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APOPTOSIS
- DR.NILESH CHANDRA
Brief glance at the apoptotic process
Role of apoptosis in healthy physiology, esp. in
Immunity
Protection of genome
Disruption of apoptosis & its consequences, viz.
Neurodegeneartive diseases
Cancer
Chronic inflammatory diseases
Potential therapeutic roles
OBJECTIVES
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.
INTRODUCTION
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 for self defense
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-α)
 Lymphotoxin (TNF-β)
 Fas ligand (FasL)
Cell death by injury
-Mechanical damage
-Exposure to toxic chemicals
Cell death by suicide
-Internal signals
-External signals
CAUSES OF CELL DEATH:
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
 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
NECROSIS VS APOPTOSIS
Wilde, 1999
STAGES OF APOPTOSIS
Sherman et al., 1997
Induction of apoptosis related genes, signal transduction
membrane
blebbing &
changes
mitochondrial
leakage
organelle
reduction
cell
shrinkage
nuclear
fragmentation
chromatin
condensation
APOPTOSIS: Morphology
Hacker., 2000
membrane blebbing & changes
mitochondrial leakage
organelle reduction
cell shrinkage
nuclear fragmentation
chromatin condensation
APOPTOSIS: Morphological events
Bleb
Blebbing & Apoptotic bodies
The control retained over the cell
membrane & cytoskeleton allows intact
pieces of the cell to separate for
recognition & phagocytosis by MΦs
Apoptotic body
MΦ MΦ
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”
MAJOR PLAYERS IN
APOPTOSIS
• Caspases
• Adaptor proteins
• TNF & TNFR family
• Bcl-2 family
LIGAND-INDUCED CELL DEATH
Ligand Receptor
FasL Fas (CD95)
TNF TNF-R
TRAIL DR4 (Trail-R)
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
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
p53
External
Internal
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
H2O2
Growth factor
receptors
casp9
Bcl2
PI3K
Akt
BAD
Apaf1
Cyt.C
ATP
The mitochondrial pathway
casp3
casp3
IAPs
Smac/
DIABLO
AIF
Bax
Bax
p53
Fas
Casp8
Bid
Bid
Bid
DNA
damage
Pollack etal., 2001
Importance of Apoptosis
• Important in normal physiology / development
– Development:
– Immune system maturation
– Morphogenesis
– Neural development
– Adult:
– Immune privilege
– DNA Damage
– Wound repair.
Immune system maturation:
Positive selection of thymocytes in the
thymus. Thymic selection involves
thymic stromal cells (epithelial cells,
dendritic cells, and macrophages), and
results in mature T cells that are both
self-MHC restricted and self-tolerant.
Immune system maturation:
Negative selection of thymocytes in the
thymus. Thymic selection involves
thymic stromal cells (epithelial cells,
dendritic cells, and macrophages), and
results in mature T cells that are both
self-MHC restricted and self-tolerant.
Morphogenesis:
 Molecular basis:
 Morphogens
 Transcription factors
 Cell adhesion molecules
 Cellular basis:
 Cell-cell adhesion
 Cell contractility
 Extracellular matrix
 Apoptosis
Immune Privilege:
 Fas-ligand (FasL; also called CD95L or Apo-1L)
 required for tissues to display a privileged status
 FasL functions to induce apoptotic cell death in most
cells that express its receptor, Fas.
 Fas-bearing cells include cells of the immune
system
 Tissues that naturally express FasL kill
infiltrating lymphocytes and inflammatory cells.
DNA Damage
Transcriptional Up-Regulation
of Target Genes
p21
(CDK inhibitor)
GADD45
(DNA repair)
BAX
(apoptosis gene)
Ionizing Radiation,
Carcinogens & Mutagens
DNA Damage
p53 activated and binds to DNA
G1 Arrest
Successful repair
Repair fails
APOPTOSIS
Role of apoptosis
In maintaining
Integrity of genomic
DNA in normal cells
Disruption of apoptosis
Two major ways:
 Inappropriate activation of the
apoptotic process
Immune defect in AIDS
Neurodegenerative diseases.
Inadequate apoptosis
Cancer
Chronic inflammatory conditions
Autoimmune diseases.
Immune defect in AIDS
 Profound reduction in the population size of CD4
+ T helper cells
 Caused by excessive apoptosis
 Process includes transfer of regulatory viral gene
products (such as HIV-1 Tat) from HIV infected
cells to bystander T cells
 Renders them susceptible to T cell receptor-
induced, CD95-mediated apoptosis.
Neurodegenerative Disease
 Apoptosis triggered by
 amyloid β
 neurotoxic abnormal protein structures or aggregates
 In adult neurodegenerative diseases including
 Alzheimer's
 Huntington's chorea
 Parkinson's disease,
 Amyotrophic lateral sclerosis
 Amyloid β can exert neurotoxic effects by
 generation of intracellular oxidative stress
 increases in calcium ions
 Both of these can trigger apoptosis in susceptible
cell types.
