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https://www.readbyqxmd.com/read/28969054/usp21-regulates-hippo-pathway-activity-by-mediating-mark-protein-turnover
#1
Hung Thanh Nguyen, Jan-Michael Kugler, Anand C Loya, Stephen M Cohen
The Hippo pathway, which acts to repress the activity of YAP and TAZ trancriptional co-activators, serve as a barrier for oncogenic transformation. Unlike other oncoproteins, YAP and TAZ are rarely activated by mutations or amplified in cancer. However, elevated YAP/TAZ activity is frequently observed in cancer and often correlates with worse survival. The activity and stability of Hippo pathway components, including YAP/TAZ, AMOT and LATS1/2, are regulated by ubiquitin-mediated protein degradation. Aberrant expression of ubiquitin ligase complexes that regulate the turnover of Hippo components and deubiquitylating enzymes that counteract these ubiquitin ligases have been implicated in human cancer...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28837553/data-driven-flexible-backbone-protein-design
#2
Mark G F Sun, Philip M Kim
Protein design remains an important problem in computational structural biology. Current computational protein design methods largely use physics-based methods, which make use of information from a single protein structure. This is despite the fact that multiple structures of many protein folds are now readily available in the PDB. While ensemble protein design methods can use multiple protein structures, they treat each structure independently. Here, we introduce a flexible backbone strategy, FlexiBaL-GP, which learns global protein backbone movements directly from multiple protein structures...
August 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28767425/usp21-regulates-hippo-pathway-activity-by-mediating-mark-protein-turnover
#3
Hung Thanh Nguyen, Jan-Michael Kugler, Anand C Loya, Stephen M Cohen
The Hippo pathway, which acts to repress the activity of YAP and TAZ trancriptional co-activators, serve as a barrier for oncogenic transformation. Unlike other oncoproteins, YAP and TAZ are rarely activated by mutations or amplified in cancer. However, elevated YAP/TAZ activity is frequently observed in cancer and often correlates with worse survival. The activity and stability of Hippo pathway components, including YAP/TAZ, AMOT and LATS1/2, are regulated by ubiquitin-mediated protein degradation. Aberrant expression of ubiquitin ligase complexes that regulate the turnover of Hippo components and deubiquitylating enzymes that counteract these ubiquitin ligases have been implicated in human cancer...
July 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28743957/ubiquitin-specific-protease-21-stabilizes-brca2-to-control-dna-repair-and-tumor-growth
#4
Jinping Liu, Alex Kruswick, Hien Dang, Andy D Tran, So Mee Kwon, Xin Wei Wang, Philipp Oberdoerffer
Tumor growth relies on efficient DNA repair to mitigate the detrimental impact of DNA damage associated with excessive cell division. Modulating repair factor function, thus, provides a promising strategy to manipulate malignant growth. Here, we identify the ubiquitin-specific protease USP21 as a positive regulator of BRCA2, a key mediator of DNA repair by homologous recombination. USP21 interacts with, deubiquitinates and stabilizes BRCA2 to promote efficient RAD51 loading at DNA double-strand breaks. As a result, depletion of USP21 decreases homologous recombination efficiency, causes an increase in DNA damage load and impairs tumor cell survival...
July 26, 2017: Nature Communications
https://www.readbyqxmd.com/read/28536428/the-molecular-determinants-for-distinguishing-between-ubiquitin-and-nedd8-by-usp2
#5
Yung-Cheng Shin, Jou-Han Chen, Shih-Chung Chang
Ubiquitin (Ub) shares the highest sequence identity with neuronal-precursor-cell-expressed developmentally downregulated protein-8 (NEDD8) in the Ub-like protein family. However, different enzyme systems are precisely employed for targeting Ub and NEDD8 to specific substrates. The molecular determinants for distinguishing between Ub and NEDD8 by Ub-specific peptidases (USPs) remain poorly characterized. By replacing the non-conserved residues of Ub with their NEDD8 equivalents by mutagenesis, and vice versa, we observed that the Ub(4K), Ub(12E), and Ub(14E) mutants partially and the Ub(4K/12E/14E/72A) mutant completely prevented their hydrolysis by USP2...
