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Российский национальный исследовательский медицинский университет им, Н. И. Пирогова

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226	CHRISTIAN TAUBE AND MARTIN SCHULER

in tumor biopsies correlates with improved outcome of NSCLC patients undergoing chemotherapy. Hence the functionality of apoptotic signal transduction pathways appears to determine – at least in part – the preclinical and clinical efﬁcacy of cytotoxic and molecularly targeted lung cancer therapies.

Although most, if not all, current anticancer drugs primarily induce apoptosis via the intrinsic pathway of caspase activation, the extrinsic pathway also provides targets for lung cancer therapy. The TNF-related apoptosis-inducing ligand (TRAIL) and its receptors are of particular interest, as recombinant TRAIL exhibits antitumor activity in preclinical models, including lung cancer. Whereas TRAIL monotherapy has modest activity, it highly sensitizes xenografted lung cancers to cytotoxic drug-induced apoptosis in vivo. In agreement, the anti-TRAIL receptor antibody mapatumumab has no apparent antitumor activity in patients with advanced lung cancers; however, due to its favorable tolerability, further development in combination therapies seems warranted. In summary, further understanding of the role of apoptosis in lung cancer will likely improve therapeutic options and outcome of patients suffering from this devastating disease.

SUGGESTED READINGS

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J Clin Pathol. 54, 132–8.

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Bruce, M.C., Honaker, C.E., and Cross, R.J. (1999). Lung ﬁbroblasts undergo apoptosis following alveolarization. Am J Respir Cell Mol Biol. 20, 228–36.

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Calabrese, F., Giacometti, C., Beghe, B., Rea, F., Loy, M., Zuin, R., Marulli, G., Baraldo, S., Saetta, M., and Valente, M. (2005). Marked alveolar apoptosis/proliferation imbalance in endstage emphysema. Respir Res. 6:14., 14.

Checinska, A., Hoogeland, B.S., Rodriguez, J.A., Giaccone, G., and Kruyt, F.A. (2007). Role of XIAP in inhibiting cisplatininduced caspase activation in non-small cell lung cancer cells: a small molecule Smac mimic sensitizes for chemotherapy-induced apoptosis by enhancing caspase-3 activation. Exp Cell Res. 313, 1215–24.

Chipuk, J.E., Maurer, U., Green, D.R., and Schuler, M. (2003). Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription. Cancer Cell 4, 371–381.

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Plate 1. 3D structure of XIAP BIR3. See Figure 2-1 for details.

NAIP/BIRC1			1403
c-IAP1/BIRC2			604
c-IAP2/BIRC3			612
XIAP/BIRC4			497
Survivin/BIRC5			142
Apollon/Bruce/BIRC6			4830
Livin/ML-IAP/BIRC7			298
Ts-IAP/ILP-2/BIRC8			237
BIR	CARD		RING
NBD	LRR	UBA	UBC

Plate 2. Domain organization of the human IAP protein family. See Figure 2-2 for details.

Plate 3. Structure of the XIAP BIR3 domain complexed with SMAC tetrapeptide. SMAC peptide bound to BIR3 of XIAP. The BIR3 domain of XIAP (shown as a space-ﬁlling model) complexed with the SMAC tetrapeptide, AVPI. See Figure 2-4 for details.

CD95 and TRAIL signaling complex

			FADD
Bax
		c-Flip
Bak
mitochondria	tBid	Bid	caspase-8/10
mitochondria	tBid	Bid
Cytochrome C			ac ve caspase-8/10
Apaf-1
apoptosome	ac ve caspase-9		ac ve caspase-3

Smac/DIABLO

XIAP

Apoptosis

Plate 4. Schematic representation of apoptotic signaling by the CD95 and TRAIL systems. See Figure 3-2 for details.

TNF-R1 signaling complex

RIP1	TRADD
	TRAF2/5
TAB2
TAK1
TAB1
NEMO IKKβ	cIAP1/2
NEMO IKKβ
IKKα

NF-κB JNK p38

Gene induction

Plate 5. Schematic representation of immunostimulatory, pro-inﬂammatory signaling by the TNF-R and DR3 systems. Binding of TNF and TL1A to their respective receptor leads to receptor trimerisation and formation of a receptor signaling complex. See Figure 3-3 for details.

