Physician Education: Apoptosis.

We have come to understand apoptosis as not merely a single form of cell
death, but as a fundamental theme in cell biology that has far-reaching
implications in the fields of physiology and pathology.

At the present time, however, the mechanism of apoptosis is not clearly
understood, as research into apoptosis is still at the initial stages.

Nevertheless, the links between apoptosis and a variety of pathological
conditions are gradually becoming clearer.

In this article, we will provide a simple explanation of apoptosis and its
mechanism as a novel concept of cell death and discuss the way in which
apoptosis has been linked to a variety of pathological conditions.

WHAT IS APOPTOSIS?: In normal tissue, cells that are no longer needed are
rapidly eliminated without affecting the overall function of the tissue.

In this process cells undergo an active and spontaneous suicide called
programmed cell death.

In fact, the majority of physiological cell deaths take the form of apoptosis.

The word apoptosis is used, in contrast to necrosis, to describe the
situation in which a cell actively pursues a course toward death upon
receiving certain stimuli [1].

The morphological changes of apoptosis found in most cell types first
involve contraction in cell volume and condensation of the nucleus.

When this happens the intracellular organelles such as the mitochondria
retain their normal morphology.

As apoptosis proceeds, blebbing of the plasma membrane occurs, and the
nucleus becomes fragmented.

Finally, the cell itself fragments to form apoptotic bodies that are
engulfed by nearby phagocytes.

With respect to biochemical changes, it is known that the chromosomes
become fragmented into nucleosome units, and DNA forms characteristic
ladder patterns when subjected to agarose gel electrophoresis.

MECHANISM OF APOPTOSIS: It has been reported that apoptosis is induced in
various cells by many kinds of irritations, but the precise mechanism is
still unclear.

Cell injuries that induce apoptosis include those that cause DNA damage
such as radiation and anticancer drugs, those that are mediated by the TNF
receptor and Fas receptor (the so-called "death signal receptors"), and the
deprivation of cytokines that supply survival signals such as IL-3 and
erythropoietin.

The tumor suppressor gene p53 plays a very important role in apoptosis
induced by damage to DNA.

This has been demonstrated by studying resistance to apoptosis of cells
derived from p53 knockout mice [2].

Other than the irritations that induce apoptosis, molecules that have been
strongly implicated as major players in the drama of apoptosis include the
Bcl-2 family proteins and the IL-1 converting enzyme (ICE) and its homolog
proteases (caspase family).

Both groups of proteins show homology with proteins that affect cell death
in nematodes.

It is believed that molecules that contribute to cell death have been well
conserved in multicellular organisms all the way from the relatively
primitive nematodes to mammals including humans.

It was discovered that Bcl-2 suppressed apoptosis induced in IL-3 dependent
cells by deprivation of IL-3 [3]. It has since become the gene around which
apoptosis research revolves.

Recently, it has become clear that cell death involving the Bcl-2 protein
is under the control of similar proteins from the same family [4].

It is interesting that the phenomenon of cell death may be regulated by the
balance of the molecules involved in it.

APOPTOSIS ABNORMALITIES AND DISEASE: Physiological cell death plays a major
role in the growth and permanent maintenance of the human body [5].

In the process of forming the nervous system, neurons that do not form
proper connections die.

Physiological cell death also accompanies the removal of virus-infected
cells by cytotoxic T cells, the elimination of autoreactive immune cells,
the formation of the gut, the reconstitution of cartilage and bone, etc.

When physiological cell death that normally should occur is inhibited,
inappropriate physiological cell death may occur that is harmful to the
body and forms the basis of disease.

For example, in patients with neural degenerative disorders such as
Alzheimer's disease and Parkinson's disease, we can find premature cell
death in a particular subset of neurons.

The death of T cells in AIDS patients is also a form of physiological cell
death.

Inhibition of cell death in the immune system enables the survival of
autoreactive B cells and T cells, and is therefore a cause of autoimmune
disorders.

Apoptosis has been particularly linked to cancer.

Normal cells are programmed for death if they are subjected to many types
of non-physiological stress such as anticancer drugs or radiation, if they
become isolated from surrounding cells and are unable to receive their
tissue-specific survival signals [6], or if oncogenes are expressed
haphazardly [7].

On the other hand, it is believed that the ability to survive is enhanced
in transformed cancer cells because they are more resistant to apoptosis,
they exhibit resistance to anticancer drugs, they are no longer dependent
on survival signals, and they can metastasize.

Therefore, the cancer progresses as the cancer cells maintain the
proliferative superiority they acquire from their oncogenes.

In other words, when cancer cells become resistant to apoptosis, they
become resistant to treatment, metastasize, and proliferate destructively.

The concept that the malignancy of cancer is due to its resistance to
apoptosis is a relatively new one and is worthy of further study.


Oncologist 1996;1(6):399-401
Kataoka S, Tsuruo T
Pharmaceutical Research Institute, Kirin Brewery Co., Ltd., Tokyo, 150-8011,
Japan.
PMID: 10388021

http://www.ncbi.nlm.nih.gov/PubMed/

janet paterson
52 now / 41 dx / 37 onset
snail-mail: PO Box 171  Almonte  Ontario  K0A 1A0  Canada
website: a new voice <http://www.geocities.com/SoHo/Village/6263/>
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