Abstract
The cyclin-dependent kinase inhibitor p27Kip1 is known as a negative regulator of cell-cycle progression and as a tumour suppressor1. Cdk2 is the main target of p27 (refs 2, 3) and therefore we hypothesized that loss of Cdk2 activity should modify the p27−/− mouse phenotype4,5,6. Here, we show that although p27−/− Cdk2−/− mice developed ovary tumours and tumours in the anterior lobe of the pituitary, we failed to detect any functional complementation in p27−/− Cdk2−/− double-knockout mice, indicating a parallel pathway regulated by p27. We observed elevated levels of S phase and mitosis in tissues of p27−/− Cdk2−/− mice concomitantly with elevated Cdc2 activity in p27−/− Cdk2−/− extracts. p27 binds to Cdc2, cyclin B1, cyclin A2, or suc1 complexes in wild-type and Cdk2−/− 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.
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Acknowledgements
The authors thank N. Jenkins and N. Copeland for advice, suggestions, reagents and support. We are thankful to C. Berthet for reagents, discussion and comments on the manuscript. We also thank M. Fortini and I. Daar for providing equipment and reagents; K. Stull and M. Beth Hilton for animal care; K. Rogers, M. Anver and the technicians of the Pathology/Histotechnology Laboratory for superb analysis of mouse pathology; and the Kaldis laboratory for support. We thank N. Copeland and S. Sharan for comments on the manuscript. This work was supported by the National Cancer Institute.
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National Cancer Institute, Mouse Cancer Genetics Program, NCI-Frederick, Bldg 560/22-56, 1050 Boyles Street, Frederick, 21702-1201, MD, USA
Eiman Aleem & Philipp Kaldis
Department of Biochemistry and Molecular Genetics, University of Illinois College of Medicine, 900 S. Ashland Avenue, Chicago, 60607, IL, USA
Hiroaki Kiyokawa
- Eiman Aleem
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- Hiroaki Kiyokawa
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- Philipp Kaldis
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Aleem, E., Kiyokawa, H. & Kaldis, P. Cdc2–cyclin E complexes regulate the G1/S phase transition. Nat Cell Biol 7, 831–836 (2005). https://doi.org/10.1038/ncb1284
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DOI: https://doi.org/10.1038/ncb1284
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