P53 – Guardian of the genome

Its structure is well characterised, over 100 proteins have been identified as interacting with it, more than 50 different types of cancer show compromised function of it and a pubmed search for ‘p53’ brings up over 70,000 articles. What can there be left to learn about this protein dubbed the ‘guardian of the genome’?

Discovered in 1984, the role for p53 in tumour suppression is well established. It operates through several mechanisms in response to DNA damage: p53 can help to repair damaged DNA within the cell by putting the brakes on cell function long enough got the cell to repair itself, if the damage can’t be repaired p53 instigates apoptosis, causing the cell to commit suicide. Mutations within this gene can lead to abnormal function, resulting in dysregulated cell growth and proliferation- ultimately cancer development and the growth of tumours. P53 can be seen in action in the peeling skin following sunburn, which is the result of its activation of the cell suicide pathway in damaged cells, helping to protect against skin cancer.
Yet, the specific molecular mechanisms that define the ultimate outcome of p53 activation remain poorly understood.
The mechanism by which p53 achieves its role in protecting the genome and suppressing tumours has recently started to be uncovered with insights from murine models suggesting that the role of p53 is context specific, with the degree to which different apoptotic machinery is involved being dependent upon the type of cancer.
It is due to its central role in many human cancers that restoring the function of the mutated p53 protein remains one of the holy grails of cancer research. Attempts to reactivate the protein in cancer cells have not as yet been successful and many researchers are still studying p53 and its related proteins searching for a way in which to either reactivate this death pathway or introduce viruses that can specifically target cancer cells, reproducing within them and killing them based on their faulty or inactive p53 status, whilst healthy cells remain untouched.
But p53 has been associated with other functions too. Roles for p53 have been proposed in cell death, cell senescence, ageing, metabolism, immunity, embryo implantation, autophagy, angiogenesis, cellular stress and host-pathogen responses. Whilst novel target genes and pathways aim to complete the picture of p53 action, its role in cancer demonstrates that as ever in biological processes context is the key, with different branches of the p53 network contributing differentially to its different functions in different cell types.