Lecture 7, BIOL 134

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
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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
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8. Figure 9.18d The Biology of Cancer (© Garland Science 2007)
An apoptotic cell
showing fragmented
Golgi bodies (green)

9. Autophagy

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Srcf.ucam.org
Autophagy: clearing out garbage

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The Face of Cell Death: Apoptosis

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Two Apoptotic Pathways: Extrinsic & Intrinsic

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

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Two Pathways that Initiate Apoptosis

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Intrinsic Pathway
Chemotherapy
Irradiation

18. Figure 9.29 The Biology of Cancer (© Garland Science 2007)
The Apoptotic Caspase Cascade: Apoptosome
The Wheel of Death
Pro-apoptotic signals open
channels
in the mitochondrial
membrane to allow
cytchrome c and
Smac/Diablo
molecules to be released.
Cytochrome c
molecules bind to Apaf1 to
form the
apoptosome. The
apoptosome activates
pro-caspase 9 to caspase 9
which in turn
activate caspase 3.
Caspase 3 activates
in turn, a series of
executioner caspases
which cleave various death
substrates
whose cleavage creates the
apoptotic
cell phenotype.

19. Figure 9.28 The Biology of Cancer (© Garland Science 2007)
The Wheel of Death - Apoptosome
The apoptosome
is assembled in the
cytosol when cytochrome
c molecules are released
from the mitochondria
into the cytosol.

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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

21. Caspase 9 activates the executioner caspases
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Active caspase 9

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Executioner caspases :
Caspase 3, 6 & 7 cleave
DNA by activating
DNAase
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APOPTOSIS

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Executioner caspases :
Caspase 3, 6 & 7 cleave DNA
by activating DNAase
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APOPTOSIS
Caspase 9 is activated
Caspase 9 activates the executioner
caspases
Mitochondrial Cyt C release
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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
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The Extrinsic Apoptotic Pathway
Disc (death inducing signal complex)
TRADD : tumor necrosis factor death domain, FADD: Fas associated death domain.
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Cleaves DNA
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26. Figure 9.19 The Biology of Cancer (© Garland Science 2007)
Apoptosis of cells forming webs between future mouse
toes. The dark dots are apoptotic cells.

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Apoptotic humor !

28. p53 and Apoptosis

29. Figure 9.8 The Biology of Cancer (© Garland Science 2007)
p53 - activating signals’s and p53 downstream effects
A variety of cell
physiologic stresses
can cause a rapid
increase in p53 levels
which proceeds to
induce a number of
responses.

30. A cancer cell does not want to undergo
apoptosis hence it initiates
anti-apoptotic strategies

31. Figure 9.34 The Biology of Cancer (© Garland Science 2007)
Anti-apoptotic strategies used by cancer cells
Cancer cells resort to
numerous strategies
in order to decrease the
likelihood of apoptosis.
This diagram indicates that
in various cancer
cell types the levels or
activity of important
pro-apoptotic proteins
are decreased (blue).
Conversely, the levels or
activity of certain
anti-apoptotic proteins
may be increased (red).

32. Figure 9.37 The Biology of Cancer (© Garland Science 2007)
The Apoptotic Circuit Board
The full array of components governing apoptosis is not
known. An initial attempt at modeling the system is shown.

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