The study by Sheaff et al. (1997) challenges the traditional view that CDK inhibitors negatively regulate cyclin-CDK complexes and instead proposes that cyclin-CDK complexes can promote cell cycle progression by directly down-regulating CDK inhibitors. The authors demonstrate that expression of cyclin E-CDK2 in murine fibroblasts causes phosphorylation of the CDK inhibitor p27Kip1 on T187, and that this phosphorylation results in the elimination of p27 from the cell, allowing cells to transit from G1 to S phase. They further show that mutation of T187 in p27 to alanine creates a p27 protein that causes a G1 block resistant to cyclin E and whose level of expression is not modulated by cyclin E. A kinetic analysis of the interaction between p27 and cyclin E-CDK2 explains how p27 can be both an inhibitor and a substrate of the enzyme. The results suggest that cyclin E-CDK2 is likely to regulate p27 directly via phosphorylation of T187, and that this process may be a specific property of cyclin E-CDK2 as cyclin D1-CDK4 does not efficiently phosphorylate p27 or induce its elimination. The study identifies p27 as a cyclin E-CDK2 substrate, demonstrates the biological consequences of p27 phosphorylation, and develops a kinetic model to explain how a CDK inhibitor can itself be effectively regulated by a CDK.The study by Sheaff et al. (1997) challenges the traditional view that CDK inhibitors negatively regulate cyclin-CDK complexes and instead proposes that cyclin-CDK complexes can promote cell cycle progression by directly down-regulating CDK inhibitors. The authors demonstrate that expression of cyclin E-CDK2 in murine fibroblasts causes phosphorylation of the CDK inhibitor p27Kip1 on T187, and that this phosphorylation results in the elimination of p27 from the cell, allowing cells to transit from G1 to S phase. They further show that mutation of T187 in p27 to alanine creates a p27 protein that causes a G1 block resistant to cyclin E and whose level of expression is not modulated by cyclin E. A kinetic analysis of the interaction between p27 and cyclin E-CDK2 explains how p27 can be both an inhibitor and a substrate of the enzyme. The results suggest that cyclin E-CDK2 is likely to regulate p27 directly via phosphorylation of T187, and that this process may be a specific property of cyclin E-CDK2 as cyclin D1-CDK4 does not efficiently phosphorylate p27 or induce its elimination. The study identifies p27 as a cyclin E-CDK2 substrate, demonstrates the biological consequences of p27 phosphorylation, and develops a kinetic model to explain how a CDK inhibitor can itself be effectively regulated by a CDK.