The extrinsic and intrinsic pathways of apoptosis

1. APOPTOSIS
Dr. Anu P. Abhimannue
Assistant Professor
Department of Biotechnology
St. Mary’s College
Thrissur.

2. Apoptosis
• The demise of cells by programmed cell death is known as apoptosis.
• Term of Greek origin meaning “dropping off” or “falling off,” as leaves
from a tree.
• Characterized by well-orchestrated events.
Anu P. Abhimannue, St. Mary's College, Thrissur 2

3. Apoptosis vs necrosis
Apoptosis
• Chromatin condensation along the
nuclear periphery.
• Chromosomal DNA fragmentation
due to cleavage between
nucleosome.
• Cell shrinkage
• Nucleus and cytoplasm fragment,
forming apoptotic bodies, which
are phagocytosed by macrophages
and other neighboring cells
Necrosis
• Cells die in response to tissue
damage
• Cells swell and burst, releasing
their intracellular contents.
• These intracellular contents can
damage surrounding cells and
frequently cause inflammation.
Anu P. Abhimannue, St. Mary's College, Thrissur 3

4. Apoptotic Pathways
• Apoptosis can be initiated by two separate pathways
Intrinsic pathway.
Extrinsic pathway.
• Both of these pathways end with a final common effector pathway,
known as the execution phase.
Anu P. Abhimannue, St. Mary's College, Thrissur 4

5. Intrinsic pathway
• Also known as mitochondrial pathway
• The intrinsic pathway mainly triggers apoptosis in response to internal stimuli:
• Biochemical stress
• DNA damage (this activates the p53 gene – which halts the cell cycle and
initiates DNA repair. If this repair attempt is unsuccessful, apoptosis can be
induced)
• Lack of growth factors
Anu P. Abhimannue, St. Mary's College, Thrissur 5

6. Intrinsic Pathway - Mechanism
Damage to mitochondria results in expression of proapoptotic
factors like Bax
Bax form oligomers in the outer membrane of mitochondria
Subsequently, results in the release of cytochrome c and other
proapoptotic molecules from the intermembrane space
This leads to the formation of apoptosomes containing Apaf-1
and caspase-9
Activation of caspase-9 and it further activates the downstream
caspases, such as caspase-3, by proteolytic cleavage
Execution pathway
NB: Action of lAPs can be down regulated by Smac/Diablo and Omi/Htr2
Anu P. Abhimannue, St. Mary's College, Thrissur 6

7. Extrinsic pathway
• The extrinsic pathway triggers apoptosis in response to external stimuli
(death signals), that bind at ‘death’ receptors on the cell surface.
• the stimulus for apoptosis is carried by an extracellular messenger protein
called tumor necrosis factor (TNF), which was named for its
• ability to kill tumor cells.
• TNF is produced by certain cells of the immune system in response to
adverse conditions, such as exposure to ionizing radiation, elevated
temperature, viral infection, or toxic chemical agents such as those used in
cancer chemotherapy.
Anu P. Abhimannue, St. Mary's College, Thrissur 7

8. Members of the Death Receptor family
• Eight members of the Death Receptor family have been characterized
so far:
• TNFR1 (Tumor Necrosis Factor Receptor-1) also known as DR1, CD120a, p55 and p60
• Fas also known as DR2, APO1 and CD95
• DR3 (Death Receptor-3) also known as APO-3, LARD, TRAMP and WSL1
• TRAILR1 (TNF-Related Apoptosis-Inducing Ligand Receptor-1) also known as DR4 and
APO-2
• TRAILR2 also known as DR5, KILLER and TRICK2
• DR6
• EDAR (Ectodysplasin-A Receptor)
• NGFR (Nerve Growth Factor Receptor)
Anu P. Abhimannue, St. Mary's College, Thrissur 8

9. Extrinsic Pathway - Mechanism
Cell death receptors TNF and ligands has three polypeptide chains
Their binding induces receptor trimerization
Caspase-8 activated via interaction with adaptor molecules
Once activated, caspase-8 can directly cleave and activate effector caspases
In addition, caspase-8 cleaves the BH3-only protein Bid
Activates the mitochondrial pathway of apoptosis
Leading to caspase-9 activation
Anu P. Abhimannue, St. Mary's College, Thrissur 9

10. REFERENCES
• Karp, G. (2010). Cell And Molecular Biology – Concepts And
Experiments (6 Eds.), Cell Signaling and Signal Transduction:
Communication Between Cells, (pp 642 – 646). John Wiley & Sons,
Inc.
• Cooper, J.M., Hausman, R. E. (2007). The Cell – A Molecular Approach
(4 Eds.), Cell Death And Cell Renewal, (Pp 689 – 698). Asm Press.
• https://teachmephysiology.com/basics/cell-growth-death/apoptosis/
Anu P. Abhimannue, St. Mary's College, Thrissur 10