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.

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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.


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]

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 for enzymes involved in nucleotide synthesis, DNA replication factors, and cell cycle regulators (cyclins E, A and B, cdc2, cdk2) and inhibitors (p21, p107, p18Ink4c, p19Ink4d), the presence of which are essential for cell cycle progression to S phase.

During early G1 phase, one of the main roles of Rb is to inhibit the E2F factors so that their transcription-active parts are not exposed, and transcription cannot be initiated. Rb/E2F complex also recruits transcription factors that influence the structure of the chromatin surrounding DNA. Chromatin must be in an ‘open’ state in order for transcription to occur. The Rb/E2F complex recruits a histone deacetylases (HDAC’s), a group of enzymes that remove the acetyl group from the chromatin-associated histones, to E2F target promoters. As histones with the acetyl group are required for the open state of chromatin, this effectively represses transcription by promoting a closed chromatin state. In this way, transcription is restricted until all of the signals required for progression into S phase have been received. When Rb becomes phosphorylated by the cyclin D/cdk4 and 6 complexes, the Rb/E2F complex dissociates, releasing the recruited HDAC’s, and also allowing E2F to recruit histone acetyl transferases (HAT’s) to re-establish the acetyl groups onto the histones, and to activate the targeted genes, thus reversing the state of repressing and actively promoting transcription. [3b]

The way in which the Rb/E2F complex is maintained is by regulation by cyclin D/ CDK4 and 6. Cyclin D/CDK4/6 complex activates pRb by phosphorylating it, causing it to dissociate from E2F. This phosphorylation must occur for the cell cycle to progress due to the role of the E2F factors in initiating transcription of genes crucial to S phase. The activity of the cyclin and cyclin-dependent kinases is dependent on stimulation of the receptor tyrosine kinases by growth factors, which initiates the Ras-Raf-MEK-ERK cascade, which in turn stimulates the transcription of cyclin D. However, cyclin D is an unstable protein that is rapidly degraded as it is has a half life of just ten minutes when located in the cytoplasm; this ensures that if the cell does not give signals to show that all of the conditions needed for proliferation are optimal, the cyclin will not accumulate and produce CDK4/6. CDKI’s (cyclin-dependent kinase inhibitors) also play a role in controlling the cyclin/CDK4/6 regulated phophorylation of pRb, these include Ink4 and Cip1/Pic1. The latter usually plays a role in cell cycle arrest when the cell is exposed to radiation.

After DNA damage is detected, p53 is activated, and begins to promote Cip1/Pic1 transcription, leading to an inactivation of cyclin D/cdk4 and cyclin E/cdk2 and subsequent blockage of entry into S phase. Ink4 inhibits Cdk4/6 associated with cyclin D and halts cell cycle. The CDKI’s have a broad range of specificity, most acting on more that one type of cdk , this makes it hard to establish the exact role of each as a down regulator of progression into S phase. I think Ink4 has a more specific role to the control of pRb, as its role in G1 phase can be shown in that when Rb does not function properly in a mutated cell, Ink4 cannot arrest the cell cycle in this phase because the cyclin D/Cdk4/6 no longer has control over the phosphorylation, thus activation of pRb, meaning that it must have a role over control of this cyclin/cdk subunit. In the normal cell, Ink4 also must play a significant role in the control of proliferation as it is a frequently mutated gene in primary tumours and tumour cell lines.

Another CDKI has an important role in the control of other CDK’s that may be present in the cell. The CDKI p27 Kip1 plays a role in inhibiting cyclin E/Cdk2 activity until late G1 phase when its upregulation is coordinated by the release of E2F from phosphorylated pRb. As displaced cyclin E/Cdk2 activity can cause prematurely, this role is important for the integrity of the Restriction point. [3b]

In the normal cell, when the external factors that signal growth are received by the receptor tyrosine kinases in the cell membrane, the cascade from Ras to Erk discussed earlier stimulates the transcription of cyclin D and also p27Kip1 and p21Cip1, which are cofactors that facilitate the union of cyclin D and the Cdk4 and Cdk6 to form the stable complex.

