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

Research output: Contribution to journalArticlepeer-review

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 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 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-p21 Cip1 and p16 INK4a-pRb pathways, p21 Cip1 and p16 INK4a 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
Pages (from-to)54-59
Number of pages6
JournalNature Cell Biology
Volume12
Issue number1
DOIs
Publication statusPublished - Jan 2010

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'Cdk2 suppresses cellular senescence induced by the c-myc oncogene'. Together they form a unique fingerprint.

Cite this