APOPTOSIS

Apoptosis is a tightly regulated form of cell death, also

called the programmed cell death. Morphologically, it is
characterized by chromatin condensation and cell
shrinkage in the early stage. Then the nucleus and
cytoplasm fragment, forming membrane-bound apoptotic
bodies which can be engulfed by phagocytes. In contrast,
cells undergo another form of cell death, necrosis, swell
and rupture. The released intracellular contents can
damage surrounding cells and often cause inflammation.

Apoptosis is an important process during normal

development. It is also involved in aging and various
diseases such as cancer, AIDS, Alzheimer's disease and
Parkinson's disease.

The Mechanism

Figure 6-G-1. Comparison between active and inactive

forms of caspases. Newly produced caspases are
inactive. Specifically cleaved caspases will dimerize and
become active.

During apoptosis, the cell is killed by a class of proteases

called caspases. More than 10 caspases have been
identified. Some of them (e.g., caspase 8 and 10) are
involved in the initiation of apoptosis, others (caspase 3, 6,
and 7) execute the death order by destroying essential
proteins in the cell. The apoptotic process can be
summarized as follows:

1. Activation of initiating caspases by specific signals

(Figure 6-G-2).
2. Activation of executing caspases by the initiating
caspases which can cleave inactive caspases at specific
sites.
3. Degradation of essential cellular proteins by the
executing caspases with their protease activity.

Figure 6-G-2. Coupling of caspase 8 or 10 to death

receptors.
 • Death receptors: Fas/CD95, DR4/DR5, DR3, and TNFR
(Tumor Necrosis Factor Receptor).

• Adaptors: FADD (Fas-associated death domain protein)

and TRADD (TNFR-associated death domain protein).

• Activation: Binding of death ligands (FasL/CD95L,

TRAIL/APO-2L, APO-3L and TNF) induces trimerization of
their receptors, which then recruit adaptors and
activate caspases.

• Note: TRADD is involved only in the coupling between

caspases and DR3 or TNFR. This adaptor can also
recruit other proteins to inhibit apoptosis through the
NF-kB pathway.

As shown in the above figure, a variety of death ligands

(FasL/CD95L, TRAIL, APO-3L and TNF) can induce apoptosis.
It is natural to see if they can kill cancer cells without
affecting normal cells. TNF was first investigated in the
1980s for cancer therapy, but with disappointing results.
Then CD95L (FasL) was tested in the 1990s. The results were
still not satisfactory. Recently, TRAIL has been
demonstrated to be highly selective for transformed cells,
with minimal effects on normal cells. It could be an effective
drug for both cancer and AIDS.
References:

1. Agency for Science, Technology and Research. "Prof Andrew H.

Wyllie - Lecture Abstract". Archived from the original on 2007-11-
13. http://web.archive.org/web/20071113101931/http://www.a-
star.edu.sg/astar/biomed/action/biomed_dvp_abstract.do?
id=2901ddeb02dH. Retrieved 2007-03-30.

2. Kerr JF, Wyllie AH, Currie AR (August 1972). "Apoptosis: a basic

biological phenomenon with wide-ranging implications in tissue
kinetics". Br. J. Cancer 26 (4): 239–57. PMID 4561027.

3. O'Rourke MG, Ellem KA (2000). "John Kerr and apoptosis". Med.

J. Aust. 173 (11-12): 616–7. PMID 11379508.
http://www.mja.com.au/public/issues/173_11_041200/orourke/orour
ke.html.

4. Apoptosis Interest Group (1999). "About apoptosis".

http://www.nih.gov/sigs/aig/Aboutapo.html. Retrieved 2006-12-15.