Apoptosis

Phil Dash
Basic Medical Sciences, St.Georges, University of London
www.sgul.ac.uk/dept/immunology/~dash
Apoptosis, or programmed cell death, is a
normal component of the development and
health of multicellular organisms. Cells
die in response to a variety of stimuli and
during apoptosis they do so in a controlled,
regulated fashion. This makes apoptosis
distinct from another form of cell death
called necrosis in which uncontrolled cell
death leads to lysis of cells, inflammatory
responses and, potentially, to serious
health problems. Apoptosis, by contrast,
is a process in which cells play an active
role in their own death (which is why
apoptosis is often referred to as cell
suicide).

in the case of cancer cells mutations may

have occurred that prevent cells from
undergoing apoptosis. In these cases there
is no check on the cellular proliferation
and consequently the disease can progress
to the formation of tumors. In many cases
these tumors can be difficult to kill as
many cancer treatments rely on damaging
the cells with radiation or chemicals and
mutations in the apoptotic pathway often
produce cells that are resistant to this type
of attack. Understanding how apoptosis is
regulated in cancer is therefore of major
interest in the development of treatments
for this disease.

Apoptosis in health and disease

If cancer is a disease where too little

apoptosis occurs there are other diseases
where too much apoptosis is thought
to be part of the problem. For example
in neurodegenerative diseases such as
Parkinsons or Alzheimers Diseases
apoptosis is thought to account for much
of the cell death and the progressive loss
of neurons.

Apoptosis occurs during the normal

development of multicellular organisms
and continues throughout adult life.
The combination of apoptosis and cell
proliferation is responsible for shaping
tissues and organs in developing embryos.
For example the apoptosis of cells located
in-between the toes allows for their
separation.
Apoptosis is also an important part of
the regulation of the immune system.
T lymphocytes are cells of the immune
system that are responsible for destroying
infected or damaged cells in the body.
They mature in the thymus, but before
they can enter the bloodstream they are
tested to ensure that they are effective
against foreign antigens and are also not
reactive against normal, healthy cells.
Any ineffective or self-reactive T-cells
are removed through the induction of
apoptosis.
Problems with the regulation of apoptosis
have been implicated in a number of
diseases. Cancer is a disease that is often
characterized by too little apoptosis.
Cancer cells typically possess a number of
mutations that have allowed them to ignore
normal cellular signals regulating their
growth and become more proliferative
than normal. Under normal circumstances
damaged cells will undergo apoptosis, but

Apoptosis is also important for normal

placental development. During pregnancy
trophoblast cells from the placenta invade
the uterine environment in order to
remodel the maternal blood vessels and
help establish and maintain a successful
pregnancy. Strict control over cell
proliferation and apoptosis is required to
achieve this. In some cases this process can
be compromised and excessive apoptosis
of the trophoblast cells is thought to be
implicated in the failure to fully remodel
the maternal environment that is observed
in complications of pregnancy such as
preeclampsia.

Apoptosis is also thought to play a

role in the progression of many autoimmune diseases. For example, in the
case of rheumatoid arthritis excessive
proliferation of synovial cells is thought
to be due in part to the resistance of
these cells to apoptotic stimuli. In other
cases poor regulation of apoptosis in Tlymphocytes can result in auto-reactive
T-cells entering the circulation and
contributing to the onset of autoimmune
diseases.
The apoptotic process
Upon receiving specific signals instructing
the cells to undergo apoptosis a number
of distinctive changes occur in the cell.
A family of proteins known as caspases
are typically activated in the early stages
of apoptosis. These proteins breakdown
or cleave key cellular components that
are required for normal cellular function
including structural proteins in the
cytoskeleton and nuclear proteins such as
DNA repair enzymes. The caspases can
also activate other degradative enzymes
such as DNases, which begin to cleave
the DNA in the nucleus.
Apoptotic cells display distinctive
morphology during the apoptotic process,
and this can be seen in Figure 1. Typically,
the cell begins to shrink following the
cleavage of lamins and actin filaments
in the cytoskeleton (A). The breakdown
of chromatin in the nucleus often leads
to nuclear condensation and in many
cases the nuclei of apoptotic cells take
on a horse-shoe like appearance (B).
Cells continue to shrink (C), packaging
themselves into a form that allows for
their removal by macrophages. These
phagocytic cells are responsible for
clearing the apoptotic cells from tissues
in a clean and tidy fashion that avoids
many of the problems associated with
necrotic cell death. In order to promote

Figure 1: Morphology of an apoptosic trophoblast cell as captured by timelapse microscopy (images taken over a 6 hour period).