This cyclin/Cdk form a complex with CDKI and then begins to phosphorylate the pRb, changing the shape of the protein and releasing part of the E2F to promote the expression of cyclin E and A. The affinity of p27Kip1 and p21Cip1 to the cyclin D/Cdk4/6 complex also releases the cylin E/Cdk2 so it can become active and so that none that are produced become inhibited by these factors. The cyclin E/Cdk2 phosphorylate the amino acids serine and threonine on the pRb at many distinct sites, rendering its property to bind to E2F inactive as E2F will only associate with hypophoshorylated pRb. In this way, the genes needed to produce the necessary factors for S phase progression are actived by E2F and the cycle can go on. [3b]

To summarise, this checkpoint is extremely important to the protection of the genome and the daughter cells produced in the inevitable mitosis of the cell. E2F is a transcription factor so crucial to the entry into S phase that overexpression of the gene for this protein is enough to drive the cell in G0 into S phase in the absence of growth factor stimulation and the nutrients required for successful DNA replication. The restraint of this protein thus is crucial to ensure that the cell does not commit to the process of DNA synthesis before the cell has reached adequate size, and until all the necessary components are present. Rb has a role as a tumour suppression therefore as it prevents the uncontrolled entry of the cell into the rest of the cycle of proliferation. The loss of the gene for this protein is therefore an event that is capable of causing tumourigenesis, an issue central to cancer and one that I will be discussing in depth in the later part of this report.

DNA damage Checkpoints and p53.

p53 is a protein coded for by the p53 gene on chromosome 17 that has been identified as a tumour suppressor gene as it is deleted in around 50% of all cancers. In a rare disease called Li-Fraumeni Syndrome, a person that has only inherited one good copy of this gene can be subject to a predisposition to cancer and often experience many tumours in their early adult life [2e]. The protein is highly toxic and can cause apoptosis when in high concentrations in the cytoplasm. It is controlled by a negative feedback loop in which the ubiquitin ligase Mdm2 marks it for degradation by attaching several ubiqutins to it. The importance of this protein is that it induces the transcription of several genes including the cyclin-dependent kinase inhibitor p21 which can deactivate the cyclin/cyclin-dependent kinase complex, causing cell cycle arrest.

This is very important in protecting the genome as it prevents mutations being either replicated S phase or being passed on to daughter cells. Another vital component in the DNA checkpoint is ATM, a kinase identified by its defective gene in the condition ataxia-telangiectasia. [2e] This is an autosomal recessive multisytem disorder characterised by progressive neurological impairment, x-ray hypersensitivity, and a predisposition to malignancy [2e]. ATM can be inhibited by caffeine and is know to be able to detect double strand breakage, the major cytotoxic lesion caused by ionizing radiation, and can directly bind to and phosphorylate p53 [7]. ATR, another kinase, is known to detect UV damage and replication arrest. [8]

There are two major DNA checkpoints in the cell cycle, one in G1, the other in G2. When DNA damage is detected in G1 phase, ATM/ATR phosphorylate p53 which stabilises and activates it.[2e] The active p53 then stimulates the transcription of several genes including that for p21, which inhibits the G1/S phase CDK’s and prevent the cell entering S phase[1a]. The phosphorylation of p53 prevents Mdm2 from binding to it and marking it for destruction by proteasomes, thus leading to an overall increase in the concentration of p53 in the cytoplasm and an increased rate of transcription of the genes it targets.

At the G2 checkpoint, p53 also plays a role. After phosphorylation by ATM/ATR, it again stimulates the transcription of p21 which is a potent inhibitor of Cdk1-cyclin A, the complex required for prophase to be initiated [1a]. Stable p53 is also able to induce 14-3-3?, which is able to bind to cyclin B – Cdk1 and sequester it in the cytoplasm. This is possible because the binding of this protein affects the way the cyclin/cdk complex is able to shuttle between the nucleus and the cytoplasm. [2e]

Cdk1 initiates mitosis when it has been dephosphorylated at Tyr15 by Cdc25c phosphatase. To prevent mitosis, Cdc25c action is prevented by the checkpoint kinases Chk1 and Chk2. These kinases are also activated by phosphorylation and they act by phosphorylating Cdc25c on the serine 216. This inactivates the molecule and allows another of the adapter proteins 14-3-3 to bind to it at the specific locus of S216 and sequester it in the cytoplasm. This prevents Cdk1 activation and, in combination with the inhibition of the cyclin/cdk complex by p53, causes cell cycle arrest.

The importance of ATM to genome integrity is highlighted by the high incidence of cancer in sufferers of ataxia- telangiectasia, in that, if DNA damage occurs before mitosis there is no way of pausing the cell cycle to repair this so any potential mutations or deletions will be passed on to daughter cells unchecked. If these mutations/deletions occur in oncogenes/tumour suppressor genes, the cell will undergo further mutations that could eventually lead to the development of a tumour. ATM also has a role in recruiting proteins that enable DNA repair to begin [9], meaning that its loss of action also impairs the cell’s ability to repair DNA after damage has occurred.

