Apoptosis

Programmed Cell Death

Oleg Zalizniak (ramaloke.bgu@gmail.com)

Igor Shulov

Department of Nuclear Engineering

Ben Gurion University

Radiobiology, 2006/I

Typeset by LATEX
Introduction Functions Apoptotic process Implication in disease References

Cell death types

There are two cell death types: Programmed cell death (PCD)
and Necrosis
PCD has been classified into two main types:
Apoptosis (or Type I cell death), is a particular form of programmed cell
death and is described in this presentation.
Autophagic (a.k.a. cytoplasmic, or Type II) cell death, characterized by the
formation of large vacuoles that eat away organelles in a
specific sequence before the nucleus is destroyed.

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Cell death types

There are two cell death types: Programmed cell death (PCD)
and Necrosis
PCD has been classified into two main types:
Apoptosis (or Type I cell death), is a particular form of programmed cell
death and is described in this presentation.
Autophagic (a.k.a. cytoplasmic, or Type II) cell death, characterized by the
formation of large vacuoles that eat away organelles in a
specific sequence before the nucleus is destroyed.

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Cell death types

There are two cell death types: Programmed cell death (PCD)
and Necrosis
PCD has been classified into two main types:
Apoptosis (or Type I cell death), is a particular form of programmed cell
death and is described in this presentation.
Autophagic (a.k.a. cytoplasmic, or Type II) cell death, characterized by the
formation of large vacuoles that eat away organelles in a
specific sequence before the nucleus is destroyed.

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Cell death types

There are two cell death types: Programmed cell death (PCD)
and Necrosis
PCD has been classified into two main types:
Apoptosis (or Type I cell death), is a particular form of programmed cell
death and is described in this presentation.
Autophagic (a.k.a. cytoplasmic, or Type II) cell death, characterized by the
formation of large vacuoles that eat away organelles in a
specific sequence before the nucleus is destroyed.

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Introduction

Apoptosis (a term derived from the

Greek word describing the falling
off of petals from a flower or leaves
from a tree) is one of the main
types of programmed cell death
(PCD)
Apoptotic process is executed in
such a way as to safely dispose of
cell corpses and fragments.
Apoptosis plays complementary but
opposite role to mitosis in the
regulation of animal cell
Figure: Cell cycle
population.
Oleg Zalizniak, Igor Shulov BGU
Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Introduction

Apoptosis (a term derived from the

Greek word describing the falling
off of petals from a flower or leaves
from a tree) is one of the main
types of programmed cell death
(PCD)
Apoptotic process is executed in
such a way as to safely dispose of
cell corpses and fragments.
Apoptosis plays complementary but
opposite role to mitosis in the
regulation of animal cell
Figure: Cell cycle
population.
Oleg Zalizniak, Igor Shulov BGU
Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Introduction

Apoptosis (a term derived from the

Greek word describing the falling
off of petals from a flower or leaves
from a tree) is one of the main
types of programmed cell death
(PCD)
Apoptotic process is executed in
such a way as to safely dispose of
cell corpses and fragments.
Apoptosis plays complementary but
opposite role to mitosis in the
regulation of animal cell
Figure: Cell cycle
population.
Oleg Zalizniak, Igor Shulov BGU
Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Apoptosis vs Necrosis

Apoptosis
Energy dependent PCD,
DNA defragmentation
one cell
several hours
membrane integrity intact
no inflammation
Dead cells eaten by neighbour
cells or macrophages
Necrosis
cell die as result of damage
(chemical, thermal, radiation,. . . )
group of cells
hours to days
membrane integrity faulty
acute inflammation
Dead cells removed by
macrophages (phagocytosis)

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Apoptosis vs Necrosis

Apoptosis
Energy dependent PCD,
DNA defragmentation
one cell
several hours
membrane integrity intact
no inflammation
Dead cells eaten by neighbour
cells or macrophages
Necrosis
cell die as result of damage
(chemical, thermal, radiation,. . . )
group of cells
hours to days
membrane integrity faulty
acute inflammation
Dead cells removed by
macrophages (phagocytosis)

