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The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway.
- Source :
-
Oncogene [Oncogene] 2016 Jan 28; Vol. 35 (4), pp. 415-26. Date of Electronic Publication: 2015 Apr 13. - Publication Year :
- 2016
-
Abstract
- 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.
- Subjects :
- Animals
Caenorhabditis elegans cytology
Caenorhabditis elegans genetics
Caenorhabditis elegans metabolism
Caenorhabditis elegans Proteins
Cell Line 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
Ribosomal Proteins genetics
Ribosomal Proteins metabolism
Ribosomes drug effects
Ribosomes genetics
Ribosomes metabolism
Ubiquitins genetics
Ubiquitins metabolism
Caenorhabditis elegans drug effects
Cell Nucleolus drug effects
Cyclopentanes pharmacology
Genes, p53 drug effects
Proto-Oncogene Proteins c-mdm2 metabolism
Pyrimidines pharmacology
Ubiquitins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 35
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 25867069
- Full Text :
- https://doi.org/10.1038/onc.2015.104