Apoptosis ppt
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APOPTOSIS Dr Vijay Marakala
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APOPTOSIS
Mid nineteenth century (1951) Many observations indicated cell death plays a considerable role during physiological processes
In 1964 LOCKSHIN Programmed cell death
IN 1972 KERR FIRST INTRODUCED TERM APOPTOSIS WYLLEI IN A PUBLICATION CURRIE
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APOPTOSIS
Apoptosis is an energy dependent programmed cell death for removal of unwanted individual cells
Definition
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CELL DEATH
• Cells die by one of two mechanisms – necrosis or apoptosis
• Two physiologically different processes – Necrosis – death by injury – Apoptosis – death by suicide• Apoptosis and necrosis have different
characteristics
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• Loss of membrane integrity
• Begins with swelling of cytoplasm and mitochondria
• Ends with total cell lysis, no vesicle formation, complete lysis
• Disintegration (swelling) of organelles
• Membrane blebbing, but no loss of integrity
• Begins with shrinking of cytoplasm and condensation of nucleus
• Ends with fragmentation of cell into smaller bodies
• Mitochondria become leaky due to pore formation involving proteins of the bcl-2 family.
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• Loss of regulation of ion homeostasis
• No energy requirement• Random digestion of DNA
(smear of DNA after agarose gel electrophoresis)
• Postlytic DNA fragmentation (= late event of death)
• Tightly regulated process• Energy (ATP)-dependent • Non-random mono- and
oligonucleosomal length fragmentation of DNA(ladder type patern)
• Prelytic DNA fragmentation• Release of various factors into
cytoplasm by mitochondria• Activation of caspase cascade• Alterations in membrane
asymmetry
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• Affects groups of contiguous cells
• Evoked by non-physiological disturbances (complement attack, lytic viruses, hypothermia, hypoxia, ischemia, metabolic poisons)
• Phagocytosis by macrophages • Significant inflammatory
response
• Affects individual cells • Induced by physiological
stimuli (lack of growth factors, changes in hormonal environment)
• Phagocytosis by adjacent cells or macrophages
• No inflammatory response
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APOPTOSIS
Apoptosis in physiologic situations
Apoptosis in pathologic situations
Examples of apoptosis
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APOPTOSIS
Apoptosis in physiologic situations
In the human body about 100,000 cells are produced every second by mitosis and a similar number die by apoptosis*
* Vaux and Korsmeyer, 1999,Cell
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Formation of free and independe
nt digits
Development of the
brain
Development of
reproductive organs
Apoptosis in physiologic situations
Programmed cell death during embryogenesis
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Apoptosis in physiologic situations
Cell loss in proliferaing cell
populations
Death of cells that have served their
useful purpose
Elimination of harmful self-reacttive
lymhocytes
Programmed cell death during adult stage
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Apoptosis in pathologic situations
DNA damageAccumulation of mis-folded
proteins
Cell injury in certain
infections
Pathological atrophy in
parenchymal organs after
duct obstruction
Apoptosis eliminates cells that are genetically altered or injured beyond repair without eliciting a severe host reaction, thus keeping the damage as contained as possible.
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Morphology of Apoptosis
CELL SHRINKAGE
CHROMATIC CONDENSATION
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Biochemical features of Apoptosis
•By activation of caspases•Caspases activate DNAses
Protein Cleavage
•Cleavage into oligonucleosomes•By Ca2+-and Mg2+-dependent endonucleases
DNA Breakdown
•Phosphatidylserine •Thrombospondin
Phagocytic Recognition
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Mechanisms of Apoptosis
The fundamental events in apoptosis is the activation of enzymes called CASPASES
Caspases are central initiators and executioners of apoptosis
Caspases
•Cysteine proteases•Cysteine-dependent ASPartate-specific proteASES
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Mechanisms of Apoptosis
CASPASES
14 different members of the caspases-family have been described in mammals
Active cysteine residue in the catalytic site
Specificity in cleavage after an Asp residue
Synthesized as inactive zymogens (PROCASPASES)
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DNA FRAGMENTATION AND GELELECTROPHORESIS
• Digestion of DNA starts after 2 hrs• 3&4 hrs after initiation of
apoptosis DNA is almost all degraded
• DNA is fragmented with restriction endonucleases
• Apoptosis induces 180 bp ladderingof DNA
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DNA FRAGMENTATION - BIOCHEMICALHALLMARK OF APOPTOSIS
• DNA cleaved into non-random fragments• 180-200 bp fragments & multiples of this unit
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Other morphological features ofapoptosis
Nuclearbreakdown(Hoechst)
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CELLS ARE BALANCED BETWEEN LIFE AND DEATH
DAMAGE Physiological death signals
DEATH SIGNAL
PROAPOPTOTICPROTEINS
ANTIAPOPTOTICPROTEINS
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Two distinct pathways converge on caspase acticvation
Mitochondrial pathway
• Intrinsic pathway
The death receptor pathway
• Extrinsic pathway
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Mitochondria contain several proteinsthat are capable of inducing apoptosis
The choice between cell survival and death is determined by the permeability of mitochondria
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The role of mitochondria in the induction of apoptosis
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• Intrinsic pathway
Mitochondria
Cytochrome c release
Pro-caspase 9 cleavage
Pro-execution caspase (3) cleavage
Caspase (3) cleavage of cellular proteins,Nuclease activation,
Etc.
Death
BAXBAKBOKBCL-XsBADBIDB IKBIMNIP3BNIP3
BCL-2BCL-XLBCL-WMCL1BFL1DIVANR-13Several viral proteins
Mitochondrial pathway
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The death receptor pathway
• Extrinsic pathway
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Antiapoptotic Proapoptotic
Bcl-2 family members
A very large family with 30 members identified and belongs to both:
Bcl -2Bcl-XL
Bcl-W
A1Mcl-1
BaxBakBok
BidBimBikBadBmfHrk
NoxaPumaBlkBNIP3Spike
BH1, BH2,BH3,BH4
BH3
BH1, BH2,BH3
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Physiological Intrinsicreceptor pathway damage pathway
MITOCHONDRIAL SIGNALS
Caspase cleavage cascade
Orderly cleavage of proteins and DNA
CROSSLINKING OF CELL CORPSES; ENGULFMENT(no inflammation)
APOPTOSIS
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TOO MUCH: Tissue atrophy
TOO LITTLE: Hyperplasia
NeurodegenerationThin skin
CancerAthersclerosis
etc
APOPTOSIS
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REFERENCES
Robin’s pathology
• 7th and 8th Edition
Introduction to apoptosis
• By Andreas Gewies ApoReview in2003