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Cdc2–cyclin E complexes regulate the G1/S phase transition

Nature Cell Biology volume 7, pages 831–836 (2005)Cite this article

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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Figure 1: Pituitary tumours in p27−/− Cdk2−/− mice.
Figure 2: Abnormal germ-cell development and ovary tumours in p27−/− Cdk2−/− female mice.
Figure 3: DNA synthesis and mitosis are increased in p27−/− Cdk2−/− thymi.
Figure 4: p27 regulates Cdc2 activity in vivo.
Figure 5: Silencing Cdc2 affects cell proliferation and entry into S phase.

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References

  1. Sherr, C. J. & Roberts, J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501–1512 (1999).

    Article  CAS  Google Scholar 

  2. Polyak, K. et al. p27Kip1, a cyclin-cdk inhibitor, links transforming growth factor-β and contact inhibition to cell cycle arrest. Genes Dev. 8, 9–22 (1994).

    Article  CAS  Google Scholar 

  3. Polyak, K. et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78, 59–66 (1994).

    Article  CAS  Google Scholar 

  4. Fero, M. L. et al. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27Kip1-deficient mice. Cell 85, 733–744 (1996).

    Article  CAS  Google Scholar 

  5. Kiyokawa, H. et al. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27Kip1 . Cell 85, 721–732 (1996).

    Article  CAS  Google Scholar 

  6. Nakayama, K. et al. Mice lacking p27Kip1 display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85, 707–720 (1996).

    Article  CAS  Google Scholar 

  7. Tsutsui, T. et al. Targeted disruption of CDK4 delays cell cycle entry with enhanced p27Kip1 activity. Mol. Cell. Biol. 19, 7011–7019 (1999).

    Article  CAS  Google Scholar 

  8. Berthet, C., Aleem, E., Coppola, V., Tessarollo, L. & Kaldis, P. Cdk2 knockout mice are viable. Curr. Biol. 13, 1775–1785 (2003).

    Article  CAS  Google Scholar 

  9. Ortega, S. et al. Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nature Genet. 35, 25–31 (2003).

    Article  CAS  Google Scholar 

  10. Geng, Y. et al. Cyclin E ablation in the mouse. Cell 114, 431–443 (2003).

    Article  CAS  Google Scholar 

  11. Parisi, T. et al. Cyclins E1 and E2 are required for endoreplication in placental trophoblast giant cells. EMBO J. 22, 4794–4803 (2003).

    Article  CAS  Google Scholar 

  12. Sotillo, R. et al. Cooperation between Cdk4 and p27kip1 in tumor development: a preclinical model to evaluate cell cycle inhibitors with therapeutic activity. Cancer Res. 65, 3846–3852 (2005).

    Article  CAS  Google Scholar 

  13. Brenner, R. M. et al. Immunocytochemical assessment of mitotic activity with an antibody to phosphorylated histone H3 in the macaque and human endometrium. Hum. Reprod. 18, 1185–1193 (2003).

    Article  CAS  Google Scholar 

  14. Koff, A. et al. Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene family. Cell 66, 1217–1228 (1991).

    Article  CAS  Google Scholar 

  15. Dai, Y., Dent, P. & Grant, S. Induction of apoptosis in human leukemia cells by the CDK1 inhibitor CGP74514A. Cell Cycle 1, 143–152 (2002).

    CAS  PubMed  Google Scholar 

  16. Russo, A. A., Jeffrey, P. D., Patten, A. K., Massagué, J. & Pavletich, N. P. Crystal structure of the p27Kip1 cyclin-dependent kinase inhibitor bound to the cyclin A-Cdk2 complex. Nature 382, 325–331 (1996).

    Article  CAS  Google Scholar 

  17. Aleem, E., Berthet, C. & Kaldis, P. Cdk2 as a master of S phase entry: fact or fake? Cell Cycle 3, 35–37 (2004).

    Article  CAS  Google Scholar 

  18. Matsumoto, Y. & Maller, J. L. A centrosomal localization signal in cyclin E required for Cdk2-independent S phase entry. Science 306, 885–888 (2004).

    Article  CAS  Google Scholar 

  19. Ayscough, K., Hayles, J., MacNeill, S. A. & Nurse, P. Cold-sensitive mutants of p34cdc2 that suppress a mitotic catastrophe phenotype in fission yeast. Mol. Gen. Genet. 232, 344–350 (1992).

    Article  CAS  Google Scholar 

  20. Hoang, A. T., Cohen, K. J., Barrett, J. F., Bergstrom, D. A. & Dang, C. V. Participation of cyclin A in Myc-induced apoptosis. Proc. Natl Acad. Sci. USA 91, 6875–6879 (1994).

    Article  CAS  Google Scholar 

  21. Truett, G. E. et al. Preparation of PCR-quality mouse genomic DNA with hot sodium hydroxide and tris (HotSHOT). Biotechniques 29, 52–54 (2000).

    Article  CAS  Google Scholar 

  22. Harborth, J., Elbashir, S. M., Bechert, K., Tuschl, T. & Weber, K. Identification of essential genes in cultured mammalian cells using small interfering RNAs. J. Cell Sci. 114, 4557–4565 (2001).

    CAS  PubMed  Google Scholar 

  23. Ahmed, S. A., Gogal, R. M. Jr & Walsh, J. E. A new rapid and simple non-radioactive assay to monitor and determine the proliferation of lymphocytes: an alternative to [3H]-thymidine incorporation assay. J. Immunol. Methods 170, 211–224 (1994).

    Article  CAS  Google Scholar 

  24. Matsushime, H. et al. D-type cyclin-dependent kinase activity in mammalian cells. Mol. Cell. Biol. 14, 2066–2076 (1994).

    Article  CAS  Google Scholar 

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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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  1. 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

  2. Department of Biochemistry and Molecular Genetics, University of Illinois College of Medicine, 900 S. Ashland Avenue, Chicago, 60607, IL, USA

    Hiroaki Kiyokawa

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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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