APOPTOSIS
their phagocytosis by macrophages,
apoptotic cells often ungergo plasma
membrane changes that trigger the
macrophage response. One such change
is the translocation of phosphatidylserine
from the inside of the cell to the outer
surface. The end stages of apoptosis are
often characterised by the appearance of
membrane blebs (D) or blisters process.
Small vesicles called apoptotic bodies are
also sometimes observed (D, arrow).
There are a number of mechanisms
through which apoptosis can be induced
in cells. The sensitivity of cells to any
of these stimuli can vary depending on a
number of factors such as the expression
of pro- and anti-apoptotic proteins (eg.
the Bcl-2 proteins or the Inhibitor of
Apoptosis Proteins), the severity of the
stimulus and the stage of the cell cycle.
Some of the major stimuli that can induce
apoptosis include virus infection, cell
stress and DNA damage.
In some cases the apoptotic stimuli
comprise extrinsic signals such as the
binding of death inducing ligands to cell
surface receptors called death receptors.
These ligands can either be soluble
factors or can be expressed on the surface
of cells such as cytotoxic T lymphocytes.
The latter occurs when T-cells recognise
damaged or virus infected cells and
initiate apoptosis in order to prevent
damaged cells from becoming neoplastic
(cancerous) or virus-infected cells from
spreading the infection. Apoptosis can also
be induced by cytotoxic T-lymphocytes
using the enzyme granzyme.

www.sgul.ac.uk/depts/immunology/~dash
alpha and TRAIL. They play an important
role in apoptosis and can activate a caspase
cascade within seconds of ligand binding.
Induction of apoptosis via this mechanism
is therefore very rapid.
Apoptotic signalling from the death
receptors
Although there are differences in the
signalling pathways activated by the
different death receptors it is possible
to outline a general apoptotic signalling
pathway. Binding of the death inducing
ligand to its receptor can lead to a
the generation of ceramide, typically
produced by acid sphingomyelinase. This
ceramide release is thought to promote
lipid raft fusion which results in a large
scale clustering of the death receptors.
The large scale receptor clustering is
important because it helps amplify the
apoptotic signalling. In the absence of
receptor clustering some cells, such as
lymphocytes, are still able to trigger
apoptosis but in most cases amplification
of the signalling pathway is needed to
activate the full apoptotic response.
Following ligand binding a conformational
change in the intracellular domains of the
receptors reveals the presence of a death
domain which allows the recruitment of
various apoptotic proteins to the receptor.
This protein complex is often called the
DISC, or Death Inducing Signalling
Complex. The final step in this process
is the recruitment of one of the caspases,
typically caspase 8, to the DISC. This
results in activation of caspase 8 and the
inititation of apoptosis.

In other cases apoptosis can be initiated

following intrinsic signals that are
produced following cellular stress.
Cellular stress may occur from exposure
to radiation or chemicals or to viral
infection. It might also be a consequence
of growth factor deprivation or oxidative
stress caused by free radicals. In general
intrinsic signals initiate apoptosis via the
involvement of the mitochondria. The
relative ratios of the various bcl-2 proteins
can often determine how much cellular
stress is necessary to induce apoptosis.

TNF receptor signalling

Death Receptors

Binding of TNF alpha to TNFR1 results

in receptor trimerisation and clustering
of intracellular death domains. This
allows binding of an intracellular adapter
molecule called TRADD (TNFR-

Death receptors are cell surface receptors

that transmit apoptotic signals initiated by
specific ligands such as Fas ligand, TNF

TNF is produced by T-cells and activated

macrophages in response to infection.
By activating its receptor, TNFR1, TNF
can have several effects (see Figure 2).
In some cells it leads to activation of NFkB and AP-1 which leads to the induction
of a wide range of genes. In some cells,
however, TNF can also induce apoptosis,
although receptor ligation is rarely enough
on its own to initiate apoptosis as is the
case with Fas ligand binding.

associated death domain) via interactions

between death domains. TRADD has the
ability to recruit a number of different
proteins to the activated receptor.
Recruitment of TRAF2 (TNF-associated
factor 2) can lead to activation of NF-kB
and the JNK pathway. TRADD can also
associate with FADD, which leads to the
induction of apoptosis via the recruitment
and cleavage of pro-caspase 8.

