A University of St Andrews scientist has been awarded £800,000 to help stimulate the human body’s natural defences against cancer.
Dr Dimitris Xirodimas has been awarded a fellowship by the Association for International Cancer Research (AICR) to help stimulate a molecule which disappears when we contract cancer, allowing damaged cells to divide again and again in a potentially deadly tumour. Dr Xirodimas will carry out cutting- edge research into how to stimulate the p53 molecule to do its job and kill off the damaged cells.
The AICR grant will fund Athens- born Dr Xirodimas (33) and two research assistants to work from the University of Dundee over the next six years. Dr Xirodimas came to the AICR’s attention after discovering the role of another protein, called Nedd8, in preventing p53 from killing cells. This is part of a delicate balancing act performed by a series of chemicals to control the repair and death of damaged cells.
Dr Xirodimas’s task is to search for a way to enable p53 to kill off cancer cells by stopping Nedd8 getting in the way.
“P53 is present in every cell and it is a vital defence mechanism against DNA damage,” he said.
“If you go to the beach and get sunburned, your DNA is getting damaged. In tumours, any DNA damage will get propagated in the new cell and that’s cancer, the accumulation of damage in DNA.
“But the cell has developed a defence mechanism to detect this damage and p53 is one of those defence mechanisms. It has two functions – to repair the damage or, if the damage is too extensive, it basically kills the cell.”
Dr Xirodimas said there was a lot of work going on in the field to try to find a way of activating p53. “In 50% of all tumours there is normal p53. What happens is its activity is over-suppressed by mechanisms ‘upstream’ of p53.
“If you inhibit p53 you promote tumour development. We want to establish whether, in tumours, this inhibition is over-expressed, if Nedd8 is suppressing p53 too much.”
Nedd8 works by attaching itself to p53 and blocking the mechanism by which it works.
When asked if blocking Nedd8 would produce a breakthrough cure for cancer, Dr Xirodimas gave a cautious response – “First of all, we have to establish that that’s why these tumours arise. If we can establish this, we can think how we can block it,” he said. That could be a way of treating cancer and we do know all the proteins and enzymes that are involved in attaching Nedd8 to p53.”
However a treatment of this kind might be problematic.
“P53 is an extremely dangerous molecule. Of course, it prevents the development of cancer but, on the other hand, if you have too much p53, you will die,” said Dr Xirodimas.
“They have to be extremely tightly regulated. Too much p53 is no good, too little and it’s no good either. That’s why all these mechanisms exist in the cell to finely tune the level of p53 to the right amount.”
Dr Mark Matfield, AICR’s scientific consultant said, “The ultimate cause of cancer is damage to certain genes that control whether and how cells divide.
“These genes work by each producing a protein and each of these proteins plays a major role in the cell’s internal control mechanism. P53 is one of the most important of these cell control proteins. The p53 molecule plays a key role in the mechanism that controls whether a cell divides, or commits suicide.
“Dimitris has evidence that the level and activity of p53 may be controlled – to what extent we don’t know – by neddylation its interaction with Nedd8 , and will investigate this during his fellowship.”
Derek Napier, chief executive of AICR said, “We are trying to give funding to the brightest and the best of the young scientists. The hope is one of them may be a Nobel Prize winner ten or 15 years from now,” he said.
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