The cell cycle is a heavily regulated process which involves many different components. Cell proliferation is an increase in the number of cells through the regulation of cell division, death and differentiation (van den Heuvel, 2005).
Cell division is made up of four main phases which need to be completed in order for cells to divide. This process takes roughly 24 hours for many mammalian cells. The G1 phase (Gap phase) prepares for deoxyribonucleic acid (DNA)
replication by synthesising the many enzymes that are needed for the process. The S phase (synthesis phase) allows for the replication of DNA and the packaging of DNA so that the chromosomes become segregated (Scholey et al, 2003). This is followed by the G2 phase where protein synthesis occurs, including the production
of microtubules to help with mitosis. During this gap phase the cell proof-reads the DNA to ensure proper replication and prepares for division (Park & Koff, 1998; Alberts et al, 2008).
The fourth phase, M phase (Mitosis phase), consists of karyokinesis and cytokinesis where nuclear and cytoplasmic division occur resulting in the formation of a new cell membrane. The cells then enter into G0 which is a rest phase until the
cell receives growth-promoting signals or pro-differentiation signals (Scholey et al, 2003).
This cell cycle is strictly controlled by cyclin-dependent kinases (Cdk) which turn specific proteins on and off through phosphorylation during the different phases of the cell cycle. Various cyclins are produced during the process and when it becomes phosphorylated it forms a cyclin-Cdk complex which then activates the production of the next cyclin (van den Heuvel & Harlow, 1993). The process can be
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inhibited by proteins such as p16, p21 and p27 which bind directly to the Cdk-cyclin complexes and inhibit their protein kinase activity (Scholey et al, 2003).
The process of proliferation allows for cells to be replaced when they have been lost to injury or death. Cell death can occur in one of two main ways; necrosis or apoptosis.
5.1.2 Apoptosis
Cell death is part of the proliferation of cells. Cells that are damaged or ageing need to be removed from the host to retain the balance of cells. All cells can commit a programmed cell death which is termed apoptosis. This is different to necrosis where cell death occurs following injury or inflammation, causing the cell membrane to become disrupted and the release of intracellular contents into the extracellular environment.
In apoptosis, cell death is highly regulated. The cells shrink in size as the cell condenses down (pyknosis), the cytoskeleton of the cell collapses, the nuclear envelope disassembles and nuclear DNA fragments (karyorrhexis) (Elmore, 2007). This allows the cell contents to accumulate in apoptotic bodies in a process called budding. These bodies are then phagocytosed, taken up into phagosomes and degraded (Elmore, 2007). This process allows the cells to die without inducing an inflammatory response since all the intracellular components are recycled by phagosomes (Elmore, 2007).
Apoptosis relies upon a family of proteases called caspases. These proteases have cysteine in the active site that is able to cleave proteins at specific aspartic acids. These caspases are synthesised as an inactive precursor termed procaspases which remain inactive until cleaved at the aspartic acids by another caspase. Once activated, these caspases will cleave other procaspases to amplify the proteolytic cascade (McIlwain et al, 2015). These caspases can also cleave cell proteins and nuclear lamina. These processes cleave the proteins that are responsible for
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keeping DNAse inactive, meaning that it is released and able to fragment the DNA in the nucleus (McIlwain et al, 2015).
Apoptosis is a complete and irreversible process which is self-amplifying and destructive. In the early phases of apoptosis, procaspases are activated by adaptor proteins which brings initiator procaspases into close proximity to one another to form a complex to then be activated by signals from the death receptors on the cell surface. This triggers the recruitment of intracellular adaptor proteins which bind and aggregate procaspase-8 in order for it become cleaved and activated. This capsase-8 can then activate downstream procaspases to induce apoptosis (McIlwain et al, 2015).
The death receptor, Fas, is expressed in stressed or damaged cells in order to trigger the caspase cascade and induce apoptosis (Elmore, 2007). DNA damage can also trigger apoptosis through p53; a tumour suppressor gene that is able to activate apoptosis that encodes a transcription factor which can bind DNA in a sequence-specific manner (Ko & Prives, 1996). P53 has control of both the intrinsic and extrinsic pathways of apoptosis and functions by transcribing the gene that encodes the protein responsible for the release of cytochrome C from the
mitochondria. These proteins belong to the Bcl-2 family, which includes Bax, Bad and Bak (Fridman & Lowe, 2003).
The members of the Bcl-2 family function in various ways. Some, like Bad, are promotors of procaspase activation in order to promote apoptosis while others are death inhibitors. Bad will bind to these death inhibiting members of the family while Bax and Bak stimulate cytochrome C being released by the mitochondria, a step which is crucial for the induction of apoptosis (Amaral et al, 2010).
There are many caspases that are involved with this process and each of them have a specific role based upon their biochemical features and role they play in the process. There are ten major caspases which can be split into three main groups. Caspases -2, -8, -9 and -10 are initiators of the apoptotic process; caspases - 3, -6 and -7 are effectors and executioners and caspases -1, -4 and -5 are
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inflammatory. There are others that have a less defined role in the process. For example, caspase-11 regulates apoptosis and cytokine maturation in instances of sceptic shock; caspase-12 mediates endoplasmic specific apoptosis and caspase-14 is expressed only in embryonic tissues (Elmore, 2007).
Apoptosis is one of the main regulators of the cell cycle. It helps to prevent against cancer by inhibiting the growth of tumour cells but also to remove damaged cells that are no longer useful in the inflammatory process.