The Theme of Regulation in The Cell Cycle, Cellular Growth, and Cancer
When we think about regulation of the cell cycle, two aspects come to mind. The first is about growth. How does a cell know how big to grow, and how does that growth correlate with when it is supposed to divide? For over 100 years, scientists have observed that cells can be a huge range of different sizes, not only within species but also within the same multicellular organism. How does the cell know how big to get? You probably expect that in one cell cycle the cell needs to roughly double its size to create daughter cells that are roughly the same size as the parent cell. That is generally true.
A few other general statements can be made about cell growth. For one, the cell volume seems to be somewhat proportional to the ploidy, or the number of chromosomes present in the cell. A diploid cell is usually larger than a haploid cell. Another observation is that cell growth and the cell cycle are coordinated. If cells are depleted of nutrients such that they cannot grow, the cells do not progress through the cell cycle and usually arrest in G1 phase. However the converse is not true – if the cell cannot continue its cell cycle for some reason, the cell keeps on getting bigger. In fact, many cell types do keep growing even if they are no longer capable of dividing, such as muscle and nerve cells (Jorgenson & Tyers, 2004).
Why do you think that cells may want to coordinate growth and cell division? Can you imagine if cells didn't grow big enough before they divided? Cells would become progressively smaller each generation. For single celled organisms like bacteria, this coupling is an understandable survival trait as they are sensitive to their environment. If there are lots of readily available nutrients, then it makes sense for the bacteria to replicate and increase their numbers. But, if there aren't many nutrients, then new bacteria wouldn't survive, so why waste all that precious energy making new ones?
The scenario for a cell within a multicellular organism like a human is more complicated though, because under these circumstances, growth doesn't depend on nutrients – it depends on signals from other cells as well. In fact, in many multicellular organisms, cell growth and cell division can even be somewhat uncoupled. Nonetheless, many recent studies have suggested that some of the same proteins that control how big a cell grows also control the progression of the cell cycle. These studies provide some insight into how these somewhat independent processes can be molecularly intertwined, and if you think that is a bit of a mouthful, imagine how the poor molecules feel.
How does the cell know when to progress from one stage of the cell cycle to another?
Just like the control of cell growth, the control of cell cycle progression is dependent on a group of cell signaling proteins that eventually give the cell the green light to proceed. While different types of cells may spend a different amount of time in different stages of the cell cycle, the regulatory system that controls the progression from one stage to another is highly conserved in different species, showing how important it is for life as we know it. But, how does it work?
One key experiment in 1970 gave scientists some insights. Scientists took two human cells, one that was in S phase and one that was in G1 phase and fused them together. The G1 nucleus immediately started S phase. When they fused an S phase and a G2 phase cell, the S phase nucleus finished completing DNA replication, but the G2 nucleus stayed in G2 (Johnson & Rao, 1970). What this event meant was that that there was some signal present in the S phase cell that stimulated the G1 nucleus to carry out DNA replication. Alternatively, there was something in the G2 cell that told the cell it had already replicated its DNA, and therefore it shouldn't attempt replication again.
What is in the S phase nucleus that stimulates the other G1 cell to begin mitosis? Well, the MVPs of cell cycle regulation are special proteins called cyclin-dependent protein kinases (Cdks for short). These kinases transfer phosphate groups to proteins that initiate or regulate important cell cycle events such as DNA replication, and this transfer event modifies the activity of these proteins. The activities of Cdks vary with regard to different stages of the cell cycle, and their activity is dependent on another group of proteins called cyclins. Cyclins, as their name suggests, are present only at certain times during the cell cycle (in other words, their appearance in the cell cycles). There are different types of cyclins for the different phases of the cell cycle, and their appearance in the cell varies because they are targeted for destruction when they are no longer needed. In our scenario, the S phase cell had S phase cyclins, and when it was combined with the G1 nucleus, those cyclins could combine with the G1/S Cdk to promote S phase initiation.
This same system is used to alert the cell when an event, such as DNA replication, has not finished as it should. In fact, if for some reason DNA replication hasn't finished, or it has gone wrong, the cell cannot proceed to G2. We call this system a 'checkpoint' system. For more information on how the checkpoint system was discovered, check out the History Lenses. The basic premise of the checkpoint system is that an alarm is tripped inside the cell if it has not completed a previous aspect of the cell cycle when it wants to progress on to another stage. For example, a checkpoint prevents the cell from continuing along the cell cycle if replication isn't finished whilst another one stops it if chromosomes aren't properly aligned on the spindle.
Cancer is often thought of as a disease of the cell cycle, although Tim Hunt, who won the Nobel Prize for his work on cell cycle regulation, says he's not sure that, strictly speaking, that is actually the case, given that cancer cells seem to have no problem dividing (Hunt, 2008). Instead, Hunt believes that the real problem lies in understanding why cancer cells grow and divide when non cancer cells do not. In his opinion, cancer is a disease of cell growth control, or of the checkpoint system, as many cancer cells do feature defective checkpoints. Since their checkpoints are already compromised, scientists are currently trying to use drugs to further weaken the checkpoint system in cancer cells. The hope is that without functional checkpoints, the cancer cells will die.
Altogether we've told you a lot, not only about how a cell divides but also about the regulatory system that makes it run flawlessly. It is a lot like driving a car really. First you need to master the actual pushing of the brake and turning, which is probably why your parents took you to a big, empty parking lot at first, right? And then, when you finally make it onto actual streets, you need to start paying attention to all the red lights and other traffic rules. To start with, make sure you remember the stages of the cell cycle and the steps of mitosis, then worry about how it is all controlled. Just be glad that the cells in your body pay more attention to their regulatory system than drivers in Italy, where the saying goes: "Green light—Avanti! Avanti! Yellow light—decoration, and red light—just a suggestion."