Introduction

Cell death is an essential part of normal development and

continues into adulthood. The human body, for instance, is
composed of approximately 1014 cells. Every day billions
of cells die an altruistic death in order to secure the functionality of the whole
organism. Thus, we remain the same size only because cell division exactly balances
cell death.
During development, cell death helps sculpt organs or separate fingers and toes. It
also eliminates structures that once served a function but are no longer needed, such
as the tail of a tadpole during amphibian metamorphosis.
Most of the neurons die during development before having any chance to function in
the nervous system.
Cell death also eliminates most newly formed lymphocytes, especially those that are
useless or dangerous, by targeting self-antigens. Neutrophils, for instance, are
produced continuously in the bone marrow, but the vast majority dies within a few
days.
This apparently futile cycle of cell proliferation and cell death serves to maintain a
supply of cells that can be readily mobilized when needed As cell death is intimately
linked to tissue homeostasis, its disruption has, not surprisingly, been implicated in
numerous pathological conditions.
Abnormalities in cell death regulation can be a significant component of diseases such
as cancer, autoimmune syndromes, AIDS, ischemia, liver diseases and

neurodegenerative disorders including Parkinsons and Alzheimers disease .

Types of Cell death:

Two types of cell death have been distinguished in mammalian cells by morphological
criteria.
Apoptosis
necrosis
Necrosis Apoptosis
Morphological features
Loss of membrane integrity Membrane blebbing, but no loss of
Begins with swelling of cytoplasm integrity
and mitochondria Begins with shrinking of cytoplasm
Ends with total cell lysis, no vesicle and condensation of nucleus
formation, complete lysis Ends with fragmentation of cell into
 Disintegration (swelling) of smaller bodies
organelles Mitochondria become leaky due to
pore formation involving proteins of
the bcl-2 family.
Biochemical Features
Loss of regulation of ion homeostasis Tightly regulated process
No energy requirement Energy (ATP)-dependent
Random digestion of DNA (smear of Non-random mono- and
DNA after agarose gel oligonucleosomal length
electrophoresis) fragmentation of DNA(ladder type
Postlytic DNA fragmentation (= late patern)
event of death) Prelytic DNA fragmentation
Release of various factors into
cytoplasm by mitochondria
Activation of caspase cascade
Alterations in membrane asymmetry
Physiological significance
Affects groups of contiguous cells Affects individual cells
Evoked by non-physiological Induced by physiological stimuli
disturbances (complement attack, (lack of growth factors, changes in
lytic viruses, hypothermia, hypoxia, hormonal environment)
ischemia, metabolic poisons) Phagocytosis by adjacent cells or
Phagocytosis by macrophages macrophages
Significant inflammatory response No inflammatory response

Significance of apoptosis
During development many cells are produced in excess which eventually undergo
programmed cell death and thereby contribute to sculpturing many organs and tissues
In human body about one lakh cells are produced every second by mitosis and a
similar number die by apoptosis
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
1. Programmed cell death is as needed for proper normal development as mitosis
Examples:
The resorption of the tadpole tail in frog.
The formation of the fingers and toes of the fetus requires
the removal, by apoptosis.
The sloughing off of the endometrium at the start of
menstruation.
The formation of the proper connections (synapses) between neurons in the brain.
2. Programmed cell death is needed to destroy cells that represent a threat to the
integrity of the organism.
Examples:
A. Cells infected with viruses
B. Cells of the immune system
C. Cells with DNA damage
D. Cancer cells (Uncontrolled proliferated cells)
3. Apoptosis in physiologic situations

Programmed destruction during embryogenesis

Involution of hormone dependent tissues
Cell loss in proliferating cell populations
Elimination of harmful self- reactive lymphocytes
Death of host cells
4. Apoptosis in pathological conditions
DNA damage
Accumulation of misfolded proteins
Cell death in certain infections
Pathological atrophy in parenchymal organs
5. Cells of the immune system
CTLs induce apoptosis in each other and even in themselves.
Defects in the apoptotic machinery are associated with autoimmune diseases such as
lupus erythematosus and rheumatoid arthritis.
6. Cells infected with viruses
One of the methods by which cytotoxic T lymphocytes (CTLs) kill virus-infected
cells is by inducing apoptosis
7. Cells with DNA damage
Damage to its genome can cause a cell to disrupt proper embryonic development
leading to birth defects to become cancerous.
Cells respond to DNA damage by increasing their production of p53. p53 is a potent
inducer of apoptosis.
Cancer cells
Radiation and chemicals used in cancer therapy induce apoptosis in some types of
cancer cells.
Mechanisms of apoptosis
A. Cell surface death receptor mediated pathway (extrinsic)
B. Mitochondrial-initiated pathway (intrinsic)