The importance of the p53 protein in the protection of the genome is obvious in that 50% of cancers have a mutated gene for this protein. The ability of p53 to bring about cell cycle arrest is integral to the idea of DNA damage repair and without this function; DNA may be only partly repaired or not at all before the cell enters either S phase or mitosis. It is crucial for the cell cycle to be stopped at these points before the mutation/deletions are replicated and/or passed on to daughter cells. The function of cell cycle arrest is not the only thing that protects the genome. p53

can also initiate cell apoptosis if the cell has damage beyond repair. If a normal cell receives inappropriate signals to grow and divide or the damage to its DNA is irreversible, the cell cycle inhibitor protein p19ARF is produced. This protein sequesters Mdm2, the p53 regulatory unit in the nucleus by binding to and inhibiting it. This leads to the build up of p53 in the cytoplasm, which leads to a series of activations of death promoting genes such as Bax, Fas (CSD95/APO-1) and APAF-1 [2f]. The function of apoptosis or programmed cell death is the protect the rest of the cellular community from the negative effects of dysfunctional cell behaviour or DNA damage. This is a vital function in the prevention of cancer and if the p53 gene is lost, this suicide of harmful cells cannot occur.

G2/M phase progression.

As stated in the description of the G2 DNA checkpoint, the cyclin-dependent kinase Cdk1 has a major role in inducing the transition of a cell into M phase. Cyclin B1 accumulates in the cell as it is synthesized at all stages of the cell cycle but its degradation decreases and synthesis increases at G2 and M phase [1a]. As the cell approaches mitosis, cyclin B1 and Cdk1 combine to form the complex that drives entry into M phase. This complex is actively phosphorylated by the enzyme CAK and simultaneously inactivated by phosphorylation by the protein kinase Wee1, leaving it in a state that it is ‘primed’ and ready for action. [2e] At a critical point in late G phase, the protein phosphatase Cdc25 removes the inhibitory phosphate placed on the complex by Wee1 and simultaneously inhibit the action of Wee1.

The CDC25 phosphatase is activated by the cyclin B1/Cdk1 complex itself, in a positive feedback loop, and also by the protein kinase Polo kinase[1a]. The positive feedback loop allows the rapid activation of the complex, so as more active complex is produced, more can be induced to the active state. The active cyclin B/Cdk1 complex is thought to initiate mitosis by phosphorylating the condensing protein complex, a protein group required for the condensation of the chromosomes in frog oocytes [1a]. The cyclin A/Cdk2 complex is also thought to have a role in changing the stability of the microtubules and chromosome condensation [2e].

The Spindle Assembly checkpoint.

Mitosis has 7 main phases: prophase, prometaphase, metaphase, anaphase A, anaphase B, telophase and cytokinesis. [2g]. At anaphase, the sister chromatids separate into what will eventually become the nuclei of the daughter cells. Before this is allowed to happen, the cell has a checkpoint that ensures that all the chromosomes are attached correctly to the spindle ready for separation. This checkpoint is refered to as the spindle assembly checkpoint or the metaphase checkpoint because the cell cannot leave metaphase until it is completed. It monitors the activity of the kineticores, the structures that allow attachment to the spindle and are related to the centromeres of the chromosomes. This, like many other checkpoints was discovered in the studying of yeast mitosis, and this system is the same in yeast and man [2g].

This process involves the kinases Bub1p (budding uninhibited by benzimidazole) and BubR1 (Bub-related kinase-1), proteins Mad1p (mitotic arrest – defective protein) and Mad2p. BubR1 associates at the kinetochore with a “giant kinesin motor protein, CENP-E”.[2g] The function of this protein is to monitor the ‘tension’ between the microtubules and the kinetocore associated BubR1. Bub kinases regulate Mad1p, which activates Mad2p when the kinetichores are not attached to the spindle. The Mad2p prevents entry into anaphase by interacting with a cofactor needed for the activation of the anaphase-promoting complex/cyclosome APC/C, without which, the events that drive entry to anaphase cannot occur.

The cofactor affected is Cdc20 and only to inactivation of BubR1 by the joining of the kinetichore and the spindle can stop the activation of Mad2p by Mad1p. In this way anaphase cannot occur until CENP-E is uncoiled and attachment is achieved. The loss of this checkpoint, either by mutations in Mad2p genes or ‘bub’ genes can have catastrophic consequences. The loss of Mad2p results in premature entry into anaphase with the resulting daughter cells being aneuploid, that is containing unequal non-haploid numbers of chromosomes.[2g] The lack of ‘bub’ genes causes uninhibited entry into anaphase regardless of the integrity of the spindle and has been identified in certain types of human colon cancers as a factor that contributes to the genetic instability that results in tumours moving from a benign to a malignant state.

The Cell Cycle and Cancer.

