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APOPTOSIS: An overview - University of Pittsburgh

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APOPTOSIS: An overview
Sanjeev Sharma*, Aarti Bhardwaj$, Shalini Jain# and Hariom Yadav#
*Animal Genetics and Breeding Division, #Animal Biochemistry Division,
National Dairy Research Institute, Karnal-132001, Haryana, India
$College of Applied Education and Health Sciences, Meerut, U.P.
INTRODUCTION
Cell death by injury
-Mechanical damage
-Exposure to toxic chemicals
Cell death by suicide
-Internal signals
-External signals
Conted…..
Apoptosis or programmed cell death, is carefully
coordinated collapse of cell, protein degradation ,
DNA fragmentation followed by rapid engulfment
of corpses by neighbouring cells.
(Tommi, 2002)
Essential part of life for every multicellular
organism from worms to humans. (Faddy et al.,1992)
Apoptosis plays a major role from embryonic
development to senescence.
Why should a cell commit suicide?
Apoptosis is needed for proper development
Examples:
– The resorption of the tadpole tail
– The formation of the fingers and toes of the fetus
– The sloughing off of the inner lining of the uterus
– The formation of the proper connections between neurons in the brain
Apoptosis is needed to destroy cells
Examples:
– Cells infected with viruses
– Cells of the immune system
– Cells with DNA damage
– Cancer cells
What makes a cell decide to commit suicide?
Withdrawal of positive signals
examples :
– growth factors for neurons
– Interleukin-2 (IL-2)
Receipt of negative signals
examples :
– increased levels of oxidants within the cell
– damage to DNA by oxidants
– death activators :
• Tumor necrosis factor alpha (TNF-)
• Lymphotoxin (TNF-β)
• Fas ligand (FasL)
History of cell death / apoptosis research
1800s
Numerous observation of cell death
1908
Mechnikov wins Nobel prize (phagocytosis)
1930-40
Studies of metamorphosis
1948-49
Cell death in chick limb & exploration of NGF
1955
Beginning of studies of lysomes
1964-66
Necrosis & PCD described
1971
Term apoptosis coined
1977
Cell death genes in C. elegans
1980-82
DNA ladder observed & ced-3 identified
1989-91
Apoptosis genes identified, including bcl-2,
fas/apo1 & p53, ced-3 sequenced
(Richerd et.al., 2001)
Necrosis vs. Apoptosis
Necrosis
•
•
•
•
Cellular swelling
Membranes are broken
ATP is depleted
Cell lyses, eliciting an
inflammatory reaction
• DNA fragmentation is
random, or smeared
• In vivo, whole areas of
the tissue are affected
Apoptosis
•
•
•
•
Cellular condensation
Membranes remain intact
Requires ATP
Cell is phagocytosed, no
tissue reaction
• Ladder-like DNA
fragmentation
• In vivo, individual cells
appear affected
NECROSIS Vs APOPTOSIS
Wilde, 1999
STAGES OF APOPTOSIS
Induction of apoptosis related genes, signal transduction
Sherman et al., 1997
APOPTOSIS: Morphology
organelle
membrane
blebbing &
changes
reduction
cell
mitochondrial
leakage
shrinkage
nuclear
fragmentation
chromatin
condensation
Hacker., 2000
APOPTOSIS: Morphological events
cell shrinkage
organelle reduction
mitochondrial leakage
chromatin condensation
nuclear fragmentation
membrane blebbing & changes
Blebbing & Apoptotic bodies
Bleb
The control retained over the cell
membrane & cytoskeleton allows intact
pieces of the cell to separate for
recognition & phagocytosis by MFs
Apoptotic body
MF
MF
Caenorhabditis elegans
1090 cells
decision
to die
131 cells
execution
ced-3
ced-4
egl-1
ced-9
ces-2
ces-1
engulfment
ced-1
ced-2
ced-5
ced-6
ced-7
ced-10
apoptosis
degradation
nuc-1
Apoptosis: Pathways
“Extrinsic Pathway”
Death