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Apoptosis vs Necrosis

Apoptosis
Energy dependent PCD,
DNA defragmentation
one cell
several hours
membrane integrity intact
no inflammation
Dead cells eaten by neighbour
cells or macrophages
Necrosis
cell die as result of damage
(chemical, thermal, radiation,. . . )
group of cells
hours to days
membrane integrity faulty
acute inflammation
Dead cells removed by
macrophages (phagocytosis)

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Apoptosis vs Necrosis

Apoptosis
Energy dependent PCD,
DNA defragmentation
one cell
several hours
membrane integrity intact
no inflammation
Dead cells eaten by neighbour
cells or macrophages
Necrosis
cell die as result of damage
(chemical, thermal, radiation,. . . )
group of cells
hours to days
membrane integrity faulty
acute inflammation
Dead cells removed by
macrophages (phagocytosis)

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Apoptosis vs Necrosis

Apoptosis
Energy dependent PCD,
DNA defragmentation
one cell
several hours
membrane integrity intact
no inflammation
Dead cells eaten by neighbour
cells or macrophages
Necrosis
cell die as result of damage
(chemical, thermal, radiation,. . . )
group of cells
hours to days
membrane integrity faulty
acute inflammation
Dead cells removed by
macrophages (phagocytosis)

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Apoptosis vs Necrosis

Apoptosis
Energy dependent PCD,
DNA defragmentation
one cell
several hours
membrane integrity intact
no inflammation
Dead cells eaten by neighbour
cells or macrophages
Necrosis
cell die as result of damage
(chemical, thermal, radiation,. . . )
group of cells
hours to days
membrane integrity faulty
acute inflammation
Dead cells removed by
macrophages (phagocytosis)

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions
Functions of apoptosis
Figure: Cell division: A -
normal (1 - apoptosis, 2 -
damaged cell); B - cancer
Oleg Zalizniak, Igor Shulov
Apoptosis
Apoptotic process Implication in disease References
Cell damage or infection.
DNA damage from ionizing
radiation or toxic chemicals can
also induce apoptosis
(tumour-suppressing gene p53).
if a cell is unable to undergo
apoptosis, due to mutation or
biochemical inhibition, it can
continue dividing and develop into
a tumour.
BGU
Introduction Functions
Functions of apoptosis
Figure: Cell division: A -
normal (1 - apoptosis, 2 -
damaged cell); B - cancer
Oleg Zalizniak, Igor Shulov
Apoptosis
Apoptotic process Implication in disease References
Cell damage or infection.
DNA damage from ionizing
radiation or toxic chemicals can
also induce apoptosis
(tumour-suppressing gene p53).
if a cell is unable to undergo
apoptosis, due to mutation or
biochemical inhibition, it can
continue dividing and develop into
a tumour.
BGU
Introduction Functions
Functions of apoptosis
Figure: Cell division: A -
normal (1 - apoptosis, 2 -
damaged cell); B - cancer
Oleg Zalizniak, Igor Shulov
Apoptosis
Apoptotic process Implication in disease References
Cell damage or infection.
DNA damage from ionizing
radiation or toxic chemicals can
also induce apoptosis
(tumour-suppressing gene p53).
if a cell is unable to undergo
apoptosis, due to mutation or
biochemical inhibition, it can
continue dividing and develop into
a tumour.
BGU
Introduction Functions Apoptotic process Implication in disease References

Homeostasis

Homeostasis (balance between cell born and die) is achieved when

the rate of mitosis (cell proliferation) in the tissue is balanced by
cell death. If this equilibrium is disturbed, one of two potentially
fatal disorders occurs:
The cells are dividing faster than they die, effectively
developing a tumor.
The cells are dividing slower than they die, which results in a
disorder of cell loss.
Between 50 billion and 70 billion cells die each day due to
apoptosis in the average human adult. In a year, this amounts
equal to an individual’s body weight.

