Apoptosis: How a cell knows it is time to cease to exist.

By: Minh-Kinh Dang

California State University, Fullerton
Introduction
Abstract Etymology

Apoptosis is a highly regulated process

within multicellular organisms where cells
are programmed to die through various
biochemical pathways that change the
morphology of a cell to the point of death.
This process is normal and necessary for
organisms.
Apoptosis is an essential process for
organisms to control growth. When looking
at an organism and its life cycle, there needs
to be a balance of growth due to limitations
to available nutrients. As an organism grows
and cell populations multiply, billions must
die or else that organism will become
infinitely larger (Perl 2005).
The term Apoptosis was introduced into
science by J. F. R. Kerr and his colleagues,
A. H. Wyllie and A. R. Currie in 1972. It
comes from the ancient Greek where apo-
means from and ptosis means falling off
(Perl 2005). Under light microscopes,
researchers observed the programmed
process is started or stopped by external
stimuli (Kerr 1976). A basic understanding
of the process can be visualized in Figure 1.
The team could differentiate apoptosis from
necrosis, by demonstrating that apoptosis
was programmed single cell deaths via
certain signals as opposed to uncontrolled
widespread cell death throughout a tissue
(Perl 2005).

Figure 1: Basic understanding of morphological, cell,structure, changes to cell envelope and

organelles under a light microscope (Perl 2005)
History
When J. F. R. Kerr and his colleagues,
described the process, they divided it into
two stages. The first stage was determined
when there was the formation of apoptotic
bodies, while in the second phase, the
apoptotic bodies are engulfed via
phagocytosis by other cells (Kerr 1976). The
cells that engulfed the
apoptotic bodies then digest the components
down to the basic building blocks of cell
development to be recycled for other uses.
Figure 2: Diagram to illustrate the morphological features and steps of apoptosis during the dinitial
discovery phase (Kerr 1976).
Referring to Figure 2, the researchers
observed apoptosis by the separation of a
cell from contact with other surrounding
cells by the shrinkage and condensation of
the cytoplasm. Next, the organelles and
cytoskeleton breakdown, causing the
collapse of the cell structure. When
examining cells, the process would then be
easily identified by the apoptotic bodies,
which are spherical cytoplasmic fragments
containing leftover parts from a cell after it
has been programmed to die (Kerr 1976).
The apoptotic bodies would therefore
contain the residues from the cell’s
organelles, cytoskeleton, and genetic
materials.
These observations, however, only represent
the fact that the cell has already begun the
process of individual cell death that is not
widespread (Perl 2005). Therefore, necrosis
could be ruled out and an external stimulus
must be responsible. These observations
don’t show the complete picture, therefore,
they would need to look at certain ways the
cells could have been signaled to die.
Certain types of caspases were discovered to
be responsible for the signaling pathways in
the cell (Perl 2005). Caspases, which are a
type of proteolytic enzyme, have shown to
be active in multiple different pathways for
apoptosis.
Apoptotic Morphology
Knowing that the process of apoptosis must
have been activated somehow, researchers
discovered the classical case of apoptosis
requires the activation of caspase-3 in the
cell (Marcel Leist 2001).
By studying the causes of apoptosis through
different experiments, new phases were
developed to show a general picture of the
process as seen in Figure 3.
The Initiation phase is now classified as the
first stage of apoptosis. Signals from various
different types of stimuli can send signals to
a cell and start a cascade of biochemical
events starting from outside the cell to the
mitochondria organelle (Mattson 2000).
In the next stage of apoptosis, Effector
phase, the mitochondria release the enzyme
cytochrome c into the intercellular fluid and
combine with caspase-9, to activate caspase-
3 and begin the next phase of apoptosis
(Mattson 2000).
Lastly, in the Degradation phase, the nucleus
begins to fragment and changes in the cell
membrane allow nearby macrophages, cells
that engulfs and digests cellular materials, to
sense the subsequent apoptotic bodies and
engulf the debris (Mattson 2000).
In order for the macrophages to engulf the
apoptotic bodies, they are signaled by the
phosphatidylserine, a fatty acid in the cell
membrane, which is exposed as the cell
membrane undergoes blubbing (Marcel
Leist 2001). The clean up by macrophages
begin.
Further experimentation is required to
understand how the caspase-3 is activated,
to then comprehend the mechanism of
programmed cell death from the beginning
to end.
If something can be activated, then there
could be a way to inhibit its activation.
Therefore, the inhibition of a caspase should
stop a cell from disintegration into tiny little
apoptotic bodies. Instead, scientists have
discovered that sometimes backup pathways
could be activated by different caspases and
the cell can continue to undergo apoptosis.
Even after the cell was initially disabled by
inhibition (Marcel Leist 2001).
Figure 3: The most current
diagram of morphological
and biochemical features of
apoptosis (Mattson 2000)
 Activation vs Inhibition
What is important to note about the path of
activation is the cascade effect. Once the
programmed cell death signals have been
sent and received, there nothing that can be
done to stop the reaction since it is occurring
at a rapid pace (Marcel Leist 2001).
Caspases were initially studied to prove
whether apoptosis can be induced or
inhibited, but other mechanisms were
discovered.
Figure 4: Summary of the general signaling pathways that promote or inhibit apoptosis
(Perl 2005).
In Figure 4, two of the most common
pathways and the components of each step
are shown. Notice that by comparing each
component to Table 1 on the next page, that
each component plays a role of either
activating or inhibiting apoptosis.
By understanding the biochemical path to
reach the activation of apoptosis, researchers
have been able to create Table 1 based on
the results of experimental tests at each step
to see when disabled, whether apoptosis is
continued to be activated or be inhibited
(Mattson 2000).
Table 1: Examples of pro-apoptotic proteins that promote apoptosis amd anti-apoptotic
proteins that inhibit apoptosis (Mattson 2006).
Discussion
The study of activation and inhibition leads
to studies regarding treating disorders we
find when apoptosis does not occur
properly.
One notable neurodegenerative disorder to
consider is Alzheimer’s disease, where
nerve cells and its synapses are degenerating
at an uncontrollable, irreversible rate due to
external stimuli in the brain (Mattson 2000).
Researchers have discovered the damage
was prevalent in the anti-apoptotic
components of the process, therefore, the
process keeps continuing without a signal to
stop the neurons from fragmenting (Mattson
2000).
Conversely, tumor formation has also been
known to occur due to the malfunctioning of
pro-apoptotic p53 genes, leading to
uncontrolled cell growth and eventual
cancerous cells developing (Marcel Leist
2001).
Conclusion
Not everything is understood yet about all
the different pathways of apoptosis.
Hopefully, as researchers continue their
research, they could better understand and
treat disorders in humans as a result of
uncontrolled cell growth and tumor
formation from failures in apoptosis.
Works Cited