Figure 2: Illustration of the main TNF

receptor signalling pathways.
Signaling by Fas (CD95)
The ligand for Fas (FasL or CD95L)
activated apoptosis in a similar way to
the TNF receptor. Binding of the ligand
promotes receptor clustering, DISC
formation and the activation of the caspase
cascade. However, signalling through
the Fas receptor is slightly simpler than
through the TNF receptor. The adapter
protein FADD can be recruited directly
to the death domain on the Fas receptor,
without requiring the prior recruitment
of TRADD. In addition the Fas receptor
is generally though to only activate
apoptosis and does not play an important
role in other aspects of cell signalling like
the TNF receptor.

APOPTOSIS
Induction of apoptosis by TRAIL
In a number of ways TRAIL (TNF-related
apoptosis inducing ligand) is similar
in action to FasL. Binding of TRAIL to
its receptors DR4 or DR5 triggers rapid
apoptosis in many cells. Interestingly there
are also decoy receptors that compete for
binding of TRAIL with the DR4 and DR5
receptors. The decoy receptors are called
DcR1 and DcR2. Both of these receptors
are capable of competing with DR4 or
DR5 receptors for binding to the ligand
(TRAIL), however ligation of these
receptors does not initiate apoptosis since
DcR1 does not possess a cytoplasmic
domain, while DcR2 has a truncated death
domain lacking 4 out of 6 amino acids
essential for recruiting adapter proteins.
Role of mitochondria in apoptosis
Mitochondria play an important role in
the regulation of cell death. They contain
many pro-apoptotic proteins such as
Apoptosis Inducing Factor (AIF), Smac/
DIABLO and cytochrome C. These
factors are released from the mitochondria
following the formation of a pore in
the mitochondrial membrane called the
Permeability Transition pore, or PT pore.
These pores are thought to form through
the action of the pro-apoptotic members
of the bcl-2 family of proteins, which in
turn are activated by apoptotic signals
such as cell stress, free radical damage or
growth factor deprivation. Mitochondria
also play an important role in amplifying
the apoptotic signalling from the death
receptors, with receptor recruited caspase
8 activating the pro-apoptotic bcl-2
protein, Bid.

www.sgul.ac.uk/depts/immunology/~dash
be important in the formation of the PT
pore.

The role of mitochondria in the induction

of apoptosis is summarised in Figure 3.

The pro-apoptotic bcl-2 proteins are

often found in the cytosol where they act
as sensors of cellular damage or stress.
Following cellular stress they relocate
to the surface of the mitochondria where
the anti-apoptotic proteins are located.
This interaction between pro- and antiapoptotic proteins disrupts the normal
function of the anti-apoptotic bcl-2
proteins and can lead to the formation of
pores in the mitochondria and the release
of cytochrome C and other pro-apoptotic
molecules from the intermembrane space.
This in turn leads to the formation of the
apoptosome and the activation of the
caspase cascade.

Caspases and apoptosis

The release of cytochrome C from the

mitochondria is a particularly important
event in the induction of apoptosis. Once
cytochrome C has been released into
the cytosol it is able to interact with a
protein called Apaf-1. This leads to the
recruitment of pro-caspase 9 into a multiprotein complex with cytochrome C and
Apaf-1 called the apoptosome. Formation
of the apoptosome leads to activation of
caspase 9 and the induction of apoptosis.

The caspases are a family of proteins

that are one of the main executors of the
apoptotic process. They belong to a group
of enzymes known as cysteine proteases
and exist within the cell as inactive proforms or zymogens. These zymogens
can be cleaved to form active enzymes
following the induction of apoptosis.
Induction of apoptosis via death receptors
typically results in the activation of an
initiator caspase such as caspase 8 or
caspase 10. These caspases can then
activate other caspases in a cascade. This
cascade eventually leads to the activation
of the effector caspases, such as caspase
3 and caspase 6. These caspases are
responsible for the cleavage of the key
cellular proteins, such as cytoskeletal
proteins, that leads to the typical
morphological changes observed in cells
undergoing apoptosis.

