For every cell, there is a time to live and a time to die.

There are two ways in which cells die:

• they are killed by injurious agents
• they are induced to commit suicide

Death by injury

• mechanical damage
• exposure to toxic chemicals

• 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 cell contents leak out, leading to
• inflammation of surrounding tissues

Death by suicide

• shrink
• have their mitochondria break down with the release of cytochrome c
• develop bubble-like blebs on their surface
• have the chromatin (DNA and protein) in their nucleus degraded
• break into small, membrane-wrapped, fragments which are usually
• engulfed by nearby phagocytic cells like macrophages
• do not induce inflammation

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?

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

• The resorption of the tadpole tail at the time of its metamorphosis into a frog occurs by apoptosis.
• The formation of the fingers and toes of the fetus requires the removal, by apoptosis, of the tissue between them.
• The sloughing off of the inner lining of the uterus (the endometrium) at the start of menstruation occurs by apoptosis.
• The formation of the proper connections (synapses) between neurons in the brain requires that surplus cells be eliminated by apoptosis

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

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.)

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 lupus erythematosus and rheumatoid arthritis.

Cells with DNA damage

Damage to its genome can cause a cell

• 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.

What makes a cell decide to commit suicide?

• the withdrawal of positive signals; that is, signals needed for continued survival
• the receipt of negative signals

Withdrawal of positive signals

• growth factors for neurons
• Interleukin-2 (IL-2), an essential factor for the mitosis of lymphocytes

Receipt of negative signals

• increased levels of oxidants within the cell
• damage to DNA by these oxidants or other agents like
  • ultraviolet light
  • x-rays
  • chemotherapeutic drugs
• molecules that bind to specific receptors on the cell surface and signal the cell to begin the apoptosis program. These death activators include:
  • Tumor necrosis factor (TNF) that binds to the TNF receptor
  • Lymphotoxin that also binds to the TNF receptor
  • Fas ligand (FasL), a molecule that binds to a cell-surface receptor named Fas (also called CD95)

The Mechanisms of Apoptosis

• one generated by signals arising within the cell
• the other triggered by death activators binding to receptors at the cell surface.
  • TNF
  • Lymphotoxin
  • Fas ligand (FasL)

Apoptosis triggered by internal signals

• In a healthy cell, the outer membranes of
  • mitochondria
  • the endoplasmic reticulum (ER)
  • the nuclear envelope
• express the protein Bcl-2 on their surface.
• Bcl-2 binds a molecule of the protein
  • Apaf-1, which is itself bound to a molecule of
  • caspase 9
• 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).
• The trimer of Bcl-2/Apaf-1/caspase 9 has been tentatively named the apoptosome.
• Internal damage in the cell causes Bcl-2 to release the heterodimer of Apaf-1 and caspase 9.
• These aggregate in the cytosol.
• Caspase 9 cleaves and, in so doing, activates other caspases.
• The sequential activation of one caspase by another 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
  • degradation of chromosomal DNA and
• death of the cell

Apoptosis triggered by external signals

• 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
• death of the cell.

Apoptosis and Cancer

• Two 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 a cause of Burkitt's lymphoma
  • 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 the cancer cell to continue to proliferate).

• Some cancer cells produce high levels of Bcl-2, thus blocking apoptotic signals they may receive.
  • melanoma is a notorious example
  • Some B-cell leukemias and lymphomas express high levels of Bcl-2 because of a translocation of the BCL-2 gene into an enhancer region for antibody production. [Discussion].
• Some cancer cells express high levels of FasL, thus killing any cytotoxic T cells (CTL) that try to kill them. (CTL also express Fas; and this mechanism is the reverse of the one shown below).
• Other 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 below.

Apoptosis and AIDS

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 by binding to their surface CD4 molecules. This binding is mediated by gp120, a surface glycoprotein (encoded by the virus's env gene). One might assume that it is infection by HIV that causes these cells to die. 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:

• gp120 is a peripheral membrane protein and much of it leaves the membrane and enters the blood and lymph in soluble form.
• soluble gp120 binds to the CD4 molecules on uninfected T cells
  • (perhaps aided by the anti-gp120 antibodies that are produced following HIV infection and that are the basis of the most common blood test for HIV infection)
• this binding cross-links the CD4 molecules on the T cell leading to
• increased expression of Fas.
• If these cells encounter a cell expressing FasL (macrophages and cytotoxic T cells [right] can), or even begin expressing FasL themselves, they
• commit suicide by apoptosis.