A. Cell surface death receptor mediated pathway (extrinsic)

Fas and the TNF receptor are integral membrane
proteins with their receptor domains exposed at the
surface of the cell
binding of the complementary death
activator (FasL and TNF respectively) transmits a
signal to the cytoplasm that leads to activation
of caspase 8
caspase 8 (like caspase 9) initiates a cascade of
caspase activation leading to
phagocytosis of the cell.
Example:
When cytotoxic T cells recognize (bind to) their
target,
They produce more FasL at their surface.
This binds with the Fas on the surface of the target cell leading to its death by
apoptosis.
B. Apoptosis triggered by internal signals: the intrinsic or mitochondrial pathway

In a healthy cell, the outer membranes of its

mitochondria display the protein Bcl-2 on their
surface. Bcl-2 inhibits apoptosis.
Internal damage to the cell
o Causes a related protein, Bax, to migrate
to the surface of the mitochondrion
where it inhibits the protective effect of
Bcl-2 and inserts itself into the outer
mitochondrial membrane punching
holes in it and causing cytochrome c to
leak out.
 The released cytochrome c binds to
the protein Apaf-1 ("apoptotic
protease activating factor-1").
Using the energy provided by ATP,
these complexes aggregate to
form apoptosomes.
The apoptosomes bind to and
activate caspase-9.
Caspase-9 is one of a family of over
a dozen caspases. They are
all proteases. They get their name
because they cleave proteins
mostly each other at aspartic acid (Asp) residues.
Caspase-9 cleaves and, in so doing, activates other caspases (caspase-3 and -7).
The activation of these "executioner" caspases creates an expanding cascade of
proteolytic activity (rather like that in blood clotting and complementactivation)
which leads to
o digestion of structural proteins in the cytoplasm,
o degradation of chromosomal DNA, and
phagocytosis of the cell.

Apoptosis and Cancer

Some viruses associated with cancers use tricks to prevent apoptosis of the cells they
have transformed.
Several human papilloma viruses (HPV) have been implicated in causing cervical
cancer. One of them produces a protein (E6) that binds and inactivates the apoptosis
promoter p53.
Epstein-Barr Virus (EBV), the cause of mononucleosis and associated with
some lymphomas
o produces a protein similar to Bcl-2
o Produces another protein that causes the cell to increase its own production of
Bcl-2. Both these actions make the cell more resistant to apoptosis (thus
enabling a cancer cell to continue to proliferate).
 o Even cancer cells produced without the participation of viruses may have
tricks to avoid apoptosis.

Some B-cell leukemias and lymphomas express high levels of Bcl-2, thus blocking
apoptotic signals they may receive. The high levels result from a translocation of
the BCL-2 gene into an enhancer region for antibody production.
Melanoma (the most dangerous type of skin cancer) cells avoid apoptosis by
inhibiting the expression of the gene encoding Apaf-1.
Some cancer cells, especially lung and colon cancer cells secrete elevated levels of a
soluble "decoy" molecule that binds to FasL, plugging it up so it cannot bind Fas.
Thus, cytotoxic T cells (CTL) cannot kill the cancer cells .
Other cancer cells express high levels of FasL, and can kill any cytotoxic T cells
(CTL) that try to kill them because CTL also express Fas (but are protected from their
own FasL).

Apoptosis in the Immune System

The immune response to a foreign invader involves the proliferation of lymphocytes
T and/or B cells.
When their job is done, they must be removed leaving only a small population of
memory cells. This is done by apoptosis.
Very rarely humans are encountered with genetic defects in apoptosis. The most
common one is a mutation in the gene for Fas, but mutations in the gene for FasL or
even one of the caspases are occasionally seen.
In all cases, the genetic problem produces autoimmune lymphoproliferative
syndrome or ALPS.
Features:
An accumulation of lymphocytes in the lymph nodes and spleen greatly enlarging
them.
the appearance of clones that are autoreactive; that is, attack "self" components
producing such autoimmune disorders as
o hemolytic anemia
o thrombocytopenia
The appearance of lymphoma a cancerous clone of lymphocytes.
 In most patients with ALPS, the mutation is present in the germline; that is, every cell
in their body carries it. In a few cases, however, the mutation is somatic; that is, has
occurred in a precursor cell in the bone marrow.
These later patients are genetic mosaics with some lymphocytes that undergo
apoptosis normally and others that do not. The latter tend to out-compete the former