Role of Bcl-2 proteins

The bcl-2 proteins are a family of proteins
involved in the response to apoptosis.
Some of these proteins (such as bcl-2
and bcl-XL) are anti-apoptotic, while
others (such as Bad, Bax or Bid) are
pro-apoptotic. The sensitivity of cells
to apoptotic stimuli can depend on the
balance of pro- and anti-apoptotic bcl2 proteins. When there is an excess of
pro-apoptotic proteins the cells are more
sensitive to apoptosis, when there is an
excess of anti-apoptotic proteins the cells
will tend to be more resistant. An excess
of pro-apoptotic bcl-2 proteins at the
surface of the mitochondria is thought to

Figure 3: Illustration of the main apoptotic signalling

pathways involving mitochondria

APOPTOSIS
The apoptosome
There are a number of other mechanisms,
aside from activation of the death receptors,
through which the caspase cascade can be
activated. Granzyme B can be delivered
into cells by cytotoxic T lymphocytes and
is able to directly activate caspases 3, 7,
8 and 10. The mitochondria are also key
regulators of the caspase cascade and
apoptosis. Release of cytochrome C from
mitochondria can lead to the activation
of caspase 9, and then of caspase 3. This
effect is mediated through the formation of
an apoptosome, a multi-protein complex
consisting of cytochrome C, Apaf-1, procaspase 9 and ATP. The formation of the
apoptosome is illustrated in Figure 4.

www.sgul.ac.uk/depts/immunology/~dash
1) Inactivation of enzymes involved in
DNA repair.
The
enzyme
poly
(ADP-ribose)
polymerase, or PARP, is an important
DNA repair enzyme and was one of the
first proteins identified as a substrate for
caspases. The ability of PARP to repair
DNA damage is prevented following
cleavage of PARP by caspase-3.
2) Breakdown of structural nuclear
proteins.
Lamins are intra-nuclear proteins that
maintain the shape of the nucleus and
mediate interactions between chromatin
and the nuclear membrane. Degradation
of lamins by caspase 6 results in the
chromatin condensation and nuclear
fragmentation.
3) Fragmentation of DNA.
The fragmentation of DNA into
nucleosomal units is caused by an enzyme
known as CAD, or caspase activated
DNase. Normally CAD exists as an
inactive complex with ICAD (inhibitor of
CAD). During apoptosis, ICAD is cleaved
by caspases, such as caspase 3, to release
CAD. Rapid fragmentation of the nuclear
DNA follows.
Role of Nitric Oxide in Apoptosis

Figure 4: Formation of the apoptosome

Nitric oxide (NO) is an important signaling

molecule that acts in many tissues to
regulate a diverse range of physiological
processes
including
vasodilation,
neuronal function, inflammation and

immune function. Nitric oxide has also

been demonstrated to be involved in the
regulation of apoptosis.
The effects of apoptosis vary depending
upon the dose of NO and the type of
cell used and has been shown to be able
to both induce apoptosis and to protect
from apoptosis in different cell types.
Nitric oxide has been demonstrated to
inhibit apoptosis in a number of cell
types including leukocytes, hepatocytes,
trophoblasts and endothelial cells.
Generally the anti-apoptotic effects of
NO can be mediated through a number
of mechanisms such as the nitrosylation
and inactivation of many of the caspases
including caspase 3, caspase 1 and caspase
8. Other mechanisms include activating
p53, upregulating heat shock protein 70
(and consequently blocking recruitment of
pro-caspase 9 to the Apaf-1 apoptosome),
upregulating Bcl-2 and Bcl-XL (with
subsequent inhibition of cytochrome
C release from the mitochondria) and
activating cGMP signaling leading to
activation of cGMP-dependent protein
kinases and suppression of caspase
activity.
The effects of NO on apoptosis are
generally classified as cGMP dependent
or independent. Nitric oxide is able to
activate cGMP signaling through the
interaction of NO with the haem group
of guanylate cyclase. The production of
cGMP leads to the activation of cGMPdependent protein kinases and possibly
to increased expression of anti-apoptotic
proteins.

Caspases and chromatin breakdown

One of the hallmarks of apoptosis is
the cleavage of chromosomal DNA into
nucleosomal units. The caspases play an
important role in this process by activating
DNases, inhibiting DNA repair enzymes
and breaking down structural proteins in
the nucleus.
The role of the caspases in the breakdown
of chromatin is illustrated in Figure 5.

Figure 5: Breakdown of chromatin during apoptosis

APOPTOSIS
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