apoptosis ii
TRANSCRIPT
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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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Why should a cell commit suicide?
Apoptosis is needed for proper development
The resorption of the tadpole tail
The formation of the fingers and toes of the fetus
The sloughing offof the inner lining of the uterus
The formation of the proper connections between neurons in
the brain
Apoptosis is needed to destroy cells
Cells infected with viruses
Cells of the immune system
Cells with DNA damage
Cancer cells
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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 woundrepair.
Excess apoptosis Neurodegenerative diseases
Deficient apoptosis Cancer
Autoimmunity
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What makes a cell decide to commit suicide?
Withdrawal of positive (Growth) signals
growth factors for neurons Interleukin-2 (IL-2)
Receipt of negative (Death) signals
increased levels of oxidants within the cell damage to DNA by oxidants
death activators : Tumor necrosis factor alpha (TNF-E) Lymphotoxin (TNF-) 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 NGF1955 Beginning of studies of lysomes
1965 Necrosis & PCD described
1971 Term apoptosis coined
1977 Cell death genes in C. elegans1980-82 DNA ladder observed & ced-3 identified
1990 Apoptosis genes identified, including bcl-2,
fas/apo1 & p53, ced-3 sequenced
(Richerd et.al., 2001)
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Apoptosisvs. N
ecrosis
Cellular condensation
Membranes remainintact
Requires ATP
Cell is phagocytosed,no tissue reaction
Ladder-like DNAfragmentation
In vivo, individual cellsappear involved
Cellular swelling
Membranes arebroken
ATP is depleted
Cell lyses, eliciting aninflammatory reaction
DNA fragmentation israndom, or smeared
In vivo, whole areas ofthe tissue are affected
Necrosis Apoptosis
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Apoptosis: Pathways
DNA
damage
& p53
Death
Ligands
Effector
Caspase 3
Death
Receptors
Initiator
Caspase 8
PCD
Mitochondria/
Cytochrome C
Initiator
Caspase 9
Extrinsic Pathway
Intrinsic Pathway
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MAJORPLAYERSIN
APO
PTOSIS
Caspases
Death signals e.g. TNF &TNFR p53
BAX
Bcl-2 family
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Aspartate- AA
proteolysis
Nuclear
BAX (proapoptotic)
Cyt C
Apaf-1
p53DNA damage
Mitochondrial
InitiatorCaspase-8E / 9I
EffectorCaspase- 3
CAD(DNA-ase)
DNA nucleosomal200 bp fragments
bcl- 2Anti-apoptotic
p21Cell Cycle
Arrest
DNARepair
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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 throughinduced proximity.
can be initiated intrinsically through DNA damage (viacytochrome c) activating initiator caspase 9 through
oligomerization.
Initiator caspases 8 and 9 cleave and activateeffector caspase 3, which leads to cell death.
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The bcl-2 family
Group I
Group II
Group III
Bcl-2
bax
Bad
bidbik
BH4 BH3 BH1 BH2 TMN C
Receptor domain
phosphorylation
Raf-1
calcineurin Pore
formation
Membrane
anchorLigand
domain
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P53 & Apoptosis
p53 is an unstable tumor suppressor protein.
It is and acts via zinc finger DNA binding model.
It arrests cell growth between G1p S, thus DNA
repair can take place.
p53 production ofCIP(p21) CDKs inhibition
Cell cycle stop.
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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