| Autor: |
Serena Mahnoor, Cristina Molnar, Diego Velázquez, Jose Reina, Salud Llamazares, Jan Peter Heinen, Jaume Mora, Cayetano Gonzalez |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Open Biology, Vol 14, Iss 7 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2046-2441 |
| DOI: |
10.1098/rsob.240043 |
| Popis: |
Ewing sarcoma (EwS) is a cancer that arises in the bones and soft tissues, typically driven by the Ewing’s sarcoma breakpoint region 1-Friend leukemia virus integration 1 (EWS-FLI) oncogene. Implementation of genetically modified animal models of EwS has proved difficult largely owing to EWS-FLI’s high toxicity. The EWS-FLI1FS frameshift variant that circumvents toxicity but is still able to perform key oncogenic functions provided the first study model in Drosophila. However, the quest for Drosophila lines expressing full-length, unmodified EWS-FLI remained open. Here, we show that EWS-FLI1FS’s lower toxicity is owed to reduced protein levels caused by its frameshifted C-terminal peptide, and report new strategies through which we have generated Drosophila lines that express full-length, unmodified EWS-FLI. Using these lines, we have found that the upregulation of transcription from GGAA-microsatellites (GGAAμSats) presents a positive linear correlation within a wide range of EWS-FLI protein concentrations. In contrast, rather counterintuitively, GGAAμSats-independent transcriptomic dysregulation presents relatively minor differences across the same range, suggesting that GGAAμSat-dependent and -independent transcriptional upregulation present different kinetics of response with regards to changing EWS-FLI protein concentration. Our results underpin the functional relevance of varying EWS-FLI expression levels and provide experimental tools to investigate, in Drosophila, the effect of the EWS-FLI ‘high’ and ‘low’ states that have been reported and are suspected to be important for EwS in humans. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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