In Part 1 of my Cancer Basics series I briefly covered the general theory on how cancer develops. To recap, basically cells become independent of replication and migration pathways through instability in their genome. This instability is brought on through different mechanisms of introducing mutations into certain genes which regulate essential functions of cooperative cell regulation. The most well known of these genes is p53, the Guardian of the Genome.
p53 is a protein that acts as a barrier to the cell cycle. In order for the cell to replicate its DNA, dissolve the nuclear envelope and initiate mitosis, and exit the mitotic cycle there are checkpoints that must be passed. From the previous article we can use the analogy of a hallway with three locked doors which must be unlocked to proceed through the cell cycle. p53 is one of the keys to these locks. When p53 is present it prevents the cell from opening the lock and proceeding into the next step of the cell cycle. So what exactly is p53 doing? Why is it the guardian of the genome? And what makes scientists and physicians so sure that this one gene out of the thousands involved in cell regulation is so important in protecting us against cancer?
This simple diagram gives a good overview of p53’s action. When the cell is proceeding through the cell cycle there is a checkpoint just before it begins to segregate its DNA into two separate compartments which will become daughter cells. It is very important that there is exactly 2 versions of each chromosome (I’m ignoring sex chromosomes here, we’ll stick with the autosomes) and that these two copies are going to be segregated equally into each daughter cell. p53 acts as a major checkpoint signal to make sure these two prerequisites are fulfilled before the cell actually tries to separate into two daughter cells.
If p53 is present at this check point it will stop the cell cycle in order to either fix the damage to the DNA, arrest the cell until the DNA can be repaired, or it can initiate apoptosis. Apoptosis is the last ditch effort of p53 to save the individual from cell division. Questions remain as to what causes p53 to initiate either a repair or apoptotic response but it depends on a multitude of different pathways. This diagram should show you just how complicated this regulation process is:
I know its hard to see but that little dark blue circle with all the lines converging on it is p53, everything else represents different pathways of regulation of the level of p53 at different points in the cell cycle. We’ve established that p53 is important in making sure that daughter cells receive their full and correct compliment of DNA and in activating pathways that will stop the cell cycle if this isn’t going to happen, but exactly why is this so important?
Recalling from Part 1, cancer is a cell lineage that breaks away from its cell cycle regulation and eventually gains the ability to break away from its neighbors and implant into other tissues, what we call metastasis. A good way to look at the importance of p53 is to see what happens when the gene that makes the protein is mutated or completely missing. Li-Fraumeni Syndrome is a disease in which people have a mutated p53 gene (either inherited from germline transmission or de novo during embryogenesis). These individuals have a very high susceptibility to cancer, which usually begins early in childhood and is a recurring problem throughout life.
This chart is a pretty good graphic for showing the rates of cancer around the world as well as how many of those cancers have a mutation in the p53 gene (green percentages on the right side). Given these two facts it can be assumed that p53 plays a huge role in the development of cancer. Well, let’s look at where p53 fits into our overall theory of cancer to find out exactly how these mutations cause such a high susceptibility to cancer.
Genetic instability is the hallmark beginning of cancer. Once the cell cannot fix DNA errors, segregate chromosomes equally to daughter cells, or fully carry out recombination events the genome becomes unstable. Without these regulations the cell is free to pass on mutated and error-filled DNA which will become further mutated and passed on to further progeny. If the environment around these uncontrolled growths is right and the right mutations take place the cell can then break away from the migration regulation and become a metastatic cell, seeding tumors in other tissues of the body. We have seen that p53 makes sure the cell has a full complement of error-free DNA for each daughter cell and that it can even initiate a suicidal response in the cell if this isn’t fulfilled. With a mutation in p53 the cell can no longer regulate whether the DNA is ready to be passed on, one of the doors that was blocking our hallway has been blown off of its hinges, it now doesn’t matter if we have the key (p53) or not. Now that p53 isn’t guarding the genome from errors it is free to pass these errors onto daughter cells, the first step in cancer generation. These daughter cells inherit the p53 mutation as well as any other chromosomal abnormalities that are passed onto it and are free to continue passing on these errors as well as generating new mutations which no longer are under apoptotic control. In this way p53 mutations initiates a complicated cascade where cells who can no longer arrest their cell cycle or commit to a suicidal ending are allowed to pass their error-prone genetic complement into the next generation of cells. The daughter cells are not able to regulate the integrity of their DNA either so as replication continues mutations will continue to build until a cell line becomes cancerous.
p53 is only one of many “tumor suppressor” genes that have been identified, but its presence in such a high number of cancer cases reflects the importance it plays in the development of cancer. This gene has truly earned its name, “The Guardian of the Genome”.