The Cell Cycle - Gateway to understanding Cancer

The most basic unit of life that we know and love is the cell.

We are made up of over a trillion of these little guys that go about doing their own little chores without ever taking a day off! Yet, like so many other things in our life, we take the optimal function of these little bundles of chemical interactions for granted. You see, the cells of our body have specialized functions, which means that cells performing different functions, are structurally and functionally different. The cells vary in shape, size, contents, strength and basically any other parameter you can think of depending on their job in the body. But two functions are a constant for all cells: replication and cell death.

You see, every cell can multiply numerous times and this ability is known as the replicative potential of the cell. Eventually, however, the cell runs out of this potential. At this point the cell goes into a programmed cell death(PCD). Basically it decides that it is no longer useful, curls up in a corner, and dies. But how does the cell know when to keep dividing and when to go into cell death? The answer to this question needs knowledge of the cell cycle.

You see, every cell goes through a four stage process in order to replicate itself. This process is known as cell division. Okay, now the intricacies of the cell cycle are a little complicated. But the basic idea is this: During cell division, the cell needs to make two copies of itself. This means that the cell needs to divide the genetic material and the cytoplasm into two equal halves. So logically, the cell needs to grow and the genetic material within the cell has to double before the cell becomes ready for proper division. With this concept, lets try to understand the various phases of the cell cycle. 

The four phases are called G1, S, G2 and M.

1. G1 Phase - The phase of growth:

The G1 phase is simply a phase of growth. The cell grows in size. The cytoplasm increases in size and more importantly the number of proteins and mitochondria increase in size. It is a phase which readies the cell for next phase.

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2. S Phase - The phase of DNA synthesis:

The S phase is the phase of DNA synthesis. Remember that the cell must eventually split into two. This means that both the resulting cells must have the same genetic material in each of them. At the end of this stage the DNA will have doubled. Because most of the cells energy is used by DNA replication, most other cellular processes are slowed in this phase.

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3. G2 Phase - The second growth phase:

The G2 phase is also known as the growth phase. The cell again diverts its energy into synthesizing more protein and grows in size to get itself ready for the mitosis stage.

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4.M phase - The Mitosis (or) Break-up phase:

The M stage of the cell cycle is also known as the mitosis stage. This is the stage of chromosome separation and the cell divides into two separate entities. Mitosis itself is a strongly regulated pathway which is further divided into four processes. But the end result of mitosis is the separation of the chromosomes and the nucleus into two. This is followed by the division of the cytoplasm into two as well resulting in two daughter cells.

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So these are the stages of the cell cycle. But you already knew that. Our endeavor is not to just know what the cell cycle is. The goal here is to understand how the cell cycle is regulated.

Imagine that the cell is travelling on a highway travelling from G1 phase to M phase. In order to get to its destination of M phase, the cell must pass two check points. The first checkpoint is known as the G1-S checkpoint and the second checkpoint is known as the G2-M checkpoint.

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At each of these points in the cell’s journey, different enzymes in the cell must be activated by phosphorylation in order to proceed to the next stage. The activation of these enzymes is done by a group of enzymes known as cyclin dependent kinases or CDKs. These cyclin dependent kinases are also inactive because they are dependent on cyclins. So the final process works like this. The cyclins bind to the cyclin dependent kinases. The cyclin dependent kinases, now active, bind to the inactive enzymes in the cell and activate them which prepares the cell to cross the checkpoint.

Now obviously there isn’t just one cyclin dependent kinase or one cyclin. There are multiple of each. So which cyclins and which cyclin dependent kinases are needed for the respective check points? The following table will show the cyclins and the CDKs involved in the two check points:

G1 S checkpoint	Cyclin D	CDK 4/6
	Cyclin E	CDK 2
G2 M checkpoint	Cyclin A	CDK 2/CDK 1
	Cyclin B	CDK 1

Okay so now we know how these cells progress forward if there is no issue. But there is always a possibility that there is something wrong with the cell. The cell maybe infected or it maybe old. It maybe harboring a microbe. The DNA maybe defective. Multiple issues can arise in a cell and in such cases, the cell is stopped at these checkpoints and one of three things can happen:

1. The cell will repair the damage
2. The cell will go into senescence
3. The cell will opt for a programmed cell death

So who or what puts the brakes on the cell cycle? Well, there are proteins known as p-proteins which inhibit the cyclin/cyclin dependent kinase complexes. Now like all things in medicine there are numbers assigned to these proteins.

Cyclin A,B, E are inhibited by p21, p27, p57 → acts on both checkpoints

Cyclin D is inhibited by p15, p16, p18, p19 → acts on only G1S checkpoint.

Now understand that the numbers and the alphabets assigned to these cyclins and proteins and the CDK molecules are not of vital importance.So what is the purpose of knowing, in such detail, the working of the cell cycle?

Such a tight regulation of the cell growth is necessary to prevent the transmission of unnecessary traits to the daughter cells. Imagine if a cell that was about to divide had some sort of malignant potential. When it divided, it would make two cells that had the malignant potential and those would in turn make four cells and so on. So this checkpoint system prevents such a dangerous trait from propagating. However, there are times when this system is over run and it leads to a uncontrolled division of the cell: Cancer.

Different cancers have different ways of popping up in our body and one of the major mechanisms of cancer pathogenesis is evasion of apoptosis and senescence. Knowing the working of the cell cycle will allow us to better target therapies towards cancers, which occur when mutations occur in the proteins that control the cell cycle.

Author: Narendran Sairam (Facebook)

Sources and citations

Kumar, Vinay, Abul K. Abbas, and Jon C. Aster. "Neoplasia/ Cyclins and Cyclin Dependent Kinases." Robbins Basic Pathology. 9th ed. Philadelphia: Elsevier Saunders, 2013. 180-84. Print.

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