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Robert Liefke, Violetta Karwacki-Neisius, Yang Shi
Gene regulatory networks are pivotal for many biological processes. In mouse embryonic stem cells (mESCs), the transcriptional network can be divided into three functionally distinct modules: Polycomb, Core, and Myc. The Polycomb module represses developmental genes, while the Myc module is associated with proliferative functions, and its mis-regulation is linked to cancer development. Here, we show that, in mESCs, the Polycomb repressive complex 2 (PRC2)-associated protein EPOP (Elongin BC and Polycomb Repressive Complex 2-associated protein; a...
November 17, 2016: Molecular Cell
Anne Forand, Eugénie Koumakis, Alice Rousseau, Yohann Sassier, Clément Journe, Jean-François Merlin, Christine Leroy, Valérie Boitez, Patrice Codogno, Gérard Friedlander, Isabelle Cohen
No abstract text is available yet for this article.
November 8, 2016: Cell Reports
Dongjun Qin, Weiwei Wang, Hu Lei, Hao Luo, Haiyan Cai, Caixia Tang, Yunzhao Wu, Yingying Wang, Jin Jin, Weilie Xiao, Tongdan Wang, Chunmin Ma, Hanzhang Xu, Jinfu Zhang, Fenghou Gao, Yingli Wu
Deubiquitinating enzyme USP7 has been involved in the pathogenesis and progression of several cancers. Targeting USP7 is becoming an attractive strategy for cancer therapy. In this study, we identified synthetic triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid (CDDO-Me) as a novel inhibitor of USP7 but not of other cysteine proteases such as cathepsin B and cathepsin D. CDDO-Me inhibits USP7 activity via a mechanism that is independent of the presence of α, β-unsaturated ketones...
October 21, 2016: Oncotarget
Liqing Wang, Suresh Kumar, Satinder Dahiya, Feng Wang, Jian Wu, Kheng Newick, Rongxiang Han, Arabinda Samanta, Ulf H Beier, Tatiana Akimova, Tricia R Bhatti, Benjamin Nicholson, Mathew P Kodrasov, Saket Agarwal, David E Sterner, Wei Gu, Joseph Weinstock, Tauseef R Butt, Steven M Albelda, Wayne W Hancock
Foxp3+ T-regulatory (Treg) cells are known to suppress protective host immune responses to a wide variety of solid tumors, but their therapeutic targeting is largely restricted to their transient depletion or "secondary" modulation, e.g. using anti-CTLA-4 monoclonal antibody. Our ongoing studies of the post-translational modifications that regulate Foxp3 demonstrated that the histone/protein acetyltransferase, Tip60, plays a dominant role in promoting acetylation, dimerization and function in Treg cells. We now show that the ubiquitin-specific protease, Usp7, controls Treg function largely by stabilizing the expression and promoting the multimerization of Tip60 and Foxp3...
October 15, 2016: EBioMedicine
Anoeska Agatha Alida van de Moosdijk, Renée van Amerongen
Cell growth and differentiation are often driven by subtle changes in gene expression. Many challenges still exist in detecting these changes, particularly in the context of a complex, developing tissue. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) allows relatively high-throughput evaluation of multiple genes and developmental time points. Proper quantification of gene expression levels by qRT-PCR requires normalization to one or more reference genes. Traditionally, these genes have been selected based on their presumed "housekeeping" function, with the implicit assumption that they are stably expressed over the entire experimental set...
October 18, 2016: Scientific Reports
Emilio Lecona, Oscar Fernandez-Capetillo
Post-translational modifications regulate each step of DNA replication to ensure the faithful transmission of genetic information. In this context, we recently showed that deubiquitination of SUMO2/3 and SUMOylated proteins by USP7 helps to create a SUMO-rich and ubiquitin-low environment around replisomes that is necessary to maintain the activity of replication forks and for new origin firing. We propose that a two-flag system mediates the collective concentration of factors at sites of DNA replication, whereby SUMO and Ubiquitinated-SUMO would constitute "stay" or "go" signals respectively for replisome and accessory factors...
September 26, 2016: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
(no author information available yet)
USP7 deubiquitinates MYCN to enhance its stability and transcriptional activity in neuroblastoma.
September 23, 2016: Cancer Discovery
Lei Yi, Yan Cui, Qingfu Xu, Yugang Jiang
The substrates and mechanisms of ubiquitin specific peptidase 7 (USP7) in glioma remain unclear. Lysine‑specific demethylase 1 (LSD1) may undergo proteasomal degradation; however, a reciprocal mechanism that stabilizes LSD1 in glioma has not been dertermined. Here co-immunoprecipitation and GST pull-down assays revealed that LSD1 is associated with USP7 in vivo and in vitro. USP7 inhibited LSD1 ubiquitination and stabilized LSD1 in A172 and T98G cells. MTT, EdU proliferation, flow cytometry and Transwell assays indicated that LSD1 played a critical role in the proliferation and invasion of glioblastoma (GBM) cells...
