Effect of the USP7 inhibitor HBX41,108 on lipopolysaccharide induced gene expression in mouse bone marrow derived macrophages.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE149478 | GEO | 2020/06/15
REPOSITORIES: GEO
Similar Datasets
Project description:Deubiquitylating enzymes (DUBs) remove ubiquitin chains from proteins and regulate protein stability and function. USP7 is one of the most compressively studied DUBs. Since USP7 has several well-known substrates important for cancer progression, such as MDM2, N-MYC and PTEN, USP7 becomes a promising drug target. However, systematic identification of USP7 substrates have not yet been performed. In this study, we carried out proteome profiling with label-free quantification using control and single/double KO cells of USP7 and its closest homolog USP47. Our proteome profiling for the first time reveal the proteome changes caused by USP7 and/or USP47 deletion. Combining protein profiling, transcriptome analysis and tandem-affinity purification of USP7-associated proteins, we compiled a list of 20 high-confidence USP7 substrates, which include known and novel USP7 substrates. We experimentally validated MGA and PHIP as new substrates of USP7. Further, we showed that MGA deletion partially phenocopied proliferation defect observed in cells with USP7 deletion. Additionally, we established that USP7 deletion repress interferon gamma response. Moreover, we showed that the cytotoxicity of USP7 inhibitors were independent of USP7. In conclusion, our study is the first proteome-wide analysis of potential USP7 substrates, which provides a resource for further functional studies.
2021-08-04 | MSV000087940 | MassIVE
Project description:DICER is an RNase III enzyme which plays a critical role in the microRNA mature process in the cytoplasm, but also is involved in other functions such as chromatin remodeling, epigenetic modification and DNA damage repair in the nucleus. The expression of DICER is almost decreased across the board in human cancers, which highlights that its expression is strictly controlled, however the underlying mechanisms still remain unknown. In this study, we find that deubiquitinase USP7 suppresses the expression of DICER at the protein level, which impacts DNA damage response (DDR) and cancer progression. MDM2, which is a well-known oncoprotein and also a substrate of USP7, is identified as a novel DICER ubiquitin E3 ligase, thus forming a new regulatory axis of USP7-MDM2-DICER. These findings may provide a new approach to the diagnosis, treatment and prognosis of malignant tumors.
2024-01-10 | GSE225307 | GEO
Project description:USP7, a dominant DUB activity in 3T3-L1 adipocytes and in mouse adipose tissue, increases Tip60 protein levels, and deubiquitinates Tip60 both in intact cells and in vitro. Treatment with a pan deubiquitinase (DUB) inhibitor, or knockdown of USP7, decreases adipogenesis. Transcriptome analysis reveals a common set of cell cycle genes to be co-regulated by both Tip60 and USP7. Knock down of either factor results in impaired mitotic clonal expansion, an early step in adipogenesis. These results therefore reveal deubiquitination of a transcriptional coregulator to be a key mechanism in the regulation of early adipogenesis Mature 3T3-L1 adipocytes were subjected to RNAi-mediated knock down with control(C), USP7(U)- or Tip60(T)-specific oligonucleotides. For this, 4 replicates of differentiated 3T3-L1 cells were transfected with Amaxa technology. Two days after transfection cells were washed twice with PBS twice and lysed in 0.5ml Trizol (Invitrogen). mRNA expression of Tip60 and USP7 was assessed by qRT-PCR. Amplified cRNA samples were labeled with either cy3 or cy5 and put on microarray together with and oppositely labeled common reference sample consisting of cRNA derived from undifferentiated 3T3-L1 cells.
2013-08-28 | E-GEOD-28587 | biostudies-arrayexpress
Project description:Ubiquitin Specific Peptidase 7 (USP7) is a deubiquitinase of several important regulatory proteins, and important regulator of TGFb pathway. To investigate their role in cell signaling, we analyzed global mRNA levels in HEK293T cells that were knocked down with shRNAs against USP7 and non-targeting control (CTRL).
