p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells

Abstract

The F-box protein p45^SKP2 is the substrate-targeting subunit of the ubiquitin–protein ligase SCF^SKP2 and is frequently overexpressed in transformed cells. Here we report that expression of p45 ^SKP2 in untransformed fibroblasts activates DNA synthesis in cells that would otherwise growth-arrest. Expression of p45^SKP2 in quiescent fibroblasts promotes p27^Kip1 degradation, allows the generation of cyclin-A-dependent kinase activity and induces S phase. Coexpression of a degradation-resistant p27^Kip1 mutant suppresses p45^SKP2-induced cyclin-A-kinase activation and S-phase entry. We propose that p45^SKP2 is important in the progression from quiescence to S phase 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 interfering with p27^Kip1 function.