September 16, 2016: Oncology Reports
Omid Tavana, Dawei Li, Chao Dai, Gonzalo Lopez, Debarshi Banerjee, Ning Kon, Chao Chen, Andrea Califano, Darrell J Yamashiro, Hongbin Sun, Wei Gu
The MYCN proto-oncogene is amplified in a number of advanced-stage human tumors, such as neuroblastomas. Similar to other members of the MYC family of oncoproteins, MYCN (also known as N-Myc) is a transcription factor, and its stability and activity are tightly controlled by ubiquitination-dependent proteasome degradation. Although numerous studies have demonstrated that N-Myc is a driver of neuroblastoma tumorigenesis, therapies that directly suppress N-Myc activity in human tumors are limited. Here we have identified ubiquitin-specific protease 7 (USP7; also known as HAUSP) as a regulator of N-Myc function in neuroblastoma...
October 2016: Nature Medicine
Chao Zhang, Jing Lu, Quan-Wu Zhang, Wei Zhao, Jia-Hui Guo, Shan-Ling Liu, Ying-Li Wu, Bin Jiang, Feng-Hou Gao
The Ki-67 antigen (Ki-67) is the most reliable immunohistochemical marker for evaluation of cell proliferation in non-small cell lung cancer. However, the mechanisms underlying the regulation of protein levels of Ki-67 in non-small cell lung cancer have remained elusive. In this study, we found that Ki-67 and ubiquitin-specific processing protease 7 (USP7) protein were highly expressed in the nucleus of non-small cell lung cancer cells. Furthermore, statistical analysis uncovered the existence of a strong correlation between Ki-67 and USP7 levels...
October 2016: International Journal of Biochemistry & Cell Biology
Anne Forand, Eugénie Koumakis, Alice Rousseau, Yohann Sassier, Clément Journe, Jean-François Merlin, Christine Leroy, Valérie Boitez, Patrice Codogno, Gérard Friedlander, Isabelle Cohen
The liver plays a central role in whole-body lipid and glucose homeostasis. Increasing dietary fat intake results in increased hepatic fat deposition, which is associated with a risk for development of insulin resistance and type 2 diabetes. In this study, we demonstrate a role for the phosphate inorganic transporter 1 (PiT1/SLC20A1) in regulating metabolism. Specific knockout of Pit1 in hepatocytes significantly improved glucose tolerance and insulin sensitivity, enhanced insulin signaling, and decreased hepatic lipogenesis...
September 6, 2016: Cell Reports
Maria Derkacheva, Shujing Liu, Duarte D Figueiredo, Matthew Gentry, Iva Mozgova, Paolo Nanni, Min Tang, Mattias Mannervik, Claudia Köhler, Lars Hennig
Polycomb group (PcG) proteins form an epigenetic memory system in plants and animals, but interacting proteins are poorly known in plants. Here, we have identified Arabidopsis UBIQUITIN SPECIFIC PROTEASES (USP; UBP in plant and yeasts) 12 and 13 as partners of the plant-specific PcG protein LIKE HETEROCHROMATIN PROTEIN 1 (LHP1). UBP12 binds to chromatin of PcG target genes and is required for histone H3 lysine 27 trimethylation and repression of a subset of PcG target genes. Plants lacking UBP12 and UBP13 developed autonomous endosperm in the absence of fertilization...
2016: Nature Plants
H Yim, S-B Shin, S U Woo, P C-W Lee, R L Erikson
Although 53BP1 has been established well as a mediator in DNA damage response, its function in mitosis is not clearly understood. We found that 53BP1 is a mitotic-binding partner of the kinases Plk1 and AuroraA, and that the binding with Plk1 increases the stability of 53BP1 by accelerating its interaction with the deubiquitinase USP7. Depletion of 53BP1 induces mitotic defects such as chromosomal missegregation, misorientation of spindle poles and the generation of extra centrosomes, which is similar phenotype to USP7-knockdown cells...
