Free p53 by Sue Armstrong Page B

and suggestive of a common
evolutionary ancestor) to an oncogene found in a virus – in this case the rat sarcoma virus that had been discovered in the 1960s.
    The following year, 1983, Mike Waterfield at the ICRF in London found that a virus that causes sarcomas in monkeys had, some time way back in evolutionary history, hijacked a gene from us that
is involved in growth and repair, and is especially important in healing wounds. This was further proof that we humans have in us genes that are part and parcel of our normal DNA – and have a
regular job to do in our cells – that can, under certain circumstances, cause us harm.
    But what are the circumstances? At the time the first human oncogene was found, no one yet knew that carcinogens – whether they be chemicals, infections or radiation – typically work
by scrambling our DNA. Bob Weinberg, however, had a hunch that mutation would be the key to activating would-be oncogenes, and once again he faced down the doubters who pointed out that some
chemical carcinogens don’t actually cause mutations. ‘I was not troubled,’ he commented wryly in an essay on the discovery of human oncogenes. ‘I thought that a good simple
idea should not be undermined by complicated facts.’
    Weinberg’s hunch proved correct, and he and his co-discoverers soon found that the Ras gene – which has a central role in orchestrating the growth, division and differentiation of
our cells in the normal course of events – can be turned nasty by an alteration in a single nucleotide, representing just one letter in its protein recipe. In a sensitive position in the
gene, such a mutation can result in Ras being permanently ‘switched on’, heedless of any signals it may be receiving, thereby driving the cell to grow and divide unchecked. It was an
important revelation, another vital insight into the mechanics of cancer at the most basic level.
Nature
hailed the discovery of the human Ras gene and its activating mechanism by naming
1982 ‘The Year of the Oncogene’.
    No one could know then just how important a find Ras would turn out to be. We now know that this gene is mutated in around a quarter of all human tumours, including roughly a half of all colon
cancers and 90 per cent of pancreatic cancers. But as scientists continued to investigate oncogenes – of both viral and cellular origin – they became aware of a vital caveat: a single
oncogene acting alone cannot create a tumour; in order to mess up a cell’s machinery enough to cause cancer, oncogenes need to co-operate with one another. Researchers had no idea initially
why this should be, only that it was so. When, for example, Ras is put into cells together with Myc – another powerful oncogene found in the DNA of a virus as well as in animals, including us
– the effect is clear cut and often dramatic.
    p53
LOOKS
LIKE AN ONCOGENE
    In 1984, when researchers began working with the new p53 clones to find out how the gene functions, they quickly concluded it too was an oncogene. This was one of the first
ideas they tested and they did so by taking the classic experiment – pairing the powerful Myc with another oncogene – but replacing the Myc with p53 to see if it had the same effect.
‘We put p53 with Ras; some others put it with other oncogenes; and we all got positive results,’ said Moshe Oren. ‘From the beginning the results were similar to Myc, though less
dramatic and less efficient. So the feeling was: p53 is an oncogene. Not as good as Myc, but okay, Myc is the king; this is just a regular knight!’
    An essential condition for cancer to get going is that cells become ‘immortalised’ – that is, able to override the limits set by nature to the number of times they can divide.
An individual oncogene acting alone can accomplish this vital step, which leaves the cell on the brink of cancer, vulnerable to a second hit by another oncogene that will take it all the way.
Jenkins’ group at the Marie