BBB Seminar: Lars-Gunnar Larsson
Regulation of cellular senescence by the Myc oncoprotein
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
Oncogenes like MYC and RAS are frequently activated in cancer and together are sufficient to transform primary rodent cells. The basis for this cooperativity remains unclear. Both oncogenes induce compensatory tumor-suppressive responses, Ras mainly cellular senescence, while Myc primarily induces apoptosis. We found that while Ras interfered with Myc-induced apoptosis, Myc repressed Ras-induced senescence in rat embryo fibroblasts, together abrogating two main barriers of tumorigenesis. Inhibition of cellular senescence required phosphorylation of Myc at Ser-62 by cyclin E/cyclin-dependent kinase 2 (Cdk2). Cdk2 interacted with Myc at promoters where it affected Myc-dependent regulation of genes known to control senescence. Repression of senescence by Myc was abrogated by the Cdk-inhibitor p27Kip1, which is induced by anti-proliferative signals like IFN-g, or by pharmacological inhibitors of Cdk2, but not by inhibitors of other Cdks. Phosphorylation at Ser-62 seems to affect the association of Myc with chromatin. TGF-b also induced senescence in Myc-transformed cells. This was dependent on induction of the Myc antagonist Mad1, which displaced Myc from its target promoters. IFN-g and TGF-b signaling therefore both seem to induce senescence by reducing the association of Myc with DNA. We next investigated the consequence of Cdk2 depletion in primary murine cells overexpressing Myc in the absence of Ras. In Cdk2 knockout mouse embryonic fibroblasts (MEFs) the initial Myc-induced hyper-proliferative response was followed by cellular senescence. Loss of Cdk2 also caused sensitization to Myc-induced senescence in splenic B-cells in vivo, correlating with delayed lymphomagenesis. In MEFs, Myc-induced senescence was genetically dependent on the ARF–p53–p21Cip1 and p16INK4a–pRb pathways. Thus, although redundant for cell-cycle progression and development, Cdk2 has a unique role in suppressing oncogene-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 Ras-driven tumors.
Host: Marit Bakke, Department of Biomedicine