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Development

Development of an organ or tissue

Figure: Incomplete
differentiation in two toes
due to lack of apoptosis
is often preceded by the extensive
division and differentiation of a
particular cell, with the resultant
mass is then “pruned” into the
correct form by apoptosis.
Apoptosis allows the cells to be
efficiently phagocytosed and their
components reused without
releasing potentially harmful
intracellular substances into the
surrounding tissue.

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Development

Development of an organ or tissue

Figure: Incomplete
differentiation in two toes
due to lack of apoptosis
is often preceded by the extensive
division and differentiation of a
particular cell, with the resultant
mass is then “pruned” into the
correct form by apoptosis.
Apoptosis allows the cells to be
efficiently phagocytosed and their
components reused without
releasing potentially harmful
intracellular substances into the
surrounding tissue.

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Figure: Examples
Introduction Functions Apoptotic process Implication in disease References

Initiation

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 hormones, growth factors,
nitric oxide (NO) or cytokines, and therefore must either cross
the plasma membrane or transduce to effect a response.
Intracellular apoptotic signalling is a response initiated by a
cell in response to stress, and may ultimately result in cell
suicide. The binding of nuclear receptors by heat, radiation,
nutrient deprivation, viral infection and hypoxia are all factors
which can lead to the release of intracellular apoptotic signals
by a damaged cell.

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Initiation

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 hormones, growth factors,
nitric oxide (NO) or cytokines, and therefore must either cross
the plasma membrane or transduce to effect a response.
Intracellular apoptotic signalling is a response initiated by a
cell in response to stress, and may ultimately result in cell
suicide. The binding of nuclear receptors by heat, radiation,
nutrient deprivation, viral infection and hypoxia are all factors
which can lead to the release of intracellular apoptotic signals
by a damaged cell.

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Initiation

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 hormones, growth factors,
nitric oxide (NO) or cytokines, and therefore must either cross
the plasma membrane or transduce to effect a response.
Intracellular apoptotic signalling is a response initiated by a
cell in response to stress, and may ultimately result in cell
suicide. The binding of nuclear receptors by heat, radiation,
nutrient deprivation, viral infection and hypoxia are all factors
which can lead to the release of intracellular apoptotic signals
by a damaged cell.

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Preparations

Before the actual process of cell

death is carried out by enzymes,
apoptotic signals must be
connected to the actual death
pathway by way of regulatory
proteins. This step allows apoptotic
signals to either culminate in cell
death, or be aborted should the cell
no longer need to die.
Figure: Animal cell

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Preparations

Two main methods of achieving

regulation are targeting
mitochondria functionality, or
direct signal (via adapter proteins)
to the apoptotic mechanisms.

Figure: Animal cell

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Preparations

Mitochondria (convert food

molecules into energy) are essential
to multicellular life, without them a
cell ceases to respirate aerobically
and quickly dies - a fact exploited
by some apoptotic pathways.
The whole preparation process
requires energy and functioning cell
Figure: Diagram of a human machinery.
mitochondrion

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Preparations

Mitochondria (convert food

molecules into energy) are essential
to multicellular life, without them a
cell ceases to respirate aerobically
and quickly dies - a fact exploited
by some apoptotic pathways.
The whole preparation process
requires energy and functioning cell
Figure: Diagram of a human machinery.
mitochondrion

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Execution

Cell shrinkage and rounding due to

Figure: Apoptosis process
the breakdown of the proteinaceous
cytoskeleton by caspases.
The cytoplasm appears dense, and
the organelles appear tightly
packed.
The nuclear envelope becomes
discontinuous and the DNA inside
it is fragmented (karyorrhexis).
Nucleus breaks into several discrete
bodies due to the degradation of
DNA.

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Execution

The cell membrane shows irregular

buds known as blebs.
The cell breaks apart into several
vesicles called apoptotic bodies,
which are then phagocytosed.

