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Oncogene ; 35(4): 415-26, 2016 Jan 28.
Article in English | MEDLINE | ID: mdl-25867069

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.


Subject(s)
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 , 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
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