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					Apoptosis                                                                                      Apoptosis is also thought to play a
                                                                                               role in the progression of many auto-
                                                                                               immune diseases. For example, in the
Phil Dash                                                                                      case of rheumatoid arthritis excessive
Basic Medical Sciences, St.George’s, University of London                                      proliferation of synovial cells is thought                                                           to be due in part to the resistance of
                                                                                               these cells to apoptotic stimuli. In other
Apoptosis, or programmed cell death, is a      in the case of cancer cells mutations may       cases poor regulation of apoptosis in T-
normal component of the development and        have occurred that prevent cells from           lymphocytes can result in auto-reactive
health of multicellular organisms. Cells       undergoing apoptosis. In these cases there      T-cells entering the circulation and
die in response to a variety of stimuli and    is no check on the cellular proliferation       contributing to the onset of autoimmune
during apoptosis they do so in a controlled,   and consequently the disease can progress       diseases.
regulated fashion. This makes apoptosis        to the formation of tumors. In many cases
distinct from another form of cell death       these tumors can be difficult to kill as        The apoptotic process
called necrosis in which uncontrolled cell     many cancer treatments rely on damaging
death leads to lysis of cells, inflammatory    the cells with radiation or chemicals and       Upon receiving specific signals instructing
responses and, potentially, to serious         mutations in the apoptotic pathway often        the cells to undergo apoptosis a number
health problems. Apoptosis, by contrast,       produce cells that are resistant to this type   of distinctive changes occur in the cell.
is a process in which cells play an active     of attack. Understanding how apoptosis is       A family of proteins known as caspases
role in their own death (which is why          regulated in cancer is therefore of major       are typically activated in the early stages
apoptosis is often referred to as cell         interest in the development of treatments       of apoptosis. These proteins breakdown
suicide).                                      for this disease.                               or cleave key cellular components that
                                                                                               are required for normal cellular function
Apoptosis in health and disease                If cancer is a disease where too little         including structural proteins in the
                                               apoptosis occurs there are other diseases       cytoskeleton and nuclear proteins such as
Apoptosis occurs during the normal             where too much apoptosis is thought             DNA repair enzymes. The caspases can
development of multicellular organisms         to be part of the problem. For example          also activate other degradative enzymes
and continues throughout adult life.           in neurodegenerative diseases such as           such as DNases, which begin to cleave
The combination of apoptosis and cell          Parkinson’s or Alzheimer’s Diseases             the DNA in the nucleus.
proliferation is responsible for shaping       apoptosis is thought to account for much
tissues and organs in developing embryos.      of the cell death and the progressive loss      Apoptotic cells display distinctive
For example the apoptosis of cells located     of neurons.                                     morphology during the apoptotic process,
in-between the toes allows for their                                                           and this can be seen in Figure 1. Typically,
separation.                                    Apoptosis is also important for normal          the cell begins to shrink following the
                                               placental development. During pregnancy         cleavage of lamins and actin filaments
Apoptosis is also an important part of         trophoblast cells from the placenta invade      in the cytoskeleton (A). The breakdown
the regulation of the immune system.           the uterine environment in order to             of chromatin in the nucleus often leads
T lymphocytes are cells of the immune          remodel the maternal blood vessels and          to nuclear condensation and in many
system that are responsible for destroying     help establish and maintain a successful        cases the nuclei of apoptotic cells take
infected or damaged cells in the body.         pregnancy. Strict control over cell             on a “horse-shoe” like appearance (B).
They mature in the thymus, but before          proliferation and apoptosis is required to      Cells continue to shrink (C), packaging
they can enter the bloodstream they are        achieve this. In some cases this process can    themselves into a form that allows for
tested to ensure that they are effective       be compromised and excessive apoptosis          their removal by macrophages. These
against foreign antigens and are also not      of the trophoblast cells is thought to be       phagocytic cells are responsible for
reactive against normal, healthy cells.        implicated in the failure to fully remodel      clearing the apoptotic cells from tissues
Any ineffective or self-reactive T-cells       the maternal environment that is observed       in a clean and tidy fashion that avoids
are removed through the induction of           in complications of pregnancy such as           many of the problems associated with
apoptosis.                                     preeclampsia.                                   necrotic cell death. In order to promote

