Health Information

Apoptosis: programmed cell death

Eukaryotic cells have genetically regulated mechanisms for programmed cell death, termed apoptosis. Programmed cell death is important during embryogenesis and throughout older life and occurs when a cell has fulfilled its biological function. It is distinct from necrotic death of a cell caused by injury due to radiation or anoxia. Initiation of apoptosis has three phases an initiation signal, activation of a cascade of reactions involving protein factors, and activation of specific proteolytic enzymes.

Different cells have highly specific receptors on the plasma membrane, termed death receptors that bind specific proteins instructing the cell to initiate apoptosis. Various proteins such as tumor necrosis factor (TNF) have been identified as death signals. The specificity of receptors and of death signals determines which cells will undergo apoptosis. Death receptors are transmembrane proteins with intracellular domains, termed death domains. When binding of the extracellular signal activates the receptor, the death domain binds specific proteins and promotes a cascade of protein-protein interactions. Proteases, termed caspase 8 and 9, are activated, which then activate other caspases. The caspase family of enzymes is present as proenzymes (inactive) and is activated by the cleavage to three subunits, two of which will form an active heterodimer. They catalyze hydrolysis of very specific cellular proteins that leads to disassembly of the cell.

Apoptosis is also caused by intracellular stress, such as a disruption of the mitochondrial membrane. This mechanism involves the release of cytochrome c from mitochondria, which along with another protein factor, Apaf-1, activates caspase 9 and initiates the cell death cascade. Pro and antiapoptoic proteins, such as Bcl-2/Bax, control the cascade. A change in the balance between these factors can lead either to premature cell death or to unchecked cell division.

Dysfunctions in the apoptotic pathway have been implicated in a variety of diseases including autoimmune, inflammatory, malignant, and neurodgenerative diseases, and in viral infections such as HIV that attack the immune system. An understanding of the different pathways of apoptosis may lead to therapeutic approaches may lead to therapeutics approaches for these diseases.