Letter abstract

Nature Cell Biology 12, 54 - 59 (2010)
Published online: 13 December 2009 | doi:10.1038/ncb2004

Cdk2 suppresses cellular senescence induced by the c-myc oncogene

Stefano Campaner1, Mirko Doni1, Per Hydbring2,3, Alessandro Verrecchia1, Lucia Bianchi1, Domenico Sardella1,4, Thomas Schleker1, Daniele Perna1, Susanna Tronnersjö2, Matilde Murga5, Oscar Fernandez-Capetillo5, Mariano Barbacid6, Lars-Gunnar Larsson2,3 & Bruno Amati1


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.

  1. Department of Experimental Oncology, European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16, Milan 20139, Italy.
  2. Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77 Stockholm, Sweden.
  3. Department of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden.
  4. Cogentech, IFOM-IEO Campus, Via Adamello 16, Milan 20139, Italy.
  5. Genomic Instability and
  6. Experimental Oncology groups, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncologicas (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.

Correspondence to: Bruno Amati1 e-mail: bruno.amati@ifom-ieo-campus.it.


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