Guardian of the genome's missing anti-cancer link uncovered
Cancer Research UK scientists have discovered a missing link in the way cells protect themselves against cancer, according to research published in Genes & Development* today.
Cancer Research UK-funded scientists based at the The Univeristy of Dundee ** and the Agency for Science Technology and Research in Singapore (A*STAR) have discovered how cells switch p53, the tumour-suppressor gene known as the guardian of the genome, on and off. The discovery comes 30 years after it was co-discovered by Professor Sir David Lane, who is also Cancer Research UK's chief scientist. This has important implications for cancer treatment and diagnosis.
The scientists used a genetic trick to make zebrafish turn green when the p53 gene was switched on to explore the way this gene was regulated.
They found that the p53 gene makes not only the well-established p53 protein, but also an alternative 'control switch' variation of the p53 protein - known as an isoform***. It is the isoform that feeds back to regulate the p53 gene. In its active state p53 will trigger cell death - called apoptosis - or arrest cell division to make repairs to DNA.
Normally zebrafish can survive low doses of radiation. But zebrafish which couldn't make this isoform ‘switch’, died when exposed to low levels of radiation. This proved that the isoform was critical in controlling p53’s normal function to protect cells against the development of cancer - which includes ordering cells to die when they are badly damaged.
Scientists from Professor Sir David's lab had previously discovered that cells contained more than one isoform of p53 - but they didn’t know how the isoforms were produced or what they did.
Zebrafish carry the same p53 gene as humans.
P53 is damaged or inactive in half of all cancers and has roles in cell development and ageing. In normal cells it is activated in response to cell damage and one of its functions is to order cells to die - a process called apoptosis - when DNA is damaged beyond repair. It is critical that p53 functions normally to prevent genetic mistakes being passed on to daughter cells which can lead to cancer. But until now no-one understood how this gene was controlled.
Professor Sir David Lane, lead author, said: "We are delighted by these findings. Our research is focused on this p53 gene because it is so often damaged in cancer cells.
"The function of p53 is critical to the way that many cancer treatments kill cells since radiotherapy and chemotherapy act in part by triggering cell suicide in response to DNA damage - so understanding more about how this gene is controlled in cells is really important in finding ways to prevent cells from turning cancerous."
Lesley Walker, Cancer Research UK's director of cancer information, said: "This is a really exciting study which improves our understanding of how the p53 gene works.
"Cancer Research UK scientists co-discovered p53 30 years ago so discovering how it is regulated will have incredibly important implications in the development of better drugs and ways to diagnose cancer."
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Notes to Editor
Image available on request.
*Jun Chen et al. p53 isoform 113p53 is a p53 target gene that antagonizes p53 apoptotic activity via BclxL activation in zebrafish. Genes & Development 2009 1 February 2009. **Work on this study was carried out in labs based in both the University of Dundee and Singapore's A*STAR Institute of Molecular and Cell Biology (IMCB). ***Protein isoforms Different versions of one protein can be formed. They can be coded for by several genes and stuck together in a slightly different way or coded for by sections of the same gene.