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.