p45(SKP2) promotes p27(Kip1) degradation and induces S phase in quiescent cells

The F-box protein p45(SKP2) is the substrate-targeting subunit of the ubiqu itin-protein ligase SCFSKP2 and is frequently overexpressed in transformed cells. Here we report that expression of p45(SKP2) in untransformed fibrobl asts activates DNA synthesis in cells that would otherwise growth-arrest. E xpression of p45(SKP2) in quiescent fibroblasts promotes p27(Kip1) degradat ion, allows the generation of cyclin-A-dependent kinase activity and induce s S phase. Coexpression of a degradation-resistant p27(Kip1) mutant suppres ses p45(SKP2)-induced cyclin-A-kinase activation and S-phase entry. We prop ose that p45(SKP2) is important in the progression from quiescence to S pha se and that the ability of p45(SKP2) to promote p27(Kip1) degradation is a key aspect of its S-phase-inducing function. In transformed cells, p45(SKP2 ) may contribute to deregulated initiation of DNA replication by interferin g with p27(Kip1) function.