1. The Biology of Cancer Chapter 9:
p53 and Apoptosis: Master Guardian and Executioner
Cell Death
2. Apoptosis Autophagy Necrosis
Programmed
cell death.
Death cycle is
programmed
by the cell itself
‘Self-eating’
Catabolic process
involving lysosomes.
‘Death’ caused
by external factors
like trauma or toxins.
Not programmed.
Cell Death
3. The term was originally used by
Wyllie and his colleagues and is from
the Greek meaning “dropping away”
as the leaves from a tree.
Apoptosis: Programmed Cell Death
Cell Suicide
The Face of Cell Death: Apoptosis
4.
5.
6.
7. Active cell death
• Specific gene expression
• Specific intracellular signals
• Requires energy and RNA and protein synthesis
• Characteristic morphological features
• DNA cleaved, chromatin condenses
• Cells shrink
• Formation of apoptotic body
• Cleared by phagocytosis
• No inflammation=no tissue damage
Passive cell death
• Physical or chemical trauma
• Cells swell up
• Membrane breaks down and cellular contents
leak out
• Nucleus disintegrates
• Cell ghosts
• Inflammatory=tissue damage
Apoptosis Necrosis
15. Two Pathways that Initiate Apoptosis
Intrinsic/ Mitochondrial Apoptosis
Regulated by Mitochondrial
Cytochrome C release
Extrinsic/ Death Receptor Apoptosis
Activated by ligation of Death Receptors
Fas, TNF alpha
These pathways intersect at the effector
caspases
20. The apoptosome
associates with Apaf1.
this causes the assembly
of the 7 spoked wheel
in which Apaf-1 forms the spokes
and the cyt c forms the tips.
Once assembled this attracts
procaspase 9 into the
hub of the wheel which converts
procaspase 9 into active caspase 9.
The resulting caspase 9
proceeds in turn to cleave and
activate other caspase molecules
thereby triggering the apoptotic
cascade.
Caspase 9 is activated
23. Executioner caspases :
Caspase 3, 6 & 7 cleave DNA
by activating DNAase
APOPTOSIS
Caspase 9 is activated
Caspase 9 activates the executioner
caspases
Mitochondrial Cyt C release
INTRINSIC APOPTOTIC PATHWAY
24. The Extrinsic Pathway: In
the extrinsic pathway, signal
molecules known as ligands,
which are released by other
cells, bind to transmembrane
death receptors on the target
cell to induce apoptosis. For
example, the immune
system’s natural killer cells
possess the Fas ligand
(FasL) on their surface. The
binding of the FasL to Fas
receptors (a death receptor)
on the target cell will trigger
multiple receptors to
aggregate together on the
surface of the target cell. The
aggregation of these
receptors recruits an adaptor
protein known as Fas-
associated death domain
protein (FADD) on the
cytoplasmic side of the
receptors. FADD, in turn,
recruits caspase-8, an
initiator protein, to form the
death-inducing signal
complex (DISC). Through
the recruitment of caspase-8
to DISC, caspase-8 will be
activated and it is now able
to directly activate caspase-
3, an effector protein, to
initiate degradation of the
cell.
The extrinsic apoptotic pathway
25. The Extrinsic Apoptotic Pathway
Disc (death inducing signal complex)
TRADD : tumor necrosis factor death domain, FADD: Fas associated death domain.
Cleaves DNA
33. Cancer cells invent numerous ways to inactivate the
apoptotic machinery in order to survive
Among these are the activation of Akt pathway,
inactivation of p53 and also inhibition of caspases
Loss of apoptotic functions allows cancer cells
to survive a variety of cell physiological stresses
such as DNA damage