Primarily apoptotic signaling systems	Primarily immunostimulatory, proinflammatory
(CD95 and TRAIL systems)	signaling systems (TNF and DR3 systems)
Complex I			Complex I
FADD	RIP1		TRADD
FADD	RIP1
Complex II			TRAF2/5	Complex II
Caspase- 8	TAB2	TAK1
	TAB1	TAK1
NEMO	NEMOIKKβ		cIAP1/2
	IKKα

NF-κB

MAPK

APOPTOSIS

Gene induction

APOPTOSIS

Plate 6. Complex I and complex II: spatial dissociation between proapoptotic and proinﬂammatory signaling in death receptor signal transduction. See Figure 3-4 for details.

- BIM or BID

- sensitizer BH3-only proteins - cytochrome c

- BCL-2 protein

- BAX/BAK protein

Normal cell

“Idealized” cancer cell

Plate 7. Cartoon representation of an unprimed mitochondrion versus a primed mitochondrion. See Figure 5-3 for details.

Plasma membrane

					se	nCDase
			Ma
			aS		Cer	Sph
		SM			Cer	Sph
	L	SM			Cer	Sph
	L
M	GS
S		SM			e
		SM			e
				Mas
			nS

S1P

GSL

Golgi

L S G

GSL

Lysosomes

Cer

aSMase

S		CS
S	MS	G
		G

			r
		e
C		C
er

CERT

Serine

palmitoyl-CoA

h p S H d

rS e C

		r	Des
	e
C
dH

Cer

Sph

CerS

SPP

hpS

aCDase

GSL

C					r
e	GCase				e
r	GCase			C
			lc
S1P		G
S1P						ia
						ia
						r
						d
					n		h
				o			p
			h			?	p
			h			?	S
		c					S
		c
	to					r
	i				e
	M				e
	M	?		C
				C

S		M
P	S
L	S

S	P	T

Nucleus

M A

M s

Plate 8. Compartmentalization of sphingolipid metabolism. See Figure 9-2 for details.

extracellular ligand e.g., CD95L

aSMase

SM Cer

(a)

ExogenousCer	UV, IR,
Sph	DNA-damaging
Sph	agents
Receptor clustering

CDase	aSMase
	Cer SM
flip-flop?
?	?
promotion of
apoptosis

Sphingomyelin

Ceramide

Sphingosine

Glycerophospholipid

extracellular ligands	cellular stresses		salvage
(e.g., cannabinoids)	(e.g., DNA damage)		pathway
			promotion of
			apoptosis
	p53		SK
			SK
?			Sph
?			PP1, PP2A,
			PP1, PP2A,
Bcl-2-like			SR proteins, p8, ???
proteins	acyl-CoA		acyl-CoA
	acyl-CoA
	dhSph	dhCer	Cer
SPT	CerS	Des	CerS
Myriocin	FB1		FB1

pro-survival pathways

	ethano-
S1P	lamine
	phosphate
	+
	hexa-
	decenal

SPL

(b)

Plate 9. Summary of ceramide-mediated pathways. See Figure 9-8 for details.

Plate 10. Several hypotheses have been proposed to explain how granzymes enter the target cell to mediate their cell death functions. See Figure 10-1 for details.

TARGET CELL

grA

grB

Human grB

Bid

Mouse grB

Bcl2

tBid

ROS

Procaspase-3

Bax / Bak

Caspase-3

Caspase-9

SET complex

Cytochrome c

CAD	ICAD	IAP
		IAP

SMAC/DIABLO

DNAse

Procaspase-9

Apaf-1

APOPTOSOME

Plate 11. GrA and grB show di erent substrate speciﬁcities within the target cell. GrA induces the release of ROS from the mitochondrial inner membrane, which mediates the translocation of the SET complex from the ER to the nucleus. See Figure 10-2 for details.

