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Dual Regulation of Fbw7 Function and Oncogenic Transformation by Usp28

Please always quote using this URN: urn:nbn:de:bvb:20-opus-118219
  • Fbw7, the substrate recognition subunit of SCF(Fbw7) ubiquitin ligase, mediates the turnover of multiple proto-oncoproteins and promotes its own degradation. Fbw7-dependent substrate ubiquitination is antagonized by the Usp28 deubiquitinase. Here, we show that Usp28 preferentially antagonizes autocatalytic ubiquitination and stabilizes Fbw7, resulting in dose-dependent effects in Usp28 knockout mice. Monoallelic deletion of Usp28 maintains stable Fbw7 but drives Fbw7 substrate degradation. In contrast, complete knockout triggers Fbw7Fbw7, the substrate recognition subunit of SCF(Fbw7) ubiquitin ligase, mediates the turnover of multiple proto-oncoproteins and promotes its own degradation. Fbw7-dependent substrate ubiquitination is antagonized by the Usp28 deubiquitinase. Here, we show that Usp28 preferentially antagonizes autocatalytic ubiquitination and stabilizes Fbw7, resulting in dose-dependent effects in Usp28 knockout mice. Monoallelic deletion of Usp28 maintains stable Fbw7 but drives Fbw7 substrate degradation. In contrast, complete knockout triggers Fbw7 degradation and leads to the accumulation of Fbw7 substrates in several tissues and embryonic fibroblasts. On the other hand, overexpression of Usp28 stabilizes both Fbw7 and its substrates. Consequently, both complete loss and ectopic expression of Usp28 promote Ras-driven oncogenic transformation. We propose that dual regulation of Fbw7 activity by Usp28 is a safeguard mechanism for maintaining physiological levels of proto-oncogenic Fbw7 substrates, which is equivalently disrupted by loss or overexpression of Usp28.show moreshow less

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Metadaten
Author: Christina Schülein-Völk, Elmar Wolf, Jing Zhu, Wenshan Xu, Lyudmyla Taranets, Andreas Hellmann, Laura A. Jänicke, Markus E. Diefenbacher, Axel Behrens, Martin Eilers, Nikita Popov
URN:urn:nbn:de:bvb:20-opus-118219
Document Type:Journal article
Faculties:Medizinische Fakultät / Theodor-Boveri-Institut für Biowissenschaften
Language:English
Parent Title (English):CELL REPORTS
ISSN:2211-1247
Year of Completion:2014
Volume:9
Issue:3
Pagenumber:1099-1109
Source:Cell Reports 9, 1099–1109, November 6, 2014. DOI:10.1016/j.celrep.2014.09.057
DOI:https://doi.org/10.1016/j.celrep.2014.09.057
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=25437563
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:Fbw7; oncogenic transformation
Release Date:2015/10/02
Note:
The sequencing data have been submitted to the GEO repository under accession number GSE59354.
Licence (German):License LogoCC BY-NC-ND: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Keine Bearbeitung