Discovering the p53 cancer protein

Since its discovery by Professor Sir David Lane – Cancer Research UK’s chief scientist – in the 1970s, a small molecule called p53 has revolutionised our understanding of how cells, including cancer cells, grow and divide. p53 was the first natural ‘tumour suppressor’ found within our cells – something that usually acts to protect us from cancer. We now know that p53 is faulty or inactivated in the majority of human cancers and a wide range of different functions have been ascribed to it.

As part of Our Milestones series, we’ll look at how p53 was discovered, and the impact this has had on cancer research.

To start off, here’s a short video of Professor Lane talking about his research and its importance.

The background

In 1979 Professor Sir David Lane was simply Dr Lane, working with Lionel Crawford at the Imperial Cancer Research Fund (now Cancer Research UK).

Over the preceding few years, modern cancer biology as we know it had begun to emerge. Researchers were starting to understand more about the faulty genes and molecules involved in cancer cells.

Against this backdrop, many scientists – including Lane and Crawford – were investigating a monkey virus called simian virus 40, or SV40, which was known to cause cancer in mouse cells. The virus ‘immortalised’ cells grown in the lab, giving them many of the properties of cancer cells.

Researchers had suspected for a while that two proteins made by the virus – known as the “large T” and “small t” antigens – interacted with as yet unidentified mouse proteins to trigger cancerous changes. Identifying these proteins was thought to be the key to understanding how cancers developed.

What did they do and what did they find?

In a molecular ‘fishing expedition’, Lane and Crawford set out to look for molecules that stuck to the viral proteins. Their efforts were rewarded. They found one, publishing their findings in the journal Nature – the 1979 paper seems almost ridiculously brief, compared to the bulky tomes of today.

The scientists began by developing an antibody that recognised the SV40 large T antigen. This allowed them to pluck out large-T molecules – and anything stuck to them – from a jumbled up protein mixture taken from mouse cells that had been infected with the SV40 virus.

When they analysed what was stuck to the large T protein using a technique called gel electrophoresis – which sorts proteins by size – they saw that the T antigen seemed much heavier than expected.

Something was indeed sticking to it. There also seemed to be another, smaller protein present – although they needed to work out if it was actually a new protein, or just a smaller fragment of a known viral protein.

Further experiments showed that this was indeed a new protein, with a molecular weight of 53,000 Daltons (53 kiloDaltons). Hence the name p53 – ‘protein of 53kiloDaltons’.

Since there was simply not enough genetic ‘room’ in the SV40 virus’s DNA to make an additional protein, the only conclusion that Lane and Crawford could draw was that the protein was originating from the mouse cells.

The paper predicts that:

“It is possible that [the mystery protein] … may normally act as a regulator of certain cellular functions related to growth control…It is of prime importance to determine the level of this … protein in [normal] cells and to see if it is induced by other carcinogenic agents. ”

On the other side of the Atlantic, while Lane and Crawford were carrying out their experiments, researchers Arnold Levine at Princeton University and Lloyd Old at Sloane-Kettering Memorial Hospital were also coming to the same conclusion via a different route.

What impact has the research had?

Twenty years later, researchers are only just getting to grips with the complex role that p53 plays within the cell, how it is involved in cancer, and whether they can use this knowledge to design new treatments for the disease.

A recent review by Professor Carol Prives and Cancer Research UK’s Professor Karen Vousden highlights how far we have come – and how far we still have to go – in understanding this complicated molecule.

The human gene that encodes p53, TP53, was uncovered in 1984. We now know that one of p53’s key jobs is to act as a ‘transcription factor’, responsible for turning genes on in response to DNA damage.

This has earned p53 the nickname “the guardian of the genome”. It helps to protect us from cancer by causing cells to stop growing – or even die – in response to damage.

You can see it at work if you’ve ever been sunburnt – the resulting peeling skin is the result of p53 switching on a cell ‘suicide’ pathway inside damaged cells, helping to protect us from skin cancer (at least most of the time).

Molecular ‘Swiss Army knife’

But p53 may perform other jobs too. Since its discovery, it’s been proposed to be involved in cell death, cell ‘sleep’ (senescence), ageing, metabolism, immunity, embryo implantation, cell ‘eating’ (autophagy), DNA repair, growth of new blood vessels (angiogenesis) and cellular stress. It probably makes the tea and does the washing-up as well!

On top of this, and highlighting its ubiquitous role in ‘normal’ cell function, researchers now know that p53 is faulty or switched off in many human cancers. But despite this, attempts to reactivate it in cancer cells haven’t been altogether successful so far. Scientists, including Professor Lane, are still studying p53 and related proteins, looking for ways to reactivate the death pathway in cancer cells.

It’s a highly active research field – for example, we’ve blogged about advances in p53 research, and press-released the discovery of chemicals called Tenovins that can bypass faulty p53 and ‘flick the switch’ on the death pathway.

Just as interesting is research that directly uses the lack of p53 in cancer cells to our advantage. Scientists are now working on viruses and other treatments that only reproduce within and kill cancer cells, because they contain faulty or inactive p53. Healthy cells, with working p53, should be left untouched.

For example, early clinical trials have been carried out using a virus – called Onyx15 – in head and neck cancer, with promising results. Although this work is still at quite an early stage, it holds potential for the future.

This year marks the 30th anniversary of the discovery of p53 – a discovery that changed our understanding of cancer biology, and that Cancer Research UK is proud to have been part of. Over the coming years, we hope to understand more about this enigmatic molecule, and use our knowledge to move forward in beating cancer.

Kat

References:
Vousden, K., & Prives, C. (2009). Blinded by the Light: The Growing Complexity of p53 Cell, 137 (3), 413-431 DOI: 10.1016/j.cell.2009.04.037

Lane, DP & Crawford, LV. (1979). T antigen is bound to a host protein in SV40-transformed cells. Nature, 278 (5701), 261-3