Plate 12. The unfolded protein response (UPR), a coordinated regulated response involving three sensor proteins: PERK (PKR-like ER kinase), ATF6 (activating transcription factor 6), and IRE1 (inositol requiring transmembrane kinase/endoribonuclease). See Figure 12-1 for details.

Plate 13. Proteins implicated in ER stress-pcd pathways. See Figure 12-2 for details.

Isolated intact mito

subcellular	Purified intact nuclei
fractionation	Intact DNA

Ca2+ overload

supernatant Supernatant containing AIF

~50 kb DNA fragments

pellet

Swollen, permeabilized

mito Condensed, fragmented nuclei

Plate 14. Identiﬁcation of a caspase-independent mitochondrial apoptosis-inducing factor using an in vitro reconstitution assay with subcellular fractions. See Figure 14-4 for details.

Plate 15. Extrinsic and intrinsic signals of cell death and survival after spinal cord injury. See Figure 15-1 for details.

Plate 16. Retinal neovascularization in age-related macular degeneration (AMD). See Figure 16-2 for details.

Plate 17. The ear. See Figure 17-1 for details.

Plate 18. The cochlea. See Figure 17-2 for details.

corpus callosum

medial olfactory stria

olfactory tract

olfactory bulb

olfactory epithelium

lateral olfactory stria

striae medullares

longitudinal striae

medial forebrain bundle

to amygdala	brainstem
and prepyriform cortex

cerebellum

Plate 19. Gross anatomy. See Figure 18-1 for details.

olf. bulb	RMS	SVZ
		SVZ

fila		lateral ventricle
fila		lateral ventricle

olfactoria

olf. epithelium

brainstem	spinal
brainstem	cord
olf. bulb	RMS
fila olf.	RMS
basal cell		newborn
basal cell		granule cell
developing	olf. tract	newly integrating
ORN		granule cell
supporting		apoptotic
supporting		granule cell
cell		granule cell
cell
		mitral cell
ORN		tufted cell
		tufted cell
apoptotic	ORN axon
ORN	ORN axon
mucus

glomerulum

periglomerular cell mature granule cell

Plate 20. Olfactory life and death on a microscopic level. See Figure 18-2 for details.

Plate 21. Signaling pathways leading to beta cell destruction in type 1 diabetes. See Figure 19-1 for details.

Plate 22. Shift in lipid partitioning associated with apoptosis in diabetic beta cells. See Figure 19-2 for details.

(a)

(b)

Plate 23. Signaling pathways in response to unfolded proteins. See Figure 19-3 for details.

A) Alteration in the BAX/BCL-2 ratio			C) Activation of caspase-9
CON	2d	5d	14d
M	M	M	M
BCL-2
BAX			D) Activation of caspase-3
			D) Activation of caspase-3
COX IV
B) Release of cytochrome c and DIABLO
CON	2d	5d	14d
DIABLO			TUNEL	Caspase-3	Merged
			TUNEL	Caspase-3	Merged
			E) PARP cleavage
Cyt.C				CON 2d	5d 14d
				CON 2d	5d 14d

89 kDa

Actin

Plate 24. Hormonal deprivation results in activation of the intrinsic pathway signaling. See Figure 25-3 for details.

CON 2d

5d 14d

p-ATF-2

Total ATF-2

III

TUNEL

p-p38 MAPK

Merged

Plate 25. Activation of p38 MAPK in rat testes after GnRH-A treatment. See Figure 25-4 for details.

Plate 26. Testicular hyperthermia results in serine phosphorylation of BCL-2 in germ cells. See Figure 25-5 for details.

A B C

XII

Plate 27. Activation of ERK in the Sertoli cells. See Figure 25-6 for details.

Tunica adventitia connective tissue

Plate 28. Normal human artery consists of three layers. See Figure 26-1 for details.

Tunica intima

endothelium

internal elastic lamina

external elastic lamina

smooth muscle cells

Tunica media

Control Apoe-/-

SM22α-hDTR Apoe-/-

Control Apoe-/-

SM22α-hDTR Apoe-/-

Plate 29. Vascular smooth muscle cell apoptosis accelerates atherosclerotic plaque progression and induces plaque vulnerability. See Figure 26-3 for details.

