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Final Report Summary - ND8-NOS (The role of the ubiquitin-like molecule NEDD8 in nucleolar signalling)

Cell growth (increase in size) and cell cycle (increase in cell number) are fundamental aspects of cell behaviour in all organisms. Deregulation of mechanisms that control cell growth often leads to a variety of pathological conditions, including cancer, inflammatory and metabolic diseases. Similarly, mutations in genes that control cell cycle such as p53, contribute to genomic instability and cancer development. While cell growth and cell cycle are separable processes, it is clear that there is an interconnection, with cell growth being rate limiting for cell cycle. It is now established that the nucleolus, a nuclear structure where the production of ribosomes (protein synthesis “machines”) takes place, is also essential for transmitting cell growth defects to cell cycle regulators.
Our group’s research is focussed on a family of small proteins called ubiquitin and ubiquitin-like proteins. A key discovery of our team, which formed the basis for the MC-CIG proposal, was the identification of the ubiquitin-like protein NEDD8 as regulator of the coordination between cell growth and the cell cycle. We found that NEDD8 is covalently attached to proteins that compose the ribosome (Ribosomal Proteins) in the nucleolus. This allows the correct localisation of Ribosomal Proteins in the nucleolus allowing normal cell growth. The objective of the proposal was to expand our studies on the role of NEDD8 in nucleolar function; To determine how NEDD8 controls the organisation of the nucleolar proteome and function and understand the implication of such findings in the co-ordination between cell growth and cell cycle. Additionally, our aim was to develop genetic model systems to determine the evolutionary conservation of our findings.
Overview of Results
We employed quantitative mass-spectrometry in combination with microscopy in human cells and determined how the nucleolar proteome and morphology changes upon inhibition of NEDD8. For this, we used a recently developed small molecule (MLN4924) that specifically and potently inhibits the NEDD8 pathway. Our studies show that inhibition of NEDD8 has a profound effect both on nucleolar morphology and distribution of nucleolar proteins, beyond our original findings on Ribosomal Proteins. We also determined the biological outcome for these effects. We found that the observed disruption of the nucleolus upon NEDD8 inhibition causes the activation of the p53 tumour suppressor, resulting in cell cycle arrest. Importantly, these findings were confirmed in C.elegans nematodes (worms), a model organism that is separated from humans by over 600 million years of evolution. Our studies revealed a role for the NEDD8 pathway in controlling nucleolar morphology and cell cycle regulation that is highly conserved throughout evolution.

Impact of Results
Post-translational modification of proteins with ubiquitin and ubiquitin-like molecules is a major mechanism of protein function regulation. The realisation that these pathways are involved in the regulation of almost every biological process in the cell has created a huge interest amongst scientists, including major Pharmaceutical industries. These pathways are now targets for therapeutic intervention for the treatment of diseases such as cancer. The inhibitor of the NEDD8 pathway (MLN4924) is the second developed inhibitor targeting the ubiquitin/ubiquitin-like molecules pathways that advanced into clinical trials. Therefore, it is important to elucidate the pathways controlled by NEDD8. Our studies provide an example of co-ordination between cell growth (nucleolus) and the cell cycle (p53 tumour suppressor) and potential mechanistic insights on the anti-tumour activity of NEDD8 inhibitors.
Dr Dimitris Xirodimas
CRBM-CNRS
1919 Route de Mende
34293, Cedex 5
Montpellier
France
Email: dimitris.xirodimas@crbm.cnrs.fr
Website: http://www.crbm.cnrs.fr/index.php/en/dimitris-xirodimas-uk

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CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
France
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