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 journalArticle

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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Cyclin-Dependent Kinase 2
myc Genes
Cell Aging
Embryonic Structures
Fibroblasts
Oncogenes
Knockout Mice
Cell Cycle
Neoplasms
Insulin-Secreting Cells
Heat-Shock Proteins
DNA Repair
Shock
Lymphoma
B-Lymphocytes
Pharmacology
Apoptosis
Oxygen
Cell Line

ASJC Scopus subject areas

  • Cell Biology

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Cdk2 suppresses cellular senescence induced by the c-myc oncogene. / Campaner, Stefano; Doni, Mirko; Hydbring, Per; Verrecchia, Alessandro; Bianchi, Lucia; Sardella, Domenico; Schleker, Thomas; Perna, Daniele; Tronnersjö, Susanna; Murga, Matilde; Fernandez-Capetillo, Oscar; Barbacid, Mariano; Larsson, Lars Gunnar; Amati, Bruno.

In: Nature Cell Biology, Vol. 12, No. 1, 01.2010.

Research output: Contribution to journalArticle

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, LG & Amati, B 2010, 'Cdk2 suppresses cellular senescence induced by the c-myc oncogene.', Nature Cell Biology, vol. 12, no. 1.
Campaner, Stefano ; Doni, Mirko ; Hydbring, Per ; Verrecchia, Alessandro ; Bianchi, Lucia ; Sardella, Domenico ; Schleker, Thomas ; Perna, Daniele ; Tronnersjö, Susanna ; Murga, Matilde ; Fernandez-Capetillo, Oscar ; Barbacid, Mariano ; Larsson, Lars Gunnar ; Amati, Bruno. / Cdk2 suppresses cellular senescence induced by the c-myc oncogene. In: Nature Cell Biology. 2010 ; Vol. 12, No. 1.
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