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               Figure 1: Morphology of an apoptosic trophoblast cell as captured by time-
than normal. Under normal circumstances            lapse microscopy (images taken over a 6 hour period).
damaged cells will undergo apoptosis, but


their phagocytosis by macrophages,              alpha and TRAIL. They play an important         associated death domain) via interactions
apoptotic cells often ungergo plasma            role in apoptosis and can activate a caspase    between death domains. TRADD has the
membrane changes that trigger the               cascade within seconds of ligand binding.       ability to recruit a number of different
macrophage response. One such change            Induction of apoptosis via this mechanism       proteins to the activated receptor.
is the translocation of phosphatidylserine      is therefore very rapid.                        Recruitment of TRAF2 (TNF-associated
from the inside of the cell to the outer                                                        factor 2) can lead to activation of NF-kB
surface. The end stages of apoptosis are        Apoptotic signalling from the death             and the JNK pathway. TRADD can also
often characterised by the appearance of        receptors                                       associate with FADD, which leads to the
membrane blebs (D) or blisters process.                                                         induction of apoptosis via the recruitment
Small vesicles called apoptotic bodies are      Although there are differences in the           and cleavage of pro-caspase 8.
also sometimes observed (D, arrow).             signalling pathways activated by the
                                                different death receptors it is possible
There are a number of mechanisms                to outline a general apoptotic signalling
through which apoptosis can be induced          pathway. Binding of the death inducing
in cells. The sensitivity of cells to any       ligand to its receptor can lead to a
of these stimuli can vary depending on a        the generation of ceramide, typically
number of factors such as the expression        produced by acid sphingomyelinase. This
of pro- and anti-apoptotic proteins (eg.        ceramide release is thought to promote
the Bcl-2 proteins or the Inhibitor of          lipid raft fusion which results in a large
Apoptosis Proteins), the severity of the        scale clustering of the death receptors.
stimulus and the stage of the cell cycle.       The large scale receptor clustering is
Some of the major stimuli that can induce       important because it helps amplify the
apoptosis include virus infection, cell         apoptotic signalling. In the absence of
stress and DNA damage.                          receptor clustering some cells, such as
                                                lymphocytes, are still able to trigger
In some cases the apoptotic stimuli             apoptosis but in most cases amplification
comprise extrinsic signals such as the          of the signalling pathway is needed to
binding of death inducing ligands to cell       activate the full apoptotic response.
surface receptors called death receptors.       Following ligand binding a conformational
These ligands can either be soluble             change in the intracellular domains of the
factors or can be expressed on the surface      receptors reveals the presence of a “death
of cells such as cytotoxic T lymphocytes.       domain” which allows the recruitment of
The latter occurs when T-cells recognise        various apoptotic proteins to the receptor.
damaged or virus infected cells and             This protein complex is often called the
initiate apoptosis in order to prevent          DISC, or Death Inducing Signalling
damaged cells from becoming neoplastic          Complex. The final step in this process
(cancerous) or virus-infected cells from        is the recruitment of one of the caspases,      Figure 2: Illustration of the main TNF
spreading the infection. Apoptosis can also     typically caspase 8, to the DISC. This          receptor signalling pathways.
be induced by cytotoxic T-lymphocytes           results in activation of caspase 8 and the
using the enzyme granzyme.                      inititation of apoptosis.
                                                                                                Signaling by Fas (CD95)
In other cases apoptosis can be initiated       TNF receptor signalling
following intrinsic signals that are                                                            The ligand for Fas (FasL or CD95L)
produced following cellular stress.             TNF is produced by T-cells and activated        activated apoptosis in a similar way to
Cellular stress may occur from exposure         macrophages in response to infection.           the TNF receptor. Binding of the ligand
to radiation or chemicals or to viral           By activating its receptor, TNFR1, TNF          promotes receptor clustering, DISC
infection. It might also be a consequence       can have several effects (see Figure 2).        formation and the activation of the caspase
of growth factor deprivation or oxidative       In some cells it leads to activation of NF-     cascade. However, signalling through
stress caused by free radicals. In general      kB and AP-1 which leads to the induction        the Fas receptor is slightly simpler than
intrinsic signals initiate apoptosis via the    of a wide range of genes. In some cells,        through the TNF receptor. The adapter
involvement of the mitochondria. The            however, TNF can also induce apoptosis,         protein FADD can be recruited directly
relative ratios of the various bcl-2 proteins   although receptor ligation is rarely enough     to the death domain on the Fas receptor,
can often determine how much cellular           on its own to initiate apoptosis as is the      without requiring the prior recruitment
stress is necessary to induce apoptosis.        case with Fas ligand binding.                   of TRADD. In addition the Fas receptor
                                                                                                is generally though to only activate
Death Receptors                                 Binding of TNF alpha to TNFR1 results           apoptosis and does not play an important
                                                in receptor trimerisation and clustering        role in other aspects of cell signalling like
Death receptors are cell surface receptors      of intracellular death domains. This            the TNF receptor.
that transmit apoptotic signals initiated by    allows binding of an intracellular adapter
specific ligands such as Fas ligand, TNF        molecule called TRADD (TNFR-


