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SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation.

Nature | Jul 1, 2010

http://www.ncbi.nlm.nih.gov/pubmed/20596027

Generally, F-box proteins are the substrate recognition subunits of SCF (Skp1-Cul1-F-box protein) ubiquitin ligase complexes, which mediate the timely proteolysis of important eukaryotic regulatory proteins. Mammalian genomes encode roughly 70 F-box proteins, but only a handful have established functions. The F-box protein family obtained its name from Cyclin F (also called Fbxo1), in which the F-box motif (the approximately 40-amino-acid domain required for binding to Skp1) was first described. Cyclin F, which is encoded by an essential gene, also contains a cyclin box domain, but in contrast to most cyclins, it does not bind or activate any cyclin-dependent kinases (CDKs). However, like other cyclins, Cyclin F oscillates during the cell cycle, with protein levels peaking in G2. Despite its essential nature and status as the founding member of the F-box protein family, Cyclin F remains an orphan protein, whose functions are unknown. Starting from an unbiased screen, we identified CP110, a protein that is essential for centrosome duplication, as an interactor and substrate of Cyclin F. Using a mode of substrate binding distinct from other F-box protein-substrate pairs, CP110 and Cyclin F physically associate on the centrioles during the G2 phase of the cell cycle, and CP110 is ubiquitylated by the SCF(Cyclin F) ubiquitin ligase complex, leading to its degradation. siRNA-mediated depletion of Cyclin F in G2 induces centrosomal and mitotic abnormalities, such as multipolar spindles and asymmetric, bipolar spindles with lagging chromosomes. These phenotypes were reverted by co-silencing CP110 and were recapitulated by expressing a stable mutant of CP110 that cannot bind Cyclin F. Finally, expression of a stable CP110 mutant in cultured cells also promotes the formation of micronuclei, a hallmark of chromosome instability. We propose that SCF(Cyclin F)-mediated degradation of CP110 is required for the fidelity of mitosis and genome integrity.

Pubmed ID: 20596027 RIS Download

Mesh terms: Animals | Cell Cycle Proteins | Cell Line | Cell Line, Tumor | Centrioles | Centrosome | Cyclins | G2 Phase | Homeostasis | Humans | Mice | Microtubule-Associated Proteins | Mitosis | Multiprotein Complexes | Phenotype | Phosphoproteins | Protein Binding | SKP Cullin F-Box Protein Ligases | Substrate Specificity | Ubiquitination

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Associated grants

  • Agency: NIGMS NIH HHS, Id: R01 GM057587
  • Agency: NIGMS NIH HHS, Id: R01 GM057587-12
  • Agency: NIGMS NIH HHS, Id: R01-GM057587
  • Agency: NIA NIH HHS, Id: R21 AG032560
  • Agency: NIA NIH HHS, Id: R21 AG032560-02
  • Agency: NIA NIH HHS, Id: R21-AG032560
  • Agency: NCI NIH HHS, Id: R37 CA076584
  • Agency: NCI NIH HHS, Id: R37 CA076584-12
  • Agency: NCI NIH HHS, Id: R37-CA076584
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

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