Death of a Cellsman

It's not easy, being a cell. They have to make accurate copies of DNA while constantly bombarded with radiation, harmful chemicals, invading viruses and other hazards. There's a good chance the vital genetic code will be miscopied or even damaged, leaving the cell with mutations. A mutant cell is dangerous to have around, because it may start to grow when it shouldn't and cause cancer.

Luckily, cells have specialized proteins, called tumour suppressors, which constantly survey the cell and its DNA to counteract these dangers. One of these is p53, a protein which has been dubbed "the guardian of the genome" [1]. If p53 detects a problem, it can halt much of the cell machinery and make sure the cell does not attempt to continue growing until the danger has been dealt with and any damage to the DNA has been repaired. If the damage is so severe that the cell can not repair it, or if a cell is caught trying to slip past p53's controls, p53 will force the cell to commit suicide [Figure 1]. This protects the whole body from cancer, because a single dead cell can easily be replaced, whereas if the cell were allowed to continue growing, the mutation would spread and a tumour could form.

But what happens if p53 itself is struck down by a mutation? Well, the bad news is you are quite likely to get cancer. There is a rare hereditary disease called Li-Fraumeni syndrome, where people are born with defective p53. People with this disease usually have multiple tumours by the time they reach their early 30s [2]. Some people who don't have this syndrome also get tumours, and when these tumours are examined, more than half of them contain mutant p53 [3]. These people have lost their p53 in some cells, and without p53, it is much easier for cells to grow into tumours. In the past few years, some cancer sufferers have been successfully cured with gene therapy, by delivering the p53 gene directly to cancer cells [4], making them self-destruct but leaving the healthy cells unharmed.

Many people get cancer even though their p53 gene is intact. Their cells may have something else wrong which stops p53 from working properly, such as a viral infection, or damage to some of p53's helper proteins. If scientists could find a drug to turn p53 on for these people, it would force cancer cells to commit suicide. One way of doing this is treatments like chemotherapy and radiotherapy, which turn on p53 because they are so dangerous to cells. Of course, radiotherapy and chemotherapy have terrible side-effects, and because they damage the patient's DNA they can cause new mutations and new cancers after the original cancer is cured.

My lab at the University of Dundee are looking for new drugs that fool p53 into thinking cancer cells are in danger without actually damaging the DNA. We use genetically engineered cells, so that instead of dying when p53 is active, they make a protein which reacts with a yellow dye to turn it pink. I investigated several thousand different chemicals to find which ones switch on p53. Thirty of the chemicals I tried worked, but many of them worked like standard chemotherapy drugs by damaging DNA. But a few turned on p53 without this problem. I found that if I treated cancer cells with these chemicals, the cancer cells died, but if I treated normal cells, they just stopped growing for a while and eventually started again [5].

We hope that one day chemicals like these will be made into a new generation of safer cancer drugs. Because they work by turning on the body's natural protector, p53, they are much less harmful to normal cells than traditional chemotherapy drugs. They could be used as long-term treatments to keep cancer at bay, or perhaps even given to people who are at risk of cancer before any symptoms develop.

  1. Lane DP: p53, guardian of the genome Nature 1992 volume 358 p 15-16
  2. Varley JM: Germline TP53 mutations and Li-Fraumeni syndrome Human Mutation 2003 volume 21 p313-320
  3. Soussi T, Dehouche K & Béroud C: p53 website and analysis of p53 gene mutations in human cancer: forging a link between epidemiology and carcinogenesis Human Mutation 2002 volume 15 p 105-113
  4. McCormick F: Cancer gene therapy: fringe or cutting edge Nature Reviews Cancer 2001 volume 1 p 130-138
  5. Berkson RG, Hollick JJ, Westwood NJ, Woods JA, Lane DP & Lain S: Pilot screening programme for small molecule activators of p53 International Journal of Cancer 2005 volume 115 p 701-710

© RGB May 2005