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

A. Bailly, A. Perrin, L. J. Bou Malhab, E. Pion, M. Larance, M. Nagala, P. Smith, M.-F. O'Donohue, P.-E. Gleizes, J. Zomerdijk, A. I. Lamond, D. P. Xirodimas (Lead / Corresponding author)

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    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.Oncogene advance online publication, 13 April 2015; doi:10.1038/onc.2015.104.

    Original languageEnglish
    Pages (from-to)415-426
    Number of pages12
    JournalOncogene
    Volume35
    Issue number4
    Early online date13 Apr 2015
    DOIs
    Publication statusPublished - 28 Jan 2016

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  • Cite this

    Bailly, A., Perrin, A., Bou Malhab, L. J., Pion, E., Larance, M., Nagala, M., Smith, P., O'Donohue, M-F., Gleizes, P-E., Zomerdijk, J., Lamond, A. I., & Xirodimas, D. P. (2016). The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway. Oncogene, 35(4), 415-426. https://doi.org/10.1038/onc.2015.104