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Apoptosis

For every cell, there is a time to live and a time to die.
There are two ways in which cells die:

Death by injury

Cells that are damaged by injury, such as by undergo a characteristic series of changes:

Death by suicide

Cells that are induced to commit suicide:

The pattern of events in death by suicide is so orderly that the process is often called programmed cell death or PCD. The cellular machinery of programmed cell death turns out to be as intrinsic to the cell as, say, mitosis.

Programmed cell death is also called apoptosis. (There is no consensus yet on how to pronounce it; some say  APE oh TOE sis; some say  uh POP tuh sis.)

Why should a cell commit suicide?

There are two different reasons.

1. Programmed cell death is as needed for proper development as mitosis is.

Examples:

2. Programmed cell death is needed to destroy cells that represent a threat to the integrity of the organism.

Examples:
Cells infected with viruses
One of the methods by which cytotoxic T lymphocytes (CTLs) kill virus-infected cells is by inducing apoptosis [diagram of the mechanism]. (And some viruses mount countermeasures to thwart it — Link)
Cells of the immune system
As cell-mediated immune responses wane, the effector cells must be removed to prevent them from attacking body constituents. CTLs induce apoptosis in each other and even in themselves. Defects in the apoptotic machinery is associated with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis.
Cells with DNA damage
Damage to its genome can cause a cell Cells respond to DNA damage by increasing their production of p53. p53 is a potent inducer of apoptosis. Is it any wonder that mutations in the p53 gene, producing a defective protein, are so often found in cancer cells (that represent a lethal threat to the organism if permitted to live)?
Cancer cells
Radiation and chemicals used in cancer therapy induce apoptosis in some types of cancer cells.

What makes a cell decide to commit suicide?

The balance between:

Withdrawal of positive signals

The continued survival of most cells requires that they receive continuous stimulation from other cells and, for many, continued adhesion to the surface on which they are growing. Some examples of positive signals:

Receipt of negative signals

The Mechanisms of Apoptosis

There are 3 different mechanisms by which a cell commits suicide by apoptosis.
  1. One generated by signals arising within the cell;
  2. another triggered by death activators binding to receptors at the cell surface:
  3. A third that may be triggered by dangerous reactive oxygen species.

1. Apoptosis triggered by internal signals: the intrinsic or mitochondrial pathway

2. Apoptosis triggered by external signals: the extrinsic or death receptor pathway

Example (right): When cytotoxic T cells recognize (bind to) their target,

The early steps in apoptosis are reversible — at least in C. elegans. In some cases, final destruction of the cell is guaranteed only with its engulfment by a phagocyte.

3. Apoptosis-Inducing Factor (AIF)

Neurons, and perhaps other cells, have another way to self-destruct that — unlike the two paths described above — does not use caspases.

Apoptosis-inducing factor (AIF) is a protein that is normally located in the intermembrane space of mitochondria. When the cell receives a signal telling it that it is time to die, AIF

Apoptosis and Cancer

Some viruses associated with cancers use tricks to prevent apoptosis of the cells they have transformed. Even cancer cells produced without the participation of viruses may have tricks to avoid apoptosis.

Apoptosis in the Immune System

The immune response to a foreign invader involves the proliferation of lymphocytes — T and/or B cells [Link]. When their job is done, they must be removed leaving only a small population of memory cells [Link]. This is done by apoptosis.

Very rarely humans are encountered with genetic defects in apoptosis. The most common one is a mutation in the gene for Fas, but mutations in the gene for FasL or even one of the caspases are occasionally seen. In all cases, the genetic problem produces autoimmune lymphoproliferative syndrome or ALPS.

Features:

In most patients with ALPS, the mutation is present in the germline; that is, every cell in their body carries it. In a few cases, however, the mutation is somatic; that is, has occurred in a precursor cell in the bone marrow. These later patients are genetic mosaics — with some lymphocytes that undergo apoptosis normally and others that do not. The latter tend to out-compete the former and grow to become the major population in the lymph nodes and blood.

Apoptosis and Organ Transplants

For many years it has been known that certain parts of the body such as are "immunologically privileged sites". Antigens within these sites fail to elicit an immune response.

It turns out that cells in these sites differ from the other cells of the body in that they express high levels of FasL at all times. Thus antigen-reactive T cells, which express Fas, would be killed when they enter these sites. (This is the reverse of the mechanism described above.)

This finding raises the possibility of a new way of preventing graft rejection.

If at least some of the cells on a transplanted kidney, liver, heart, etc. could be made to express high levels of FasL, that might protect the graft from attack by the T cells of the host's cell-mediated immune system. If so, then the present need for treatment with immunosuppressive drugs for the rest of the transplant recipient's life would be reduced or eliminated.

So far, the results in animal experiments have been mixed. Allografts engineered to express FasL have shown increased survival for kidneys but not for hearts or islets of Langerhans.

Apoptosis in Plants

Plant, too, can turn on a system of programmed cell death; for example, in an attempt to halt the spread of virus infection.

The mechanism differs from that in animals although it, too, involves a protease that — like caspases — cleaves other proteins at Asp (and Asn) residues.

Activation of this enzyme destroys the central vacuole, which is followed by disintegration of the rest of the cell.

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8 March 2014