They (and their organelles like mitochondria) swell (because the ability of the plasma membrane to control the passage of ions and water is disrupted).
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.)
to disrupt proper embryonic development leading to birth defects
to become cancerous.
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.
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:
growth factors for neurons
Interleukin-2 (IL-2), an essential factor for the mitosis of lymphocytes
Caspase-9 is one of a family of over a dozen caspases. They are all proteases. They get their name because they cleave proteins — mostly each other — at aspartic acid (Asp) residues).
Caspase-9 cleaves and, in so doing, activates other caspases (caspase-3 and -7).
The activation of these "executioner" caspases creates an expanding cascade of proteolytic activity (rather like that in blood clotting and complement activation) which leads to
digestion of structural proteins in the cytoplasm,
Fas and the TNF receptor are integral membrane proteins with their receptor domains exposed at the surface of the cell
binding of the complementary death activator (FasL and TNF respectively) transmits a signal to the cytoplasm that leads to
activation of caspase 8
caspase 8 (like caspase 9) initiates a cascade of caspase activation leading to
phagocytosis of the cell.
Example (right): When cytotoxic T cells recognize (bind to) their target,
they produce more FasL at their surface.
This binds with the Fas on the surface of the target cell leading to its death by apoptosis.
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.
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
is released from the mitochondria (like the release of cytochrome c in the first pathway);
migrates into the nucleus;
binds to DNA, which
triggers the destruction of the DNA and cell death.
Some viruses associated with cancers use tricks to prevent apoptosis of the cells they have transformed.
Several human papilloma viruses (HPV) have been implicated in causing cervical cancer. One of them produces a protein (E6) that binds and inactivates the apoptosis promoter p53.
Epstein-Barr Virus (EBV), the cause of mononucleosis and associated with some lymphomas
produces a protein similar to Bcl-2
produces another protein that causes the cell to increase its own production of Bcl-2. Both these actions make the cell more resistant to apoptosis (thus enabling a cancer cell to continue to proliferate).
Even cancer cells produced without the participation of viruses may have tricks to avoid apoptosis.
Some B-cell leukemias and lymphomas express high levels of Bcl-2, thus blocking apoptotic signals they may receive. The high levels result from a translocation of the BCL-2 gene into an enhancer region for antibody production. [Discussion].
Melanoma (the most dangerous type of skin cancer) cells avoid apoptosis by inhibiting the expression of the gene encoding Apaf-1.
Some cancer cells, especially lung and colon cancer cells, secrete elevated levels of a soluble "decoy" molecule that binds to FasL, plugging it up so it cannot bind Fas. Thus, cytotoxic T cells (CTL) cannot kill the cancer cells by the mechanism shown above.
Other cancer cells express high levels of FasL, and can kill any cytotoxic T cells (CTL) that try to kill them because CTL also express Fas (but are protected from their own FasL).
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:
an accumulation of lymphocytes in the lymph nodes and spleen greatly enlarging them.
the appearance of clones that are autoreactive; that is, attack "self" components producing such autoimmune disorders as
the appearance of lymphoma — a cancerous clone of lymphocytes.
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.
The hallmark of AIDS (acquired immunodeficiency syndrome) is the decline in the number of the patient's CD4+ T cells (normally about 1000 per microliter (µl) of blood). CD4+ T cells are responsible, directly or indirectly (as helper cells), for all immune responses. When their number declines below about 200 per µl, the patient is no longer able to mount effective immune responses and begins to suffer a series of dangerous infections.
What causes the disappearance of CD4+ T cells?
HIV (human immunodeficiency virus) invades CD4+ T cells, and one might assume that it this infection by HIV that causes the great dying-off of these cells. However, that appears not to the main culprit. Fewer than 1 in 100,000 CD4+ T cells in the blood of AIDS patients are actually infected with the virus.
So what kills so many uninfected CD4+ cells?
The answer is clear: apoptosis.
The mechanism is not clear. There are several possibilities. One of them:
All T cells, both infected and uninfected, express Fas.
Expression of a HIV gene (called Nef) in a HIV-infected cell causes
the cell to express high levels of FasL at its surface
while preventing an interaction with its own Fas from causing it to self-destruct.
However, when the infected T cell encounters an uninfected one (e.g. in a lymph node), the interaction of FasL with Fas on the uninfected cell kills it by apoptosis.
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.
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.