Induction of apoptosis by TRAIL                be important in the formation of the PT      The role of mitochondria in the induction
                                               pore.                                        of apoptosis is summarised in Figure 3.
In a number of ways TRAIL (TNF-related
apoptosis inducing ligand) is similar          The pro-apoptotic bcl-2 proteins are         Caspases and apoptosis
in action to FasL. Binding of TRAIL to         often found in the cytosol where they act
its receptors DR4 or DR5 triggers rapid        as sensors of cellular damage or stress.     The caspases are a family of proteins
apoptosis in many cells. Interestingly there   Following cellular stress they relocate      that are one of the main executors of the
are also decoy receptors that compete for      to the surface of the mitochondria where     apoptotic process. They belong to a group
binding of TRAIL with the DR4 and DR5          the anti-apoptotic proteins are located.     of enzymes known as cysteine proteases
receptors. The decoy receptors are called      This interaction between pro- and anti-      and exist within the cell as inactive pro-
DcR1 and DcR2. Both of these receptors         apoptotic proteins disrupts the normal       forms or zymogens. These zymogens
are capable of competing with DR4 or           function of the anti-apoptotic bcl-2         can be cleaved to form active enzymes
DR5 receptors for binding to the ligand        proteins and can lead to the formation of    following the induction of apoptosis.
(TRAIL), however ligation of these             pores in the mitochondria and the release
receptors does not initiate apoptosis since    of cytochrome C and other pro-apoptotic      Induction of apoptosis via death receptors
DcR1 does not possess a cytoplasmic            molecules from the intermembrane space.      typically results in the activation of an
domain, while DcR2 has a truncated death       This in turn leads to the formation of the   initiator caspase such as caspase 8 or
domain lacking 4 out of 6 amino acids          apoptosome and the activation of the         caspase 10. These caspases can then
essential for recruiting adapter proteins.     caspase cascade.                             activate other caspases in a cascade. This
                                                                                            cascade eventually leads to the activation
Role of mitochondria in apoptosis              The release of cytochrome C from the         of the effector caspases, such as caspase
                                               mitochondria is a particularly important     3 and caspase 6. These caspases are
Mitochondria play an important role in         event in the induction of apoptosis. Once    responsible for the cleavage of the key
the regulation of cell death. They contain     cytochrome C has been released into          cellular proteins, such as cytoskeletal
many pro-apoptotic proteins such as            the cytosol it is able to interact with a    proteins, that leads to the typical
Apoptosis Inducing Factor (AIF), Smac/         protein called Apaf-1. This leads to the     morphological changes observed in cells
DIABLO and cytochrome C. These                 recruitment of pro-caspase 9 into a multi-   undergoing apoptosis.
factors are released from the mitochondria     protein complex with cytochrome C and
following the formation of a pore in           Apaf-1 called the apoptosome. Formation
the mitochondrial membrane called the          of the apoptosome leads to activation of
Permeability Transition pore, or PT pore.      caspase 9 and the induction of apoptosis.
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.

