Apoptosis

Apoptosis is a process by which cells in a multicellular organism undergo a controlled death. It is one of the main types of programmed cell death, and involves a series of cellular reactions which cause a cell to break down its internal components while maintaining its cell membrane integrity. In contrast to necrosis, apoptotic cells remain in control of their physiology and maintain their energy balance and osmotic potential. This is important because by avoiding osmotic lysis, apoptotic cells do not spill their contents into the local tissue, and so avoid initiating inflammation that can cause further tissue damage and cell death.

Apoptosis is a normal, physiological process important for the growth, development and maintenance of multicellular organisms. It can be activated by cells that have been injured or stressed before they become unable to control their metabolism, avoiding necrosis. Cells may also apoptose if they undergo changes (e.g. genetic mutations) that lead to uncontrolled or inappropriate cell division; this benefits the organism by removing cells that are functioning abnormally and which could potentially become cancerous. Apoptosis is also important in allowing cells no longer needed by the body to be removed efficiently and safely. For example, this is important for the development of digits in the embryo, where cells between digits undergo apoptosis, allowing them to become separated from each other.

Defects in apoptosis are implicated in a large variety of diseases. For example, underactivity or loss of apoptotic pathways in cells is one of the contributing factors to the formation of cancer; reversing this by encouraging apoptosis in cancerous cells is one method used by some anti-cancer treatments to treat it.

The process of apoptosis

Apoptosis is controlled by a number of tightly regulated signalling pathways that control a cell's survival based on its local environment and internal condition. All of these terminate on a final effector pathway involving a group of proteases called caspases, many of which are the final effectors of apoptosis. Caspases recognise specific sequences containing aspartate residues in certain proteins and can cleave them when active. They perform apoptosis both by breaking down cellular proteins directly and also by activation of other hydrolytic enzymes such as caspase activated DNAse (CAD); together the enzymes break down the cell's contents in a controlled fashion.

The extrinsic pathway

This pathway involves the direct activation of the apoptotic cascade by an external signalling molecule, called a death ligand, which allow cells to order other cells to undergo apoptosis. Two important examples of this apoptotic mechanism in mammals are the tumour necrosis factor (TNF) induced model and the Fas-Fas ligand-mediated model. TNF is a cytokine produced by activated macrophages, and plays important roles in both apoptotic and cell survival processes. It has two receptors, called TNF-R1 and TNF-R2, both of which are found on most cells in the human body. In the apoptotic pathway, TNF binding to TNF-R1 allows the receptor to bind the membrane proteins TNF receptor 1-associated death domain (TRADD) and Fas-associated death domain (FADD) via a special sequence on the intracellular portion of the receptor called a death domain. Both FADD and TRADD can then recruit inactive caspase-8 via another domain called a death effector domain to the receptor complex. Once recruited, caspase-8 can undergo autoproteolysis, activating itself; it can then activate caspase-3 by proteolysis, which starts the signalling cascade that leads to apoptosis.