Apoptosis Mekanisme
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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.
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INTRODUCTION
Cell death by injury
-Mechanical damage
-Exposure to toxic chemicals Cell death by suicide
-Internal signals-External signals
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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.
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Why should a cell commit suicide?
Apoptosis is needed for proper developmentExamples: – 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
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What makes a cell decide to commit suicide?
Withdrawal of positive signalsexamples : – 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)
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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)
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NECROSIS Vs APOPTOSIS
Wilde, 1999
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Necrosis vs. Apoptosis
• Cellular condensation• Membranes remain intact• Requires ATP• Cell is phagocytosed, no
tissue reaction • Ladder-like DNA
fragmentation• In vivo, individual cells appear
affected
• 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
Necrosis Apoptosis
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STAGES OF APOPTOSIS
Sherman et al., 1997
Induction of apoptosis related genes, signal transduction
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membrane blebbing & changes
mitochondrial leakage
organelle
reduction
cell
shrinkage
nuclear fragmentation
chromatin condensation
APOPTOSIS: Morphology
Hacker., 2000
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membrane blebbing & changes
mitochondrial leakage
organelle reduction
cell shrinkage
nuclear fragmentationchromatin condensation
APOPTOSIS: Morphological events
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Bleb
Blebbing & Apoptotic bodies
The control retained over the cell membrane & cytoskeleton allows intact pieces of the cell to separate for recognition & phagocytosis by Ms
Apoptotic body
M M
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Caenorhabditis elegans
1090 cells 131 cells apoptosis
ced-1ced-2ced-5ced-6ced-7ced-10
ced-3ced-4
ced-9egl-1
ces-1ces-2
nuc-1
executiondecision to die
engulfment degradation
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Apoptosis: Pathways
Death Ligands
Effector Caspase 3
Death Receptors
Initiator Caspase 8
PCD
DNA damage & p53
Mitochondria/Cytochrome C
Initiator Caspase 9
“Extrinsic Pathway”
“Intrinsic Pathway”
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MAJOR PLAYERS IN APOPTOSIS
• Caspases
• Adaptor proteins
• TNF & TNFR family
• Bcl-2 family
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Ligand-induced cell death
Ligand ReceptorFasL Fas (CD95)TNF TNF-RTRAIL DR4 (Trail-R)
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Ligand-induced cell death
“The death receptors”
Ligand-induced trimerization
Death Domains
Death Effectors
Induced proximity of Caspase 8
Activation of Caspase 8
FasL
Trail
TNF
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p53
Apoptosis events
Initiator caspases 6, 8, 9,12
Activators of initiator enzymes
Apoptotic signals
Execution caspases 2, 3, 7
APOPTOSIS: Signaling & Control pathways I
Externally driven
Internally driven
Cytochrome C
Externally driven
Activation
mitochondrion
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p53
ExternalInternal
Apoptosis events
Initiator caspases 6, 8, 9,12
Activators of initiator enzymes
Apoptotic signals
Execution caspases 2, 3, 7 Inhibitors of
apoptosis
APOPTOSIS: Signaling & Control pathways II
Inhibitors
Externally driven
Internally driven
Cytochrome C
Externally driven
Survival factors
Bcl2
Inhibition
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H2O2
Growth factorreceptors
casp9Bcl2
PI3KAkt
BAD
Apaf1
Cyt.CATP
The mitochondrial pathway
casp3
casp3
IAPs
Smac/DIABLO
AIF
Bax
Bax
p53
Fas
Casp8
Bid
Bid
Bid
DNA damage
Pollack etal., 2001
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REGULATION OF APOPTOSIS
Stimuli apoptosis selection of targets (Rich et al., 2000)
Apoptosis by conflicting signals that scramble the normal status of cell (Canlon & Raff, 1999)
Apoptotic stimulicytokines, death factors (FasL)
(Tabibzadeh et al., 1999)
DNA breaks p53 is activated arrest cell cycle or activate self destruction (Blaint & Vousden, 2001)
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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
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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
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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.
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DNA DAMAGE
p53
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The bcl-2 family
BH4 BH3 BH1 BH2 TMN C
Receptor domain
phosphorylation
Raf-1calcineurin Pore
formation
Membraneanchor
Liganddomain
Group I
Group II
Group III
Bcl-2
bax
Badbidbik
Back
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P53 & Apoptosis
p53 first arrests cell growth between G1 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
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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
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Cytolytic lymphocyte/CTL (& natural killer lymphocyte) presents Fas ligand/CD178 on its surface to tell the infected cell to die
Apoptosis events
Initiator caspases
Apoptotic signals
Execution caspases
Externally driven
Cytochrome c
Fas ligand
Apoptosis signal to kill infected cells
CTL Virally infected cell
Fas/ CD95 is the ‘death receptor’
The immunological synapse holds the cells much tighter together than shown here