Cancer can be seen fundamentally as a disease of the cell cycle [4]. In this discussion I have highlighted the complexity of cell cycle agents involved and thus shown the broad range in possibilities of alterations that can result in cancer occurring.

Although deviancies in the controls that normally restrict cell growth and proliferation are required for tumourigenesis, the cancer cell needs to retain functional cell cycle processes in order to proliferate. Therefore, there are two main types of regulators that are affected in cancer: the alteration of regulators involved in limiting cell cycle progression and those regulators concerned with protecting the integrity of the genome. The loss of the former results in accelerated and unquestioned cell growth and division, and the loss of the later allow mutations/deletions of genes to gradually accumulate in the genome of the tumour. It is also true that genes that code for molecules involved in cell cycle progression can become overactive and may cause tumourigenesis in this way. At this point it is helpful to look at the molecules whose genes can be described as cancer causing or oncogenic and those that are cancer preventing, or tumour suppressant. [1c]

Oncogenes and their types.

An oncogene is one that is a mutation of a proto-oncogene which would normally be involved in the promotion of cell growth and differentiation. Oncogenes occur when proto-oncogenes are permanently switched on and so are constantly promoting growth/differentiation in the absence of external factors. This can lead to the development of cancer.

Although hundred of oncogenes have been named, there are categories into which we can place them. These are: growth factors, growth factor receptors, signal transducers, transcription factors and programmed cell death regulators.

Growth factors such as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) were discussed earlier in reference to their initiation of the cell cycle by interaction with receptor tyrosine kinases. This process is usually controlled by the cellular environment only releasing growth factors when necessary for the health of the cellular community. In reality, this is not always the case. For example, the accidental stimulation of growth by release of PDGF when a blood vessel is injured can cause unnecessary proliferation of the smooth muscle cells in larger blood vessels, an event which can happen early in the development of arteriosclerosis development.

Although this illness does not relate directly to a cancerous formation, it does show the vulnerability of this system to manipulation by cancer cells. An example that does relate to the development of tumours however is the well documented sis oncogene, the protogene product of which is the beta chain of PDGF. This gene was first isolated from Simian Sarcoma virus and when this gene is activated, overproduction of PDGF factor can cause overstimulation of growth receptors and result in tumourigenesis (if other significant tumour suppressor genes are also deactivated).

For example, normal human fibroblasts do not synthesize platelet-derived growth factor (PDGF), but they respond to its mitogenic action. In contrast, cells from several human fibrosarcomas have been shown to synthesize PDGF at significant levels.[14] This means that the tumour itself is stimulating its own proliferation by overexpressing the sis gene. This is an example of autocrine signaling where by secreting factors that act on its own receptors, the cancer cell can promote its own survival [1d].

Growth factor receptors can also have oncogenes. For example, the oncogenes erbB and erbB2 cause oversensitivity to growth factors by the cell. The proto-oncogene of erbB2 codes for HER2/neu receptors, so overexpression of this gene results in oversensitivity of cells to extracellular growth factors. This oncogene is particularly prominent in breast cancer, where it is found in one third of all tumours.

Signal transducers are the molecules downstream of the receptor tyrosine kinases and these propagate and amplify the message to grow/differentiate within the cell. One of the most commonly manipulated proteins in this category is Ras. Ras mutations in cancers are most commonly located at the amino acids essential for Ras GTP-ase activity.

The combination of amino acids at the ‘active’ site of Ras are essential for it’s ability to bind to and release GTP, switching from an active to an inactive state. In a normal Ras molecule, the amino acids Gly13, Gly13, Ala59 and Gln61 are seen as essential for GTPase activity [15]. It follows then that these are most commonly mutated in human cancers containing a mutant Ras gene. The result of these mutations is the loss of the Ras proteins intrinsic ability to deactivate itself to GDP-Ras thus remaining in a permanently active or oncogenic state. Although every gene has two copies, the mutation of just one of these coding Ras is sufficient to cause excessive stimulation of growth/differentiation, in other words the effect is dominant.

This means that is the mutation is passed on to daughter cells, they will never have an properly functioning Ras protein.

Transcription factors are the elements in the cell cycle that tell the cell to prepare to divide by initiating events that induce cell cycle progression. A well studied example of this is the Myc oncogene, the proto-oncogene product of which is overexpressed in nearly all cell cancers, including solid human tumours and leukemias. The activated oncogene causes the deregulation of cell growth and cell death checkpoints due to the fact that it is usually tightly regulated in cells. The result is rapid acceleration of cell growth and carcinogenesis.