Percent survival

LVEDP (mmHg)

100				C360A (n = 19)
80			WT (n = 197)
60			Line 169 (n = 34)
60
40
20
0	50 100 150 200 250 300
0	50 100 150 200 250 300
		Time (d)

30			(mmHg/s)	20000
30
				15000
				15000
20				10000
			+dP/dt	10000
10			+dP/dt	5000
10

0	WT	Tg		0
	WT	Tg
n	7	6		n

IVS

LV-cavity

– + – + WT Tg

–	–
WT	Tg

–dP/dt (mmHg/s)

IVS

LVcavity PW

10000
7500
5000
2500
0	–	+	–	+
	–	+	–	+
n	WT		Tg
n	7	5	6	3
	–		–	TUNEL-positive myocytes per
WT			Tg

	c	4
(mm)		3
		3
EDD		2
EDD		1
		1
		0	WT	Line 7	Line 169	C360A
		n	WT	Line 7	Line 169	C360A
		n	9	9	5	3
		100
(%)		75
(%)		50
FS		50
FS		25
		25
		0	WT	Line 7	Line 169	C360A
		n	WT	Line 7	Line 169	C360A
		n	9	9	5	3
nuclei	30
nuclei	20
cardiac	20
cardiac	10
	10
5
10		0
		0	WT	Line 7 C360A
			WT	Line 7 C360A
		n	5	6	4

Plate 30. Modest, but elevated, rates of cardiac myocyte apoptosis are su cient over time to induce lethal heart failure. See Figure 26-4 for details.

	Bone	Skeletal Muscle
		Skeletal Muscle
		Vein	Muscle
A		Vein	Fascicle
			Fascicle

			Myofiber
	Tendon	Capillary Myonucleus
	Tendon
	Sarcomere
	A-band I-band
	M-line Z-line	Myofibril
		Myofibril
		ENDURANCE
		TRAINING

T-tubule		Sarcoplasmic
T-tubule		reticulum
		reticulum
Myonucleus	Subsarcolemmal
Myonucleus	(SS) mitochondria		Intermyofibrillar (IMF) mitochondria
B	OMM	Holoenzyme	MITOCHONDRION
	OMM	assembly
	IMM
	Incorporation
	into ETC

	Electron transport	mtDNA
	chain (ETC)
		ATP

Nuclear pore

Import machinery

Translation

+1	Transcription
NUGEMPS
NUCLEUS	mRNA

Plate 31. Unique morphology of skeletal muscle and exercise-induced mitochondrial biogenesis. See Figure 27-1 for details.

Loss of Myonuclei +

Satellite cells

Myonuclear

domain

Myofiber

Myonuclear

Domains

Satellite cell activation, proliferation

Atrophy

Hypertrophy

Fusion of satellite cells, myonuclear addition and resultant fiber hypertrophy

Myonuclear Domain is constant

Plate 32. Myonuclear domains during muscle hypertrophy and atrophy. See Figure 27-2 for details.

Plate 33. UVB signaling in keratinocytes. UVB can lead to di erent e ects in keratinocytes, ranging from cell cycle arrest, apoptosis, and inﬂammasome activation. UVB radiation primarily damages nuclear DNA as a result of direct absorption and generates ROS that can induce oxidative damage to DNA and cellular proteins. See Figure 28-3 for details.

Extrinsic pathway

Ligand

	Death
	receptors
	FADD
FLIP	DISC
	DISC
	Procaspases
	-8 and -10
	Active caspases-8
	and -10

Pro-caspases-3, -6, -7

Intrinsic pathway

Cytokine withdrawal, chemotherapeutic drugs, radiations…

BH3-only

proteins

Anti-apoptotic Bcl-2 family members

Bid

Bax/Bak

tBid

Cytochrome C

Apaf-1

Active effector
caspases-3, -6 and -7	Active caspase-9	Pro-caspase-9
	Active caspase-9	Pro-caspase-9

Apoptosome

Plate 34. Two signaling pathways leading to apoptosis. See Figure 29-1 for details.

