The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway

Oncogene. 2016 Jan 28;35(4):415-26. doi: 10.1038/onc.2015.104. Epub 2015 Apr 13.


The ubiquitin-like molecule NEDD8 is essential for viability, growth and development, and is a potential target for therapeutic intervention. We found that the small molecule inhibitor of NEDDylation, MLN4924, alters the morphology and increases the surface size of the nucleolus in human and germline cells of Caenorhabditis elegans in the absence of nucleolar fragmentation. SILAC proteomics and monitoring of rRNA production, processing and ribosome profiling shows that MLN4924 changes the composition of the nucleolar proteome but does not inhibit RNA Pol I transcription. Further analysis demonstrates that MLN4924 activates the p53 tumour suppressor through the RPL11/RPL5-Mdm2 pathway, with characteristics of nucleolar stress. The study identifies the nucleolus as a target of inhibitors of NEDDylation and provides a mechanism for p53 activation upon NEDD8 inhibition. It also indicates that targeting the nucleolar proteome without affecting nucleolar transcription initiates the required signalling events for the control of cell cycle regulators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / cytology
  • Caenorhabditis elegans / drug effects*
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins
  • Cell Line / drug effects
  • Cell Nucleolus / drug effects*
  • Cyclopentanes / pharmacology*
  • Genes, p53 / drug effects*
  • Humans
  • MCF-7 Cells / drug effects
  • Metabolic Networks and Pathways / drug effects
  • Metabolic Networks and Pathways / genetics
  • Mice, Mutant Strains
  • NEDD8 Protein
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Pyrimidines / pharmacology*
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism
  • Ribosomes / drug effects
  • Ribosomes / genetics
  • Ribosomes / metabolism
  • Ubiquitins / antagonists & inhibitors*
  • Ubiquitins / genetics
  • Ubiquitins / metabolism


  • Caenorhabditis elegans Proteins
  • Cyclopentanes
  • NED-8 protein, C elegans
  • NEDD8 Protein
  • NEDD8 protein, human
  • Pyrimidines
  • Ribosomal Proteins
  • Ubiquitins
  • ribosomal protein L11
  • MDM2 protein, human
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • pevonedistat