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."
One of the main characteristics that defines the different functional types of cells in your body is their capacity for cell division. Within your own body you can find amazing examples of how different types of cells have adapted their cell cycles. Some cells divide quickly, while others divide slowly. Other cells spend different relative amounts of time in the different phases of interphase. Some cells, if they are in G, stop prior to S phase and don't divide at all.
All the cells in your body can be broken down into three categories. Some cells, like muscle or nerve cells, are specialized for their functions and can no longer undergo cell division. Other cells, like some of the cells in your immune system, can be stimulated to divide under particular conditions, such as the appearance of a certain 'flu bug in your system. Finally, the last category of cells is continuously undergoing division, such as the cells that produce sperm and the cells that give rise to blood cells.
Once cells in the body become specialized, or differentiated, they take on specialized structures unique to their specific functions. These structures are not always compatible with cell division. A red blood cell, for example, loses its nucleus in the process of gaining its specialized structure so it can have lots of room for all that lovely oxygen-carrying hemoglobin. Other cells, such as heart muscle cells, do rounds of mitosis without an accompanying cytokinesis, resulting in cells with many nuclei. Basically, in a nutshell, a cell's cell cycle helps determine whom it is and what it can do, or in other words, structure and function unit.
Cell division is one of the most exciting basic biological processes to watch because it involves some dynamic changes to a cell's structure. A cell in interphase suddenly rounds up, the nuclear envelope breaks down, the chromosomes condense, the mitotic spindle forms, and the chromosomes are pulled to opposite poles of the cell and the cell divides into two. All great examples of the structure and function theme.
The spindle is an amazing biological structure that contributes to its function in pulling apart the chromosomes. In many animal cells it begins to assemble when chromosomes are condensing and is a dynamic structure. In fact, the ends of the microtubules are in a constant flux of growing and expanding. When a microtubule attaches to the centromere region of a condensed chromosome, the microtubule becomes somewhat stabilized and the microtubules pull back and forth until the chromosomes align in the center of the cell. Think about a tug-a-war where the teams are equally matched.
How about cytokinesis? How does the cell physically separate into two separate cells? In animal cells, a ring comprising actin and myosin filaments, called the contractile ring, forms right below the plasma membrane. As the ring contracts, in a mechanism similar to that used by your muscles, the membrane is pulled inward, at a place known as the cleavage furrow, resulting in the physical pinching of the cell into two. The spindle is also required to maintain a functional contractile ring, and the relationship between these two structures helps to ensure that cytokinesis happens after mitosis.
Plant cells have a cell wall to deal with, and therefore, they actually do cytokinesis differently. Instead of pinching off, they reconstruct a cell wall in the middle of the cell using a structure called a phragmoplast. Cool word, huh? Try that out on that cute someone that sits next to you in biology class—how about: "No phragmoplast can keep me away from you." Okay, okay, maybe not, then... While plants and animals may divide into two using different cellular machinery, they share the common theme that they have adapted specialized structures to complete this critical mitotic function. If this sounds like an example of another theme in biology, unity and diversity, give yourself a pat on the back. You're on your way to becoming a science theme guru.
We have given you a few examples of how some of the structures involved in mitosis are critical for the success of the whole process. Can you apply this theme to other structures generated in mitosis and meiosis? For example, how is chromosome structure important for chromosome segregation? How is the alignment of chromosomes during the different stages of division important for accurate segregation? Why are chiasmata excellent examples of this theme? Can you apply this theme to some of the interphase events such as DNA replication?
Usually when we talk about evolution we talk about cool organisms and about how they have acquired traits over time that have given them a better chance of survival. But, not this time—nope, we are going microscopic again. This time we will talk about your body as its own ecosystem. Unlike the ecosystem outside of our bodies, our internal ecosystem isn't about competition or survival of the fittest. Instead, pretty much all of the cells in our body cooperate, one way or another. Many cell types never reproduce and other cells dedicate their cellular lives to the production of other cell types.
Cancer disrupts this society of cells where balance and collaboration are the rule. A cancer cell develops the ability to survive and divide better than its neighbors. The invasive cancer cell can quickly become a cancer clone, which in turn out-competes adjacent cells in the human body. Cancer cells therefore transform a collaborative environment into an environment where only the fittest survive, the same principles that govern the evolution of organisms over time.
Cancers can usually be attributed to one, single founder cell that experienced some sort of heritable change that gave it a selective advantage over other cells. This change allows the cancer cell to grow and divide under conditions where a normal cell does not, and allows it to colonize areas of the human body usually reserved for other cells. Does this sound familiar? A genetic change, which is passed onto offspring, enables the colonization of a unique niche. We could just as well be talking about a change in a complete organism.
It is estimated that 1016 cell division events occur in a human during his lifetime (Alberts et al, 2003). Over time, mutations, which sometimes happen when the cell makes a mistake during DNA replication or that can be induced by special agents, like cigarettes, that can cause damage to your DNA, accumulate in the dividing cells. Sometimes the sequence of the cancer cell's DNA itself may not be changed, but instead the structure of the DNA is altered in a heritable way, and these types of changes are called epigenetic. It is believed that what makes a cell cancerous is usually more than one heritable change. This is why cancer is largely thought to be an old age disease, because mutations that accumulate over time allow the cancer cell to outcompete other cells in the body. As cancerous cells reproduce, they acquire even more heritable changes that allow them to better invade surrounding tissues. A highly progressed cancer cell usually has many, many genetic changes, including gross changes in the number of chromosomes they contain.