Following on from his last article, “A Cell’s Life: In the End“, where Shu described the life cycle of cells, here he delves into the process in more detail, using a rather unusual magical metaphor.
Your Majesty, these are your servants
I admit that I have been following the BBC series Merlin with great interest, not for its riveting plot or top-notch production qualities (the fact that I never see a mythical creature in full in the same frame as one of the characters speaks for itself). I was curious as to how Merlin would be portrayed, given that many stories have been written around the character. In watching the series and thinking about my last post, I realized that all the players of Camelot are represented in the cell, especially when it comes to the all-important decision of life and death. I am going to relate each important role to a typical character found in a castle town such as Camelot. In subsequent posts, I will go into much more detail about each of the roles and the function they serve in cell death.
This is the black-hooded, nameless character that always appears after Uther Pendragon’s frequent fits of rage and thirst for blood. He is responsible for ending the lives of whatever poor citizen, druid or sorcerer crosses his path. In cells, the executioner has a name – called caspase. Actually there is more than one executioner in the cell (more than one caspase). The caspase sits at the end of a chain of command that starts with the king making the royal decree for a public execution in his throne room. It is responsible for chopping up proteins inside the cell and generally ruining their otherwise happy lives (apoptosis). Uncontrolled activation of caspases is akin to a rampant executioner (also known as a mass murderer) – they will chop up proteins without orders to do so, which can spell disaster for the cell. Keeping the executioner under tight control is what the cell death signaling pathway is all about and thankfully it is subdued under normal circumstances.
The Outer Wall Sentries
In Merlin, the sentries on the outer walls of Camelot are useless – all manners of creatures and people, including King Arthur, Merlin and Lady Morgana have easy access into and out of the castle town. Sometimes even on horseback. At night. Fortunately, the outer wall sentries in our cells are much more useful. They are proteins of the death receptor family, responsible for sensing signals sent to them to start the cell death process. These receptors are partially outside the cell, or more specifically on the side of the cell membrane that faces outside, and partially inside. Once the external portions of the receptors – sentries – bind to signaling proteins certain changes occur to their internal portions, which can start the death cycle. If only the sentries of Camelot were half as useful.
The Executioner’s Platform
Not specifically a character, the executioner needs a platform to conduct his business. Without it, nobody would be able to see him and it would not be a public execution. Similarly, in the cell, the executioner caspase requires a platform, not to do its job but to become activated. Caspases start off in an inactive state and require changes to their protein structure to become activated.
These changes are effected by the apoptosome or death inducing signaling complex (DISC), depending on the type of cell death that is occurring (more on that later). Without these components, the executioner cannot be activated (he has no orders from above) and cell death cannot take place. Both the apoptosome and DISC are composed of a number of different proteins – messengers – that together form the complex of proteins required for cell death. If the platform is broken, so is cell death.
There are a number of proteins that act as messengers for cell death to occur. Most are dispatched by the king – these are generally called BH3-only proteins. Some are already floating around inside the cell, just waiting for the right signal to start relaying the message to other parts of the cell. In all cases, they work to spread the word that the king has decreed a public execution. They do so mainly by stopping those who act out against the public executions. In essence, they are similar to the king’s thugs – making sure that the royal decree is carried out at all costs. Just like the executioner, rampant messengers can wreak havoc on a cell (the ultimate havoc of death) and so they are kept under tight control in a healthy cell.
The gatekeepers keep some of the messengers (or king’s thugs) in check by putting them to work in the energy factory for the cell. They are a part of the BCL2 family of proteins. Functionally, they act to keep the thugs inside the factory until other messengers (of the BH3-only family mentioned above, among others) overwhelm the gatekeepers and are no longer able to contain the thugs. BCL2 family members are integral to the survival of a cell and many cancers are formed because of an increased number of gatekeepers, keeping the cells from dying.
These are the hapless extras that are running away from danger or have already met their unfortunate ends. In the cell, the townsfolk refer to all other proteins not involved in the cell death process. These proteins are important for keeping the cell alive, just as townsfolk are vital for a healthy castle town. But when the king decides that it is time to die, all of the proteins in the cell are fair game for the executioner.
Most often centrally located, the most important part of many cells is the nucleus. Akin to the keep in the castle town of Camelot, the nucleus is where all of the important decisions for the cell are made. It contains all of the necessary genetic information to realize its decisions. In terms of cell death, this is also the location where the first messengers (BH3-only genes/proteins) are dispatched, by direct order of the king. Importantly, the inhabitants of the keep are not immune to the cell death process: the DNA and nucleus undergo significant changes as the cell dies. When the king orders death for Camelot in the cell world, not even it is safe.
At last we come to one of the best-studied proteins in the cell world: p53. I call p53 the king because it is also referred to as the master regulator of cell death – p53 is responsible for waking up the harbingers of cell death and sending them off to the lower town. Without it, cells are unable to die and this is clearly indicated in the fact that about 50% of cancers have inactive p53. Research about how p53 is controlled and what kinds of roles it plays in cell death are vitally important to understanding cancer. In Camelot, p53 is more like the vengeful Uther Pendragon who ordered the execution of everybody that would cross his path. Thankfully, p53 only kills cells when absolutely necessary (unless mutated or otherwise compromised of course).
Off with their heads!
Over the next couple of posts, I will explore each of these roles in more detail, so I have specifically left out references for this introduction post until I mention them again in more detail. Until then, the next time you are watching Merlin or thinking about castle towns, remember that there are between 50 and 75 trillion Camelots in your body, all deciding whether to take the route of Uther Pendragon or the more benevolent Arthur Pendragon.