Figure: Apoptosis vs necrosis

cycle

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Removal of dead cells

Dying cells that undergo the final

stages of apoptosis display
phagocytotic molecules on their
cell surface.
These molecules mark the cell for
phagocytosis by cells possessing
the appropriate receptors, such as
macrophages.

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions
Removal of dead cells
Figure: A macrophage of a
mouse stretching its arms to
engulf two particles, possibly
pathogens
Oleg Zalizniak, Igor Shulov
Apoptosis
Apoptotic process Implication in disease References
Upon recognition, the phagocyte
reorganizes its cytoskeleton for
engulfment of the cell.
The removal of dying cells by
phagocytes occurs in an orderly
manner without eliciting an
inflammatory response.
BGU
Figure: Normal white blood cell vs apoptotic
Figure: Cell undergoing apoptosis
Introduction Functions Apoptotic process Implication in disease References

Implication in disease

Defective apoptotic pathways

p53 dysregulation - p53 prevents
the cell from replicating by
stopping the cell cycle at G1 to
give the cell time to repair, however
it will induce apoptosis if damage
is extensive and repair efforts fail.
HIV progression (AIDS) - Th
lymphocytes depleted.
Figure: Apoptosis due to
injury
Oleg Zalizniak, Igor Shulov BGU
Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Implication in disease

Defective apoptotic pathways

p53 dysregulation - p53 prevents
the cell from replicating by
stopping the cell cycle at G1 to
give the cell time to repair, however
it will induce apoptosis if damage
is extensive and repair efforts fail.
HIV progression (AIDS) - Th
lymphocytes depleted.
Figure: Apoptosis due to
injury
Oleg Zalizniak, Igor Shulov BGU
Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Implication in disease

Defective apoptotic pathways

p53 dysregulation - p53 prevents
the cell from replicating by
stopping the cell cycle at G1 to
give the cell time to repair, however
it will induce apoptosis if damage
is extensive and repair efforts fail.
HIV progression (AIDS) - Th
lymphocytes depleted.
Figure: Apoptosis due to
injury
Oleg Zalizniak, Igor Shulov BGU
Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Radiation induced apoptosis

Cancer treatments, radiation and

chemotherapeutic agents can
destroy tumours by triggering
cancer cell apoptosis. On the other
hand, cancer cells can develop
numerous mechanisms to evade
apoptosis through either
inactivation of proapoptotic or
up-regulation of antiapoptotic
factors.[Marsoni, 2004]
Figure: Cell in apoptosis

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

Radiation induced apoptosis

Moderate irradiation with γ or

X-rays or UV light causes
apoptosis, and exerts strong
anti-inflammatory and
immunosuppressive effects.
[Reinhard, 2003, Sluyser, 2005]
Many tumors display not only an
increased proliferation rate, but
also an increased rate of
apoptosis.[Reinhard, 2003]
Figure: Cell in apoptosis

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

References I

Wikipedia
www.wikipedia.org
B. Fadeel & S. Orrenius
Apoptosis: a basic biological phenomenon with wide-ranging
implications in human disease.
Journal of Internal Medicine 2005; 258: 479–517
S. Marsoni & G. Damia
Molecular targeting: new therapeutic strategies to improve
tumour apoptosis.
Annals of Oncology 15 (Supplement 4); iv229 – iv231, 2004

Oleg Zalizniak, Igor Shulov BGU

Apoptosis
Introduction Functions Apoptotic process Implication in disease References

References II

Reinhard E. Voll, Martin Herrmann, Irute Girkontaite, Wasilis

Kolowos and Joachim R. Kalden
Anti-inflammatory and Immunoregulatory Effects of Apoptotic
Cells
Apoptosis and Autoimmunity, Wiley-vch 2003, 53-54
Mohammed Al-Rubeai & Martin Fussenegger
Cell Engineering
Kluwer Academic Publishers, 2004; vol.4
Mels Sluyser
Application of Apoptosis to Cancer Treatment
Springer, 2005

Oleg Zalizniak, Igor Shulov BGU

Apoptosis