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] ).

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.

Evolutionary origin of the apoptotic process

Biologists had long suspected that mitochondria originated from bacteria
that had been incorporated as endosymbionts (that is, a living body "living
together inside") of larger, eukaryotic cells. It was Lynn Margulis who,
since 1967, began championing this theory, that has since been widely
accepted (see "The Birth of Complex Cells", by Christian de Duve, Scientific
American Vol. 274, 4, April, 1996). The most convincing evidence for this
theory is the fact that mitochondria have their own DNA, and are equipped
with their own genes and replication apparatus.

This evolutionary step must have been more than risky for the eukaryotes
that began to engulf energy-producing prokaryotic bacteria, the ancestors of
mitochondria. The drama is still enacted today in our own white blood cells
(which, it must be said, are are much better equipped to entrap and destroy
bacteria that intend to invade our bodies). Most of the time, invading
bacteria are destroyed by the white blood cells; but, oftentimes, the
chemical warfare waged by the prokaryotes succeeds, with the known
consequences of infection, and the resulting damage.

One of those rare events in evolution, about two billion years before the
present, must have made it possible for certain eukaryotes and
energy-producing prokaryotes not only to coexist, but to mutually benefit
from their symbiosis.

In a very real and immediate sense, it can be said that eukaryotic cells
live poised between life and death, because mitochondria still retain their
repertoire of molecules that can trigger cell suicide (see "PARP-1 -a
Perpetrator of Apoptotic Cell Death?", by Alberto Chiarugi and Michael A.
Moskowitz, in Science, Vol. 297, No. 5579, p. 200). Given certain signals or
insults to cells --such as feed-back from neighbors, stress or DNA damage--
mitochondria release caspase activators that produce the cell-death-inducing
biochemical cascade.

As has been previously explained at the beginning of this article, however,
this fine equilibrium between life and death that all of us eukaryotic
beings carry most intimately and deeply, is essential to life.

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