeed, in all catabolic treatments, USP19 mRNA was inversely correlated with muscle mass and provided an index of muscle mass that may be useful in many pathological conditions, using small human muscle biopsies. The increased expression of this deubiquitinating enzyme under conditions of increased proteolysis suggests that it may play a role in regeneration of free ubiquitin either coincident with or after proteasome-mediated degradation of substrates. USP19 may also be involved in posttranslational processing of polyubiquitin produced de novo in response to induction of the polyubiquitin genes seen under these conditions. Deubiquitinating enzymes thus appear involved in muscle wasting and implicate a widening web of regulation of genes in the ubiquitin system in this process.

scholarly journals Ubiquitin‐specific protease 7 as a potential therapeutic target in dogs with hematopoietic malignancies

2021 ◽  
Author(s):  
Aleksandra Pawlak ◽  
Joanna Bajzert ◽  
Katarzyna Bugiel ◽  
Beatriz Hernández Suárez ◽  
Justyna Kutkowska ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Potential Therapeutic Target ◽  
Hematopoietic Malignancies ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

scholarly journals The role of the deubiquitinating enzyme DUB3/USP17 in cancer: a narrative review

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Guang-Fei Yang ◽  
Xin Zhang ◽  
Yi-Ge Su ◽  
Ren Zhao ◽  
Yan-Yang Wang
Keyword(s):  
Central Nervous System ◽  
Cancer Research ◽  
Soft Tissue Sarcomas ◽  
Regulatory Mechanisms ◽  
Deubiquitinating Enzyme ◽  
Biological Functions ◽  
Deubiquitinating Enzymes ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

AbstractThe balance between ubiquitination and deubiquitination is critical for the degradation, transport, localization, and activity of proteins. Deubiquitinating enzymes (DUBs) greatly contribute to the balance of ubiquitination and deubiquitination, and they have been widely studied due to their fundamental role in cancer. DUB3/ubiquitin-specific protease 17 (USP17) is a type of DUB that has attracted much attention in cancer research. In this review, we summarize the biological functions and regulatory mechanisms of USP17 in central nervous system, head and neck, thoracic, breast, gastrointestinal, genitourinary, and gynecologic cancers as well as bone and soft tissue sarcomas, and we provide new insights into how USP17 can be used in the management of cancer.

scholarly journals A novel frameshift mutation in ubiquitin-specific protease 26 gene in a patient with severe oligozoospermia

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
Leilei Li ◽  
Qi Xi ◽  
Hongguo Zhang ◽  
Jia Fei ◽  
Yuting Jiang ◽  
...  
Keyword(s):  
Male Infertility ◽  
Frameshift Mutation ◽  
Bioinformatics Analysis ◽  
Chinese Patient ◽  
Deubiquitinating Enzyme ◽  
Deubiquitinating Enzymes ◽  
Severe Oligozoospermia ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Testis Tissue

Abstract Ubiquitin-specific protease 26 (USP26) encodes a predicted protein containing his- and cys- domains that are conserved among deubiquitinating enzymes. USP26 is specifically expressed in testis tissue and is a potential infertility gene. In the present study, we performed genetic testing related to spermatogenesis impairment in a patient with idiopathic severe oligozoospermia to identify the cause. The patient underwent clinical examination and reproductive hormone testing. Genes associated with male infertility, including USP26, were assessed by targeted exome sequencing. A novel frameshift mutation, c.2195delT (p.Phe732Serfs*14), was identified in USP26. This frameshift mutation was located in residue 732 of USP26 gene, leading to loss of the conserved deubiquitinating enzyme His-domain and producing a truncated protein of 744 amino acids. Bioinformatics analysis revealed this mutation to be pathogenic. A novel framshift mutation c.2195delT (p.Phe732Serfs*14) in USP26 gene was reported to be associated with male infertility in a Chinese patient with severe oligozoospermia.

scholarly journals Positional-scanning fluorigenic substrate libraries reveal unexpected specificity determinants of DUBs (deubiquitinating enzymes)

2008 ◽  
Vol 415 (3) ◽  
pp. 367-375 ◽  
Author(s):  
Marcin Drag ◽  
Jowita Mikolajczyk ◽  
Miklos Bekes ◽  
Francisca E. Reyes-Turcu ◽  
Jonathan A. Ellman ◽  
...  
Keyword(s):  
High Specificity ◽  
Ovarian Tumour ◽  
Full Length ◽  
Activation Mechanism ◽  
Respiratory Syndrome Virus ◽  
Deubiquitinating Enzymes ◽  
Positional Scanning ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Insight Into

