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Cdk2 suppresses cellular senescence induced by the c-myc oncogene

Nature Cell Biology volume 12, pages 54–59 (2010)Cite this article

Abstract

Activated oncogenes induce compensatory tumour-suppressive responses, such as cellular senescence or apoptosis, but the signals determining the main outcome remain to be fully understood1,2. Here, we uncover a role for Cdk2 (cyclin-dependent kinase 2) in suppressing Myc-induced senescence. Short-term activation of Myc promoted cell-cycle progression3 in either wild-type or Cdk2 knockout4,5 mouse embryo fibroblasts (MEFs). In the knockout MEFs, however, the initial hyper-proliferative response was followed by cellular senescence. Loss of Cdk2 also caused sensitization to Myc-induced senescence in pancreatic β-cells or splenic B-cells in vivo, correlating with delayed lymphoma onset in the latter. Cdk2−/− MEFs also senesced upon ectopic Wnt signalling or, without an oncogene, upon oxygen-induced culture shock6. Myc also causes senescence in cells lacking the DNA repair protein Wrn7. However, unlike loss of Wrn8, loss of Cdk2 did not enhance Myc-induced replication stress, implying that these proteins suppress senescence through different routes. In MEFs, Myc-induced senescence was genetically dependent on the ARF–p53–p21Cip1 and p16INK4a–pRb pathways, p21Cip1 and p16INK4a being selectively induced in Cdk2−/− cells. Thus, although redundant for cell-cycle progression and development4,5,9,10,11,12, Cdk2 has a unique role in suppressing oncogene- and/or stress-induced senescence1. Pharmacological inhibition of Cdk2 induced Myc-dependent senescence in various cell types, including a p53-null human cancer cell line. Our data warrant re-assessment of Cdk2 as a therapeutic target in Myc- or Wnt-driven tumours.

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Figure 1: Myc-induced senescence in Cdk2−/− cells.
Figure 2: Genetic analysis of MycER-induced senescence in MEFs.
Figure 3: Cdk2-null MEFs are sensitized to O2-induced culture shock.
Figure 4: Pre-tumoural analysis and lymphomagenesis in Eμ-Myc Cdk2−/− mice.
Figure 5: CDK2 inhibitors trigger a Myc-dependent senescence response in rodent and human cells.

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Acknowledgements

We thank C. Gorrini, E. Guccione, A, Magnifico, G. Natoli, S. Piccolo and P.-G. Pelicci for discussions, comments and support, F. Contegno for laboratory management, A. Gobbi, M. Capillo and B. Giulini for mouse management, I. Muradore, S. Ronzoni and M. Faretta for FACS analysis, S. Volorio and S. Minardi for DNA sequencing, K. Igarashi (Hiroshima University Graduate School of Biomedical Sciences, Japan) for sharing unpublished information, F. Liu (The State University of New Jersey, USA) for antibodies, G. Evan and L. Brown-Swigart (both at the University of California, USA) for pIns-MycERTAM and RIP-Bcl-xL mice, J. Cleveland (The Scripps Research Institute, USA) and J.-C. Marine (VIB-UGent, Belgium) for Eμ-myc mice, A. Berns for INK4a−/− mice (Netherlands Cancer Institute), C. Sherr and M. Roussel (both at St. Jude Children's Research Hospital, USA) for ARF−/− mice, and J. Zablocki at CV Therapeutics for compounds. This work was supported by grants from the Italian Association for Cancer Research (AIRC), the 'Ricerca Finalizzata' and 'Ricerca Corrente' programs of the Italian Health Ministry to B.A., and from the Swedish Cancer Society, the Swedish Childhood Cancer Foundation, the Swedish Research Council, Olle Enqkvists's Foundation and the Stockholm Cancer Society.to L.G.L.

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Authors and Affiliations

  1. Department of Experimental Oncology, European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16, Milan, 20139, Italy

    Stefano Campaner, Mirko Doni, Alessandro Verrecchia, Lucia Bianchi, Domenico Sardella, Thomas Schleker, Daniele Perna & Bruno Amati

  2. Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, SE-171 77, Sweden

    Per Hydbring, Susanna Tronnersjö & Lars-Gunnar Larsson

  3. Department of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences, Uppsala, SE-750 07, Sweden

    Per Hydbring & Lars-Gunnar Larsson

  4. Cogentech, IFOM-IEO Campus, Via Adamello 16, Milan, 20139, Italy

    Domenico Sardella

  5. Genomic Instability and,

    Matilde Murga & Oscar Fernandez-Capetillo

  6. Experimental Oncology groups, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncologicas (CNIO), Melchor Fernandez Almagro 3, Madrid, 28029, Spain

    Mariano Barbacid

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Contributions

S.C. and B.A. conceived the work and designed the experiments. B.A. supervised the project and wrote the manuscript. S.C. performed all of the experimental work on mice, tissues and cells, with expert technical assistance from M.D. for cell culture and tissue analysis, and from A.V. for molecular biology and biochemical analysis. L.B., T.S and D.P. helped in the characterization of senescence and INK4/Arf regulation. D.S. performed the genotyping of all mice. M.B. constructed and provided the Cdk2 knockout mice. P.H., S.T. and L.-G.L. contributed to part of the experiments with pharmacological Cdk2 inhibitors. M.M. and O.F.-C. contributed to the quantitative analysis of γH2AX.

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Correspondence to Bruno Amati.

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Campaner, S., Doni, M., Hydbring, P. et al. Cdk2 suppresses cellular senescence induced by the c-myc oncogene. Nat Cell Biol 12, 54–59 (2010). https://doi.org/10.1038/ncb2004

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