Apoptosis and Organ Transplants

For many years it has been known that certain parts of the body

• the anterior chamber of the eye
• the testes

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 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.

Welcome&Next Search

Apoptosis in medicine is one of the most hot area of research today. Understanding its mechanism will help in treating cancer,AIDS,ARTHRITIS,Aging. and many untreatable diseases. The name "APOPTOSIS"(second p is silent) was coined by

KERR and his colleagues for their seminal work in 1972.

What's the intriguing relationship between Apoptosis, EFA( Essential Fatty Acids). and Honey.

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ALL FORMS OF SYNTHETIC VITAMINES ARE USELESS.
APOPTOSIS--part-#3

Apoptosis

T. Fernandes-Alnemri, A. Takahashi, R. Armstrong, J. Krebs, L. Fritz, K.J. Tomaselli, L. Wang, Z. Yu, C.M. Croce, G. Salveson, W.C. Earnshaw, G. Litwack, E.S. Alnemri, "Mch3, a novel human apoptotic cysteine protease highly related to CPP32," Cancer Research, 55:6045-52, 1995. (Cited in more than 140 publications through November 1997)

Comments by Emad S. Alnemri, Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia

In the past five years, knowledge of apoptosis, or programmed cell death, has advanced rapidly and attracted wide attention, as it seems to touch on many areas of cell research. Through apoptosis, the tadpole loses its tail and becomes a frog. In human embryos, apoptosis carves fingers from mitt-like hands. It is a fundamental biological process that plays a critical role in the normal development of multicellular organisms through cellular differentiation and tissue homeostasis.

INSIGHTS ON DEATH: Emad Alnemri has led research teams that discovered six of at least 10 proteins essential in apoptosis. Apoptosis occurs during normal aging and sometimes during irreversible cell injury resulting from exposure to radiation or other poisons. Scientists also believe faulty apoptosis underlies neurodegenerative disorders like Alzheimer's and Parkinson's diseases, and autoimmune diseases like systemic lupus erythematosus. Under certain conditions, the inability of a cell to undergo apoptosis may even lead to the development of cancer. "Obviously, the more that is learned about this critical cellular process, the better our chances are of developing treatments for the diseases associated with it," says Emad R. Alnemri, an associate professor of microbiology and immunology at the Kimmel Cancer Center of Thomas Jefferson University in Philadelphia.

At the molecular level, a family of at least 10 proteins or caspases, which make up the basic structure of the apoptotic cascade or sequence, has been identified in humans. Six of these have been discovered by Alnemri's team (E.S. Alnemri, Journal of Cellular Biochemistry, 64:33-44, 1997; S.M. Srinivasula et al., Journal of Biological Chemistry, 271:27099-106, 1996). These death-related proteins are Mch2, Mch3, Mch4, Mch5, Mch6, and the well-known caspase CPP32. In a multicellular organism, the proteolytic or protein-cleaving activity of these proteins is needed to fragment and shrink unwanted dying cells so they can be scavenged by neighboring cells.

Mch3 was the third apoptotic protein identified in Alnemri's laboratory. Interestingly, Mch3 is similar to CPP32 with respect to its amino acid sequence and its ability to cleave a DNA repair enzyme called PARP. Previously, CPP32 was believed to be the "death protease" because of its ability to cleave PARP. Alnemri's team observed not only that Mch3 was able to cleave PARP as efficiently as CPP32, but also that the recombinant subunits of Mch3 were able to substitute for recombinant subunits of CPP32. Like CPP32, Mch3 is poorly inhibitable by the cowpox virus antiapoptotic protein CrmA. Such similarity between CPP32 and Mch3 suggests that Mch3 may well substitute for CPP32 activity. Tissues and cell lines like breast carcinoma MCF7, which do not express high levels of CPP32, may in fact have their CPP32-like activity contributed by Mch3.

The discovery by Alnemri's research team has received significant attention because it could explain why CPP32-deficient mice experience abnormal growth only in the brain. In studies directed by Richard A. Flavell, a Howard Hughes Medical Institute investigator and an immunobiologist at Yale University School of Medicine, CPP32-deficient mice died within three weeks of age"

ask me why, ask me how ? e-mail me for details. Please for the rest of the discussion,consult Alnemri's cited work. C U SOON.