Cell cycle abnormalities in cancer

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Cell Cycle Abnormalities in Cancer.

Introduction

The cell cycle is a complex topic, parts of which are still being explored today. As cancer grows more prolific in today’s society, affecting 1 in 3 of us in the UK in our lifetime, the topic is under scrutiny as the complete understanding of these processes could one day give us a cure for cancer.

In this report, I plan to outline the processes that lead to cell proliferation, identify and explain the checkpoints that protect and maintain the integrity of the genome of all human cells, identify key processes that, when mutated, can lead to unchecked cell proliferation, and to highlight the oncogenes involved in most cancers. I will show, that in many of the processes, the loss of key factors could lead to damaged DNA being passed on to daughter cells, leading to mutations that cause tumour genesis. I will also identify, explain the relevance of, and explain the role of key genes that have been discovered to have a major role in cancer.

Abstract.

The cell cycle consists of five main phases: G0, G1, S, G2 and M phase. G0 phase is described as cells senescence, when, due to signals from checkpoints, such as a cyclin cascade initiated by p53, a prevalent cell cycle blockade, the cell halts all cell cycle progress. This may be due to a signal being shown that DNA has been damaged; this would mean that cell cycle progress would be halted until the damage had been rectified. This would prevent any harmful mutations being passed on to daughter cells, thus protecting the genome. It is in this phase also that specialised cells such as neurons and skeletal muscle cells are in a terminally differentiated state, where they will never grow and divide again. The cell-cycle control system is completely dismantled and genes that code for the cyclins and cyclin dependent kinases are never expressed. Other cells may enter this phase and retain the ability to reactivate their cell cycle control mechanisms as they need to; this is true of hepatocytes [1a].

G1 phase is the growth phase of the cell. For a cell to move into this phase, growth factors from extracellular sources must be received by the cell’s specific receptors and initiate a cascade of cyclin-dependent kinases, that have an effect of promoting transcription of DNA in preparation for mitosis. This will be explored in more depth in my discussion. This phase also encompasses the growing of the cell in size, the duplication of centrosomes, and the synthesis of the cell’s vital organelles, such as mitochondria, ribosomes, Golgi apparatus and endoplasmic reticulum. Progress from this phase into S phase is determinant of environmental conditions and cell size [2a]

S phase can be described as the ‘synthetic phase’, the time when the cell’s chromosomal DNA is replicated. This is a large task when you consider that the average human chromosome consists of about 150 X 106 base pairs of DNA. The site of replication on the chromosome is shown by a cluster of replicons, each of which replicate at prescribed times during S phase. As this phase has no major checkpoints of interest integral to cancer, I will not be going into great detail in explaining the process of chromosomal replication in this report [2b].

G2 is the phase where the cell’s DNA is prepared for mitosis. The DNA is checked for damage and misreplication, and if any is detected, the G2 DNA damage checkpoint is employed. This checkpoint is integral to the progression of cancer, in that it prevents the cell entering mitosis by inhibiting the cyclin-dependent kinases specific to the entry of M phase. I will explain this checkpoint in further detail in my discussion [2b].

M phase is the mitotic phase of the cell, at the end of which, the cell divides to produce two daughter cells. Another important checkpoint is found at this phase, the spindle assembly checkpoint. This delays progression from metaphase to anaphase by checking that all chromosomes are attached properly to the spindle before the chromatids separate. This checkpoint is another important protector of the genome and prevents harmful mutations being passed on to daughter cells [2b].

In this article, I will show how the loss of the checkpoints that normally restrict and monitor cell growth and proliferation are fundamental events that can cause cancer, and how, without the normal prompts for the cell to halt cyclic events, cell cycle progression will persist with neoplastic consequences. In doing so, I will also show the importance of the role of cyclin-dependent kinases in the progression from G1 phase to S phase, and from G2 to M phase.

Discussion

Model Organisms

The yeast strains Schizosaccharomyces pombe and Saccharomyces cerevisiae were used in the discovery of many of the molecules involved in cell proliferation that I will be talking about in this discussion. They were very useful in identifying a multitude of mutations that if induced in mammalian cells would have been lethal and thus impossible to characterise [world cancer report]. An S.pombe yeast cell coordinates its growth and division in G2 phase and was used to identify cdc2 and Wee1 as crucial genes in restricting progression into M phase. When these genes were mutated, smaller cells entered mitosis too soon. S.cerevisiae has a restriction point similar to our R point and begin their coordination of growth and development in G1 like mammalian cells [2c].

