Details

Autor(en) / Beteiligte

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

Titel

Isoform- and Cell Cycle-Dependent Substrate Degradation by the Fbw7 Ubiquitin Ligase

Ist Teil von

• The Journal of cell biology, 2008-06, Vol.181 (6), p.913-920

Ort / Verlag

United States: Rockefeller University Press

Erscheinungsjahr

2008

Quelle

MEDLINE

Beschreibungen/Notizen

• The$\text{SCF}^{\text{FBW}7}$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 Fbw7α 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.