Cdk2 suppresses cellular senescence induced by the c-myc oncogene.

Stefano Campaner, Mirko Doni, Per Hydbring, Alessandro Verrecchia, Lucia Bianchi, Domenico Sardella, Thomas Schleker, Daniele Perna, Susanna Tronnersjö, Matilde Murga, Oscar Fernandez-Capetillo, Mariano Barbacid, Lars Gunnar Larsson, Bruno Amati

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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 understood. Here, we uncover a role for Cdk2 (cyclin-dependent kinase 2) in suppressing Myc-induced senescence. Short-term activation of Myc promoted cell-cycle progression in either wild-type or Cdk2 knockout 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 beta-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 shock. Myc also causes senescence in cells lacking the DNA repair protein Wrn. However, unlike loss of Wrn, 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 development, Cdk2 has a unique role in suppressing oncogene- and/or stress-induced senescence. 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.

Original languageEnglish
JournalNature Cell Biology
Volume12
Issue number1
Publication statusPublished - Jan 2010

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Campaner, S., Doni, M., Hydbring, P., Verrecchia, A., Bianchi, L., Sardella, D., Schleker, T., Perna, D., Tronnersjö, S., Murga, M., Fernandez-Capetillo, O., Barbacid, M., Larsson, L. G., & Amati, B. (2010). Cdk2 suppresses cellular senescence induced by the c-myc oncogene. Nature Cell Biology, 12(1).