Apoptosis

1. By Michael A. Medez

2. APOPTOSIS
• First described by Carl Vogt in 1842
• 1965, distinguished from necrosis
• Greek word “falling off”
• Programmed Cell Death
• Biochemical reactions lead to cell changes and
death
• Around 50 to 70 billion cells die each day due to
apoptosis

3. APOPTOSIS vs NECROSIS
• Apoptosis • Necrosis
 Natural Cell Death  Traumatic Cell Death
 Stimulated by cell signals  Stimulated by factors
 Beneficial external to the cells
 Produces cell fragments that  Fatal
are able to send signals that  Cannot send signals, leads to
facilitate phagocytosis build up of dead tissue and
cell debris

4. PROCESS
• Controlled by a diverse range of cell signals
 Extracellular (Extrinsic Inducers)
• Toxins, hormones, cytokines
• Positive Induction or Negative Induction
 Intracellular (Intrinsic Inducers)
• Initiates in response to stress
(heat, radiation, hypoxia, nutrient deprivation)

5. REGULATION
• Mitochondrial Regulation
 Mitochondria is essential to cell life
 Exploited by apoptotic pathways
 Cause mitochondrial swelling or may increase the
permeability of the membrane
• Direct Signal Transduction
 TNF (Tumor Necrotic Factor) Pathway
 Fas Pathway

6. TNF and Fas
 TNF Pathway
• Fas Pathway
 TNF is a cytokine produced
 Binds the Fas Ligand
by macrophages
 Formation of Death
 Major extrinsic mediator of
Inducing Signaling Complex
apoptosis
(DISC)
 Leads to caspase activation
 Caspase activation via the
via membrane proteins
FADD
TRADD and FADD
 Indirectly leads to activation
of transcription factors
involved in cell survival and
inflammatory response

7. COMPONENTS
• Following activation of TNF and Fas, a balance
between proapoptotic and anti-apoptotic members
of the Bcl-2 family is established
• Proportion of proapoptotic homodimers that form
in the outer membrane of the mitochondria,
required to make the membrane permeable for the
release of caspase activators

8. CASPASES
• Cysteine-dependent aspartate-secific proteases
• Play a central role in transduction of apoptopic
signals
• Highly conserved proteins
• Intiator Caspases
 Activates by binding to specific oligomeric
adaptor protein
• Effector Caspases
 Activated by active initiator caspases through
proteolytic cleavage
 Degrade intracellular proteins to carry out cell
death program

9. MECHANISM
1. Cell receives stimulus
2. Shrinks (breakdown of cytoskeleton)
3. Dense cytoplasm, packing of organelles
4. Condensation of chromatin (PYKNOSIS)
5. Fragmentation of DNA, breaking of nucleus
6. Formation of blebs
7. Cell breaks, formation of apoptotic bodies
8. Phagocytosis

12. REMOVAL OF DEAD CELLS
• Efferocytosis
• Dying cells display phagocytotic molecules,
phosphatidylserine
• Mark the cell for phagocytosis

13. DEFECTS in APOPTOSIS
• p53
 Tumor suppressor protein
 Accumulates when DNA is damaged
 Prevents the cell fro replicating to give it time to
repair
 Induce apoptosis if damage is extensive and repair
efforts fail
 Any disruption to its regulation results in impaired
apoptosis and possible formation of tumors

14. INHIBITION and HYPERACTIVITY
• INHIBITION • HYPERACTIVITY
 Decrease in cell  Loss of control of cell
death death
 Most common is  HIV
CANCER