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Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols
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Cdk2: a key regulator of the senescence control function of Myc

Per Hydbring1, Lars-Gunnar Larsson

  • 1Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden.

Aging
|May 7, 2010
PubMed

Insights

MYC and RAS oncogenes cooperate to drive cancer by suppressing cell death and senescence. MYC, via cyclin-dependent kinase 2 (Cdk2), inhibits senescence, revealing Cdk2 as a therapeutic target for MYC/RAS-driven tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Proto-oncogenes MYC and RAS are crucial for cell growth but drive tumor development when deregulated.
  • Overactivated MYC and RAS trigger tumor suppressor mechanisms: apoptosis and senescence, respectively.
  • The cooperative oncogenic transformation by MYC and RAS was previously unexplained.

Purpose of the Study:

  • To elucidate the cooperative mechanism between MYC and RAS in oncogenic transformation.
  • To investigate the role of MYC in repressing RAS-induced senescence.
  • To identify potential therapeutic targets for MYC/RAS-driven cancers.

Main Methods:

  • Investigated the interaction between MYC and RAS in oncogenic transformation.
  • Examined MYC's role in suppressing RAS-induced senescence.
  • Analyzed the phosphorylation of MYC at Ser 62 by cyclin-dependent kinase 2 (Cdk2).
  • Studied the direct control of senescence-related genes by MYC/Cdk2.
  • Evaluated the effect of Cdk2 inhibition on MYC/RAS-expressing cells.

Main Results:

  • MYC actively represses RAS-induced senescence, complementing RAS's suppression of MYC-induced apoptosis.
  • MYC's senescence suppression is dependent on its phosphorylation at Ser 62 by Cdk2.
  • MYC, with Cdk2 as a cofactor, directly regulates key senescence-associated genes.
  • Pharmacological inhibition of Cdk2 re-establishes senescence in MYC/RAS-expressing cells.

Conclusions:

  • MYC and RAS cooperate to drive tumorigenesis by jointly evading apoptosis and senescence.
  • MYC's regulation of senescence via Cdk2 is a novel, non-redundant function with implications for stemness and regeneration.
  • Cdk2 is a promising therapeutic target for treating cancers driven by MYC or RAS activation.

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