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Robert A. Weinberg
The Biology of Cancer
First Edition
Chapter 9:
p53 and Apoptosis: Master
Guardian and Executioner
Copyright © Garland Science 2007
Li--Fraumeni syndrome
Li
Figure 9.20 The Biology of Cancer (© Garland Science 2007)
Anoikis
p53--independent apoptosis
p53
Detachment of MEC from ECM
triggers apoptosis
MEC: mammary epithelial cells
Red: Integrin
Blue: Nuclei
Green:Activated caspasecaspase-3
Figure 9.21 The Biology of Cancer (© Garland Science 2007)
Actions of the antianti-apoptotic Bcl2Bcl2-like genes
Table 9.3 The Biology of Cancer (© Garland Science 2007)
Motochondria : Life or Death
Between outermembrane & innermembrane
1) Metabolism
- Oxidative phosphorylation
- Metabolite production
p
2) Determination of cell death
Figure 9.23a The Biology of Cancer (© Garland Science 2007)
Release of cytochrome c from mitochondria
Treatment of staurosporine
Figure 9.24 The Biology of Cancer (© Garland Science 2007)
Bcl--2 and related proteins
Bcl
24 Bcl
Bcl--2-related proteins: six of antianti-apoptotic and
eighteen of propro-apoptotic
Bcl--2 and related proteins
Bcl
Figure 9.25b The Biology of Cancer (© Garland Science 2007)
The delicate balance between propro- and
antianti
ti-apoptotic
t ti proteins
t i
Normal
Bcl-2 knockout triggers
Bclsevere polycystic kidney
disease through apoptosis
Figure 9.26 The Biology of Cancer (© Garland Science 2007)
One copy deletion of
proapoptotic gene (bim(bim-2)
rescues PKD
Proapoptotic signals acting through
various Bcl
Bcl--2-related proteins
A. Various cell
cell--physiologic stresses
B. Inactivation of propro-apoptotic proteins
Partnership between antianti- and pro
pro--apoptotic proteins
Figure 9.27c The Biology of Cancer (© Garland Science 2007)
The apoptotic caspase cascade - 1
The wheel of death
- Apoptosome 7 Apaf
Apaf--1: spokes of wheel
7 cyt c: tips of spokes
Dome: procaspaseprocaspase-9
Caspase: cycteine
aspartyl--specific prote
aspartyl
protease
ase
ICAD: Inhibitor of Caspase-activated DNase
Actin, Vimentin: cytoskeletal protein
Lamin: Nuclear membrane protein
Figure 9.28 The Biology of Cancer (© Garland Science 2007)
The apoptotic caspase cascade - 2
IAP: Inhibitors of apoptosis
Death Receptors
Trimerization of TNFTNF-a
FAS--FASL:Apoptotis of cancer cell by
FAS
cytotoxic T cell
FAS-associated
FASdeath protein
(death--inducing
(death
signaling complex)
CTL
Injection of
granzyme
Apoptotic
Cancer cell
Figure 9.31a The Biology of Cancer (© Garland Science 2007)
Convergence of intrinsic and extrinsic apoptotic pathway
Activation of apoptosis by p53
Table 9.5 The Biology of Cancer (© Garland Science 2007)
Anti--apoptotic strategies used by cancer cells
Anti
Blue: decreased propro-apoptotic proteins
Red: increased antianti-apoptotic proteins
Figure 9.35 The Biology of Cancer (© Garland Science 2007)
Autophagy
A second cell death program by nutrient starvation
Multilayered vesicle: autophagosome
Beclin--1: a key protein for autophagy
Beclin
Figure 9.37 The Biology of Cancer (© Garland Science 2007)