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Tipping the balance: Cdk2 enables Myc to suppress senescence

Per Hydbring1, Lars-Gunnar Larsson

  • 1Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

Cancer Research
|August 18, 2010
PubMed

Insights

MYC and RAS oncogenes cooperate to drive tumor formation by overriding cell-protective mechanisms. MYC actively represses RAS-induced senescence, a key step in tumorigenesis, highlighting cyclin-dependent kinase 2 as a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Tumor-suppressor pathways like apoptosis and senescence normally prevent cancer. Oncogenes MYC and RAS can cooperate to evade these protective mechanisms and initiate tumorigenesis.
  • While RAS is known to suppress MYC-induced apoptosis, the role of MYC in this oncogenic cooperation remained unclear.

Purpose of the Study:

  • To define the role of MYC in the cooperative oncogenic transformation driven by MYC and RAS.
  • To investigate the mechanism by which MYC and RAS cooperate to overcome cellular barriers to tumorigenesis.

Main Methods:

  • Investigated the interplay between MYC and RAS in cellular transformation models.
  • Utilized biochemical assays to determine the role of MYC phosphorylation by cyclin-dependent kinase 2 (Cdk2) in repressing senescence.
  • Assessed the efficacy of pharmacologic Cdk2 inhibitors in blocking MYC-driven repression of senescence.

Main Results:

  • MYC actively represses RAS-induced cellular senescence, thus overcoming a critical barrier to tumor formation.
  • This repression of senescence by MYC is dependent on its specific phosphorylation by Cdk2.
  • Pharmacologic inhibition of Cdk2 abrogated MYC's ability to repress RAS-induced senescence.

Conclusions:

  • MYC plays an active role in cooperating with RAS to drive tumorigenesis by inhibiting senescence.
  • The phosphorylation of MYC by Cdk2 is a crucial event in this process.
  • Cdk2 represents a potential therapeutic target for tumors driven by MYC or RAS oncogenes.

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