APOPTOSIS: PROGRAMMED CELL DEATH
The nature of apoptosis
Cell death is a necessary event in the life of a multicellular organism. During the process of development, for example, structures are formed that will be removed before the process is complete (flaps of tissues between the fingers, for example). It is also advantageous to have a mechanism for removing cells that are damaged and dysfunctional. This “programmed” cell death is referred to as apoptosis.
Apoptosis involves a number of readily observable cellular changes. In cells that are undergoing apoptosis, the cellular chromatin condenses near the nuclear membrane, the nucleus and cytoplasm shrink, and then dissociate into fragments that are then phagocytized. This is in contrast to another type of cell death called necrosis, which is characterized by swelling of the cell and the nucleus, swelling of mitochondria, and membrane disruption. Necrosis is typically triggered by injury to the cell.
The molecular steps involved in apoptosis
Research in recent years has been focused on understanding the molecular steps involved in apoptosis. It is clear that in most cells, proteins known as caspases are the ultimate “executioners”. These proteases (also called ICE-like proteases because of their similarity to interleukin- 1 converting enzyme) attack various structural and functional protein targets within the cell, leading to cellular death. But what triggers caspase activation? Evidence indicates that a mitochondrial protein called cytochrome c may play a significant role. Cytochrome c is released from the mitochondria during the process of apoptosis, where it binds to a protein called Apaf-1, and initiates a cascade of caspase activation.
To back up one more step, we must ask the question: what causes release of cytochrome c? Release of this molecule from the mitochondria appears to occur as part of what has been called the “mitochondrial permeability transition”, where the opening of a channel termed the PTP (permeability transition pore) leads to a dramatic increase in permeability that allows the release of cytochrome c. Evidence has indicated that the influence of pro-apoptotic regulator molecules including the proteins Bax and Bad, as well as anti-apoptotic regulators like Bcl-2 and Bcl-xL are mediated through their ability to stimulate or block the mitochondrial permeability transition. Other molecules that may play a role in regulation of apoptosis include:
Trophic or growth factors that may prevent cells from entering the apoptotic pathway.
These factors may phosphorylated and inactivate pro-apoptotic regulatorsTumor necrosis factor (TNF), which binds to a receptor and leads to direct activation of a caspase (caspase-8)
Some studies have also pointed to alternative mechanisms for apoptosis that do not involve the caspsases. This is based on evidence that cell death can and does occur in mice that are genetically engineered to be deficient in certain caspases. A protein called AIF, which can induce apoptotic changes, has been identified, and may play a role in these pathways.
Further reading on this topic:
Duke, Richard C., Ojcius, David M., and Young, John Ding-E. 1996. Cell suicide in health and disease. Scientific American, December 1996 pp.80-87.
Hayes, A.W., editor. 2001. Principles and Methods of Toxicology. Taylor and Francis, Philadelphia.
Karp, Gerald. 2002. Cell and Molecular Biology. John Wiley and Sons, New York.
Lodish, H., Berk, A., Zipursky, S.L., Matsudaira, P., Baltimore, D., Darnell, J. 2000. Molecular Cell Biology. W.H. Freeman and Company, New York
Weaver, Robert F. 1999. Molecular Biology. WCB McGraw-Hill, New York.
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