ArticleThe Journal of biological chemistry2016
Proteasomal Degradation of the EWS-FLI1 Fusion Protein Is Regulated by a Single Lysine Residue.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 30 citations in OpenAlex.
- EWSR1::FLI1 promotes neocentromere formation in ewing sarcoma cells.Cell reports · 2026Article
- Suppressing the Aberrant Transcriptional Functionality of EWS::FLI1 Oncoprotein by Designer polyQ Fusions with Its Homologous Peptides.Biomedicines · 2026Article
- Characterization of a novelHaematologica · 2025Article
- Endogenous EWSR1-FLI1 degron alleles enable control of fusion oncoprotein expression in tumor cell lines and xenografts.bioRxiv : the preprint server for biology · 2024Article
- CD9 Counteracts Liver Steatosis and Mediates GCGR Agonist Hepatic Effects.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- PROTAC-Based Protein Degradation as a Promising Strategy for Targeted Therapy in Sarcomas.International journal of molecular sciences · 2023Review
- Targeted Therapy for EWS-FLI1 in Ewing Sarcoma.Cancers · 2023Review
- EWSR1 maintains centromere identity.Cell reports · 2023Article
- Shifting from a Biological-Agnostic Approach to a Molecular-Driven Strategy in Rare Cancers: Ewing Sarcoma Archetype.Biomedicines · 2023Review
- Regulation of EWSR1-FLI1 Function by Post-Transcriptional and Post-Translational Modifications.Cancers · 2023Review
- Ewing sarcoma from molecular biology to the clinic.Frontiers in cell and developmental biology · 2023Review
- TrkC, a novel prognostic marker, induces and maintains cell survival and metastatic dissemination of Ewing sarcoma by inhibiting EWSR1-FLI1 degradation.Cell death & disease · 2022Article
- ERG activity is regulated by endothelial FAK coupling with TRIM25/USP9x in vascular patterning.Development (Cambridge, England) · 2022Article
- AT-hook DNA-binding motif-containing protein one knockdown downregulates EWS-FLI1 transcriptional activity in Ewing's sarcoma cells.PloS one · 2022Article
- The importance of fusion protein activity in Ewing sarcoma and the cell intrinsic and extrinsic factors that regulate it: A review.Frontiers in oncology · 2022Review
- One oncogene, several vulnerabilities: EWS/FLI targeted therapies for Ewing sarcoma.Journal of bone oncology · 2021Article
- Article
- SPOP and OTUD7A Control EWS-FLI1 Protein Stability to Govern Ewing Sarcoma Growth.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2021Article
- Ubiquitin-Mediated Control of ETS Transcription Factors: Roles in Cancer and Development.International journal of molecular sciences · 2021Review
- Targeting the undruggable: exploiting neomorphic features of fusion oncoproteins in childhood sarcomas for innovative therapies.Cancer metastasis reviews · 2019Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
E-26 transformation-specific (ETS) proteins are transcription factors directing gene expression through their conserved DNA binding domain. They are implicated as truncated forms or interchromosomal rearrangements in a variety of tumors including Ewing sarcoma, a pediatric tumor of the bone. Tumor cells express the chimeric oncoprotein EWS-FLI1 from a specific t(22;11)(q24;12) translocation. EWS-FLI1 harbors a strong transactivation domain from EWSR1 and the DNA-binding ETS domain of FLI1 in the C-terminal part of the protein. Although Ewing cells are crucially dependent on continuous expression of EWS-FLI1, its regulation of turnover has not been characterized in detail. Here, we identify the EWS-FLI1 protein as a substrate of the ubiquitin-proteasome system with a characteristic polyubiquitination pattern. Using a global protein stability approach, we determined the half-life of EWS-FLI1 to lie between 2 and 4 h, whereas full-length EWSR1 and FLI1 were more stable. By mass spectrometry, we identified two ubiquitin acceptor lysine residues of which only mutation of Lys-380 in the ETS domain of the FLI1 part abolished EWS-FLI1 ubiquitination and stabilized the protein posttranslationally. Expression of this highly stable mutant protein in Ewing cells while simultaneously depleting the endogenous wild type protein differentially modulates two subgroups of target genes to be either EWS-FLI1 protein-dependent or turnover-dependent. The majority of target genes are in an unaltered state and cannot be further activated. Our study provides novel insights into EWS-FLI1 turnover, a critical pathway in Ewing sarcoma pathogenesis, and lays new ground to develop novel therapeutic strategies in Ewing sarcoma.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.