SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27

Degradation of the mammalian cyclin-dependent kinase (CDK) inhibitor p27 is required for the cellular transition from quiescence to the proliferative state. The ubiquitination and subsequent degradation of p27 depend on its p hosphorylation by cyclin-CDK complexes. However, the ubiquitin-protein liga se necessary for p27 ubiquitination has not been identified. Here we show t hat the F-box protein SKP2 specifically recognizes p27 in a phosphorylation -dependent manner that is characteristic of an F-box-protein-substrate inte raction. Furthermore, both in vivo and in vitro, SKP2 is a rate-limiting co mponent of the machinery that ubiquitinates and degrades phosphorylated p27 , Thus, p27 degradation is subject to dual control by the accumulation of b oth SKP2 and cyclins following mitogenic stimulation.