The critical nature of the tumor suppressor p53 is indicated by the fact that it is present in a mutated form in somewhere around one third of all human cancers (and in virtually 100% of all ovarian cancers). The "p" in its name stands for "protein"; the "53" for 53,000 daltons, the molecular weight of the protein that was estimated when it was first discovered. In actuality, the technique that had been used to measure its size is imprecise. In actuality its molecular weight is closer to 48,500 daltons. That's a bit misleading too. 53,000 is the size of a single p53 chain. But the protein doesn't function as a monomer. It is a tetramer inside cells (4 x 48,500), thereby increasing the error in p53's name still further. The picture below shows a half molecule of p53 attached to DNA.
p53 is an amazing protein. It, and the gene that specifies its sequence, has been the subject of 10's of thousands of papers to date. And the list is growing. It is a transcription factor that somehow monitors the health of cells, particularly the integrity of the genetic material. If it finds something amiss, it can slow division so that the cell can repair existing damage. Alternatively it can direct the cell into a state called "senescence", where it ceases to divide. Or, if the problem is so serious that the damage can't be undone or avouded, it sets the cell on the pathway for programmed cell death, or apoptosis. Since the molecular mechanism apparatus for apoptosis is built into the circuitry of most human cells, cancer cells can also be forced to undergo the process. And since cancer cells often carry damaged DNA or appear unhealthy in other ways, p53 acts as as an essential guardian against tumors, ridding the body of tumors or stopping division in its tracks. It's no wonder that avoiding the p53 barrier is one of the primary concerns of cancer cells.
A New Reference
In this post, I'm going to offer an overview of the way that p53 works. Some of the information that I hope to get on the subject comes from a source that I recently discovered – a book published in 2013 called "p53: The Gene that Cracked the Cancer Code" by Sue Armstrong.
Armstrong's book tells the story of p53 from a historical perspective. She interviewed many of the scientists who made significant contributions to our understanding of how p53 works. The book sparkles because many offered candid tales about the errors that they had made, the troubles that they encountered in trying to convince others, and the contributions of people in their laboratories that are often unacknowledged. It's written in an easygoing style and is aimed at readers that don't have a strong grounding in molecular biology. And there's little jargon! All in all, I highly recommend it.
A New Kind of Tumor Suppressor
From early on p53 didn't act like other tumor suppressors. For one thing, tumor suppressors usually require two separate events in order to cause malignancies. There's an initial step that renders the protein inactive, and another that often knocks out the corresponding gene on the other chromosome. However, some p53 mutants didn't seem to work like that. They sometimes increase the risk of cancer when present in only a single copy. For another, most tumor suppressors profoundly perturb normal embryonic development when both copies are absent. Mice lacking both copies of the p53 gene develop normally, although they are very prone to cancer after birth. This second peculiarity was particularly instructive (I'm going to ignore the mechanism governing the first because it isn't essential to this narrative). Because it wasn't required during embryonic and fetal life, it appeared that p53 was solely specialized for cancer suppression, not for normal cell activity.
An observation that fits with this second characteristic is that p53 is present in extremely minute quantities in most cells under normal conditions. Some sophisticated studies showed that its lack of abundance wasn't because it was synthesized at a low rate. Its scarcity was due to the fact that most of it was being destroyed as soon as it appeared. But isn't that wasteful? What's the point of making a lot of protein and then rapidly degrading it? Actually, other proteins have been shown to turn over quickly and the explanation offered by molecular biologists is that it allows cells to react swiftly to events. If you're constantly making a protein at a rapid rate and breaking it down just as fast, you can cause the protein to quickly accumulate if you stop its degradation. By contrast, if you want to increase a proteins concentration by increasing its rate of synthesis, you first have to increase the transcription of its gene, push its mRNA out of the nucleus, and begin translating it in the cytoplasm. If that process is already underway, it makes for a more expeditious response.
Increasing the Levels of p53
What specifically are the factors that decrease the rate of degradation of p53 and thereby increase its concentration? The list is remarkably long. It includes radiation, lack of oxygen, DNA damaging agents of various sorts, blockage of transcription, blockage of replication, and many more. p53 appears to monitor the health of cells, and when that health is impaired, it acts. That's what makes it so important, especially, but not exclusively, for the prevention of cancer. How does it sense these disturbances? What does it do about them? How does it do it? These are all questions for the next post.