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Isoform- and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase
Divisions of Clinical Research and Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Mayo Clinic, Rochester, MN 55905, USA.
Division of Hematology, University of Washington School of Medicine, Seattle, WA 98109, USA.
Divisions of Clinical Research and Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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2008 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 181, no 6, 913-920 p.Article in journal (Refereed) Published
Abstract [en]

The SCF(FBW7) ubiquitin ligase degrades proteins involved in cell division, growth, and differentiation and is commonly mutated in cancers. The Fbw7 locus encodes three protein isoforms that occupy distinct subcellular localizations, suggesting that each has unique functions. We used gene targeting to create isoform-specific Fbw7-null mutations in human cells and found that the nucleoplasmic Fbw7alpha isoform accounts for almost all Fbw7 activity toward cyclin E, c-Myc, and sterol regulatory element binding protein 1. Cyclin E sensitivity to Fbw7 varies during the cell cycle, and this correlates with changes in cyclin E-cyclin-dependent kinase 2 (CDK2)-specific activity, cyclin E autophosphorylation, and CDK2 inhibitory phosphorylation. These data suggest that oscillations in cyclin E-CDK2-specific activity during the cell cycle regulate the timing of cyclin E degradation. Moreover, they highlight the utility of adeno-associated virus-mediated gene targeting in functional analyses of complex loci.

Place, publisher, year, edition, pages
2008. Vol. 181, no 6, 913-920 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-17592DOI: 10.1083/jcb.200802076ISI: 000257058500006PubMedID: 18559665OAI: oai:DiVA.org:uu-17592DiVA: diva2:45363
Available from: 2008-07-11 Created: 2008-07-11 Last updated: 2011-03-18Bibliographically approved

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Ericsson, Johan
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