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RPL23 Links Oncogenic RAS Signaling to p53-Mediated Tumor Suppression

Xuan Meng1, Nicole R Tackmann2, Shijie Liu3

  • 1Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China. Hospital and Institute of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing, China. School of Basic Medical Sciences and Institute of System Biomedicine, Peking University, Beijing, China.

Cancer Research
|July 13, 2016
PubMed

Insights

The ribosomal protein (RP)-MDM2-p53 pathway prevents cancer. Researchers found that while RPL11-MDM2-p53 combats c-MYC, RPL23-MDM2-p53 fights RAS-induced tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • The ribosomal protein (RP)-MDM2 interaction with p53 is a critical pathway for preventing oncogenic c-MYC-induced tumorigenesis.
  • Investigating the broader antioncogenic role of the RP-MDM2-p53 pathway is essential for understanding cancer development.

Purpose of the Study:

  • To determine if the RP-MDM2-p53 pathway serves as a general mechanism against oncogenesis.
  • To compare the pathway's response to oncogenic c-MYC versus oncogenic RAS (Hras(G12V)).

Main Methods:

  • Crossed mice with an MDM2(C305F) mutation (disrupting RPL11 binding) with mice expressing an oncogenic Hras(G12V) transgene.
  • Analyzed the effects of RAS overexpression on ribosomal protein expression (RPL11, RPL23) and p53 induction.
  • Investigated the signaling pathways (MEK, PI3K, mTOR) involved in RPL23 induction and its interaction with MDM2.

Main Results:

  • MDM2(C305F)-mutant mice, sensitive to c-MYC, were not hypersensitive to Hras(G12V)-induced tumorigenesis.
  • RAS overexpression increased RPL23 but not RPL11, involving MEK, PI3K, and mTOR pathways.
  • Increased RPL23 correlated with p53 levels in MDM2(C305F) cells, and RAS-induced p53 required RPL23, independent of p19ARF.

Conclusions:

  • The RPL11-MDM2-p53 pathway combats c-MYC-induced tumors, while the RPL23-MDM2-p53 pathway combats RAS-induced tumors.
  • Both pathways coordinate with the p19ARF-MDM2-p53 pathway in tumor suppression.
  • This highlights distinct RP-MDM2-p53 axis roles in response to different oncogenic drivers.

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