Abstract

The cyclin-dependent kinase inhibitor p27Kip1 is known as a negative regulator of cell-cycle progression and as a tumour suppressor. Cdk2 is the main target of p27 (refs 2, 3) and therefore we hypothesized that loss of Cdk2 activity should modify the p27|[minus]|/|[minus]| mouse phenotype. Here, we show that although p27|[minus]|/|[minus]| Cdk2|[minus]|/|[minus]| mice developed ovary tumours and tumours in the anterior lobe of the pituitary, we failed to detect any functional complementation in p27|[minus]|/|[minus]| Cdk2|[minus]|/|[minus]| double-knockout mice, indicating a parallel pathway regulated by p27. We observed elevated levels of S phase and mitosis in tissues of p27|[minus]|/|[minus]| Cdk2|[minus]|/|[minus]| mice concomitantly with elevated Cdc2 activity in p27|[minus]|/|[minus]| Cdk2|[minus]|/|[minus]| extracts. p27 binds to Cdc2, cyclin B1, cyclin A2, or suc1 complexes in wild-type and Cdk2|[minus]|/|[minus]| extracts. In addition, cyclin E binds to and activates Cdc2. Our in vivo results provide strong evidence that Cdc2 may compensate the loss of Cdk2 function.