Myc, Cdk2 and cellular senescence: Old players, new game

Stefano Campaner, Mirko Doni, Alessandro Verrecchia, Giovanni Fagà, Lucia Bianchi, Bruno Amati

Research output: Contribution to journalArticlepeer-review


The aberrant activation of oncogenic pathways promotes tumor progression, but concomitantly elicits compensatory tumor-suppressive responses, such as apoptosis or senescence. For example, Ras induces senescence, while Myc generally triggers apoptosis. Myc is in fact viewed as an anti-senescence oncogene, as it is a potent inducer of cell proliferation and immortalization, bypasses growth-inhibitory signals, and cooperates with Ras in cellular transformation. Recent reports prompt re-evaluation of Myc-induced senescence and of its role in tumor progression and therapy. We have shown that the cyclin-dependent kinase Cdk2, although redundant for cell cycle progression, has a unique role in suppressing a Myc-induced senescence program: Myc activation elicited expression of p16INK4a and p21Cip1, and caused senescence in cells lacking Cdk2, but not in Cdk2-proficient cells. We show here that suppression of Myc-induced senescence by Cdk2 does not occur through phosphorylation of its purported substrate residue in Myc (Ser 62). Additional cellular activities have been identified that suppress Myc-induced senescence, including the Wrn helicase, Telomerase and Miz1. These senescence-suppressing activities were critical for tumor progression, as deficiency in either Cdk2, telomerase or Miz1 reduced the onset of Myc-induced lymphoma in transgenic mice. Other gene products like p53, SUV39H1 or TGFβ promoted senescence, which together with apoptosis contributed to tumor suppression. Paradoxically, Myc directly counteracted the very same senescence program that it potentially elicited, since it positively regulated Wrn, Telomerase and Cdk2 activity. Furthermore, Cdk2 inhibition re-activated the latent senescence program in Myc expressing cells. Hence, while these molecules are instrumental to the oncogenic action of Myc, they may simultaneously constitute its Achille's heel for therapeutic development.

Original languageEnglish
Pages (from-to)3655-3661
Number of pages7
JournalCell Cycle
Issue number18
Publication statusPublished - Sept 15 2010


  • ARF
  • Cdk2
  • INK4a
  • Myc
  • p53
  • Senescence
  • TGFβ
  • Tumor suppression

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology


Dive into the research topics of 'Myc, Cdk2 and cellular senescence: Old players, new game'. Together they form a unique fingerprint.

Cite this