Plate 35. Lymphocyte apoptosis in spleen of septic patient. Hematoxylin and eosin staining of spleen of septic patient (400 × magniﬁcation). See Figure 31-1 for details.

Plate 36. Colonic epithelial apoptosis in a septic patient. See Figure 31-2 for details.

Gram-negative bacteria

Porin

Gram-positive bacteria

Lipopolysaccharide

Outer membrane

lipoprotein

Peptidoglycan

Plasma membrane

Plate 37. A representation of the cell wall from Gram-negative and Gram-positive bacteria. See Figure 32-2 for details.

teichoic acid

Peptidoglycan

Lipoteichoic acid

Plasma membrane

Mammalian

Insect

TNF TNF

TNF

TNFRTNFRTNFR

Complex II

Complex I

DISC

TRADD

RIP1

DED

TRADD RIP1

TRAF2

RING

DED

TRAF2

RING

p20

DED

FADD

TRADD RIP1

TRAF2

RING

DEDDED

BIR BIR BIRCARD RING

p10

cIAP1/2

TAB2

TAK1

p20

Pro-caspase-8/10

IKK

p10

NEMO

Caspase-3/6/7

I B

p10p10

p20

p50

RelA

Substrate processing

Apoptosis

DAP-type

Peptidoglycan

derivatives

PGRP

-LC

IMD

BIR BIR BIRCARD RING

DIAP2

TAB2

TAK1

IKK Ird5

Kenny

Rel

Gram-negative

bacteria

dFADD

	DED	DD
DED	DED

p20

Dredd

p10

Relish

ANK

Rel

	NF B			NF B
p50	RelA		Rel	Rel
Induction of survival and		DNA fragmentation	Induction of Diptericin and other
inflammatory genes		Chromatin condensation	antimicrobial genes

Plate 38. Schematic representation of the mammalian TNF and insect Imd pathways. See Figure 32-6 for details.

Mammalian

Gram-positive and Gram-negative

bacteria

Insect

		Gram-positive
		bacteria
-		Lysine-type
PGRP	S
PGRP		Peptidoglycan

derivatives

Flagellin

LPS

Bacterial

TIR

TLR4TIR

TIR

TIRTLR5

TIR

TLR1/6

TLR2

lipoproteins

TIR

TIR TIR

Mal

TRIF

MyD88

TRAM

MyD88

IRAK1

IRAK4

Mal

TRAF6

FADD

TAB2

Apoptosis

DED

TAK1

TRIF RIP1

TAB1

TRAF6

TIR

TLR3

TRAF3

Nucleic

MKK3

MKK7

IKK

TBK1

TIR

TLR7

acids

TIR

TLR8

MKK6

NEMO

TIR

TLR9

p38

JNK

Endosome

IRF3

IRF7

Fungi

Spätzle

Yeast

Toll

TIR
dMyD88		TIR
dMyD88		DD
		DD	DD
			DD
	DD			Pelle
Tube				Pelle
Tube
	Cactus
		ANK
Dif	Rel		Rel	Dorsal

Rel

	Induction of the interferon
	response
NF B	NF B

p50 RelA

Induction of survival and inflammatory genes

Rel Rel

Induction of Drosomycin and other antimicrobial genes

Plate 39. A schematic representation of the mammalian TLR and insect Toll pathways. See Figure 32-7 for details.

NOD1			CARD	NBD
NOD2		CARD CARD		NBD
NOD3/9/27			X	NBD
(NLRC3/X1/5)			X	NBD
(NLRC3/X1/5)

NALP1			PYD	NBD	FIIND CARD
(NLRP1)			PYD	NBD	FIIND CARD
(NLRP1)
NALP2-14			PYD	NBD
(NLRP2-14)			PYD	NBD
(NLRP2-14)

IPAF			CARD	NBD
(NLRC4)			CARD	NBD
(NLRC4)
NAIP	BIR	BIR BIR	CARD	NBD
(NLRB)	BIR	BIR BIR	CARD	NBD
(NLRB)