August 1, 2016: Oncogene
Guihai Feng, Man Tong, Baolong Xia, Guan-Zheng Luo, Meng Wang, Dongfang Xie, Haifeng Wan, Ying Zhang, Qi Zhou, Xiu-Jie Wang
How do different cell types acquire their specific identities and functions is a fundamental question of biology. Previously significant efforts have been devoted to search for cell-type-specifically expressed genes, especially transcription factors, yet how do ubiquitously expressed genes participate in the formation or maintenance of cell-type-specific features remains largely unknown. Here, we have identified 110 mouse embryonic stem cell (mESC) specifically expressed transcripts with cell-stage-specific alternative transcription start sites (SATS isoforms) from 104 ubiquitously expressed genes, majority of which have active epigenetic modification- or stem cell-related functions...
September 2016: EMBO Reports
Hu Chen, Renqiang Yuan, Ying Zhang, Xumeng Zhang, Luxi Chen, Xingyu Zhou, Zhuning Yuan, Yaping Nie, Ming Li, Delin Mo, Yaosheng Chen
Activating transcription factor 4 (ATF4), which is highly expressed in 3T3-L1 adipocytes after adipogenic induction, is essential for adipocytes differentiation. ATF4 also plays a vital role in regulating fatty acids biosynthesis, whereas the detailed mechanism of this process is still unclear. Here we demonstrated that siRNA-based ATF4 depletion in 3T3-L1 adipocytes significantly reduced the accumulation of fatty acids and triglycerides. Moreover, SREBP1c protein, which is an important transcription factor of lipogenesis, appreciably decreased while Srebp1c mRNA increased...
November 2016: Biochimica et Biophysica Acta
Lionel Rougé, Travis W Bainbridge, Michael Kwok, Raymond Tong, Paola Di Lello, Ingrid E Wertz, Till Maurer, James A Ernst, Jeremy Murray
The deubiquitinating enzyme USP7 has a pivotal role in regulating the stability of proteins involved in fundamental cellular processes of normal biology and disease. Despite the importance of USP7, the mechanisms underlying substrate recognition and catalytic activation are poorly understood. Here we present structural, biochemical, and biophysical analyses elucidating the molecular mechanism by which the C-terminal 19 amino acids of USP7 (residues 1084-1102) enhance the ubiquitin cleavage activity of the deubiquitinase (DUB) domain...
August 2, 2016: Structure
Paola Di Lello, Lionel Rougé, Borlan Pan, Till Maurer
The deubiquitinase Ubiquitin Specific Protease 7 (USP7) is part of the regulatory cascade of proteins that modulates the activity of the tumor suppressor protein p53. Deubiquitination of its target Murine Double Minute 2 (MDM2) leads to increased proteosomal degradation of p53. Consequently, USP7 has emerged as an attractive oncology target because its inhibition stabilizes p53, thereby promoting p53-dependent apoptosis in cancer cells. Here we report the backbone resonance assignment for the 40.5 kDa catalytic domain of USP7...
October 2016: Biomolecular NMR Assignments
Veronique A J Smits, Raimundo Freire
DNA replication is both highly conserved and controlled. Problematic DNA replication can lead to genomic instability and therefore carcinogenesis. Numerous mechanisms work together to achieve this tight control and increasing evidence suggests that post-translational modifications (phosphorylation, ubiquitination, SUMOylation) of DNA replication proteins play a pivotal role in this process. Here we discuss such modifications in the light of a recent article that describes a novel role for the deubiquitinase (DUB) USP7/HAUSP in the control of DNA replication...
September 2016: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
Umberto Malapelle, Francesco Morra, Gennaro Ilardi, Roberta Visconti, Francesco Merolla, Aniello Cerrato, Virginia Napolitano, Roberto Monaco, Gianluca Guggino, Guglielmo Monaco, Stefania Staibano, Giancarlo Troncone, Angela Celetti
OBJECTIVES: CCDC6 gene product is a tumor-suppressor pro-apoptotic protein, substrate of ATM, involved in DNA damage response and repair. Altered levels of CCDC6 expression are dependent on post-translational modifications, being the de-ubiquitinating enzyme USP7 responsible of the fine tuning of the CCDC6 stability. Thus, our aim was to investigate CCDC6 and USP7 expression levels in Lung-Neuroendocrine Tumors (L-NETs) to verify if they correlate and may be exploited as novel predictive therapeutic markers...
June 17, 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Anastasia Zlatanou, Grant S Stewart
RAD18 functions to promote DNA damage tolerance (DTT), a process that ensures faithful genome duplication. Protein ubiquitylation/deubiquitylation is a critical regulatory mechanism controlling DTT. Recently, we have identified the deubiquitylating enzyme USP7 as a component of the DTT machinery that acts to protect RAD18 from proteasome-dependent degradation.
January 2016: Molecular & Cellular Oncology
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