Author:
Obaidullah Khan and Mam Hafiza Masooma, Department of Plant Breeding and
Genetics, University of Agriculture Faisalabad.
Apoptosis is the process of programmed cell death that may occur in
multicellular organisms. It was first discovered by scientists over 100 years
ago. A German scientist Carl Vogt was first to describe the principle of
apoptosis in 1842. In Greek, apoptosis translates to "dropping off" of petals or
leaves from plants or trees. Cormack, professor of Greek language, reintroduced
the term for medical use as it had a medical meaning for the Greeks over two
thousand years before. Hippocrates used the term to mean "the falling off of the
bones". Galen extended its meaning to "the dropping of the scabs".
Programmed cell death involves a series of biochemical events leading to a
characteristic cell morphology and death; in more specific terms, a series of
biochemical events that lead to a variety of morphological changes, including
blebbing, changes to the cell membrane such as loss of membrane asymmetry and
attachment, cell shrinkage, nuclear fragmentation, chromatin condensation, and
chromosomal DNA fragmentation. In contrast to necrosis, which is a form of
traumatic cell death that results from acute cellular injury, apoptosis, in
general, confers advantages during an organism's life cycle. For example, the
differentiation of fingers and toes in a developing human embryo occurs because
cells between the fingers apoptose; the result is that the digits are separate.
Between 50 and 70 billion cells die each day due to apoptosis in the average
human adult. For an average child between the ages of 8 and 14, approximately 20
billion to 30 billion cells die a day. In a year, this amounts to the
proliferation and subsequent destruction of a mass of cells equal to an
individual's body weight.
PROCESS OF APOPTOSIS
The process of apoptosis is controlled by a diverse range of cell signals, which
may originate either extracellularly (extrinsic inducers) or intracellularly
(intrinsic inducers). Extracellular signals may include toxins, hormones, growth
factors, nitric oxide orcytokines, and therefore must either cross the plasma
membrane or transduce to effect a response. These signals may positively (i.e.,
trigger) or negatively (i.e., repress, inhibit, or dampen) affect apoptosis. A
cell initiates intracellular apoptotic signalling in response to a stress, which
may bring about cell suicide. The binding of nuclear receptors by
glucocorticoids, heat, radiation, nutrient deprivation, viral infection, hypoxia
and increased intracellularcalcium concentration, for example, by damage to the
membrane, can all trigger the release of intracellular apoptotic signals by a
damaged cell. A number of cellular components, such as poly ADP ribose
polymerase, may also help regulate apoptosis.Before the actual process of cell
death is precipitated by enzymes, apoptotic signals must cause regulatory
proteins to initiate the apoptosis pathway. This step allows apoptotic signals
to cause cell death, or the process to be stopped, should the cell no longer
need to die. Several proteins are involved, but two main methods of regulation
have been identified: targeting mitochondria functionality, or directly
transducing the signal via adaptor proteins to the apoptotic mechanisms. Another
extrinsic pathway for initiation identified in several toxin studies is an
increase in calcium concentration within a cell caused by drug activity, which
also can cause apoptosis via a calcium binding protease calpain.
Many pathways and signals lead to apoptosis, but there is only one mechanism
that actually causes the death of a cell. After a cell receives stimulus, it
undergoes organized degradation of cellular organelles by activatedproteolytic
caspases. A cell undergoing apoptosis shows a characteristic morphology:
1. Cell shrinkage and rounding are shown because of the breakdown of the
proteinaceous cytoskeleton by caspases.
2. The cytoplasm appears dense, and the organelles appear tightly packed.
3. Chromatin undergoes condensation into compact patches against the nuclear
envelope in a process known as pyknosis, a hallmark of apoptosis.
4. The nuclear envelope becomes discontinuous and the DNA inside it is
fragmented in a process referred to as karyorrhexis. The nucleus breaks into
several discrete chromatin bodies or nucleosomal units due to the degradation of
DNA.
5. The cell membrane shows irregular buds known as blebs.
6. The cell breaks apart into several vesicles called apoptotic bodies, which
are then phagocytosed.
Cell Termination
Apoptosis occurs when a cell is damaged beyond repair, infected with a virus, or
undergoing stressful conditions such as starvation. Damage to DNA from ionizing
radiation or toxic chemicals can also induce apoptosis via the actions of the
tumor-suppressing gene p53. The "decision" for apoptosis can come from the cell
itself, from the surrounding tissue, or from a cell that is part of the immune
system. In these cases apoptosis functions to remove the damaged cell,
preventing it from sapping further nutrients from the organism, or halting
further spread of viral infection.Apoptosis also plays a role in preventing
cancer. If a cell is unable to undergo apoptosis because of mutation or
biochemical inhibition, it continues to divide and develop into a tumor. For
example, infection by papillomaviruses causes a viral gene to interfere with the
cell's p53protein, an important member of the apoptotic pathway. This
interference in the apoptotic capability of the cell plays a role in the
development of cervical cancer.
Homeostasis
In the adult organism, the number of cells is kept relatively constant through
cell death and division. Cells must be replaced when they malfunction or become
diseased, but proliferation must be offset by cell death. This control mechanism
is part of the homeostas is required by living organisms to maintain their
internal states within certain limits. Some scientists have suggested
homeodynamics as a more accurate term. The related term allostasis reflects a
balance of a more complex nature by the body. Homeostasis is achieved when the
rate of mitosis (cell division resulting in cell multiplication) in the tissue
is balanced by the rate of cell death. If this equilibrium is disturbed, one of
two potentially fatal disorders occurs:
the cells divide faster than they die, resulting in the development of a
tumor.
the cells divide slower than they die, causing cell loss.
