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An ARF-independent c-MYC-activated tumor suppression pathway mediated by ribosomal protein-Mdm2 Interaction

Everardo Macias1, Aiwen Jin, Chad Deisenroth

  • 1Department of Radiation Oncology, School of Medicine, the University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7512, USA.

Cancer Cell
|September 14, 2010
PubMed

Insights

Ribosomal protein (RP) interaction with Mdm2 is crucial for activating p53 in response to ribosome stress. This pathway safeguards against c-MYC-driven lymphomagenesis.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • In vitro studies suggest ribosomal biogenesis inhibition activates p53 via ribosomal protein (RP)-Mdm2 interaction.
  • This interaction suppresses Mdm2 E3 ligase activity, a key regulator of p53.

Purpose of the Study:

  • To investigate the physiological role of the RP-Mdm2 interaction in vivo.
  • To determine if this interaction is essential for p53 activation by ribosome biogenesis stress and its role in tumorigenesis.

Main Methods:

  • Generated mice with a specific Mdm2 mutation disrupting RP binding (RPL5/RPL11).
  • Assessed p53 responses to DNA damage and ribosome biogenesis perturbations.
  • Evaluated lymphomagenesis in Eμ-Myc-driven lymphoma models.

Main Results:

  • Mice with the Mdm2 mutation showed normal p53 response to DNA damage but lacked response to ribosome biogenesis stress.
  • Loss of RP-Mdm2 interaction accelerated Eμ-Myc-induced lymphomagenesis.
  • The p53 response to ribosomal perturbation did not require p19ARF.

Conclusions:

  • The RP-Mdm2 interaction is a critical p53 stress-signaling pathway activated by aberrant ribosome biogenesis.
  • This pathway is essential for preventing c-MYC-induced tumorigenesis.

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