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Abstract
Many tumorigenic processes affect cell-cycle progression by their effects on the levels
of the cyclin-dependent kinase inhibitor p27(Kip1) [1,2]. The phosphorylation- and
ubiquitination-dependent proteolysis of p27 is implicated in control of the G1-S transition
in the cell cycle [3-6]. 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 SCF(Skp2), a protein complex implicated in targeting phosphorylated proteins for
ubiquitination [7-10]. Immunodepletion of components of the complex - Cul-1, Skp1,
or Skp2 - from the extract abolished p27 degradation, while addition of purified SCF(Skp2)
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 SCF(Skp2)
contained an E3 ubiquitin ligase activity towards p27. Our data thus suggest that
SCF(Skp2) specifically targets p27 for degradation during cell-cycle progression.