Programmed cell death regulators are elements that prevent apoptosis by inhibiting pro-apoptotic factors. Bcl-2 proper is an anti-apoptotic element, the gene for which is recognised as an oncogene. This gene is targeted for chromosome translocation in B-cell lymphoma, leading to its irregular management and resulting in overexpression and cell survival in those B-lymphocytes that would normally commit suicide. This has an impact on cancer in that DNA damage that was unable to be repaired could be passed on to daughter cells, leading to an accumulation of mutations that may result in cancer developing

Tumour Suppressor genes and their types.

Tumour suppressor genes are normal genes that regulate the cell cycle and protect the integrity of the genome by initiating DNA repair, preventing premature entry into the cell cycle and causing programmed cell death if the cell’s survival would jeopardise the rest of the organism. In this class of genes, the inactivation of them results in tumourigenesis when combined with the effects of oncogene activation and inactivation of one or more tumour suppressor genes. I will now discuss three genes that are crucial in the prevention of cancer; the loss of these would result in unchecked cell proliferation.

A major gene that controls cell division is Rb or Retinoblastoma gene, the protein product of which, pRb actively suppresses cell cycle progression when the conditions are not optimal. The loss of this gene is typified in the fact that those with the deletion of one of the pairs for this gene, a hereditary predisposition are likely to develop cancer in the retina or retinoblastoma. The loss of the healthy gene by a mutation can cause cancer, showing that pRb has a major role in preventing tumourigenesis. Cancer can either occur through knock out of the one healthy gene in those with the heterozygous trait, or by knocking out both pairs in a normal cell, an event far less likely to happen spontaneously.

However, the importance of the Rb is so that even mutations in molecules that affect the Rb pathway and the way in which the Restriction point works, is sufficient to cause tumourigenesis. For example, amplified Cdk4 or cyclin D1 expression is found in some glioblastomas and breast cancer. These are both agents that phosphorylate pRb to render it partially inactive during the transition from G1 phase into S phase. Another example is the effect of the deletion or inactivation of the gene that codes for p16, an event seen in many human cancers, or the silencing of this gene through methylation of its regulatory DNA. The role of p16 is to inhibit the Cdk4/6 subunit by associating with the active site and preventing the attachment of cyclin D1.

Genes that repair and/or detect DNA damage are also classed as tumour suppressor genes, a good example of which is ATM, a gene lost in the condition ataxia- telangiectasia which I discussed earlier when explaining the DNA damage checkpoint.

Cell suicide genes, namely p53 are crucial to protecting the integrity of the genome in those cells with active oncogenes Ras and Myc show p53 response in cell cycle arrest. This highlights p53 as the major brake in the cell cycle and that some mutations alone are not sufficient to cause tumourigenesis, so long as the integrity of others in maintained. Saying this, the loss of p53 allows faulty cells with mutant DNA to continue through the cell cycle, escape apoptosis and allows cells with no genetic integrity to proliferate, allowing the accumulation of more mutations that can promote cancer.

The loss of the p53 gene in human cancer can also be related to its repression of the c-Myc gene, probabley by some transcriptional mechanism [11]. The c-Myc gene product is a virile promoter of cell cycle progression, in fact its presence in the cell is both sufficient and necessary to drive the quiescent cell into S phase [12]. Therefore the loss of p53 can directly cause the overexpression of the c-Myc gene and can lead to “aggressive cell growth, genomic instability and transformation” [13].

The importance of the tumour suppressor genes can also be shown in the way that Papillomaviruses that cause benign warts on the surface of the skin can also cause cervical cancer by sequestering the products of tumour suppressor genes and preventing their action. When viral DNA is incorporated into the human DNA accidentally, viral oncogenes are activated, the proto-oncogene products of which bind to p53 and pRb and inactivate them. The result of this is uncontrolled cell proliferation and the development of a malignant tumour.

Mutated tumour suppressor genes differ from oncogenes in that they can be inherited as well as acquired. I have included a table of those genes that are related to specific familial cancers, although cancer does not develop in every individual with a recessive faulty tumour suppressor gene:

Inherited cancer

Abnormal gene

Other non-inherited cancers seen with this gene



Many different cancers

Li-Fraumeni Syndrome (sarcomas, brain tumours, leukemia)


Many different cancers



Many different cancers

Colorectal cancer (due to familial polyposis)


Most colorectal cancers

Colorectal cancer (without polyposis)

MLH1, MSH2, or MSH6

Colorectal, gastric, endometrial cancers

Breast and/or ovarian


Only rare ovarian cancers

Wilms Tumour


Wilms tumours

Nerve tumours, including brain

NF1, NF2

Small numbers of colon cancers, melanomas, neuroblastoma

Kidney cancer


Certain types of kidney cancers

Figure 1: Table of inherited cancers, the affected gene and the incidence of this gene being faulty in those without the inherited mutation.[10]

