Isoform- and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase

Jonathan E. Grim, Michael Gustafson, Roli K. Hirata, Amanda C. Hagar, Jherek Swanger, Markus Welcker, Harry C. Hwang, Johan Ericsson, David W. Russell, Bruce E. Clurman

Research output: Contribution to journalArticle

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Abstract

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 α 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.

Original languageEnglish (US)
Pages (from-to)913-920
Number of pages8
JournalJournal of Cell Biology
Volume181
Issue number6
DOIs
StatePublished - Jun 16 2008

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Cyclin E
Ligases
Ubiquitin
Cell Cycle
Protein Isoforms
Cyclin-Dependent Kinase 2
Gene Targeting
Sterol Regulatory Element Binding Protein 1
Dependovirus
Ubiquitin-Protein Ligases
Cell Division
Cell Differentiation
Phosphorylation
Mutation
Growth
Neoplasms

ASJC Scopus subject areas

  • Cell Biology

Cite this

Grim, J. E., Gustafson, M., Hirata, R. K., Hagar, A. C., Swanger, J., Welcker, M., ... Clurman, B. E. (2008). Isoform- and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase. Journal of Cell Biology, 181(6), 913-920. https://doi.org/10.1083/jcb.200802076

Isoform- and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase. / Grim, Jonathan E.; Gustafson, Michael; Hirata, Roli K.; Hagar, Amanda C.; Swanger, Jherek; Welcker, Markus; Hwang, Harry C.; Ericsson, Johan; Russell, David W.; Clurman, Bruce E.

In: Journal of Cell Biology, Vol. 181, No. 6, 16.06.2008, p. 913-920.

Research output: Contribution to journalArticle

Grim, JE, Gustafson, M, Hirata, RK, Hagar, AC, Swanger, J, Welcker, M, Hwang, HC, Ericsson, J, Russell, DW & Clurman, BE 2008, 'Isoform- and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase', Journal of Cell Biology, vol. 181, no. 6, pp. 913-920. https://doi.org/10.1083/jcb.200802076
Grim, Jonathan E. ; Gustafson, Michael ; Hirata, Roli K. ; Hagar, Amanda C. ; Swanger, Jherek ; Welcker, Markus ; Hwang, Harry C. ; Ericsson, Johan ; Russell, David W. ; Clurman, Bruce E. / Isoform- and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase. In: Journal of Cell Biology. 2008 ; Vol. 181, No. 6. pp. 913-920.
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