Cancer is an all-too-common disease, affecting one in three people at some point in their lives. But – on a biological level – cancer is actually extremely rare.
Of the billions of cells that make up our bodies, millions divide every day with virtually every single division going according to plan. And when rare mistakes do arise, they tend to get nipped in the bud pretty quickly.
This is because our cells have evolved a battery of defence mechanisms which spot any defective, cancer-prone cells that might arise.
In the front row of this defensive array is a family of proteins called ‘tumour suppressor’ proteins. And this week, Cancer Research UK scientists have published two papers (press releases here and here) that further our understanding of these intracellular defenders.
The p53 protein
P53 is a tumour suppressor protein found in the cells of all higher organisms. It’s a complicated protein, and can protect our DNA in a number of different ways.
One of its main functions is to detect damage to DNA.
If the damage is relatively mild, it can kick-start a chain of events that repairs the damage, while preventing the cell from dividing further.
But if the DNA is too badly damaged, then p53 instead orchestrates the suicidal death of the cell by kick-starting another chain of reactions called apoptosis. Exactly how p53 ‘decides’ which course of action to take, has been the subject of intense research.
You can see p53 in action if you’re ever foolish enough to get sunburnt – the oh-so-attractive peeling dead skin is the result of UV rays damaging the DNA in your skin cells. But the cells’ p53 proteins spot this damage and trigger apoptosis inside your skin cells. Although it may be unsightly and painful, p53 is doing you a favour by protecting you from skin cancer.
P53 and cancer
But this protection isn’t infallible – in the late 80s, scientists found that many human cancers have a damaged version of p53, meaning that the loss of its protective power is an important – and possibly fundamental- step towards developing the disease.
So understanding more about exactly how p53 works is a pressing concern for many cancer researchers.
Professor Sir David Lane, Cancer Research UK’s Chief Scientist, is probably the world’s leading authority on p53, and played a fundamental role in its discovery back in 1982.
Lane, along with colleagues in Dundee and Singapore, has now made another important discovery, published in the journal Genes & Development, showing how p53 is controlled in response to DNA damage.
P53 – not one but many
Professor Lane and his team had previously discovered that there are, in fact, several different ‘versions’, or isoforms, of p53 within each of our cells, and that different cells, at different stages of development, have different amounts of each isoform.
This posed a question – what exactly did each of these isoforms do? Professor Lane’s latest research has started to answer this puzzle.
“Delta113 p53” is an isoform of p53 that which has previously been found in high levels in certain human breast cancers. This is a bit of a paradox – normally cancer cells lack p53. How could this isoform be involved in cancer?
To find out more, the researchers studied the protein in zebrafish, whose p53 is very similar to the human version. To make their studies easier, they used a genetic trick to engineer the fish so that their p53 proteins glowed green when they were activated.
Firstly, they showed that zebrafish engineered to lack ‘normal’ p53 – but not delta113 p53 – were unable to activate delta113 p53 when their DNA was damaged. This showed that the two isoforms were somehow affecting each others’ behaviour.
They then found that fish that lacked the delta113 isoform died when they were exposed to relatively low levels of radiation, which wouldn’t normally be enough to kill normal fish.
They then showed precisely how, at a molecular level, the delta113 isoform blocked normal p53 from causing the cells to commit suicide. It seems the isoform switches on a protein called bcl2L, which prevents cell death.
What does it mean?
Given their results, Professor Lane and his team think that the delta113 p53 isoform helps healthy cells to maintain the fine balance between life and death.
They propose that, if the cell’s DNA suffers relatively minor damage, p53 is switched on and its levels in the cell start to rise. But p53 also activates its own isoform – delta113 p53 – preventing the cell from dying straight away as a result of relatively trivial damage.
On the flip side, the scientists suggest that if the DNA damage is too severe then p53 levels soar, over-riding the restraining effect of the delta113 isoform and triggering cell suicide.
This multi-layered control mechanism gives normal cells exquisite control over how they sense and respond to DNA damage.
But in cancer cells, where these controls are haywire, high levels of delta113 p53 enable a faulty cell to cheat death and multiply out of control. This explains the paradoxically high levels of this particular p53 isoform in tumours.
And another tumour suppressor – Cep63
Not only have Professor Lane and his team published their findings about p53, but in the same week, Cancer Research UK’s Dr Vincenzo Costanzo has discovered an entirely new tumour suppressor, called Cep63.
Writing in the journal Nature Cell Biology, Costanzo and his team studied how frog cells divide – and how their DNA is replicated – to track down their new protein. They found that a protein, Cep63, patrols the cell’s centrosomes [wiki] – the molecular machines that control the distribution of DNA when a cell divides.
Cep63 seems to be able to block cells from dividing if anything seems amiss. And the protein appears to be involved in cancer – other scientists have recently discovered that Cep63 is faulty in invasive bladder cancers.
So, like p53, Cep63 seems to be another one of our cells’ guardians – keeping an eye on our DNA, and preventing cells from dividing if things are awry.
Over the years, Cancer Research UK has invested heavily in this kind of science, and discoveries made in previous decades are now bearing fruit in cancer treatments that are available today.
And it’s only by increasing our understanding of the basic mechanisms that control both healthy and cancer cells that we will come up with new and more effective ways to beat cancer in the future.
Janice M. Nigro et al(1989). Mutations in the p53 gene occur in diverse human tumour types Nature, 342 (6250), 705-708 DOI: 10.1038/342705a0
J. Chen et al (2009). p53 isoform 113p53 is a p53 target gene that antagonizes p53 apoptotic activity via BclxL activation in zebrafish Genes & Development, 23 (3), 278-290 DOI: 10.1101/gad.1761609
J.-C. Bourdon et al (2005). p53 isoforms can regulate p53 transcriptional activity Genes & Development, 19 (18), 2122-2137 DOI: 10.1101/gad.1339905
Eloise Smith et al (2009). An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63 Nature Cell Biology DOI: 10.1038/ncb1835
Marcilei E. Buim, et al (2005). The Transcripts of SFRP1,CEP63 and EIF4G2 Genes Are Frequently Downregulated in Transitional Cell Carcinomas of the Bladder Oncology, 69 (6), 445-454 DOI: 10.1159/000090984