The knowledge that these genes are hereditary can be useful in screening for the genes, in order for the person to know the risks they are subject to. This is a necessary process as lifestyle choices can be made to reduce the persons risk of developing cancer in their lifetime. Below is a table of genes that screening is available for [10]:

Oncogene/Tumour Suppressor Gene

Related Cancers


Breast and ovarian cancer


Chronic myelogenous leukemia


B-cell lymphoma

HER2/neu (erbB-2)

Breast cancer, ovarian cancer, others




Ewing tumour


Burkitt lymphoma, others


Brain tumours, skin cancers, lung cancer, head and neck cancers, others


Colorectal cancers


Colorectal cancers

Screening is useful in predicting the pattern of cancer in the population. Knowledge of gene faults that are specific to certain types of cancer are also useful in the design of treatments.


The cell cycle is a complex process involving hundreds of different molecules. The ones that are important to the development off cancer however are involved in the regulation of cell cycle progression and those concerned with protecting the integrity of the genome. There are an estimated 1014 cells in the human body, billions of which will experience mutations, so if every mutation resulted in cancer, the human body could not exist. Instead it is the activation of oncogenes and the inactivation of tumour suppressor genes that results in cancer.

In saying this, singular activations and deletions of these genes as separate events is not sufficient to cause cancer, as the cell has many safeguards to protect the integrity of the genome and the cellular community. When combinations of tumour suppressor and oncogenes are mutated, the unchecked cell division, along with the unrepaired DNA mutations, avoidance of apoptosis, replicative senescence and differentiation, and unstable genome can result in the cancer cell that can escape from their home tissues and survive and proliferate in foreign sites.[1c]


1. Molecular Biology of The Cell, 4th Edition,. Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter.

a) Chapter 17: Extracellular Control of Cell division, Cell Growth and Apoptosis. References listed:

* Assoian RK (1997) Anchorage-dependent cell cycle progression. J.Cell Biol. 136, 1-4

* Conlon I & Raff M (1999) Size control in animal development. Cell 96, 235-244

* Raff MC (1992) Social controls on cell survival and cell death Nature 356, 397-400

* Sherr CJ & DePinho RA (2000) Cellular senescence: mitotic shock or culture shock? Cell 102, 407-410

* Stocker H & Hafen E (2000) Genetic control of cell size. Curr. Opin. Genet. Dev. 10, 529-535

b) Chapter 15: Cell Communication; Signalling through Enzyme-linked Cell Surface Receptors. References listed:

* Downward J(1996) Control of ras activation. Cancer Surv. 27, 87-100

* Downward J (1998) Mechanisms and consequences of activation of protein kinase B/Akt. Curr. Opin. Cell. Biol. 10, 262-267

* Leevers SJ, Vanhaesebroeck B & Waterfield MD (1999) Signalling through phosphoinositide 3-kinases: the lipids take centre stage. . Curr. Opin. Cell. Biol.11, 219-225

* Pawson T (1995) Protein modules and signalling networks. Nature 373, 573-580

* WidmannC, Gibson S, Jarpe B & Johnson GI (1999) Mitogen activation protein kinase: conservation of a three-kinase module from yeast to human. Physiol. Rev. 79, 143-180

* Schlessinger J (2000) Cell signalling by receptor tyrosine kinases Cell 103, 211-225

* Neel BG & Tonks NK (1997) Protein tyrosine phosphatises in signal transduction. Curr. Opin. Cell. Biol. 9, 192-204

* Thomas SM & Brugge JS (1997) Cellular functions regulated by Src family kinases. Annu. Rev. Cell Dev. Biol. 13, 513-609

c) Chapter 23: Cancer; The molecular basis of cancer-cell behaviour. References:

* Artandi SE & DePinho RA (2000) Mice without telomerase: what can they tell us about human cancer? Nat. Med. 6, 852-855

* Chambers AF, Naumov GN, Vantyghem S & Tuck AB (2000) Molecular biology of breast cancer metastasis: clinical implications of experimental studies on metastatic inefficiency. Breat Cancer Res. 2:400-407

* Edwards PAW (1999) The impact of developmental biology on cancer research: an overview. Cancer Metastasis Rev 18:175-180

* Hanahan D & Weinburg RA (2000) The hallmarks of cancer. Cell 100:57-70

* Karran P(1996) Microsatellite instability and DNA mismatch repair in human cancer. Semin. Cancer Biol 7:15-24

* Kinzler KW & Vogelstein B(1996) Lessons from hereditary colorectal cancer. Cell 87:159-170