May 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28257702/gene-resistance-to-transcriptional-reprogramming-following-nuclear-transfer-is-directly-mediated-by-multiple-chromatin-repressive-pathways
#6
Jerome Jullien, Munender Vodnala, Vincent Pasque, Mami Oikawa, Kei Miyamoto, George Allen, Sarah Anne David, Vincent Brochard, Stan Wang, Charles Bradshaw, Haruhiko Koseki, Vittorio Sartorelli, Nathalie Beaujean, John Gurdon
Understanding the mechanism of resistance of genes to reactivation will help improve the success of nuclear reprogramming. Using mouse embryonic fibroblast nuclei with normal or reduced DNA methylation in combination with chromatin modifiers able to erase H3K9me3, H3K27me3, and H2AK119ub1 from transplanted nuclei, we reveal the basis for resistance of genes to transcriptional reprogramming by oocyte factors. A majority of genes is affected by more than one type of treatment, suggesting that resistance can require repression through multiple epigenetic mechanisms...
March 2, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28254948/p38-inhibition-provides-anti-dna-virus-immunity-by-regulation-of-usp21-phosphorylation-and-sting-activation
#7
Yunfei Chen, Lufan Wang, Jiali Jin, Yi Luan, Cong Chen, Yu Li, Hongshang Chu, Xinbo Wang, Guanghong Liao, Yue Yu, Hongqi Teng, Yanming Wang, Weijuan Pan, Lan Fang, Lujian Liao, Zhengfan Jiang, Xin Ge, Bin Li, Ping Wang
Stimulator of IFN genes (STING) is a central adaptor protein that mediates the innate immune responses to DNA virus infection. Although ubiquitination is essential for STING function, how the ubiquitination/deubiquitination system is regulated by virus infection to control STING activity remains unknown. In this study, we found that USP21 is an important deubiquitinating enzyme for STING and that it negatively regulates the DNA virus-induced production of type I interferons by hydrolyzing K27/63-linked polyubiquitin chain on STING...
April 3, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28223825/usp21-promotes-cell-proliferation-and-metastasis-through-suppressing-ezh2-ubiquitination-in-bladder-carcinoma
#8
Yong Chen, Bo Zhou, Daihui Chen
Bladder cancer (BC) is the second most common malignant tumor of the urinary tract in the world. In this study, we found that ubiquitin-specific protease (USP21) was upregulated in BC and the ectopic expression of USP21 was closely associated with tumor size and metastasis. Moreover, patients with higher levels of USP21 had poorer survival rate. Multiple function analysis such as CCK-8, colony formation, wound healing, and transwell analysis indicated that USP21 regulated cell proliferation and metastasis in bladder carcinoma cell lines...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28105162/ubiquitin-specific-protease-21-upregulation-in-breast-cancer-promotes-cell-tumorigenic-capability-and-is-associated-with-the-nod-like-receptor-signaling-pathway
#9
Liang Peng, Yi Hu, Demeng Chen, Ruixia Linghu, Yingzhe Wang, Xiaoxue Kou, Junlan Yang, Shunchang Jiao
Ubiquitination and deubiquitination have emerged as critical regulators in cancer. In the present study, the expression pattern of 50 ubiquitin-specific proteases (USPs) was summarized in breast cancer using a bioinformatics approach, and USP21 was identified as the most altered gene in breast cancer. In particular, expression of USP21 in triple negative breast cancer (TNBC) cell lines was greater compared with other subtypes of breast cancer. Knockdown of USP21 in TNBC cells inhibited cell proliferation, migration and invasion...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/27956178/ubiquitin-specific-protease-21-regulating-the-k48-linked-polyubiquitination-of-nanog
#10
Seul-Ki Kwon, Da-Hye Lee, Soo-Yeon Kim, Jung-Hyun Park, Jihye Choi, Kwang-Hyun Baek
