Expanding Complexity of p53

Researchers at the University of Dundee have discovered new levels of complexity in the regulation of the tumour suppressor gene p53, findings which could have a significant impact on the identification of patients at risk of developing aggressive cancer and in determining more efficient drug treatments.

The research has been led by Professor Sir David Lane and Dr Jean-Christophe Bourdon of the Cancer Research UK Cell Transformation Group at the University of Dundee. Prof Lane famously discovered the p53 protein, and continues to lead cutting edge research in this field.

The new findings, which are to be published on the 15 September in the journal, “Genes and Development”, show that the p53 gene, the most frequently inactivated gene in human cancer, does not produce only one unique p53 protein as previously thought, but at least six different p53 proteins (isoforms). They also established that expression of p53 isoforms is abnormal in breast tumours.

“The discovery of p53 isoforms is a major breakthrough in the understanding of cancer formation,” said Dr Bourdon.

“The determination of p53 isoform expression in human cancers will help to identify patients at risk of developing aggressive cancer and to define their drug sensitivity in order to treat the patient with the most efficient drugs.”

“The deregulation of p53 isoform expression in tumours provides an explanation on how tumours can develop while they express a non-mutated p53 gene. As p53 isoforms are abnormally expressed in tumour cells, p53 is not fully active and does not destroy every cell which leads to cancer formation.”

The different isoforms of p53 contain sections of the normal p53 protein, each put together in a slightly different way. All six isoforms can be found in normal human cells, though their levels vary in different tissues. Some of these isoforms can interact with full-length p53 to affect its tumour suppressing activity, suggesting that interactions between the different protein isoforms may be key in regulating p53’s normal role.

p53 activity is lost in over half of human tumours, which emphasises the importance of the p53 protein in preventing tumour formation. However, one of the puzzles facing workers in the p53 field is the role of p53 in tumours where it remains apparently normal.

Dr Bourdon and Prof Lane have examined the levels of these newly discovered p53 isoforms in breast tumours and find that some isoforms are present at abnormal levels in tumours which have otherwise normal p53.

This suggests that, in these tumours, p53 activity is being lost by altered isoform expression, rather than by mutation of the p53 gene itself. This important new finding tells us that alterations in levels of specific isoforms may play an essential role in tumour formation by regulating p53 activity. This new model will help to explain how p53 function in individual tumours is linked to the sensitivity of that tumour to drug treatment and give us new tools in the treatment of breast and other cancers.