The in vivo role of the RP-Mdm2-p53 pathway in signaling oncogenic stress induced by pRb inactivation and Ras overexpression

PLoS One. 2011;6(6):e21625. doi: 10.1371/journal.pone.0021625. Epub 2011 Jun 29.

Abstract

The Mdm2-p53 tumor suppression pathway plays a vital role in regulating cellular homeostasis by integrating a variety of stressors and eliciting effects on cell growth and proliferation. Recent studies have demonstrated an in vivo signaling pathway mediated by ribosomal protein (RP)-Mdm2 interaction that responds to ribosome biogenesis stress and evokes a protective p53 reaction. It has been shown that mice harboring a Cys-to-Phe mutation in the zinc finger of Mdm2 that specifically disrupts RP L11-Mdm2 binding are prone to accelerated lymphomagenesis in an oncogenic c-Myc driven mouse model of Burkitt's lymphoma. Because most oncogenes when upregulated simultaneously promote both cellular growth and proliferation, it therefore stands to reason that the RP-Mdm2-p53 pathway might also be essential in response to oncogenes other than c-Myc. Using genetically engineered mice, we now show that disruption of the RP-Mdm2-p53 pathway by an Mdm2(C305F) mutation does not accelerate prostatic tumorigenesis induced by inactivation of the pRb family proteins (pRb/p107/p130). In contrast, loss of p19Arf greatly accelerates the progression of prostate cancer induced by inhibition of pRb family proteins. Moreover, using ectopically expressed oncogenic H-Ras we demonstrate that p53 response remains intact in the Mdm2(C305F) mutant MEF cells. Thus, unlike the p19Arf-Mdm2-p53 pathway, which is considered a general oncogenic response pathway, the RP-Mdm2-p53 pathway appears to specifically suppress tumorigenesis induced by oncogenic c-Myc.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Animals
  • Antigens, Viral, Tumor / genetics
  • Cell Line
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p16 / deficiency
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Disease Progression
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Genes, ras / genetics*
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / metabolism
  • Male
  • Mice
  • Mutation
  • Organ Size / genetics
  • Prostate / pathology
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Ribosomal Proteins / metabolism*
  • Signal Transduction / genetics*
  • Simian virus 40 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Up-Regulation / genetics

Substances

  • Antigens, Viral, Tumor
  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Ribosomal Proteins
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2