Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication

The ubiquitin-proteasome pathway plays an important role in control of the abundance of cell cycle regulators. Mice lacking Skp2, an F-box protein and substrate recognition component of an Skp1-Cullin-F-bos protein (SCF) ubiq uitin ligase, were generated. Although Skp2(-/-) animals are viable, cells in the mutant mice contain markedly enlarged nuclei with polyploidy and mul tiple centrosomes, and show a reduced growth rate and increased apoptosis, Skp2(-/-) cells also exhibit increased accumulation of both cyclin E and p2 7(Kip1). The elimination of cyclin E during S and G(2) phases is impaired i n Skp2(-/-) cells, resulting in loss of cyclin E periodicity. Biochemical s tudies showed that Skp2 interacts specifically with cyclin E and thereby pr omotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is medi ated by the SCFSkp2 ubiquitin ligase complex, and that Skp2 may control chr omosome replication and centrosome duplication by determining the abundance of cell cycle regulators.