Cancer
 Mutations affect the control mechanisms of
apoptosis and cell survival .
 Bcl-2 in follicular lymphoma
 increased bcl-2 expression confers resistance to
chemotherapy in ALL and some forms of AML
 Bcl-2 blocks the endonucleolytic cleavage of DNA
that is so characteristic of apoptosis.
 BCR-ABL in CML
 Inappropriately prolongs cell survival by inhibiting
apoptosis
 Recent evidence indicates that BCR-ABL can mimic
the modularity signals provided by some cytokines
involved in apoptosis.
Chronic Inflammatory conditions:
 Intact neutrophils are engulfed by macrophages
at the sites of inflammation.
 Morphological changes and a chromatin
fragmentation pattern, characteristic of
apoptosis, within the neutrophils triggers
recognition by the macrophages.
 Rheumatoid arthritis may reflect prolonged
survival of leucocytes that are normally
programmed to die by apoptosis.
Therapeutic Significance:
 Approaches to counter inappropriate apoptosis:
Caspases
 are critical to the control of apoptosis
 several pharmaceutical companies are developing
potent and specific caspase inhibitors
 have shown great promise in murine models of
inappropriate neuronal apoptosis.
 The treatment of certain lymphomas by antisense
oligonucleotides to bcl-2
 Death-inducing cytokines of the tumour necrosis
factor family, such as TRAIL
SUMMARY:
 Apoptosis: mechanism & regulation
 Importance of apoptosis during early
development
 Importance of apoptosis during adulthood
 Disruption of apoptotic pathway
 Therapeutics
References:
 Why is apoptosis important to clinicians; Haslett C; BMJ.
2001 June 23; 322(7301): 1499–1500.
 Association of Tumor Necrosis Factor-Related Apoptosis
Inducing Ligand with Total and Cardiovascular Mortality
in Older Adults; Stefano V et al; Atherosclerosis. 2011
April ; 215(2): 452–458.
doi:10.1016/j.atherosclerosis.2010.11.004.
 Apoptosis: a basic biological phenomenon with wide-
ranging implications in tissue kinetics; Kerr JF, Wyllie
AH, Currie AR; Br J Cancer. Aug;26(4):239-57
 Pathologic Basis of Disease; Robbins & Cotran
 Immunology, 5th
Ed; Kuby
DNA DAMAGE
p53
The bcl-2 family
BH4 BH3 BH1 BH2 TMN C
Receptor domain
phosphorylation
Raf-1
calcineurin Pore
formation
Membrane
anchor
Ligand
domain
Group I
Group II
Group III
Bcl-2
bax
Bad
bid
bik
Back
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
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
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

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Apoptosis seminar f

  • 2. Brief glance at the apoptotic process Role of apoptosis in healthy physiology, esp. in Immunity Protection of genome Disruption of apoptosis & its consequences, viz. Neurodegeneartive diseases Cancer Chronic inflammatory diseases Potential therapeutic roles OBJECTIVES
  • 3. 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. INTRODUCTION
  • 4. 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 for self defense Examples:  Cells infected with viruses  Cells of the immune system  Cells with DNA damage  Cancer cells
  • 5.
  • 6.
  • 7. 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-α)  Lymphotoxin (TNF-β)  Fas ligand (FasL)
  • 8. Cell death by injury -Mechanical damage -Exposure to toxic chemicals Cell death by suicide -Internal signals -External signals CAUSES OF CELL DEATH:
  • 9. 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)
  • 10. 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
  • 12. STAGES OF APOPTOSIS Sherman et al., 1997 Induction of apoptosis related genes, signal transduction
  • 14. membrane blebbing & changes mitochondrial leakage organelle reduction cell shrinkage nuclear fragmentation chromatin condensation APOPTOSIS: Morphological events
  • 15. Bleb Blebbing & Apoptotic bodies The control retained over the cell membrane & cytoskeleton allows intact pieces of the cell to separate for recognition & phagocytosis by MΦs Apoptotic body MΦ MΦ
  • 16. 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”
  • 17. MAJOR PLAYERS IN APOPTOSIS • Caspases • Adaptor proteins • TNF & TNFR family • Bcl-2 family
  • 18. LIGAND-INDUCED CELL DEATH Ligand Receptor FasL Fas (CD95) TNF TNF-R TRAIL DR4 (Trail-R)
  • 19. 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
  • 20. 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
  • 21. p53 External Internal 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
  • 22. H2O2 Growth factor receptors casp9 Bcl2 PI3K Akt BAD Apaf1 Cyt.C ATP The mitochondrial pathway casp3 casp3 IAPs Smac/ DIABLO AIF Bax Bax p53 Fas Casp8 Bid Bid Bid DNA damage Pollack etal., 2001
  • 23. Importance of Apoptosis • Important in normal physiology / development – Development: – Immune system maturation – Morphogenesis – Neural development – Adult: – Immune privilege – DNA Damage – Wound repair.
