A Form of Preprogrammed Cell Death
Apoptosis is a form of preprogrammed cell death. It can occur if DNA is too damaged or if a cell is infected and cannot complete its function anymore. There are two pathways to trigger cell death. The extrinsic pathway begins the process through external ligand binding. The intrinsic pathway begins by releasing mitochondrial proteins into the cell. Both pathways lead to the cell diminishing in size before beginning to break apart. Once this happens, adjacent cells and macrophages take in the pieces quickly so that none of the inner materials are leaked out into the extracellular matrix. When abnormalities arise either in the cellular receptors or the major checkpoints along the pathway, it can lead to autoimmune disorders and cancers.
Apoptosis is a very important process that not only becomes activated during a problem but also is utilized with precision during embryonic development. During human development the embryo has webs that connect digits in the hands and feet. The cells that make up this webbing undergo apoptosis. Human embryos also develop with a tail which must also be absorbed through the specifically timed cell death. Another point in a cells lifespan where apoptosis becomes beneficial is when that cell has reached the point where it can no longer divide without serious damage to the integrity of the daughter cell’s DNA. During each division the length of telomeres is shortened just a little from the original cellular composition. This is called the Hayflick phenomena and refers to the predetermined available number of divisions. If a cell has reached its limit senescence occurs, division stops, and eventually cellular mechanics break down leading to cell death. This cell death is important for the function of quality control. Any cells that don’t function in the necessary way, aren’t in the right location, have served their purpose, or even dangerous need to be eradicated before they become a threat to the overall organism. In the case of every one of these cell processes there is tight regulation and control of the timing of the events.
The extrinsic pathway utilizes death receptors located on the outside surface of the cell on the end of the transmembrane proteins. These proteins consist of three regions; the ligand binding domain located on the extracellular surface, the transmembrane domain located within the lipid bilayer, and the death domain located on the cytosol end of the protein. The receptor is a member of the TNF family, tumor necrosis factor. A well-known example of a death receptor is Fas. The ligand specific for the Fas receptor is found on the surface of cytotoxic lymphocytes. Once activated the tails of the protein bind adaptor proteins, that bind initiators, that then build DISCs, that then are cleaved by initiators and the cascade is continued.
The intrinsic pathway uses molecules from inside the cell as inducers of the apoptotic pathway. Proteins normally located between the bilayer membrane of the mitochondria are released into the cell, specifically cytochrome c which plays a major role in the electron transport chain. Cytochrome c binds to Apaf1 or apoptotic protease activating factor 1, which then binds several monomers together to create an apoptosome. Apoptosomes then activate initiators.
Regardless of the pathway used, the proteolytic cascade leading to apoptosis is initiated by the cleavage of caspases. They cleave certain proteins at aspartic acid residues within specific sequences. Within the cell there are several that undergo cleavage by the different caspases. This cleavage initiates the breakdown of important organelles and components leading to phagocytosis and the recycling of usable cellular materials. Caspases are synthesized inside the cell and can be found in their inactive form under normal circumstances and only become active during apoptosis. There are two major classes of caspases, initiators and executioners.
Initiators do exactly as their name suggests. They initiate the apoptosis cascade. In a healthy cell, initiators exist as monomers until signaled to bring together a larger complex called a DISC, death inducing signaling complex. The DISC holds sets of dimers, a set of two proteins bound together, of caspases that signal protease activation. Each caspase within the dimer cleaves its partner. This cleavage is what stabilizes the active sites within them. Each initiator can activate many dimers of the second class of caspases.
Executioners are found in the cell in their inactive form until acted upon by initiators. The cleavage of the executioners by initiators catalyzes the next event. Mass protein cleavage throughout the cell that lead to its death. The breakdown of proteins that prevent DNA from being digested and important pieces of the cytoskeleton are all effected
. Cells invest a lot of energy in being created, through mitosis or meiosis, as well as in the maintenance of structures within. For that reason, there are several mechanisms in place to not only initiate the process of apoptosis but also in halting the process should the cell decide that survival would be more beneficial than death. IAPs and Bcl2 proteins are just two proteins that have been shown to interfere with or regulate the apoptotic pathway.
Bcl2 proteins are found universally throughout the animal kingdom. They serve to regulate the process of apoptosis in one of two ways. They can be pro-apoptotic and stimulate the release of cytochrome c into the cytosol. They can also be anti-apoptotic and block the release of cytochrome c from the mitochondria. These proteins have the ability to bind to each other and inhibit the function of one another meaning the whatever type is most abundant in the cell would either stimulate or inhibit the release of cytochrome c. When the intrinsic pathway has been stimulated Bcl2s trigger the release cytochrome c.
IAP proteins, inhibitors of apoptosis, contain a set of repeating amino acids called BIRs, baculoviral IAP repeats and can suppress apoptosis. In humans IAPs actively recruit caspases competing directly with initiators and blocking the intrinsic pathway. IAPs are often up-regulated in many types of cancers. They can associate with Tumor Necrosis Factor, TNF, which allows the damaged cell to avoid immune detection. One specific IAP called survivin has shown that the levels of this protein in undifferentiated tissues are directly linked to survivability of colorectal cancer.
Cancer is defined by having two major properties that are passed on to daughter cells. The first is that regardless of whether the proper checkpoints have been passed the damaged cells have the ability to reproduce. The second is that these aberrant cells invade the space designated for other cell types. These cells create new growths, neoplasms, that develop into tumors that become malignant once cells from the original growth travel to other locations. Proto-oncogenes are genes that if mutated have the chance to push cells toward cancer. Many of these genes are linked to major cell processes including apoptosis.
The genes that code for IAPs, Bcl2s and other inhibitors or regulators of apoptosis have been found in a form that inhibits the process in much higher numbers than in that of a healthy cell in many forms of cancer. As previously stated, an increase in IAPs has been linked to colorectal cancer. Cancer cells have been shown to make an increased amount of the protein p-53 upregulated modulator of apoptosis (PUMA) which binds to the class of Bcl2s that are pro-apoptotic. P53 mutation has been found in approximately 50 percent of cancer incidences.
Apoptosis plays a vital role in not only embryonic development but also in maintaining the overall health of the organism in its entirety. In healthy cells the process is tightly controlled and regulated. Dysregulation of this cellular process can lead to cataclysmic and potentially fatal consequences like the formation of metastatic cancers. The complexities of the events leading to programmed cell death although better understood still require a deeper understanding before it becomes possible to fully utilize the cells own processes to combat cancers that become unresponsive to traditional treatments. Once determined, the ability for patients to survive previously fatal cancers will hopefully become the new standard.