AICR Fellow and Independant Investigator
University of Dundee, United Kingdom (Scotland)
Period of Award
1st October 2005 - 30th September 2011
Regulation of p53 function through the NEDD8 conjugation pathway.
Many types of cancer are caused by damage to genes that control the way cells grow and multiply. In fact, several of these genes have to be damaged before a cell becomes cancerous. Research has found that one of the most frequent is p53 – damaged in over half of all human tumours. In most of the other half, the p53 protein is inactivated by a variety of mechanisms. Some of these involve attaching the p53 protein to another protein, called ubiutin, which marks it for breakdown by the cell’s recycling mechanism. Recent research identified a second protein with the same function – called Sumo – and then a third, called NEDD8. Dr Xirodimas has found that p53 is neddylated (ie attached to NEDD8 to cause it to be broken down). He will now investigate how this neddylation mechanism is used to control p53 activity in normal cells and when it goes wrong, whether it makes cells become cancerous.
Aims and Outcomes So Far
The main interest of our group is to understand mechanisms of tumour cell growth. We are working with a small protein called NEDD8, which is expressed in the great majority of human tissues. The mechanism by which NEDD8 operates is to bind to other proteins in the cell and alter their function. We have evidence that NEDD8 can control tumour cell growth, especially under stressed conditions. Chemotherapeutic drugs such as actinomycin D (or Dactinomycin), which is used for the treatment of different types of cancer such as testicular and bone sarcomas, inhibits tumour cell growth. Our preliminary experiments show that actinomycin D elicits its effects, at least partly, through NEDD8. More detailed characterisation suggests that NEDD8 controls the function of p53, a protein that plays an important role in tumour formation and progression.
We believe that is important to understand and establish the role of NEDD8 in tumour cell growth as Pharmaceutical companies are developing drugs against NEDD8 for the treatment of cancer.
Stevenson LF, Sparks A, Allende-Vega N, Xirodimas DP, Lane DP, Saville MK. The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO J. 2007; 26(4):976-86
Xirodimas DP. Ubiquitin-like molecule NEDD8. Targetted Proteins database. 2007 (in press).
Dimitris P. Xirodimas, Anders Sundqvist1, Akihiro Nakamura, Linnan Shen1, Catherine Botting, and Ronald T. Hay. Proteomic identification of ribosomal proteins as a target for the NEDD8 conjugation pathway. (Manuscript in preparation)
Xirodimas DP. Regulation of the p53 tumour suppressor protein by ubiquitin and ubiquitin-like molecules. Protein Degradation. 2007