NANOG, one of homeobox proteins, plays a crucial role in regulating self-renewal and pluripotency for embryonic stem cells (ESCs). Since the ubiquitin-mediated degradation of NANOG protein has been implicated in its cellular functions involved in not only maintenance of pluripotency and pluripotent epiblast, but also prevention of primitive endoderm differentiation, the identification of ubiquitin ligases and deubiquitinating enzymes (DUBs) for NANOG is required to elucidate its protein stability and the regulation of cellular functions in these processes...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27886188/the-deubiquitinase-usp21-maintains-the-stemness-of-mouse-embryonic-stem-cells-via-stabilization-of-nanog
#11
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/27857073/usp21-prevents-the-generation-of-t-helper-1-like-treg-cells
#12
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/27621083/the-centrosomal-deubiquitylase-usp21-regulates-gli1-transcriptional-activity-and-stability
#13
Claire Heride, Daniel J Rigden, Erithelgi Bertsoulaki, Danilo Cucchi, Enrico De Smaele, Michael J Clague, Sylvie Urbé
USP21 is a centrosome-associated deubiquitylase (DUB) that has been implicated in the formation of primary cilia - crucial organelles for the regulation of the Hedgehog (Hh) signaling pathway in vertebrates. Here, we identify KCTD6 - a cullin-3 E3-ligase substrate adapter that has been previously linked to Hh signaling - as well as Gli1, the key transcription factor responsible for Hh signal amplification, as new interacting partners of USP21. We identify a cryptic structured protein interaction domain in KCTD6, which is predicted to have a similar fold to Smr domains...
November 1, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27436899/saturation-scanning-of-ubiquitin-variants-reveals-a-common-hot-spot-for-binding-to-usp2-and-usp21
#14
Isabel Leung, Ayelet Dekel, Julia M Shifman, Sachdev S Sidhu
A detailed understanding of the molecular mechanisms whereby ubiquitin (Ub) recognizes enzymes in the Ub proteasome system is crucial for understanding the biological function of Ub. Many structures of Ub complexes have been solved and, in most cases, reveal a large structural epitope on a common face of the Ub molecule. However, owing to the generally weak nature of these interactions, it has been difficult to map in detail the functional contributions of individual Ub side chains to affinity and specificity...
August 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27259257/ubiquitin-specific-peptidase-21-regulates-interleukin-8-expression-stem-cell-like-property-of-human-renal-cell-carcinoma
#15
Liang Peng, Yi Hu, Demeng Chen, Shunchang Jiao, Shengkun Sun
USP family proteins play essential roles in cancer cell proliferation and apoptosis and represent as candidate targets for cancer therapeutics. However, the effects and underlying mechanism of USP21 on renal cell carcinomas (RCC) remain unclear. In the present study, we investigate the effects of USP21 on proliferation, invasion and cancer stem cells (CSCs) property of RCC cell lines. As a result, siRNA-mediated depletion of USP21 inhibits cell proliferation, invasion ability and decreases the CSCs percentage of RCC cell lines...
July 5, 2016: Oncotarget
https://www.readbyqxmd.com/read/27190257/brief-communication-featured-article-histone-h2a-mono-ubiquitination-and-cellular-transformation-are-inversely-related-in-n-nitrosodiethylamine-induced-hepatocellular-carcinoma
#16
Saikat Bhattacharya, Divya Reddy, Arvind Ingle, Bharat Khade, Sanjay Gupta
Aberrant changes in histone post-translational modifications are encountered frequently in diseases like cancer. Although histone H3 post-translational modifications have been extensively studied in context of diseases, the functionally important histone H2A PTM H2A119ub (H2Aub) has not gained much attention. In this study, we report that H2Aub markedly decreases in hepatocellular carcinoma. Usp21, a H2A deubiquitinase, is probably responsible for decrease in H2Aub. In addition, the H2Aub levels showed an inverse correlation with H3S10 phosphorylation (H3S10p) and the proliferative state of the cells...