Another basis for study of the cell cycle was in frog or Xenopus oocytes where MPF (maturation promoting factor) was revealed as a CDK enzyme (cyclin/cyclin-dependent kinase complex) and again showed the importance of CDK’s in cell cycle development. This was discovered when the injection of MPF into germline cell caused the cells to mature and develop in the absence of hormones, showing that it was potent enough to drive the cell cycle. [6]

I will now begin the main body of my discussion.

Most cancer cells are genetically unstable in some way. This could be in their ability to repair DNA damage, maintain chromosomal integrity, or prevention of proliferation when the cell is deficient in essential ingredients for replication (such a nucleotide precursors).

In the normal cell cycle, there are physiological safeguards to prevent tumorigenesis, referred to as checkpoints. These checkpoints combined effect is to protect the genome and prevent the proliferation of mutant daughter cells.

In order to put these checkpoints in the context of the cell cycle, I will now describe the normal process of proliferation in the cell cycle.

In Homo sapiens, cells are part of a larger multicellular environment, such as an organ. Thus cells communicate with each other to signal when proliferation is necessary.

In order for cells to enter G1 phase, and the cell cycle that will eventually lead to mitosis, the cell must receive extracellular signals that prompt this.[2d] These are generally named ‘growth factors’ and are proteins, notable examples of which are epidermal growth factor (EGF), insulin, all of the neurotrophins, and hepatocyte growth factor (HGF). These factors bind to extracellular receptors with intracellular domains, in order to trigger events in the cell that will lead to cell growth and cell cycle entry. These growth factors all interact with receptor tyrosine kinases, a type of transmembrane receptor that uses autophosphorylation to propagate their message across the phospholipid bilayer. [1b]

Ras is a protein associated with receptor tyrosine kinases that helps to amplify signals received at the cell surface to other parts of the cell [1b]. It is a GTPase and so is active when bound to GTP and inactive when bound to GDP.

However, the hyperactive form of Ras found in 30% of cancers is resistant to GAP stimulation and remain permanently active in the GTP-bound state. The result of this is permanent stimulation to grow and divide, even in the absence of external stimulus. This can promote the development of cancer and if other checkpoints in the cell cycle are lost, can lead to tumourigenesis. [3a]

The activation of Ras leads to a cascade of signals along several pathways which lead the cell into preparation for S phase entry. This is a chain of serine/threonine phosphorylations, the first of which is to Raf, a kinase that activates another kinase called MEK through phosphorylation. MEK is the only kinase that can activate MAP-kinase, a molecule that can activate the genes that code for the cyclins required for entry into S phase. MEK stands for MAP kinase-kinase and must phosphorylate the MAP-kinase on a threonine and tyrosine for it to become active. Once activated, the MAP-kinase can alter gene expression by entering the nucleus and phosphorylating one or more gene regulatory complexes, activating the transcription of a set of “immediate early genes, so named as they are activated within minutes of the first extracellular signal being received”.[1b] The products of this transcription go on to activate other gene regulatory proteins and leads to the expression and translation of other genes encoding proteins that are needed to help the cell prepare for division. The MAP-kinase is deactivated when either or both of the phosphates on the tyrosine or threonine residues is removed. [3a]

The activation of MAP-kinase also results in increased levels of the protein Myc, a gene regulator that influences cell cycle progression. It does this by stimulating the transcription of the genes for cyclin D and E2F both of which are needed for progression to S phase and by stimulating transcription of genes for SCF ubiquitin ligase, a molecule that degrades p27, the CDKI, so stopping the suppression of Cdk activity, resulting in phosphorylation of pRb and the subsequent transcription of the factors required for S phase transition. Overexpression of this gene is therefore a cancer promoting event in that cell proliferation is stimulated excessively. [1a]

Ras can also activate PI 3-kinase, a kinase that promotes the cell to grow by phosphorylating inositol phospholipid P(4,5) biphosphate to generate PI (3,4,5) triphosphate. The protein kinases PKB and PDK1 then associate with the PI(3,4,5) triphosphate and are phosphorylated, PKB is also activated by phosphorylation by the PDK1. The end product, PKB in capable of inhibiting target proteins that promote cell apoptosis such as BAD, which is phosphorylated and inactivated so that cell growth can be achieved. As stated earlier, Ras is a gene that is commonly mutated in cancer and its importance is that it can initiated a chain of events that will cause a cell to express genes and target proteins necessary for growth and proliferation. [1b]

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The Restriction Point in G1  

It is the point in the cell cycle where a cell no longer needs to be stimulated by growth factor in order to progress. The restriction point in the cell cycle is typified by the Retino Blastoma gene, and the activity of its expressed protein, Rb. The Rb protein is part of a gene family, of which p107 and p130 are part. All the proteins in this family are associated cyclin/CDK dependent phosphorylation and associate with E2F factors. E2F factors are primarily involved in promoting the transcription of genes that code ...

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