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Cell Cycle, Cell Death, and Senescence

Fbw7 Isoform Interaction Contributes to Cyclin E Proteolysis

Department of Genetics, Cell Biology and Development, University of Minnesota-Twin Cities, Minneapolis, Minnesota

Requests for reprints: Deanna M. Koepp, Department of Genetics, Cell Biology and Development, University of Minnesota, 6-160 Jackson Hall, 321 Church Street Southeast, Minneapolis, MN 55455. Phone: 612-624-4201; Fax: 612-625-4648. E-mail: koepp015{at}umn.edu

The ubiquitin proteasome system plays important roles in regulating cell growth and proliferation. Many proteins that function in ubiquitin-mediated destruction have been linked to tumorigenesis. The putative tumor-suppressor protein Fbw7 (hAgo/hCdc4) is a specificity factor for the Skp1-Cul1-F-box protein ubiquitin ligase complex and targets a number of proto-oncogene products for ubiquitin-mediated destruction, including the cell cycle regulator cyclin E. In mammals, there are three splice variants of Fbw7 that use distinct first exons, resulting in proteins that have unique NH₂ termini but are otherwise identical. Here, we show that the Fbw7 splice variants interact with each other through an NH₂-terminal region common to all of the Fbw7 isoforms. Other F-box proteins have been shown to regulate substrate binding or turnover by forming homodimeric or heterodimeric complexes, which are dependent on a sequence motif called the D domain. Fbw7 and its orthologues exhibit significant sequence similarity to such F-box proteins, including the D domain. Fbw7 mutants that lack the region encompassing the D domain fail to bind other Fbw7 isoforms, despite being properly localized and binding both cyclin E and Skp1. Finally, we show the functional significance of this region as mutants lacking the NH₂-terminal region involved in Fbw7 binding exhibit reduced rates of cyclin E protein turnover, indicating that Fbw7 isoform interaction is important for the efficiency of cyclin E turnover. Overall, this study contributes to the current understanding of the regulation of the Fbw7 tumor-suppressor protein. (Mol Cancer Res 2006;4(12):935–43)

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