Current Biology
Volume 9, Issue 12, 17 June 1999, Pages 661-664, S1-S2
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Brief Communication
p27Kip1 ubiquitination and degradation is regulated by the SCFSkp2 complex through phosphorylated Thr187 in p27

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Abstract

Many tumorigenic processes affect cell-cycle progression by their effects on the levels of the cyclin-dependent kinase inhibitor p27Kip1[1], [2]. The phosphorylation- and ubiquitination-dependent proteolysis of p27 is implicated in control of the G1–S transition in the cell cycle [3], [4], [5], [6]. To determine the factors that control p27 stability, we established a cell-free extract assay that recapitulates the degradation of p27. Phosphorylation of p27 at Thr187 was essential for its degradation. Degradation was also dependent on SCFSkp2, a protein complex implicated in targeting phosphorylated proteins for ubiquitination [7], [8], [9], [10]. Immunodepletion of components of the complex – Cul-1, Skp1, or Skp2 – from the extract abolished p27 degradation, while addition of purified SCFSkp2 to Skp2- depleted extract restored the capacity to degrade p27. A specific association was observed between Skp2 and a p27 carboxy-terminal peptide containing phosphorylated Thr187, but not between Skp2 and the non-phosphorylated peptide. Skp2-dependent associations between Skp1 or Cul-1 and the p27 phosphopeptide were also detected. Isolated SCFSkp2 contained an E3 ubiquitin ligase activity towards p27. Our data thus suggest that SCFSkp2 specifically targets p27 for degradation during cell-cycle progression.

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LM Tsvetkov, KH Yeh, SJ Lee, H Sun and H Zhang, Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.

E-mail address for H Zhang (corresponding author): [email protected].