Cdk2 suppresses cellular senescence induced by the c-myc oncogene

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(1,2). Here, we uncover a role for Cdk2 (cyclin-dependent kinase 2) in suppressing Myc-induced senescence. Short-term activation of Myc promoted cell-cycle progression(3) in either wild-type or Cdk2 knockout(4,5) 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 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(6). Myc also causes senescence in cells lacking the DNA repair protein Wrn(7). However, unlike loss of Wrn(8), 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(Clp1) and p16(INK4a)-pRb pathways, p21(Clp1) and p16(INK4a) being selectively induced in Cdk2(-/-) cells. Thus, although redundant for cell-cycle progression and development(4,5,9-12), Cdk2 has a unique role in suppressing oncogene- and/or stress-induced senescence(1). 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.