Ligands
Death
Receptors
“Intrinsic Pathway”
DNA
damage
& p53
Mitochondria/
Cytochrome C
Initiator
Caspase 8
Effector
Caspase 3
Initiator
Caspase 9
PCD
MAJOR PLAYERS IN
APOPTOSIS
•
•
•
•
Caspases
Adaptor proteins
TNF & TNFR family
Bcl-2 family
Ligand-induced cell death
Ligand
FasL
TNF
TRAIL
Receptor
Fas (CD95)
TNF-R
DR4 (Trail-R)
Ligand-induced cell death
“The death receptors”
FasL
Ligand-induced trimerization
Trail
TNF
Death Domains
Death Effectors
Induced proximity
of Caspase 8
Activation of
Caspase 8
APOPTOSIS: Signaling & Control pathways I
Externally driven
Apoptotic signals
p53
Internally Cytochrome C
driven
Externally driven
Activators of
initiator enzymes
Initiator caspases
mitochondrion
6, 8, 9,12
Execution caspases
2, 3, 7
Apoptosis events
Activation
APOPTOSIS: Signaling & Control pathways II
Externally driven
Apoptotic signals
p53
Internally Cytochrome C
Bcl2
driven
Externally driven
Inhibitors
Activators of
initiator enzymes
Initiator caspases
6, 8, 9,12
External Survival
Internal factors
Execution caspases
2, 3, 7
Apoptosis events
Inhibitors of
apoptosis
Inhibition
The mitochondrial pathway
DNA
Fas
damage
Casp8
p53
Growth factor
receptors
PI3K
Bid
Bid
Bax
Bid
Bax
Akt
casp3
BAD
Bcl2
casp9
Apaf1
ATP
Cyt.C
IAPs
casp3
Smac/
DIABLO
H2O2
AIF
Pollack etal., 2001
REGULATION OF APOPTOSIS
Stimuliп‚® apoptosis п‚®selection of targets
(Rich et al., 2000)
Apoptosis by conflicting signals that scramble the
normal status of cell
(Canlon & Raff, 1999)
Apoptotic stimuliп‚®cytokines, death factors (FasL)
(Tabibzadeh et al., 1999)
DNA breaks п‚® p53 is activated п‚®arrest cell cycle or
activate self destruction
(Blaint & Vousden, 2001)
Importance of Apoptosis
• Important in normal physiology / development
– Development: Immune systems maturation,
Morphogenesis, Neural development
– Adult: Immune privilege, DNA Damage and wound
repair.
• Excess apoptosis
– Neurodegenerative diseases
• Deficient apoptosis
– Cancer
– Autoimmunity
FUTURE PERSPECTIVES
The biological roles of newly identified death
receptors and ligands need to be studied
Need to know whether defects in these ligands
and receptors contribute to disease
CONCLUSION
an important process of cell death
can be initiated extrinsically through death ligands
(e.g. TRAIL, FasL) activating initiator caspase 8 through
induced proximity.
can be initiated intrinsically through DNA damage (via
cytochrome c) activating initiator caspase 9 through
oligomerization.
Initiator caspases 8 and 9 cleave and activate
effector caspase 3, which leads to cell death.
DNA DAMAGE
p53
The bcl-2 family
N
BH4
BH3
BH1
Receptor domain
Ligand
Pore
domain
formation
phosphorylation
Raf-1
calcineurin
BH2
TM
C
Membrane
anchor
Group I
Bcl-2
Group II
bax
Group III
Bad
bid
bik
Back
P53 & Apoptosis
p53 first arrests cell growth between G1 п‚® S
This allows for DNA repair during delay
If the damage is too extensive then p53
induces gene activation leading to
apoptosis (programmed cell death)
BACK
3 mechanisms of caspase activation
a. Proteolytic cleavage e.g.
pro-caspase 3
b. Induced proximity, e.g.
pro-caspase 8
c. Oligomerization, e.g. cyt c,
Apaf-1 & caspase 9
Back
Apoptosis signal to kill infected cells
Cytolytic lymphocyte/CTL (& natural killer lymphocyte)
presents Fas ligand/CD178 on its surface to tell the infected
cell to die
Fas ligand
Externally driven
Apoptotic signals
Cytochrome c
Initiator caspases
The immunological
synapse holds the cells
much tighter together
than shown here
Fas/ CD95 is the
�death receptor’
Execution caspases
Apoptosis events
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