How changes in control of the cell cycle contribute to cancer development
Cancer is a multifarious disease, with a common feature that most tumours harbour one or more genetic mutations that allow them to advance outside their normal growth restraints. This proliferation is normally harnessed by the control of the cell division cycle, which in turn, is majorly regulated by the cyclin dependent kinases (Cdks) family of serine/threonine kinases and their regulatory partners, the cyclins (Errico, et al. , 2009).
In this essay, the roles of Cdks, cyclin complexes, regulatory proteins and other cell-cycle regulatory processes will be underlined, followed by an analysis of the genetic lesions in these regulators which may contribute to tumorigenesis. Fundamentally, cancer, or a neoplasm is a disease where cellular proliferation is no longer under normal growth control. The growth of this clone of cells exceeds, and is uncoordinated with that of normal surrounding tissues (NHS, 2009).
Ultimately, this deregulation of growth and division of the cancer cells disrupts and interferes with the normal functioning of the body, either at its origin or through spreading to another location, eventually resulting in the potential death of the sufferer if left untreated. Other complex characteristics include the ability of the cancer cells to induce vascularisation of the tumour in order to receive oxygen and nutrients (angiogenesis), thus sustaining their survival.
They can also disperse from the site of origin and travel to distant parts of the body by metastasis and also display the ability to suppress programmed cell death (apoptosis) (Okudela, et al, 2009) Such atypical proficiencies are also detailed further in this essay. To appreciate both the phenomenon and capacity for a cell to develop into a cancerous cell, it is pivotal to understand the concept of cell proliferation and how it is controlled. Populations of cells in complex organisms, such as humans, undergo replacement and turnover of their macromolecular compounds.
This is known as cell renewal. Exceptional to this are cardiac muscle and many nerve cells, which are mitotically inactive, but even such differentiated cells replenish their molecules and structures under the influence of appropriate stimuli (Avers, 1986). At the core of cellular proliferation is the cell division cycle, the process by which a cell grows, replicates its DNA and then divides to produce two genetically identical daughter cells. This intricate process is divided into four sequential phases, as depicted by the diagram below (Figure 1:1).
Figure 1:1 The Cell Cycle, representing the critical G1, S, G2 and M phases The M phase is devoted to mitosis, and the G1, S, and G2 phases constitute the biosynthetically active time of interphase. DNA replication takes place during S phase, and it is separated from mitosis by the pre-replication G1 phase and the post-replication premitotic G2 phase, or time gaps (Lodish, et al. , 2000). Cellular activities occurring during mitosis, which includes prophase, prometaphase, metaphase, anaphase, telophase and cytokinesis are outlined in Appendix 1:1.
The proportion of a cell cycle occupied by each phase varies, but the mitotic phase is usually brief. The G1 phase is the most variable in duration in different kinds of cells; it may even be lacking in some cell cycles. The two most important of these are the S phase and mitosis (M), the key concept of the cell cycle is that S phase must always follow M phase and that M phase must not commence until S phase has been completed.
Underlining that DNA replication must not commence until mitosis is complete, ensuring that the integrity of the genome is maintained. Additionally, there is a fifth state, the G0 (known as quiescence) into which the cell may reversibly exit from G1, if it is deprived of the appropriate and correct growth-promoting signals (Cell Cycle Research, 2007). The movement through each phase of the cell cycle and transition from one phase to the next is controlled at a number of positions within the cell division cycle known as checkpoints.
Checkpoints are intricate sensor mechanisms within the cell which monitor the cellular environment and determine whether appropriate conditions have been fulfilled before it progresses further through the cell division cycle (Beck, et al. , 2009). Ergo a major function of these checkpoints is to oversee that the integrity of the genome remains intact throughout the cell cycle. This assures that cellular growth and the coordination of DNA synthesis with cell-size increase and cytokinesis are monitored and do not fall out of regulated synchrony (Lodish, et al. 2000). Each checkpoint is made up of three critical components. Firstly is a sensor mechanism that detects abnormal or incomplete cell cycle events such as DNA damage. Following is the signal transduction pathway, which carries the signal from the sensor to the third component, the effector that can invoke a cell cycle arrest until the problem has been resolved (WormBook, 2007). The major cell cycle checkpoints are depicted in Figure 1:2 below: The first checkpoint occurs at the G1/S phase transition and is a major sensor of DNA damage.
The cell may also arrest later in S phase due to incomplete DNA replication or again, damage to the DNA. Next is the G2/M checkpoint, which monitors the conformity of DNA replication and like the G1/S checkpoint is an important sensor of DNA damage. This is followed by the spindle checkpoint, which is invoked during mitosis if a functional mitotic spindle has not been formed appropriately (McKinnell, et al. , 2006). To highlight also, there is the restriction point (R) which occurs between mid and late G1 phase.
