Breakthrough in p53 cancer research
Published On Tue 17 Jun 2014 by Roddy Isles
Scientists at the University of Dundee have made a significant breakthrough in understanding the activity of the p53 tumour suppressor, one of the most important molecules in cancer research.
The p53 protein was discovered by Professor Sir David Lane, formerly of the University of Dundee, and is one of the most widely studied factors in cancer research due to its role in a wide variety of cancers. Studies of p53, dating to its discovery in 1979 and its identification as a tumour suppressor ten years later, represent some of the most important contributions to current understanding of the molecular and genetic events that occur in cancer.
Now a team at Dundee led by Dr David Meek in the Medical Research Institute has discovered new details of how the protein works.
The p53 protein displays many mechanisms of anti-cancer function, including activation of DNA repair proteins, activation of cell cycle check-points (which block a potential cancer cell's ability to grow and multiply), and initiation of apoptosis or programmed cell death (which ultimately eliminates the cancer cell).
p53 is mutated in a wide variety of cancers and is thus rendered unable to perform these crucial anti-cancer functions. The p53 protein is activated by a wide variety of cellular stresses and signals, some of which act through a process called phosphorylation. Dr Meek’s team were particularly interested in the role it played in a particular part of p53 – serine 15 or ser15 - where it modifies the protein’s activities and functions.
Phosphorylation of serine 15 in the p53 protein was first described in 1992, but the precise role of that modification in modifying p53's activities and functions has not been well understood.
In their research, published in the journal Nucleic Acids Research (NAR), Dr Meek and colleagues have shown two advances in understanding. They found that
phosphorylation of Ser15 is crucial in activating transcription of genes responsive to p53, the process where vital DNA information is copied in the cell leading to the manufacture of the proteins (functional components) through which the cell responds to cancer-promoting stresses or events
They also found the same phosphorylation event has a much wider and more fundamental involvement in controlling the activity of p53 than was previously envisaged.
“p53 is a protein that is of huge interest to cancer researchers yet there is still a lot of what it does that we don’t fully understand,” said Dr Meek. “Our work has linked several pieces of the jigsaw by describing how this process of phosphorylation in a particular part of p53 has a significant effect on its activity. A good analogy would be that p53 is akin to a 999 call centre: it receives distress messages from various sources in the cell and then has to orchestrate a response at the molecular level to alleviate or counteract the effects of the stress. Our study shows that phosphorylation is a vital part of this communication line.”
Reviewers and editors at NAR who have examined the Dundee study described its results as a long-awaited advance in the field. Dr Carl Anderson at Brookhaven National Laboratory stated that, “This manuscript provides the first convincing evidence for the functional importants of p53 Ser15 phosphorylation in human cells. Ser15 was first identified as a p53 phosphorylation site in 1992, so it has taken greater than 20 years to reach this conclusion.”
Dr Meek’s laboratory focuses on the molecular signalling events and protein-protein interactions that regulate the p53 network in the context of normal physiology and in the development of cancer. Their work, including this study, has been funded by Cancer Research UK, the Association for International Cancer Research, Medical Research
Scotland, Breast Cancer Campaign and the Medical Research Council.
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