A comprehensive and current overview of p53 biology can be found in a review article by Edward Kastenhuber and Scott Lowe of Sloan Kettering Institute in New York (Cell 170:1062 - 1078 (2017)). Unfortunately, the article is behind a paywall - but you already know my opinion at that. Let me borrow from the article to recapitulate some of the main take home lessons about p53.
I'll end this short post with a few unexpected pieces of information that I came across in preparing this essay. The first has to do with one of my favorite animals: elephants. It turns out that elephants don't often get tumors, despite the enormous number of cells in their body and their long lives. That is, from a statistical point of view, given their cell numbers and the rate of mutation, they shouldn't reach old age before they become riddled with tumors. The unexpectedly low incidence of cancer in elephants (2 to 5 times less susceptible) and other large vertebrates has been given a name – Peto’s Paradox. I quote from Wikipedia:
"Peto's paradox is the observation, named after Richard Peto, that at the species level, the incidence of cancer does not appear to correlate with the number of cells in an organism. For example, the incidence of cancer in humans is much higher than the incidence of cancer in whales. This is despite the fact that a whale has many more cells than a human. If the probability of carcinogenesis were constant across cells, one would expect whales to have a higher incidence of cancer than humans."
How then do whales (and elephants) avoid cancer despite being at greater risk? For whales it isn't known. However, African elephants are remarkable in that they have 20 p53 genes, 19 more than normal (Indian elephants have somewhat less). What's more, it appears that elephant cells respond better to DNA damage via apoptosis than cells from humans. And this improved response is not only correlated with, but seems to be dependent on these extra copies of the p53 gene.
The supernumerary p53 genes are peculiar – they appear to be DNA copies of p53 mRNA. Somehow, back millions of years ago, p53 mRNA was converted into DNA and integrated into the elephant genome. This phenomenon has been observed previously, although not for p53. Genes formed this way are called "retrogenes" because they've been generated backwards – from RNA to DNA rather then the other way around. Only a few of these extra copies produce a protein, but apparently they are sufficient, at least to some extent, to protect elephants from the scourge of cancer.
These extra elephantine p53 genes suggest a therapeutic strategy. Why not introduce a more active version of p53 genes into the human population to protect us from cancer? Actually, experiments have been attempted whose results bear on this issue. A variant p53 gene, one that produced the p53 protein uncontrollably, was introduced into the germ-line of mice. Those with one copy of this overactive gene had a greatly reduced chance of contracting cancer. That's the good news. The bad was that they died sooner, apparently aging faster, than controls. Apparently, cells strike a balance. Too little p53 and the risk of cancer goes up. Too much p53, and cells don't divide sufficiently to keep up with natural losses that occur with time.
In the next post, I'll discuss the aging of cells. That'll be the last post before I finally get to the topic that brought this blog about: cancer innunotherapy.