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Progress through mitosis is controlled by the sequential destruction of key regulators including geminin, mitotic cyclins, Emi-I, securin, Plk-I, and Aurora kinases. One key to understanding the regulation of mitosis is to determine how the right protein is degraded at the right time. Here, we have described the destruction of p21 WAF1, which we found act as an activator following its phosphorylation by cyclinA-CdK2 at the S-G2 boundary. CyclinA-CDK2 phosphorylation of p21 changes the p21 protein into an assembly factor and an activator of cyclin B1-Cdc2 in G2/M progression. However, GSK3 phosphorylation at the Serine 27 and Serine 31 targets the p21 protein for its destruction by ubiquitination through Skp1-Cul1 and F-box protein Skp2. The presence of hyper-phosphorylated p21 protein stabilizes cyclin B1 and cyclin A complexes and delays exit from anaphase. p21 interacts with the APC/C complex, which degrades the F-box protein Skp2 at the mitotic/G1 phase. Thus, hyper-phosphorylated p21 gets degraded by GSK3-SCF, while hypo-phosphorylated p21 protein is degraded through APC/C CdhI.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]