* Lowe SW & Lin AW (2000) Apoptosis in cancer. Carcinogenesis 21:485-495

* Macleod KF & Jacks T (1999) Insights into cancer from transgenic mouse models. J. Pathol 187:43-60

* McCormick F (1999) Signalling networks that cause cancer. Trends Cell Biol 9:M53-56

* Mendelsohn J, Howley PM, Israel MA & Liotta LA (eds) (2001) Molecular basis of cancer, 2nd ed. Philadelphia, Saunders

* Vogelstein B, Lane DP & Levine AJ (2000) Surfing the p53 network. Nature 408:307-310

* Weinburg RA (1995) The retinoblastoma protein and cell-cycle control. Cell 81:323-330

d) Chapter 15: Cell Communication; General principals of cell communication

2. Cell Cycle and Growth Control: Biomolecular Regulation and Cancer, 2nd Edition., edited by Gary S. Stein, Ph.D., Arthur B. Pardee, Ph.D

a) Ekholm SV, Reed SI: Regulation of G1 cyclin-dependent kinases in the mammalian cell cycle.

b) Chapter 43: Introduction to the Cell Cycle

c) Russell P: Checkpoints on the road to mitosis. Trends in Biochemical Sciences 23:399-402, 1998

d) Planas-Silva MD, Weinburg RA: The Restriction point and control of cell proliferation. Curr. Opin. Cell Biol 9:768-722,1997

e) Chapter 46: The G2 phase transition and control of entry into mitosis

* Kitazano A, Matsumoto T: “Isogaba Maware”: Quality control of genome DNA by checkpoints. BioEssays 20;391-399, 1998

* Johnson DG, Walker CL: Cyclins and cell cycle checkpoints. Annu Rev Pharmacol Toxicol 39:295-312, 1999

* O’Connell MJ, Walworth NC Carr AM: The G2-phase DNA-damage checkpoint. Trends Cell Biol 10:296-303, 2000

* Ohi R, Gould KL: Regulating the onset of mitosis. Curr. Opin. Cell Biol 11:267-273, 1999

* Wahl GM, Carr AM: The evolution of diverse biological responses to DNA damage: Insights from yeast and p53. Nat Cell Biol 3:E277-E286, 2001

* Weinert T: DNA damage and checkpoint pathways: Molecular anatomy and interactions with repair. Cell 94:555-558, 1998

f) Chapter 49: programmed cell death. References:

* Nagata S: Apoptosis by death factor. Cell 88:355-365, 1997

* Kaufmann SH, Hengartner MO: Programmed cell death: Alive and well in the new millennium. Trends Cell Biol 11:526-534, 2001

* Rich T, Allen RL, Wyllie AH: Defying death after DNA damage. Nature 407:784-788, 2000

* Wyllie AH, Kerr JFR, Currie AR: Cell death: The significance of apoptosis. Int Rev Cytol 68:251-305, 1980

g) Chapter 47: Mitosis. References:

* Mitchison TK, Salmon ED: Mitosis: A history of division. Nat Cell Biol 3:E17-E21, 2001

* Collas P, Courvalin J-C: Sorting nuclear membrane proteins at mitosis. Trends Cell Biol 10:5-8, 2000

* Hirano T: Chromosome cohesion, condensation, and separation. Annu Rev Biochem 69:115-144, 2000

* Nasmyth K, Peters JM, Uhlmann F: Splitting the chromosome: Cutting the ties that bind sister chromatids. Science 288:1379-1385, 2000

* Adams RR, Carmena M, Earnshaw WC: Chromosomal passengers and the ABC’s of mitosis. Trends Cell Biol 11:49-54, 2000

* Rappaport, R: Cytokinesis in animal cells. Developmental and cell biology series, Cambridge University Press, 1996

* Robinson DN, Spudich JA: Towards a molecular understanding of cytokinesis. Trends Cell Biol 10:228-237, 2000

* Sawin KE: Cytokinesis: Sid signals septation. Curr Biol 10:R547-550, 2000

* Straight AF, Field CM: Microtubules, membranes and cytokinesis. Curr Biol 10:R760-770, 2000

3. Cell Biology., Thomas D. Pollard, M.D., William C. Earnshaw, Ph.D., FRSE

a) Chapter 4: Membrane receptors and Signal Transduction pathways in G1: Regulation of Liver Regeneration and T cell proliferation. References:

* Aktas H, Cai H, Cooper G (1997). Ras links growth factor signalling to the cell cycle machinery via regulation of cyclin D1 and the cdk inhibitor p27KIP1. Mol. Cell Biol 17:3850-7