Homeostasis involves a complex series of reactions, an ongoing process inside an
organism that calls for different types of cell signaling. Any impairment can
cause a disease. For example, dysregulation of signaling pathway has been
implicated in several forms of cancer. The pathway, which conveys an
anti-apoptotic signal, has been found to be activated in pancreatic
adenocarcinoma tissues.
Development
Programmed cell death is an integral part of both plant and animal tissue
development. Development of an organ or tissue is often preceded by the
extensive division and differentiation of a particular cell, the resultant mass
is then "pruned" into the correct form by apoptosis. Unlikenecrosis, cellular
death caused by injury, apoptosis results in cell shrinkage and fragmentation.
Such shrinkage and fragmentation allow the cells to be phagocytosed and their
components reused without releasing potentially harmful intracellular substances
such as hydrolytic enzymes into the surrounding tissue.During development,
apoptosis is tightly regulated and different tissues use different signals for
inducing apoptosis. In birds, bone morphogenetic proteins (BMP) signaling is
used to induce apoptosis in the interdigital tissue. In Drosophila flies,
steroid hormonesregulate cell death. Developmental cues can also induce
apoptosis, such as the sex-specific cell death of hermaphrodite specific
neuronsin C. elegans males through low TRA-1 transcription factor activity.
Defective Apoptotic Pathways
The many different types of apoptotic pathways contain a multitude of different
biochemical components, many of them not yet understood. (Thompson et al., 1995)
. As a pathway is more or less sequential in nature, it is a victim of
causality; removing or modifying one component leads to an effect in another. In
a living organism this can have disastrous effects, often in the form of disease
or disorder. A discussion of every disease caused by modification of the various
apoptotic pathways would be impractical, but the concept overlying each one is
the same: the normal functioning of the pathway has been disrupted in such a way
as to impair the ability of the cell to undergo normal apoptosis. This results
in a cell that lives past its "use-by-date" and is able to replicate and pass on
any faulty machinery to its progeny, increasing the likelihood of the cell
becoming cancerous or diseased.A recently-described example of this concept in
action can be seen in the development of a lung cancer called NCI-H460. (Yang et
al., 2003). The X-linked inhibitor of apoptosis protein (XIAP) isoverexpressed
in cells of the H460 cell line. XIAPs bind to the processed form of caspase-9,
and suppress the activity of apoptotic activator cytochrome c, therefore
overexpression leads to a decrease in the amount of pro-apoptotic agonists. As a
consequence, the balance of anti-apoptotic and pro-apoptotic effectors is upset
in favour of the former, and the damaged cells continue to replicate despite
being directed to die.
HIV Progression
The progression of the human immunodeficiency virus infection to AIDS is
primarily due to the depletion of CD4+ T-helper lymphocytes, which leads to a
compromised immune system. One of the mechanisms by which T-helper cells are
depleted is apoptosis, which results from a series of biochemical pathways
(Judie et al., 2003).
1. HIV enzymes deactivate anti-apoptotic Bcl-2 This does not directly cause cell
death, but primes the cell for apoptosis should the appropriate signal be
received. In parallel, these enzymes activate pro-apoptotic procaspase-8, which
does directly activate the mitochondrial events of apoptosis.
2. HIV may increase the level of cellular proteins which prompt Fas-mediated
apoptosis.
3. HIV proteins decrease the amount of CD4 glycoprotein marker present on the
cell membrane.
4. Released viral particles and proteins present in extracellular fluid are able
to induce apoptosis in nearby "bystander" T helper cells.
5. HIV decreases the production of molecules involved in marking the cell for
apoptosis, giving the virus time to replicate and continue releasing apoptotic
agents and virions into the surrounding tissue.
6. The infected CD4+ cell may also receive the death signal from a cytotoxic T
cell.
Cells may also die as a direct consequence of viral infection.
Viral Infection
Viruses can trigger apoptosis of infected cells via a range of mechanisms
including:
Receptor binding.
Activation of protein kinase R (PKR).
Interaction with p53.
Expression of viral proteins coupled to MHC proteins on the surface of the
infected cell, allowing recognition by cells of the immune system (such as
Natural Killer and cytotoxic T cells) that then induce the infected cell to
undergo apoptosis. (Everett et al., 1999).
Most viruses encode proteins that can inhibit apoptosis. Several viruses encode
viral homologs of Bcl-2. These homologs can inhibit pro-apoptotic proteins such
as BAX and BAK, which are essential for the activation of apoptosis. Examples of
viral Bcl-2 proteins include the Epstein-Barr virus BHRF1 protein and the
adenovirus E1B 19K protein. Some viruses express caspase inhibitors that inhibit
caspase activity and an example is the CrmA protein of cowpox viruses. Whilst a
number of viruses can block the effects of TNF and Fas. For example the M-T2
protein of myxoma viruses can bind TNF preventing it from binding the TNF
receptor and inducing a response. Furthermore, many viruses express p53
inhibitors that can bind p53 and inhibit its transcriptional transactivation
activity. Consequently p53 cannot induce apoptosis since it cannot induce the
expression of pro-apoptotic proteins. The adenovirus E1B-55K protein and the
hepatitis B virus HBx protein are examples of viral proteins that can perform
such a function. ( Wang et al., 1995).
Interestingly, viruses can remain intact from apoptosis particularly in the
latter stages of infection. They can be exported in the apoptotic bodies that
pinch off from the surface of the dying cell and the fact that they are engulfed
by phagocytes prevents the initiation of a host response. This favours the
spread of the virus. (Hay et al., 2002).
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