Apoptosis, or programmed cell death, characterized by nuclear condensation, cell shrinkage, membrane blebbing, and DNA fragmentation, plays an important role in many physiological and diseased conditions.
Apoptosis can be initiated by one of two separate pathways; the intrinsic or extrinsic pathway. Both of these end with a final common effector pathway, known as the execution phase.
The intrinsic pathway triggers apoptosis in response to internal stimuli:
Biochemical stress
DNA damage (this activates the p53 gene – which halts the cell cycle and initiates
DNA repair. If this repair attempt is unsuccessful, apoptosis can be induced)
Lack of growth factors
The intrinsic pathway is modulated by two groups of molecules, Bcl-2 and Bax. Activation of Bax leads to the formation of Bax-Bax dimers, which in turn enhances the action of a variety of apoptotic stimuli – increasing a cell’s susceptibility to apoptosis. The Bcl-2 family consists of both pro- and anti-apoptotic members, and it is the balance between these that determines how susceptible a cell may be to apoptosis.
The extrinsic pathway triggers apoptosis in response to external stimuli, namely by specific ligands binding at ‘death’ receptors on the cell surface.
These receptors are typically members of the Tumour Necrosis Factor Receptor(TNFR) gene family, such as TNFR1 or FAS. Binding at these receptors leads to downstream activation of caspase enzymes.
The extrinsic and intrinsic pathways both end at the point of the execution phase, considered the final pathway of apoptosis. It is the activation of the execution caspases that begins this phase of apoptosis. Execution caspases activate cytoplasmic endonuclease, which degrades nuclear material, and proteases that degrade the nuclear and cytoskeletal proteins. Caspase-3, caspase-6, and caspase-7 function as effector or “executioner” caspases, cleaving various substrates including cytokeratins, PARP, the plasma membrane cytoskeletal protein alpha fodrin, the nuclear protein NuMA and others, that ultimately cause the morphological and biochemical changes seen in apoptotic cells.Caspase-3 is the most important protein of the executioner caspases and is activated by any of the initiator caspases (caspase-8, caspase-9, or caspase-10). Caspase-3 precisely activates the endonuclease Caspase-activated DNase (CAD). CAD then causes chromatin condensation by degrading chromosomal DNA within the nuclei.
Caspase-3 also causes cytoskeletal reorganization and disintegration of the cell into apoptotic bodies. Gelsolin, an actin-binding protein, is considered as one of the critical substrates of activated caspase-3. Caspase-3 cleaves gelsolin and the cleaved fragments of gelsolin, in turn, cleave actin filaments, resulting in disruption of the cytoskeleton and formation of apoptotic bodies.The later stages of apoptosis cause the appearance of phosphatidylserine on the outer leaflet of apoptotic cells.
Regulation of Apoptosis
There are a variety of factors responsible for regulating apoptosis, which can be intracellular or extracellular. External signals include growth factors or specific signals from other cells, whereas internal factors include DNA damage or failure of cell division.
Apoptosis Inducers | Apoptosis Inhibitors |
· Withdrawal of growth factors · Loss of matrix attachment · Glucocorticoids · Some viruses · Free radicals · Ionising radiation · DNA damage · Ligand binding at ‘death receptors’ | · Presence of growth factors · Extracellular cell matrix · Sex steroids · Some viral proteins |
Selected Reviews
Degterev A, Yuan J (2008) Expansion and evolution of cell death programmes. Nat. Rev. Mol. Cell Biol. 9(5), 378–90.
Fuchs Y, Steller H (2011) Programmed cell death in animal development and disease. Cell147(4), 742–58.
SUSAN ELMORE (2007).Apoptosis: A Review of Programmed Cell Death Toxicologic Pathology, 35:495–516.
Mark S D’Arcy (2019). Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int 43: 582–592.