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Figure 2. Schematic of common pathways that can lead to apoptosis. Apoptosis can be activated in two ways: First, at the plasma membrane, a ligand must be bound to a death receptor to activate apoptosis. Binding leads to oligomerization of the receptors, recruitment of an adaptor protein, and activation of FADD. Caspase-8 is then bound to this death complex and activated. This enzyme then binds and activates caspase-3, the executioner caspase, which then activates Caspase-Activated Deoxyribonucleases (CAD). These enzymes are responsible for degrading chromatin and generating the DNA fragments that are characteristic of apoptosis. CADs have their own inhibitor, appropriately named Inhibitors of Caspase-Activated Deoxyribonucleases (ICADs). The second pathway requires that apoptogens enter the cell and stimulate synthesis and activation of Bax and Bid, two pro-apoptotic members of the Bcl-2 family, while inhibiting or inactivating Bcl-2 and Bcl-x, two anti-apoptotic proteins. Removal of Bcl-2 from the mitochondrial membrane causes a decrease in the mitochondrial membrane potential (
m) and the generation of a mitochondrial membrane permeability transition (MMPT). When this occurs, there is release of cytochrome c, APAF-1, and other proteins from the intramembrane space to form an apoptosome that binds procaspase-9. Caspase 9 then activates caspase-3, which then goes on to cause the nuclear changes described above. Mitochondria release yet another protein, Smac/Diablo. This protein promotes caspase activation by associating with the apoptosome and inhibiting the activity of another set of proteins, the IAPs (Inhibitor of Apoptosis Proteins). These proteins bind to and inhibit caspase-9 and thereby block the apoptotic process. The MMPT also causes other cellular changes. Thus, there is generation of Reactive Oxygen Radicals (ROS) which lower the thiol reserve (GSH) of the cell. There is also activation of Nitric Oxide Synthase enzymes (NOS) which release Nitric Oxide (NO) from arginine. NO and ROS can activate caspases and cause loss of cell viability.