  • 24. Immune system maturation: Positive selection of thymocytes in the thymus. Thymic selection involves thymic stromal cells (epithelial cells, dendritic cells, and macrophages), and results in mature T cells that are both self-MHC restricted and self-tolerant.
  • 25. Immune system maturation: Negative selection of thymocytes in the thymus. Thymic selection involves thymic stromal cells (epithelial cells, dendritic cells, and macrophages), and results in mature T cells that are both self-MHC restricted and self-tolerant.
  • 26. Morphogenesis:  Molecular basis:  Morphogens  Transcription factors  Cell adhesion molecules  Cellular basis:  Cell-cell adhesion  Cell contractility  Extracellular matrix  Apoptosis
  • 27. Immune Privilege:  Fas-ligand (FasL; also called CD95L or Apo-1L)  required for tissues to display a privileged status  FasL functions to induce apoptotic cell death in most cells that express its receptor, Fas.  Fas-bearing cells include cells of the immune system  Tissues that naturally express FasL kill infiltrating lymphocytes and inflammatory cells.
  • 28. DNA Damage Transcriptional Up-Regulation of Target Genes p21 (CDK inhibitor) GADD45 (DNA repair) BAX (apoptosis gene) Ionizing Radiation, Carcinogens & Mutagens DNA Damage p53 activated and binds to DNA G1 Arrest Successful repair Repair fails APOPTOSIS Role of apoptosis In maintaining Integrity of genomic DNA in normal cells
  • 29. Disruption of apoptosis Two major ways:  Inappropriate activation of the apoptotic process Immune defect in AIDS Neurodegenerative diseases. Inadequate apoptosis Cancer Chronic inflammatory conditions Autoimmune diseases.
  • 30. Immune defect in AIDS  Profound reduction in the population size of CD4 + T helper cells  Caused by excessive apoptosis  Process includes transfer of regulatory viral gene products (such as HIV-1 Tat) from HIV infected cells to bystander T cells  Renders them susceptible to T cell receptor- induced, CD95-mediated apoptosis.
  • 31. Neurodegenerative Disease  Apoptosis triggered by  amyloid β  neurotoxic abnormal protein structures or aggregates  In adult neurodegenerative diseases including  Alzheimer's  Huntington's chorea  Parkinson's disease,  Amyotrophic lateral sclerosis  Amyloid β can exert neurotoxic effects by  generation of intracellular oxidative stress  increases in calcium ions  Both of these can trigger apoptosis in susceptible cell types.
  • 32. Cancer  Mutations affect the control mechanisms of apoptosis and cell survival .  Bcl-2 in follicular lymphoma  increased bcl-2 expression confers resistance to chemotherapy in ALL and some forms of AML  Bcl-2 blocks the endonucleolytic cleavage of DNA that is so characteristic of apoptosis.  BCR-ABL in CML  Inappropriately prolongs cell survival by inhibiting apoptosis  Recent evidence indicates that BCR-ABL can mimic the modularity signals provided by some cytokines involved in apoptosis.
  • 33. Chronic Inflammatory conditions:  Intact neutrophils are engulfed by macrophages at the sites of inflammation.  Morphological changes and a chromatin fragmentation pattern, characteristic of apoptosis, within the neutrophils triggers recognition by the macrophages.  Rheumatoid arthritis may reflect prolonged survival of leucocytes that are normally programmed to die by apoptosis.
  • 34. Therapeutic Significance:  Approaches to counter inappropriate apoptosis: Caspases  are critical to the control of apoptosis  several pharmaceutical companies are developing potent and specific caspase inhibitors  have shown great promise in murine models of inappropriate neuronal apoptosis.  The treatment of certain lymphomas by antisense oligonucleotides to bcl-2  Death-inducing cytokines of the tumour necrosis factor family, such as TRAIL
  • 35. SUMMARY:  Apoptosis: mechanism & regulation  Importance of apoptosis during early development  Importance of apoptosis during adulthood  Disruption of apoptotic pathway  Therapeutics
  • 36. References:  Why is apoptosis important to clinicians; Haslett C; BMJ. 2001 June 23; 322(7301): 1499–1500.  Association of Tumor Necrosis Factor-Related Apoptosis Inducing Ligand with Total and Cardiovascular Mortality in Older Adults; Stefano V et al; Atherosclerosis. 2011 April ; 215(2): 452–458. doi:10.1016/j.atherosclerosis.2010.11.004.  Apoptosis: a basic biological phenomenon with wide- ranging implications in tissue kinetics; Kerr JF, Wyllie AH, Currie AR; Br J Cancer. Aug;26(4):239-57  Pathologic Basis of Disease; Robbins & Cotran  Immunology, 5th Ed; Kuby
  • 37.
  • 39. The bcl-2 family BH4 BH3 BH1 BH2 TMN C Receptor domain phosphorylation Raf-1 calcineurin Pore formation Membrane anchor Ligand domain Group I Group II Group III Bcl-2 bax Bad bid bik Back
  • 40. 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
  • 41. 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
  • 42. 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