title: Dual regulation of Fbw7 function and oncogenic transformation by Usp28.
abstract: 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 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Biozentrum, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Schülein-Völk
authors.affiliation: Department of Biochemistry and Molecular Biology, Biozentrum, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Comprehensive Cancer Center Mainfranken and Department of Radiation Oncology, University Hospital Würzburg, Versbacher Strasse 5, 97078 Würzburg, Germany.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Comprehensive Cancer Center Mainfranken and Department of Radiation Oncology, University Hospital Würzburg, Versbacher Strasse 5, 97078 Würzburg, Germany.
authors.forename: Wenshan
authors.initials: W
authors.lastname: Xu
authors.affiliation: Comprehensive Cancer Center Mainfranken and Department of Radiation Oncology, University Hospital Würzburg, Versbacher Strasse 5, 97078 Würzburg, Germany.
authors.forename: Lyudmyla
authors.initials: L
authors.lastname: Taranets
authors.affiliation: Comprehensive Cancer Center Mainfranken and Department of Radiation Oncology, University Hospital Würzburg, Versbacher Strasse 5, 97078 Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hellmann
authors.affiliation: Department of Biochemistry and Molecular Biology, Biozentrum, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Jänicke
authors.affiliation: Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Markus E
authors.initials: ME
authors.lastname: Diefenbacher
authors.affiliation: Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Axel
authors.initials: A
authors.lastname: Behrens
authors.affiliation: Department of Biochemistry and Molecular Biology, Biozentrum, University of Würzburg, Am Hubland, 97074 Würzburg, Germany; Comprehensive Cancer Center Mainfranken and Department of Radiation Oncology, University Hospital Würzburg, Versbacher Strasse 5, 97078 Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
authors.affiliation: Department of Biochemistry and Molecular Biology, Biozentrum, University of Würzburg, Am Hubland, 97074 Würzburg, Germany; Comprehensive Cancer Center Mainfranken and Department of Radiation Oncology, University Hospital Würzburg, Versbacher Strasse 5, 97078 Würzburg, Germany. Electronic address: nikita.popov@biozentrum.uni-wuerzburg.de.
authors.forename: Nikita
authors.initials: N
authors.lastname: Popov
mesh_terms: D000483:Alleles; D000818:Animals; D055162:Biocatalysis; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D044783:F-Box Proteins / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D017353:Gene Deletion; D006367:HeLa Cells; D006801:Humans; D018345:Mice, Knockout; D008954:Models, Biological; D009928:Organ Specificity; D055550:Protein Stability; D059748:Proteolysis; D013379:Substrate Specificity; D014158:Transcription, Genetic; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C513272:Fbxw7 protein, mouse; C442902:USP28 protein, human; C000595271:USP28 protein, mouse; D044767:Ubiquitin-Protein Ligases; D043222:Ubiquitin Thiolesterase