2020-10-18 | GSE139094 | GEO
Project description:USP7, a dominant DUB activity in 3T3-L1 adipocytes and in mouse adipose tissue, increases Tip60 protein levels, and deubiquitinates Tip60 both in intact cells and in vitro. Treatment with a pan deubiquitinase (DUB) inhibitor, or knockdown of USP7, decreases adipogenesis. Transcriptome analysis reveals a common set of cell cycle genes to be co-regulated by both Tip60 and USP7. Knock down of either factor results in impaired mitotic clonal expansion, an early step in adipogenesis. These results therefore reveal deubiquitination of a transcriptional coregulator to be a key mechanism in the regulation of early adipogenesis
2013-08-28 | GSE28587 | GEO
Project description:The transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy. We identify a distinct nuclear interactome of TFEB, with USP7 emerging as a key post-translational modulator of TFEB. Genetic depletion and inhibition of USP7 reveal its critical role in preserving TFEB stability within both nuclear and cytoplasmic compartments. Specifically, USP7 is identified as the deubiquitinase responsible for removing the K48-linked polyubiquitination signal from TFEB at lysine residues K116, K264, and K274, thereby preventing its proteasomal degradation. Functional assays demonstrate the involvement of USP7 in preserving TFEB-mediated transcriptional responses to nutrient deprivation, while also modulating autophagy flux and lysosome biogenesis. As USP7 is a deubiquitinase that protects TFEB from proteasomal degradation, these findings provide the foundation for therapeutic targeting of the USP7-TFEB axis in conditions characterized by TFEB dysregulation and metabolic abnormalities, particularly in certain cancers.
2024-09-17 | PXD055937 | Pride
Project description:Modification by ubiquitin controls the stability of most cellular proteins, and deregulation contributes to a variety of human diseases such as cancer. Deubiquitinases (DUBs) remove ubiquitin from proteins, and the inhibition of DUBs has been recognized as a therapeutic strategy to induce degradation of specific proteins, a concept extendable to ‘undruggable’ targets such as transcription factors. However, this potential has remained untapped; specific small molecule inhibitors for DUBs are scarce and insights into mechanisms of action are limited. Ubiquitin specific protease (USP) 7 stabilises the oncogenic E3 ligase MDM2 that destabilises the tumour suppressor p53 and inhibition of USP7 results in MDM2 degradation and p53 re-activation in a variety of cancers. We here present two small molecule inhibitors, FT671 and FT827, that inhibit USP7 with nanomolar affinity and display exquisite specificity towards USP7 in vitro and in cells. USP7-inhibitor co-crystal structures reveal that both compounds target the auto-inhibited apo-form of USP7 and bind in proximity to the misaligned catalytic triad in a dynamic hydrophobic pocket that serves as the binding site for the ubiquitin C-terminus. The unique auto-inhibited conformation of apo USP7 differs from other USP DUBs, explaining compound selectivity. Consistent with USP7 target engagement in cells, FT671 destabilises MDM2, stabilises p53 and results in transcription of p53 target genes, induction of the tumour suppressor p21, and tumour growth inhibition in vivo.
2018-04-05 | PXD006418 | Pride
Project description:USP7 substrates identified by proteomics analysis reveal the specificity of USP7
| PRJNA752331 | ENA
Project description:Ubiquitin Specific Protease 7 (USP7), also named as herpesvirus-associated ubiquitin-specific protease (HAUSP), is one of the most abundant deubiquitinase and plays multifaceted roles in many cellular functions, including the protein homeostasis, DNA repair, gene transcription, and oncogenic pathways. To investigate the role of USP7 in p53-deficient lung cancer cells, the CRISPR/Cas9-mediated gene editing was employed to inactivate the USP7 locus in H1299 cells. The alterations of transcriptional enhancers and gene expression were analyzed by H3K27ac ChIP-seq and RNA-seq, respectively, in wildtype and USP7-KO H1299 lung cancer cells.
2021-09-16 | GSE172506 | GEO
Project description:Chemical inhibitors of the deubiquitinase USP7 are currently being developed as anticancer agents, due to their capacity to activate P53. Regardless of this activity, USP7 inhibitors also generate DNA damage in a p53-independent manner. However, the mechanism of this genotoxicity remains unknown. Surprisingly, even if USP7 inhibitors stop DNA replication, this occurs concomitant to a premature activation of mitotic kinases such as CDK1, which impairs chromosome segregation and is toxic for mammalian cells. Mechanistically, we show that USP7 interacts with the phosphatase PP2A and regulates its function. Accordingly, USP7 or PP2A inhibition trigger similar changes on the phosphoproteome, with a particular bias towards mitotic targets. Supporting our model, the toxicity of USP7 inhibitors is alleviated by lowering CDK1 activity or by the chemical activation of PP2A. Our work sheds light into the mechanism of action of USP7 inhibitors and provides the first example of triggering premature mitotic entry through perturbation of ubiquitin signaling.
2021-03-09 | PXD016623 | Pride