LFS Research Project – p53 isoforms

The scientific understanding of TP53 continues to evolve and change – while it’s still known primarily because of its function in tumour suppression, we also know that it is central to how cells respond to an increasingly wide range of stresses. In terms of LFS we have long suggested that the focus purely on the tumour suppressor function is potentially missing important detail in how cancers arise (see for example my paper ‘Primed for cancer: Li Fraumeni Syndrome and the pre-cancerous niche‘). By broadening our understanding on the role of TP53 in relation to chronic inflammation, the immune system, cell aging, metabolism, and so on, we can perhaps start to explore strategies for reducing the cancer risk in people with LFS.

The new frontier in TP53 research is based on the exploration of how it works in so many different areas of cell biology. How can one gene orchestrate such a wide range of processes? This is where we have to start to revise our picture of the relationship between the gene (TP53) and the protein (p53). The old picture was that the TP53 gene coded for a single p53 protein. One way to think of this is that the gene is like a recipe (using a standard set of ingredients called amino acids) and the protein is what was produced if you followed that recipe. In the old picture you start at the beginning of the recipe and follow it through to the end and you get your protein. However, we now know that many genes can actually create multiple proteins called isoforms. Imagine we have a recipe for black forest gateau – we can start the recipe at the beginning and go through to the very end and bake a whole black forest gateau. Or else we can dip in and out of the recipe, or even skip a page, and produce a chocolate sponge. It turns out to be the same with genes, we can start at the beginning and go to the end and produce one full-length protein, or else we can skip pages, dip in and out, to produce a range of shorter or different proteins. And this is exactly what happens with TP53, there are in fact multiple p53 isoforms produced, at the same time and in varying levels, and it appears that these different proteins are involved in the many aspects of TP53 functionality.

Work at the famous TP53 laboratory at Dundee University (where p53 was co-discovered by Sir David Lane), led by Dr Jean-Christophe Bourdon, has expanded our understanding of the many different p53 isoforms and their functions. The team there have been exploring the distribution of isoforms in healthy cells, their role in cancer and other health conditions, how they impact tumour response to treatment and so on. Slowly they are starting to understand how combinations of different isoforms may be involved in different functions – these isoforms over here are involved in handling metabolic stress, those ones there involved in the response to gene damage and so on. To mix our metaphors, Dr Bourdon likens this to understanding the language of TP53. For people with LFS there is of course one hugely complicating factor: mutations.

If we continue with the recipe analogy we can think of people with a TP53 mutation as having some differences in their version of the TP53 recipe. There can be all sorts of differences in the recipe, some of these swap one ingredient for another, some cause the recipe to finish early and so on. What does this mean for p53 isoforms? It means that in some cases you may get the almost the full range of working p53 isoforms with only one or two missing or mutated. It might mean that you get some unique isoforms that don’t come out of the non-mutated recipe. This is enormously important. It means we no longer think of people having a TP53 mutation as producing a single mutated p53 protein but as possibly producing a mix of mutated and non-mutated p53 isoform proteins. And if we know what these different isoforms do, then we can more clearly understand which of the many functions of TP53 are working as standard and which are likely to be not working properly.

In practice nobody has looked at LFS in terms of p53 isoforms. Nobody knows what mix of isoforms people with different TP53 mutations produce – we don’t know how these isoforms relate to cancer risk, or how they might dispose people more to some cancers than others.
Therefore, the first part of our research collaboration with Dr Bourdon and Dundee University will look at cells from people with LFS to explore for the first time the range of isoforms present. We want to explore the range of isoforms and to look at how these compare to the range in people who don’t have LFS. We also want to see whether there are unique p53 isoforms only people with certain types of mutations have.

With this type of information we can also start to look at whether there may be active measures we can take to reduce the risk of cancer developing in people with LFS. In the second phase of our project we are going to start looking at that – as I will discuss in the next article.