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Published online June 16, 2008
doi:10.1083/jcb.200802076
The Journal of Cell Biology, Vol. 181, No. 6, 913-920
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Grim et al.
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 Isoform- and cell cycle–dependent substrate degradation by the Fbw7 ubiquitin ligase

Jonathan E. Grim1,2, Michael P. Gustafson1,3, Roli K. Hirata4, Amanda C. Hagar1,2, Jherek Swanger1,2, Markus Welcker1,2, Harry C. Hwang1,2, Johan Ericsson5, David W. Russell4, and Bruce E. Clurman1,2

1 Divisions of Clinical Research and 2 Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
3 Mayo Clinic, Rochester, MN 55905
4 Division of Hematology, University of Washington School of Medicine, Seattle, WA 98109
5 Ludwig Institute for Cancer Research, 751 24 Uppsala, Sweden

Correspondence to Bruce E. Clurman: bclurman{at}fhcrc.org

The SCFFBW7 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 Fbw7{alpha} 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.

Abbreviations used in this paper: AAV, adeno-associated virus; CPD, Cdc4 phosphodegron; P382, proline 382; SREBP, sterol regulatory element binding protein; Y15, tyrosine 15.


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