title: 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. 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.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16, Milan 20139, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Campaner
authors.forename: Mirko
authors.initials: M
authors.lastname: Doni
authors.forename: Per
authors.initials: P
authors.lastname: Hydbring
authors.forename: Alessandro
authors.initials: A
authors.lastname: Verrecchia
authors.forename: Lucia
authors.initials: L
authors.lastname: Bianchi
authors.forename: Domenico
authors.initials: D
authors.lastname: Sardella
authors.forename: Thomas
authors.initials: T
authors.lastname: Schleker
authors.forename: Daniele
authors.initials: D
authors.lastname: Perna
authors.forename: Susanna
authors.initials: S
authors.lastname: Tronnersjö
authors.forename: Matilde
authors.initials: M
authors.lastname: Murga
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernandez-Capetillo
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
authors.forename: Lars-Gunnar
authors.initials: LG
authors.lastname: Larsson
authors.forename: Bruno
authors.initials: B
authors.lastname: Amati
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D051357:Cyclin-Dependent Kinase 2 / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D051357:Cyclin-Dependent Kinase 2