Preprogrammed cell death. The genes responsible are also known as suicide genes. A natural mechanism for preventing cancer in higher organisms. Cells which are damaged, or old, or which have outlived their usefulness receive a molecular trigger that causes them to simply shrivel up and die without disrupting the cells around them. When apoptosis fails, cell lines can proliferate out of control, which can result in cancer. It should be noted that preventing these genes from acting will not grant immortality. Cells have a finite useful life, largely due to the fact that chromosomes lose some genetic material each time they replicate. Cells have to die when their chromosomes get too short, otherwise valuable genes would be lost each cycle of cell division. The ends of chromosomes are replenished using the enzyme Telomerase, which adds many repetitions of a short sequence to the end. Normal human cells have no Telomerase activity, except at a very low level in the gonads. Cancerous tumors do have telomerase activity.

Apoptosis, derived from the Greek for "falling off" (like leaves from a tree) is, by definition, physiological cell death occurring in an ordered and controlled manner. As such it is also called "programmed cell death" and is exclusive to eukaryotes.

In contrast to necrosis, which refers to the often messy death of cells due to acute injury often resulting in an inflammatory response, apoptosis is a deliberate, neat process involving the shrinking of cells and often occurs in healthy tissue. In a healthy adult human billions of cells die by apoptosis every hour, the majority of which are perfectly healthy. Defects in apoptosis can lead to autoimmune disease, due to abnormally long survival of lymphocytes, and the proliferation of cancer cells.

The molecular basis of Apoptosis:

The signals:

Apoptosis may occur in response to either an extracellular or an intracellular signal. An extracellular signal comes from killer lymphocytes which produces proteins called Fas ligands on their cell surface which bind to the membrane Fas proteins (also known as the death receptors) on the cell targeted for apoptosis. The death receptor proteins recruit adaptor proteins which aggregate a family of protease enzymes called caspases. Caspases are present in the cell in inactive forms prior to any signal and it is thought that aggregation causes activation either by conformational changes in the proteins or by causing them to cleave each other into an active form. These enzymes then amplify the death signal by activating further caspases and acheive cell death in the manner discussed below. Intracellular signals are often a response to stress or damage to the cell. In the best known example mitochondria release cytochrome c into the cytosol where it binds and activates the Apaf-1 protein which causes the aggregation of caspases and activates them as above. The release of cytochrome c can be caused by the proteins Bax and Bak, members of the Bcl-2 family. The transcription of the genes encoding these proteins is promoted by the transcription factor p53 which responds to damaged DNA (which may be due to loss of telomeres) and thus helps to prevent cancers that might otherwise form due to DNA damage. Cells are also able to undergo apoptosis in response to abnormal proliferation signals which are poorly understood. Activation of any of these pathways is irreversible.

Extracellular signals also serve to inhibit apoptosis. In this case survival factors bind to cell-surface receptors and initiate a signalling pathway that may supresses apoptosis often through inhibitory members of the Bcl-2 family of proteins such as Bcl-2 itself which appear to block cytochrome c release from mitochondria. Other pathways stimulate IAP (inhibitor of apoptosis) protein family members that prevent activation of caspases and inhibit the activity of already active caspases. Yet other pathways inhibit the production of apoptosis-promoting members of the Bcl-2 family. Thus these survival factors are necessary to prevent cells undergoing apoptosis. In this manner cell tissues can be regulated in size as they compete for a limited number of signal factors in order to ensure their survival.


After the activation of some caspase by aggregation the active proteases may cleave (and hence activate) further inactive caspases to amplify the death signal. Some of the activated caspases go on to cleave proteins essential to cell survival such as DNA fragmentation factor (DFF) which usually retains an inactive DNase enzyme but upon cleavage releases it as an active form which proceeds to destroy nuclear DNA. Other proteins cleaved by caspases include MDM2 which inactivates p53 under normal conditions, lamin and DNA repair enzymes, all of which are destroyed by this proteolysis.

The end result for the cell is that the nuclear envelope disassembles, DNA is destroyed, the cytoskeleton collapses, the cell shrinks and the cell surface is altered (called plasma membrane blebbing) which allows neighbouring cells or macrophages to recognise a cell which has undergone apoptosis and consume them by phagocytosis before cell leakage occurs, which would otherwise cause inflammation. The cell contents can then be recycled by the cell which has phagocytosed it.


Programmed cell death aids survival by destroying cells infected with a virus and prevents cancers by recognising the abnormal proliferation of mutated cells. It also helps cull cells to keep a balance with cell division and thus maintain the constant size of adult tissue, and in a manner visible under the light microscope is used to sculpt the digits out of the spade-like paws which initially grow in the mouse embryo. As such, with apoptosis it is clear as ever that death is a way of life.


Strasser A, O'Conner L & Dixit V M, Apoptosis Signalling, Annu. Rev. Biochem., 2000. 69:217-245

Molecular Biology of the Cell (4th edition), by Alberts et al., Garland Sciences, USA, (2002)

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