J F R Kerr, A H Wyllie, & A R Currie. (1972). Apoptosis: A Basic Biological Phenomenon with
Wide-ranging Implications in Tissue Kinetics. British Journal of Cancer, 26(4), 239-257.

Marcel Leist, & Marja Jäättelä. (2001). Four deaths and a funeral: From caspases to alternative
mechanisms. Nature Reviews Molecular Cell Biology,2(8), 589-98.

Mattson, M. (2000). Apoptosis in neurodegenerative disorders. Nature Reviews. Molecular Cell

Biology, 1(2), 120-9.

Minji Jo, Tae-Hyoung Kim, Dai-Wu Seol, James E. Esplen, Kenneth Dorko, Timothy R. Billiar,
& Stephen C. Strom. (2000). Apoptosis induced in normal human hepatocytes by tumor necrosis
factor-related apoptosis-inducing ligand. Nature Medicine, 6(5), 564-567.

Moghimipour, Rezaei, Ramezani, Kouchak, Amini, Angali, . . . Handali. (2018). Transferrin

targeted liposomal 5-fluorouracil induced apoptosis via mitochondria signaling pathway in
cancer cells. Life Sciences, 194, 104-110.

Perl, M., Chung, C., & Ayala, A. (2005). Apoptosis. Critical Care Medicine, 33(12 Suppl), S526-
S529.

Post Write: I used etymology to define the term and gave a historical background. There were
diagrams used to illustrate the old and new process to how apoptosis was known. Lastly, charts
were used to help compare and contrast differences in how components affect the pathways.