* Scheffzek K Ahmadian M, Wittinghofer A (1998). GTPase-activating proteins: Helping hands to compliment an active site. Trends Biochem Sci 7:257-262

* Takuwa N, Takuwa Y(2001) Regulation of cell cycle molecules by the Ras effector system. Mol Cell Endo. 177:25-33

b) Chapter 3: Cell Cycle Regulatory Cascades. References:

* Planas-Silva MD, Weinburg RA (1997): The Restriction point and control of cell proliferation. Curr. Opin. Cell Biol 9:768-72

* Zetterberg A, Larsson O, Wiman KG (1995): What is the restriction point? Curr. Opin. Cell Biol 7:835-42

* DeGregori J (2002): The Genetics of the E2F family of transcription factors: shared functions and unique roles. Biochim Biophys Acta 1602:131-50

* Dyson N (1998): The regulationof E2F by pRB-family proteins. Genes Dev 12:2245-62

* Ferreira R, Naguibneva I, Pritchard LL, Ait-Si-Ali S, Harel-Bellan A (2001): The Rb/chromatin connection and epigenetic control: Opinion. Oncogene 20: 3128-33

* Trimarchei JM, Lees JA (2002): Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol 3:11-20

4. World Cancer Report., Edited by Bernard W. Stewart, Paul Kleihues.

5. Cellular and Molecular Biology of Cancer; The Cancer Cell cycle, Author: Chris J. Norbury.

6. Kara�skou A.; Cayla X.; Haccard O.; Jessus C.; Ozon R. MPF amplication in Xenopus Oocyte extracts depends on a two-step activation of Cdc25 Phosphatase. Experimental Cell Research, 244:2:491-500; November 1998.

7. Kum Kum Khanna:Cancer risk and the ATM gene: A continuing debate. JNCI 10:795-802, 2000

8. Reviewed in the Durocher & Jackson 2001.

9. Chen G, Yuan SS, Liu W, Xu Y, Trujillo K, Song B, et al. Radiation-induced assembly of Rad51 and Rad52 recombination complex requires ATM and c-Abl. J Biol Chem 1999;274:12748-52

10. American Cancer Society Website – Oncogenes and Tumour Suppressor genes.



> Pierotti NA, Schichman SA, Sozzi G, Croce CM. Oncogenes. In: Bast RC, Kufe DW, Pollock RE, Weischselbaum RR, Holland JF, Frei E, eds. Cancer Medicine. Hamilton, Ontario: BC Decker Inc; 2000: 56-66.

> U.S. Department of Health and Human Services. Understanding Gene Testing. Available at

> Park BH, Vogelstein B. Tumor-suppressor genes. In: Kufe DW, Pollack RE, Weichselbaum RR, et al, eds. Cancer Medicine. 6th Ed. Lewiston NY: BC Decker; 2003: 87-106.

> Ringer DP, Schniper LE. Principles of Cancer Biology. In: Lenhard RE, Osteen RT, Gansler T, eds. Clinical Oncology. Atlanta, GA: American Cancer Society; 2001: 25-30.

> DeVita VT, Hellman S, Rosenberg SA. Cancer: Principles and Practice of Oncology. 6th ed. 2001; 207-215.

> Tufts University School of Medicine, Department of Anatomy and Cellular Biology. The somatic mutation theory of cancer: growing problems with the paradigm? Bioessays. 2004; 26:1097-1107.

> Kunstmann E, Vieland J, Brasch FE, et al. HNPCC: Six new pathogenic mutations. BMC Med Genet. 2004; 5:16.

> Kufe DW, Pollack RE, Weichselbaum RR, et al. Cancer Medicine.6th Ed. Lewiston, NY: BC Decker; 2003.

> Reeves, S. New cancer drug uses UT-patented gene therapy method. The Daily Texan, 9/22/03

11. Moberg KH, Tyndall WA, et al (1992): Wild type p53 represses transcription from the murine c-myc promoter in a human glial cell line. J Cell Biochem 49(2):208-15

12. Baudino TA, Cleveland JL (2001): The Max network gone mad. Mol Cell Biol 21(3):691-702

13. Yin XY, Grove L, et al. (1999): C-myc overexpression and p53 loss cooperate to promote genetic instability. Oncogene 18(5):1177-82

14. Yang D, Kohler S K, Maher V M, McCormick J J, v-sis oncogene-induced transformation of human fibroblasts into cells capable of forming benign tumors., Carcinogenesis, 15(10), 2167-75, October 1994

15. Macaluso M, Russo G, Cinti C, Bazan V, Gebbia N, Russo A (2002): Ras family genes: an interesting link between cell cycle and cancer. J Cell Physiol 192:125-30


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