Question

Describe the links between the cell cycle, it's control mechanisms, mutations and the development of cancer.

Answer 1

The whole process of cell cycle controls the growth of the cell, but in case of cancer there is uncontrolled growth of cell, this occurs because there develops an insensitivity to signals which tell a cell to undergo division or die. There is an alteration in the properties of the cell growth which leads to cancer.

When a cell grows and divides the series of events taking place in the cell is called cell cycle. Cell cycle has two major phases they are 1) interphase and 2) Mitotic phase or M-Phase.

Interphase is the resting phase in which cell spends most of its time, though it is called the resting stage yet it’s the most active phase of the cell cycle. Interphase is divided into various sub phases they are G1 Phase or first gap phase, S phase or synthesis phase where DNA replication takes place, G2 phase or second gap phase than the M-phase where the division of cell takes place. G1 is the stage where cell is preparing to divide, S is the phase a copy of DNA is produced, when complete DNA is synthesized or copied the cell moves to the next stage that is the G2 stage, where there is condensation and organization of DNA material takes place and here the cell prepares itself for division, in M-phase there is partition of two copies of the genetic material forming two daughter cells.

Control Mechanisms of cell cycle:-

It is essential to confirm that the daughter cells produced are exact copies of the parental cell if there is any error in duplication and distribution of chromosomes, it may be pass on to the future cells producing abnormal cells. To prevent this there are internal check points in the cell cycle, whether a cell has undergone proper duplication or not is internally checked at these three check points these are (i) G1 check point (ii) G2 check point and (iii) M check point.

At G1 check point, it is checked weather all conditions are favourable or not to proceed further for cell division, here also the DNA damage is checked and if there is any damage it halts the cell cycle and repair of DNA is done, else it sends the cell to the G0 stage where it waits till further signals when conditions improve.

At G2 check point, it is checked that all the chromosome are replicated or not and is there any damage in the replicated chromosomes. G2 check point prevents the cell to enter into the mitotic phase if there is any defect.

At M- checkpoint, it checks the attachment of sister chromatids to the spindle microtubules. It is also known as the spindle check point. It takes place at the end of mitotic phase.

Besides the internal check points there are two groups of intracellular molecules which regulate the cell cycle. They can allow the cell cycle to proceed which is positive regulation or negative regulation that halts the cell cycle. These regulatory molecules may act individually or may affect the activity or production of other regulatory molecules. Usually if at any time a single control mechanism fails, than there is no effect on the cell cycle because other mechanism are there to check the error. But if multiple check points gets affected by the deficient or non-functioning regulator than problem arises which leads to uncontrolled growth of cell causing cancer.

Positive regulation of cell cycle :- Two groups of proteins cyclin and cyclin-dependent kinase are responsible for progress of the cell cycle through various check points. Cyclin regulates the cell cycle when it is tightly bound to the cyclin-dependent kinase, for full activation the CdK/ cyclin complex should be phosphorylated at some locations. Like kinases Cdk’s are enzymes which phosphorylate other proteins, phosphorylation activates the protein by changing its shape, proteins phosphorylated by Cdk helps the cell to go to the next stage in the cell cycle. Without a specific concentration of fully activated Cyclin/Cdk complex, cell cannot proceed through the check points.

Though Cyclin are the main regulatory molecules which determine the forward movement of a cell in cell cycle. There are other mechanism too which help the cell cycle to proceed by negative effects.

Negative regulation of cell cycle :- Negative regulators help in halting the cell cycle, some negative regulatory molecules are retinoblastoma proteins (Rb) , P53, p21. These are tumor suppressor proteins, they usually act at G1 check point, P 53 is a multifunctional protein which acts when there is a damaged DNA in the cell undergoing preparatory phase. It halts the cell cycle at G1 stage and gets the enzymes to repair the damaged DNA. If DNA cannot be repaired, it sends the cell for apoptosis or cell death, to prevent the duplication of damaged chromosomes. when there is increase in level of P53 it triggers the production of P21, P21 halts the cell cycle detected by p53, by binding to and inhibiting the activity of cyclin/Cdk complex, when the level of stress is more in a cell there is more production of P53 and P21 as a result it stops the cell going through the S-phase.

Rb impacts other positive regulator proteins, usually Rb checks the cell size, in active dephosphorylated state, it binds to the proteins called transcription factors usually the E2F, these transition factors “turn on” certain genes, but when Rb gets attached to them production of proteins required for G1/S transition is blocked, when size of a cell increases, gradually Rb gets phosphorylated and becomes inactive, as a result there is detachment of Rb and E2F due to this the gene which form the transition factors again “turned on” producing the transition proteins, and now the cell is able to pass through the check points in the cell cycle.

Mutation and development of cancer:-

Genes which code for positive cell cycle regulators are called proto-oncogenes, these are normal genes of a cell, which are positive regulator of the cell cycle, when they get mutated they become oncogenes which cause cancer. A genetic mutation causes a change in the gene which increases the activity of a positive regulator.

Suppose for example a mutation activates Cdk, it gets activated without being combined with cyclin as a result it pushes the cell cycle through the check points without meeting the passing requirements so if the daughter cell are too much damaged, they may not undergo the cell division and the damage will not get transferred to the future generation and there will be no harm to the organism but if a particular daughter cell is able to undergo cell division than the future subsequent generations will accumulate more mutations and there will be defective genes in future generations. As a result there will be uncontrolled growth, increasing the rate of cell cycle, which will lead to cancer.

Tumor suppressor genes- These are the negative regulators of the cell cycle, they produce negative regulator proteins in a cell cycle. These are the regulators when get activated prevent the cell from undergoing uncontrolled growth. If there is a mutation in these cells, they will not be able to halt the cell cycle and there will be uncontrolled growth leading to cancer.

For example in case of p53 gene, it has the ability to play an important role in G1 check point. But when it gets mutated it fails to detect the error present in the genomic DNA. If there is also a partial mutation in P53 gene than also it will not be able to signal the DNA repair enzymes, due to which the damaged DNA will remain unrepaired and defective P53 will not be able to trigger the apoptosis or cell death and will lead to uncontrolled cell growth causing cancer.

So cancer is the result of unchecked cell division which is caused due to the breakdown of the mechanisms which regulate the cell cycle. Mutation causes alteration in the genes, which produces faulty signals destroying or de-functioning the control mechanism leading to cancer.