DUBs (deubiquitinating enzymes) are a family of proteases responsible for the specific removal of ubiquitin attached to target proteins and thus control the free cellular pools of this molecule. DUB activity is usually assayed using full-length ubiquitin, and these enzymes generally show low activity towards small substrates that constitute the P4–P1 LRGG (Lys-Arg-Gly-Gly) C-terminal motif of ubiquitin. To gain insight into the C-terminal recognition region of ubiquitin by DUBs, we synthesized positional scanning libraries of fluorigenic tetrapeptides and tested them on three examples of human DUBs [OTU-1 (ovarian tumour 1), Iso-T (isopeptidase T) and UCH-L3 (ubiquitin C-terminal hydrolase L3)] and one viral ubiquitin-specific protease, namely PLpro (papain-like protease) from SARS (severe acute respiratory syndrome) virus. In most cases the results show flexibility in the P4 position, very high specificity for arginine in the P3 position and glycine in the P2 position, in accord with the sequence of the natural substrate, ubiquitin. Surprisingly, screening of the P2 position revealed that UCH-L3, in contrast with all the other tested DUBs, demonstrates substantial tolerance of alanine and valine at P2, and a parallel analysis using the appropriate mutation of the full-length ubiquitin confirms this. We have also used an optimal tetrapeptide substrate, acetyl-Lys-Arg-Gly-Gly-7-amino-4-methylcoumarin, to investigate the activation mechanism of DUBs by ubiquitin and elevated salt concentration. Together, our results reveal the importance of the dual features of (1) substrate specificity and (2) the mechanism of ubiquitin binding in determining deubiquitination by this group of proteases.

The role of UBL domains in ubiquitin-specific proteases

2012 ◽  
Vol 40 (3) ◽  
pp. 539-545 ◽  
Author(s):  
Alex C. Faesen ◽  
Mark P.A. Luna-Vargas ◽  
Titia K. Sixma
Keyword(s):  
Catalytic Activity ◽  
Catalytic Domain ◽  
Mechanisms Of Action ◽  
Deubiquitinating Enzymes ◽  
Activated State ◽  
Ubiquitin Binding ◽  
Specific Protease ◽  
Ubiquitin Conjugation ◽  
Ubiquitin Specific Protease

Ubiquitin conjugation and deconjugation provides a powerful signalling system to change the fate of its target enzymes. Ubiquitination levels are organized through a balance between ubiquitinating E1, E2 and E3 enzymes and deubiquitination by DUBs (deubiquitinating enzymes). These enzymes are tightly regulated to control their activity. In the present article, we discuss the different ways in which DUBs of the USP (ubiquitin-specific protease) family are regulated by internal domains with a UBL (ubiquitin-like) fold. The UBL domain in USP14 is important for its localization at the proteasome, which enhances catalysis. In contrast, a UBL domain in USP4 binds to the catalytic domain and competes with ubiquitin binding. In this process, the UBL domain mimics ubiquitin and partially inhibits catalysis. In USP7, there are five consecutive UBL domains, of which the last two affect catalytic activity. Surprisingly, they do not act like ubiquitin and activate catalysis rather than inhibiting it. These C-terminal UBL domains promote a conformational change that allows ubiquitin binding and organizes the catalytic centre. Thus it seems that UBL domains have different functions in different USPs. Other proteins can modulate the roles of UBL domains in USP4 and USP7. On one hand, the inhibition of USP4 can be relieved when the UBL is sequestered by another USP. On the other, the activation of USP7 is increased, when the UBL-activated state is stabilized by allosteric binding of GMP synthetase. Altogether, UBL domains appear to be able to regulate catalytic activity in USPs, but they can use widely different mechanisms of action, in which they may, as in USP4, or may not, as in USP7, use the direct resemblance to ubiquitin.

scholarly journals Ubiquitin-specific protease 22 is critical to in vivo angiogenesis, growth and metastasis of non-small cell lung cancer

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Keqiang Zhang ◽  
Lu Yang ◽  
Jinhui Wang ◽  
Ting Sun ◽  
Yuming Guo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Repair Capacity ◽  
Mouse Xenograft Model ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Underlying Mechanisms

Abstract Background Loss of monoubiquitination of histone H2B (H2Bub1) was found to be associated with poor differentiation, cancer stemness, and enhanced malignancy of non-small cell lung cancer (NSCLC). Herein, we investigated the biological significance and therapeutic implications of ubiquitin-specific protease 22 (USP22), an H2Bub1 deubiquitinase, in non-small cell lung cancer (NSCLC). Methods USP22 expression and its clinical relevance were assessed in NSCLC patients. The effects of USP22 knockout on sensitivity to cisplatin and irradiation, and growth, metastasis of NSCLC xenografts, and survival of cancer-bearing mice were investigated. The underlying mechanisms of targeting USP22 were explored. Results Overexpression of USP22 was observed in 49.0% (99/202) of NSCLC tissues; higher USP22 immunostaining was found to be associated with enhanced angiogenesis and recurrence of NSCLC. Notably, USP22 knockout dramatically suppressed in vitro proliferation, colony formation; and angiogenesis, growth, metastasis of A549 and H1299 in mouse xenograft model, and significantly prolonged survival of metastatic cancer-bearing mice. Furthermore, USP22 knockout significantly impaired non-homologous DNA damage repair capacity, enhanced cisplatin and irradiation-induced apoptosis in these cells. In terms of underlying mechanisms, RNA sequencing and gene ontology enrichment analysis demonstrated that USP22 knockout significantly suppressed angiogenesis, proliferation, EMT, RAS, c-Myc pathways, concurrently enhanced oxidative phosphorylation and tight junction pathways in A549 and H1299 NSCLC cells. Immunoblot analysis confirmed that USP22 knockout upregulated E-cadherin, p16; reduced ALDH1A3, Cyclin E1, c-Myc, and attenuated activation of AKT and ERK pathways in these cells. Conclusions Our findings suggest USP22 plays critical roles in the malignancy and progression of NSCLC and provide rationales for targeting USP22, which induces broad anti-cancer activities, as a novel therapeutic strategy for NSCLC patient.

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