October 2016: Experimental Biology and Medicine
https://www.readbyqxmd.com/read/27174732/proteome-wide-search-for-functional-motifs-altered-in-tumors-prediction-of-nuclear-export-signals-inactivated-by-cancer-related-mutations
#17
Gorka Prieto, Asier Fullaondo, Jose A Rodríguez
Large-scale sequencing projects are uncovering a growing number of missense mutations in human tumors. Understanding the phenotypic consequences of these alterations represents a formidable challenge. In silico prediction of functionally relevant amino acid motifs disrupted by cancer mutations could provide insight into the potential impact of a mutation, and guide functional tests. We have previously described Wregex, a tool for the identification of potential functional motifs, such as nuclear export signals (NESs), in proteins...
2016: Scientific Reports
https://www.readbyqxmd.com/read/26100909/bend3-represses-rdna-transcription-by-stabilizing-a-norc-component-via-usp21-deubiquitinase
#18
Abid Khan, Sumanprava Giri, Yating Wang, Arindam Chakraborty, Archit K Ghosh, Aparna Anantharaman, Vasudha Aggarwal, Kizhakke M Sathyan, Taekjip Ha, Kannanganattu V Prasanth, Supriya G Prasanth
Ribosome biogenesis dictates the translational capacity of cells. Several mechanisms establish and maintain transcriptional output from eukaryotic ribosomal DNA (rDNA) loci. rDNA silencing is one such mechanism that ensures the inactivity and hence the maintenance of a silenced state of a subset of rRNA gene copies. Whereas oncogenic agents stimulate rRNA gene transcription, tumor suppressors decrease rRNA gene transcription. We demonstrate in mammalian cells that BANP, E5R, and Nac1 (BEN) domain 3 (BEND3), a quadruple BEN domain-containing protein, localizes in nucleoli and binds to ribosomal RNA gene promoters to help repress rRNA genes...
July 7, 2015: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/25680095/ubiquitin-specific-protease-21-is-dispensable-for-normal-development-hematopoiesis-and-lymphocyte-differentiation
#19
Jaspreet Pannu, Jad I Belle, Michael Förster, Claudia U Duerr, Shiyang Shen, Leanne Kane, Katherine Harcourt, Jörg H Fritz, Simon Clare, Anastasia Nijnik
USP21 is a ubiquitin specific protease that catalyzes protein deubiquitination, however the identification of its physiological substrates remains challenging. USP21 is known to deubiquitinate transcription factor GATA3 and death-domain kinase RIPK1 in vitro, however the in vivo settings where this regulation plays a biologically significant role remain unknown. In order to determine whether USP21 is an essential and non-redundant regulator of GATA3 or RIPK1 activity in vivo, we characterized Usp21-deficient mice, focusing on mouse viability and development, hematopoietic stem cell function, and lymphocyte differentiation...
2015: PloS One
https://www.readbyqxmd.com/read/25197364/deubiquitination-and-stabilization-of-il-33-by-usp21
#20
Lianqin Tao, Chen Chen, Huihui Song, Miranda Piccioni, Guochao Shi, Bin Li
Interleukin-33 (IL-33) is a dual-function protein that acts both as a secreted cytokine and as a nuclear factor regulating gene transcription. It has been demonstrated that IL-33 exerts its nuclear function in promoting the transcription of NF-κB p65. Here, we show that USP21-mediated deubiquitination of IL-33 affects the transcription of p65. IL-33 can be post-translationally modified by ubiquitination. Ubiquitin-specific protease 21 (USP21) interacts with IL-33 and also localizes in nucleus. The protein stability of IL-33 is maintained by USP21 through deubiquitination...
2014: International Journal of Clinical and Experimental Pathology
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