title: The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway.
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.
authors: Centre de Recherche de Biochimie Macromoléculaire-UMR 5237, CNRS, Montpellier, France.
authors: A
authors: A
authors: Bailly
authors: Centre de Recherche de Biochimie Macromoléculaire-UMR 5237, CNRS, Montpellier, France.
authors: A
authors: A
authors: Perrin
authors: Centre de Recherche de Biochimie Macromoléculaire-UMR 5237, CNRS, Montpellier, France.
authors: L J
authors: LJ
authors: Bou Malhab
authors: Centre de Recherche de Biochimie Macromoléculaire-UMR 5237, CNRS, Montpellier, France.
authors: E
authors: E
authors: Pion
authors: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, Scotland/UK.
authors: M
authors: M
authors: Larance
authors: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, Scotland/UK.
authors: M
authors: M
authors: Nagala
authors: Millennium Pharmaceuticals Inc., Cambridge, MA, USA.
authors: P
authors: P
authors: Smith
authors: Laboratoire de Biologie Moléculaire Eucaryote, UMR CNRS 5099, Bâtiment IBCG, Toulouse, France.
authors: M-F
authors: MF
authors: O'Donohue
authors: Laboratoire de Biologie Moléculaire Eucaryote, UMR CNRS 5099, Bâtiment IBCG, Toulouse, France.
authors: P-E
authors: PE
authors: Gleizes
authors: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, Scotland/UK.
authors: J
authors: J
authors: Zomerdijk
authors: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, Scotland/UK.
authors: A I
authors: AI
authors: Lamond
authors: Centre de Recherche de Biochimie Macromoléculaire-UMR 5237, CNRS, Montpellier, France.
authors: D P
authors: DP
authors: Xirodimas
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins; D002460:Cell Line / Q000187:drug effects; D002466:Cell Nucleolus / Q000187:drug effects*; D003517:Cyclopentanes / Q000494:pharmacology*; D016158:Genes, p53 / Q000187:drug effects*; D006801:Humans; D061986:MCF-7 Cells / Q000187:drug effects; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D008817:Mice, Mutant Strains; D000075687:NEDD8 Protein; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014452:Ubiquitins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D003517:Cyclopentanes; C546714:NED-8 protein, C elegans; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; D012269:Ribosomal Proteins; D014452:Ubiquitins; C027624:ribosomal protein L11; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C539933:pevonedistat