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 bcl-
2 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
                                                                Figure 3: Illustration of the main apoptotic signalling
surface of the mitochondria is thought to
                                                                pathways involving mitochondria


The apoptosome                                   1) Inactivation of enzymes involved in         immune function. Nitric oxide has also
                                                DNA repair.                                     been demonstrated to be involved in the
There are a number of other mechanisms,                                                         regulation of apoptosis.
aside from activation of the death receptors,   The      enzyme      poly     (ADP-ribose)
through which the caspase cascade can be        polymerase, or PARP, is an important            The effects of apoptosis vary depending
activated. Granzyme B can be delivered          DNA repair enzyme and was one of the            upon the dose of NO and the type of
into cells by cytotoxic T lymphocytes and       first proteins identified as a substrate for    cell used and has been shown to be able
is able to directly activate caspases 3, 7,     caspases. The ability of PARP to repair         to both induce apoptosis and to protect
8 and 10. The mitochondria are also key         DNA damage is prevented following               from apoptosis in different cell types.
regulators of the caspase cascade and           cleavage of PARP by caspase-3.                  Nitric oxide has been demonstrated to
apoptosis. Release of cytochrome C from                                                         inhibit apoptosis in a number of cell
mitochondria can lead to the activation         2) Breakdown of structural nuclear              types including leukocytes, hepatocytes,
of caspase 9, and then of caspase 3. This       proteins.                                       trophoblasts and endothelial cells.
effect is mediated through the formation of                                                     Generally the anti-apoptotic effects of
an apoptosome, a multi-protein complex          Lamins are intra-nuclear proteins that          NO can be mediated through a number
consisting of cytochrome C, Apaf-1, pro-        maintain the shape of the nucleus and           of mechanisms such as the nitrosylation
caspase 9 and ATP. The formation of the         mediate interactions between chromatin          and inactivation of many of the caspases
apoptosome is illustrated in Figure 4.          and the nuclear membrane. Degradation           including caspase 3, caspase 1 and caspase
                                                of lamins by caspase 6 results in the           8. Other mechanisms include activating
                                                chromatin condensation and nuclear              p53, upregulating heat shock protein 70
                                                fragmentation.                                  (and consequently blocking recruitment of
                                                                                                pro-caspase 9 to the Apaf-1 apoptosome),
                                                3) Fragmentation of DNA.                        upregulating Bcl-2 and Bcl-XL (with
                                                                                                subsequent inhibition of cytochrome
                                                The fragmentation of DNA into                   C release from the mitochondria) and
                                                nucleosomal units is caused by an enzyme        activating cGMP signaling leading to
                                                known as CAD, or caspase activated              activation of cGMP-dependent protein
                                                DNase. Normally CAD exists as an                kinases and suppression of caspase
                                                inactive complex with ICAD (inhibitor of        activity.
                                                CAD). During apoptosis, ICAD is cleaved
                                                by caspases, such as caspase 3, to release      The effects of NO on apoptosis are
                                                CAD. Rapid fragmentation of the nuclear         generally classified as cGMP dependent
                                                DNA follows.                                    or independent. Nitric oxide is able to
                                                                                                activate cGMP signaling through the
                                                Role of Nitric Oxide in Apoptosis               interaction of NO with the haem group
                                                                                                of guanylate cyclase. The production of
                                                Nitric oxide (NO) is an important signaling     cGMP leads to the activation of cGMP-
                                                molecule that acts in many tissues to           dependent protein kinases and possibly
                                                regulate a diverse range of physiological       to increased expression of anti-apoptotic
                                                processes      including      vasodilation,     proteins.
                                                neuronal function, inflammation and
Figure 4: Formation of the apoptosome

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


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