It is the point at which the cell determines whether it has received the necessary growth signals (extracellular in origin) so that it can transit out of G1 into the S phase, in doing so replicate its DNA and complete one cycle of cell division. If cells are sufficient, they pass the R point and for the remainder of that cell cycle will not require such signals (Beck, et al. , 2009). Contrastingly, if the cell has received insufficient cues, it does not pass the restriction point, thus instead enter the G0 phase.
Although this checkpoint does not specifically ascertain whether the genome is intact, it is an essential control point which restrains cell proliferation (thence, cancer) if appropriate growth signals have not been received. Cyclins, Cdks, and the Rb protein are all elements of the control system that regulate passage through the restriction point. The ability of these proteins to check cell-cycle progression, and hold cells in quiescence or even lead cells to commit suicide unless conditions are appropriate, means that they can prevent cells from becoming cancerous.
Altered regulation of expression of at least one cyclin as well as mutation of several proteins that negatively regulate passage through the restriction point can be oncogenic (Berg, et al. , 2002). In emphasis, if these cell cycle checkpoints are not in place then inappropriate proliferation can occur – the hallmark of cancer. It is also known that probably all human tumours harbour genetic alterations in the genes that control cell cycle progression and checkpoint function (Cooper, et al. , 2004).
At the core of the mammalian cell division cycle is the cyclin dependent kinase family. In mammalian cells, different Cdks are active and required at different phases of the cell cycle. The responsibility of Cdks is to control cell cycle progression through phosphorylation of proteins that function at specific cell cycle stages. There is a complex variety of Cdks operating in the cell cycle, each operating in its own phase. The cyclins combine with their cognate kinases causing a conformational change which, together with a single phosphorylation, activates the Cdk.
At the start of each cycle phase, genes have to be activated so that the appropriate cyclins are synthesized (Hutchinson, et al. , 1995). If this does not happen, the cycle cannot proceed through that specific phase. At the end of each phase, the cyclins are destroyed by proteasomes and new cyclin synthesis specific for the next phase is needed. This highlights such an expensive way to achieve control but it is a decisive procedure leaving no room for partial inactivation; as emphasized, cell-cycle control, above all, has to be decisive given the potential dangerous consequences of errors (Mulambres, et al. 2009). An example is the product of the retinoblastoma tumour suppressor gene; pRb is a key regulator of G1 progression and possesses 16 potential sites of Cdk phosphorylation. In early G1, pRb is found in low phosphorylated state and tightly binds and represses the activity of the E2F family of transcription factors which are functionally required for the expression of genes necessary for S phase. Additionally, pRb becomes phosphorylated at the Cdk consensus sites, disrupting its interaction with the E2F proteins, allowing E2F dependent transcription to occur.
This is required in order for the cell to pass through the restriction point late in G1 phase (Tyson, et al. , 2001). The phosphorylation of pRb at the Cdk consensus sites appears to be a sequential process, initiated by Cdk4 and Cdk6 each acting in association with one of three related cyclin subunits D1, D2 and D3. In doing so, it allows expression of cyclin E by disrupting the interaction of pRb with proteins known as histone deactylases, which are involved in chromatin remodelling.
Furthermore, the expression of cyclin E allows the formation of active Cdk2/ cyclin E complexes that continue to phosphorylate pRb. This leads to disruption of the pRb-E2F interaction such that E2F is a requirement for the cell to progress from G1 into S phase (Sashai, et al. , 2002). Advanced research has shown that cancer cells usually carry mutations that affect the final step in mitogenic signaling, where there is an increased G1/S gene expression that is driven by gene regulatory proteins of the E2F family.
These proteins are normally harnessed by members of the pRb protein family, and mitogens release the brakes on cell-cycle entry by stimulating G1 and G1/S-Cdk activities, which trigger the phosphorylation of pRb proteins. In such cancer cells, the pRb brakes are lost or defective, resulting in E2F-dependent G1/S expression even in the absence of mitogens (Pavletich, 1999). Research has also highlighted that it is likely that all cancer cells carry a mutation that disrupts some feature of pRb control. Such dominant oncogenic mutations can occur in the cyclins and Cdks that promote pRb phosphorylation.
An example is the cyclin D or Cdk4 which are overproduced in some tumours as a result of gene amplification or other cellular mechanisms. Cdk4 can also carry point mutations that render it insensitive to the Cdk inhibitors of the INK4 family, which normally help restrain the kinase. More frequently, tumour cells lose the gene for p16INK4a, which is among the most common defects in human cancers. This gene was the first tumour suppressor to be identified, in a search for the genetic backbone of retinoblastoma, a congenital syndrome that leads to cancers of the retina.
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