Apoptosis

Apoptosis describes the programmed cell death, the deliberate suicide of a cell in a multicellular organism for the greater good of the whole individual. In contrast to necrosis, apoptosis occurs naturally during development, for example, the differentiation of human fingers requires the cells in between the fingers to initiate apoptosis so that the fingers can separate.

The fact that apoptosis has been the subject of increasing attention and research efforts was highlighted by the award of the 2002 Nobel Prize in Physiology or Medicine to Sydney Brenner[?] (Great Britain), H. Robert Horvitz[?] (US) and John E. Sulston[?] (GB) "for their discoveries concerning genetic regulation of organ development and programmed cell death" (see [1] (http://www.nobel.se/medicine/laureates/2002/index) ).

Table of contents 1 Uses of apoptosis 1.1 Cell damage or infection 1.2 Immune cell regulation 1.3 Development 1.4 Homeostasis 2 Apoptotic process 2.1 Morphology 2.2 Biochemical reactions 2.3 Biochemical execution 2.4 Role of apoptotic products in tumor immunity

Uses of apoptosis

Cell damage or infection

Apoptosis also occurs when a cell is damaged beyond repair, or infected with a virus. The "decision" for apoptosis can come from the cell itself, or from a call that is part of the immune system. If the apoptosis program of a cell itself is damaged (by mutation), or if the initiation is blocked (by a virus), a damaged cell can start growing without restrictions, developing into cancer.

Immune cell regulation

Some cells of the immune systems, the B cells and T cells, can become autoreactive, attacking healthy body cells. These are destroyed via apoptosis. Also, to prevent T cells from attacking healthy body cells right away, they are tested for autoimmune reactions within their origin tissue, the thymus. About 95% of the freshly produced T cells are killed right away via apoptosis due to autoimmune reactions.

Development

Programmed cell death is an integral part of vertebrate tissue development, and it does not elicit the inflammatory response which is characteristic of necrosis. In other words, apoptosis does not resemble the sort of reaction that comes as a result of tissue damage due to accident or pathogenic infection. Instead of swelling and bursting --and, hence, spilling their internal contents into extracellular space--, apoptotic cells and their nuclei shrink, and often fragment. In this way, they can be efficiently phagocytosed (and, as a consequence of this, their components reused) by macrophages or by neighboring cells.

Homeostasis

In the adult organism, the number of cells within an organ or tissue has to be constant within a certain range. This is called homeostasis. It is achieved when the rate of mitosis in the tissue equals the rate of cells going into apoptosis. If this equilibrium is disturbed, either of two things happen:

• The cells are dividing faster than they die, effectively developing a tumor.
• The cells are dividing slower than they die, which results in the tissue shrinking until no cells are left.

Both states are usually fatal if they remain untreated.

Apoptotic process

Morphology

A cell undergoing apoptosis shows a characteristic morphology that can be seen under a microscope:

1. The cell becomes round (circular).
2. Its DNA condenses.
3. Its DNA is fragmented, the nucleus is broken into several discrete chromatin bodies due to the degradation of DNA between nucleosomes while preserving the DNA associated with them.
4. The cell breaks apart into several vesicles called apoptotic bodies.
5. The cell is phagocytosed.

Biochemical reactions

Most apoptosis-inducing messages, from both outside and inside the cell, target a central death signal. This signal activates ICE-proteases, which initiate and perform part of the apoptosis program.

Apoptotic messages from outside the cell (extrinsic factors) will be briefly desribed in the next section of this article. (For a detailed description of an extrinsic apoptotic pathway see "The Fas Signaling Pathway: More Than a Paradigm", by Harald Wajant, in Science, Vol. 296, No. 5573, p. 1635, May 31, 2002).

Apoptotic messages from inside the cell (intrinsic factors) emerge from mitochondria.

Biochemical execution

Apoptosis is executed by enzymes called caspases[?] (see "Controlling the Caspases", by Stephen W. Fesik and Yigong Shi, in Science, Vol. 294, No. 5546, p. 1477, November 16, 2001), which are normally suppressed by IAP[?] (inhibitor of apoptosis) proteins. When a cell receives an apoptotic stimulus, IAP activity is relieved after SMAC (Second Mitochondria-derived Activator of Caspases, also called DIABLO), a mitochondrial protein, is released into the cytosol.

Tumor necrosis factor (TNF[?]), a 157 amino acid inter-cellular signaling molecule (cytokine), is the major extrinsic mediator of apoptosis. The cell membrane has two specialized receptors for TNF: TNF-R1 and TNF-R2. The binding of TNF to TNF-R1 has been shown to fire-off the pathway that leads to activating the caspases (see "TNF-R1 Signaling: A Beautiful Pathway", by Guoqing Chen and David V. Goeddel, in Science, Vol. 296, No. 5573, p. 1634).

The whole process requires energy and a cell machinery not too damaged. If the cell damage is between certain levels, the cell can start the earliest events of apoptosis and then continue with a necrosis.

The link between TNF and apoptosis shows why an abnormal production of TNF plays a fundamental role in several human diseases, especially (but not only) in autoimmune diseases, such as diabetes and multiple sclerosis.

Role of apoptotic products in tumor immunity

An interesting case of re-use and feed-back of apoptotic products was presented by Matthew L. Albert in a research article that won him an Amersham Biosciences & Science Prize for Young Scientists in Molecular Biology, and published in Science Online in December, 2001. Albert described how dendritic Cells, a type of antigen-presenting cells, phagocytose (that is, engulf) apoptotic tumor cells. Upon maturation, these dendritic cells present antigen (derived from the apoptotic corpses) to killer T cells, which are then primed for the eradication of cells undergoing malignant transformation. This apoptosis-dependent pathway for T cell activation is not present during necrosis, and has opened exciting posibilities in tumor immunity research.

See also: Immunology -- Biochemistry