The F-box protein SKP2 binds to the phosphorylated threonine 380 in cyclinE and regulates ubiquitin-dependent degradation of cyclin E

Cyclin E is required for S phase entry. The subsequent ubiquitin-dependent degradation of cyclin E contributes to an orderly progression of the S phas e. Tt has been shown that phosphorylation of threonine 380 (Thr380) in cycl in E provides a signal for its ubiquitin-dependent proteolysis. We report t hat SKP2, an F-box protein and a substrate-targeting component of the SCFSK P2 ubiquitin E3 ligase complex, mediates cyclin E degradation. In vitro, SK P2 specifically interacted with the cyclin E peptide containing the phospho rylated-Thr380 but not with a cognate nonphosphorylated peptide. fn vivo ex pression of SKP2 induced cyclin E polyubiquitination and degradation. Conve rsion of Thr380 into nonphosphorylatable amino acids caused significant res istance of cyclin E to SKP2. The presence of the CDK. inhibitor p27(Kip1) a lso prevented the SKP2-dependent degradation of cyclin E. Our findings sugg est that SKP2 regulates cyclin E stability, thus contributing to the contro l of S phase progression. (C) 2001 Academic Press.