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Physical and functional interaction between ribosomal protein L11 and the tumor suppressor ARF

Mu-Shui Dai1, Kishore B Challagundla2, Xiao-Xin Sun1

  • 1Department of Biochemistry and Molecular Biology and Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202; Departments of Molecular and Medical Genetics, School of Medicine, and the OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239.

The Journal of Biological Chemistry
|April 3, 2012
PubMed

Insights

The ARF tumor suppressor protein connects to ribosomal protein L11, linking oncogenic and ribosomal stress pathways. This interaction enhances ARF

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • The ARF tumor suppressor and ribosomal protein L11 both activate p53 via MDM2 inhibition.
  • ARF responds to oncogenic stress, while L11 responds to ribosomal stress.
  • The functional connection between these two p53 activation pathways was previously unknown.

Purpose of the Study:

  • To investigate the functional connection between the ARF-MDM2-p53 and L11-MDM2-p53 pathways.
  • To determine if ARF and L11 interact and influence each other's p53-activating functions.

Main Methods:

  • In vitro and cellular binding assays to detect ARF-L11 complex formation.
  • Assessment of p53 transcriptional activity and cell cycle arrest.
  • Knockdown and overexpression studies of L11 and ARF.
  • Analysis of protein-protein interactions and protein levels.

Main Results:

  • ARF directly binds to L11, forming a complex with MDM2 and p53.
  • L11 enhances ARF-induced p53 activity and cell cycle arrest.
  • Knocking down L11 impairs ARF-mediated p53 accumulation and cell cycle arrest.
  • ARF overexpression increases ribosome-free L11 and its interaction with MDM2 and p53.

Conclusions:

  • The ARF and L11 pathways are functionally connected.
  • ARF activates p53 partly by inducing ribosomal stress, leading to L11-mediated MDM2 suppression.
  • This study reveals a novel link between oncogenic and ribosomal stress responses in p53 activation.

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