Ras activity regulates cyclin E degradation by the Fbw7 pathway.

The Skp1-Cullin1 F-box protein-Fbw7 ubiquitin ligase regulates phosphorylation-dependent cyclin E degradation, and disruption of this pathway is associated with genetic instability and tumorigenesis. Fbw7 is a human tumor suppressor that is targeted for mutation in primary cancers. However, mechanisms other than mutation of Fbw7 may also disrupt cyclin E proteolysis ...
in cancers. We show that oncogenic Ha-Ras activity regulates cyclin E degradation by the Fbw7 pathway. Activated Ras impairs Fbw7-driven cyclin E degradation, and, conversely, inhibition of normal Ras activity decreases cyclin E abundance. Moreover, activation of the mitogen-activated protein kinase pathway is the essential Ras function that inhibits cyclin E turnover, and activated Ha-Ras expression inhibits both the binding of cyclin E to Fbw7 and cyclin E ubiquitination. Last, we found that oncogenic Ras activity potentiates cyclin E-induced genetic instability but only when cyclin E is susceptible to degradation by Fbw7. Thus, we conclude that Ras activity regulates Fbw7-mediated cyclin E proteolysis and suggest that impaired cyclin E proteolysis is a mechanism through which Ras mutations promote tumorigenesis.
Mesh Terms:
Animals, Cell Cycle Proteins, Cyclin E, F-Box Proteins, Hela Cells, Humans, Immunoblotting, Immunoprecipitation, Mice, Micronucleus Tests, Microscopy, Fluorescence, NIH 3T3 Cells, Phosphorylation, Polymerase Chain Reaction, Proto-Oncogene Proteins p21(ras), Signal Transduction, Ubiquitin-Protein Ligases
Proc. Natl. Acad. Sci. U.S.A.
Date: Jul. 05, 2005
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