Caspase-induced proteolysis of the cyclin-dependent kinase inhibitor p27(Kip1) mediates its anti-apoptotic activity

The caspase-mediated cleavage of a limited number of cellular proteins is a common feature of apoptotic cell death. This cleavage usually inhibits the function of the target protein or generates peptides that actively contribute to the death process. In the present study, we demonstrate that the cyclin-dependent kinase inhibitor p27(Kip1) is cleaved by caspases in human leukemic cells exposed to apoptotic stimuli. We have shown recently that p27(Kip1) overexpression delayed leukemic cell death in response to cytotoxic drugs. In transient transfection experiments, the p23 and the p15 N-terminal peptides generated by p27(Kip1) proteolysis demonstrate an anti-apoptotic effect similar to that induced by the wild-type protein, whereas cleavage-resistant mutants have lost their protective effect. Moreover, stable transfection of a cleavage-resistant mutant of p27(Kip1) sensitizes leukemic cells to drug-induced cell death. Altogether, these results indicate that proteolysis of p27(Kip1) triggered by caspases mediates the anti-apoptotic activity of the protein.