CIITA			AD	NBD

APAF1			CARD	NBD
Ced4			CARD	NBD


ASC		PYD	CARD
CARDINAL		FIIND	CARD


Caspase-				p20	p10
3/6/7
Caspase-8/10		DED DED		p20	p10

cIAP1/2	BIR	BIR	BIR	CARD		RING
XIAP	BIR	BIR	BIR		RING
TRAF2		RING		TZ	TZ		CC	MATH
TRAF6		RING		TZ	TZ		CC	MATH
RIP1				Kinase domain				DD
RIP2				Kinase domain				CARD
IKK /				Kinase domain			LZ	HLH	Nemo BD
IKK					CC1		CC2	LZ	ZF
FADD							DED	DD
TRADD								DD
TNFR1		EC		EC	EC	EC	TM	DD
Caspase-1				CARD			p20	p12
Caspase-9				CARD			p20	p10
Ced3				CARD			p20	p10

Plate 40. E ectors of inﬂammation. The domain structures are shown. See Figure 32-8 for details.

Cytochrome C PAMPs

Ced9	Ced4	Apaf1	NLRs	Bcl-2,
				Bcl-xl
			?
	?	Apoptosome		Inflammasome
		Apoptosome		Inflammasome

Active	Active	Active
Ced3	Caspase-9	Caspase-1

APOPTOSIS	APOPTOSIS	PYROPTOSIS &
		INFLAMMATION

Plate 41. A parallel between mitochondrial apoptosis and NLR innate immunity pathways. See Figure 32-9 for details.

	FasL FasL FasL
H. pylori	Fas Fas Fas
	Fas Fas Fas
P. aeruginosa
DD	DD	DD	DD	DD
	DD		DD
DD				DD
	TRADD		TRADD
RIP1				RIP1
Ub	TRAF2 TRAF2			Ub
b				Ub
U				Ub
b				Ub
U				Ub
b	RING		RING	Ub
U				Ub
b				Ub
b
U

S. pneumoniae

BH3

IKK	IKK	B. Anthracis	Chlamydia spp.	Cytochrome c	PAMPs	Nigericin
				Cytochrome c
		(LT)	MKK			Maitotoxin
NEMO		(LT)				Maitotoxin
						Aerolysin
						F. tularensis
P	P			Apaf1	NLRs	S. flexneri
I B						S. flexneri
p50	RelA
			Apoptosome		Inflammasome	B. Anthracis
		S. typhimurium	MAPK			(LT)
R. rickettsii		(AvrA)				L. monocytogenes
R. rickettsii		Y. pestis

						(LLO)
		(YopJ)				(LLO)
		(YopJ)
NF B						S. typhimurium
p50	RelA					(TTSS)
						L. pneumophila
				Active	Active	P. aeruginosa
				Caspase-9	Caspase-1	P. aeruginosa
				Caspase-9	Caspase-1	( Exo U)
						( Exo U)
		SURVIVAL		APOPTOSIS	PYROPTOSIS &
					INFLAMMATION

Plate 42. Modulation of cell survival/death pathways by microbial e ectors. See Figure 32-10 for details.

Pyroptosis				Apoptosis	Oncosis		Autophagy
Unconventional				Apoptotic
protein secretion			Membrane	Apoptotic
protein secretion			Membrane	bodies
			rupture	bodies
			rupture
				Membrane		Membrane	Atg7
				blebbing		blebbing	Atg7
	Caspase-1			blebbing	Organelle	blebbing	Atg8/LC3
	Caspase-1				Organelle		Atg8/LC3
				Caspase-3, 7	swelling		Atg8/LC3
				Caspase-3, 7			Autophagosome
							Autophagosome
Immature	Other	Glycolysis		Cyto C			Autophago-
				Substrates release			Autophago-
			Membrane				lysosome
cytokines	substrates	enzymes	Membrane				lysosome
			vesicles			Nuclear
		m				swelling
	Nuclear			Nuclear
	Nuclear			condensation
	condensation			condensation
	condensation			DNA
				DNA
DNA				fragmentation
fragmentation				Cell		Membrane
Mature			Membrane	Cell		Membrane
Mature			Membrane	shrinkage		permeability
cytokines			swelling

Plate 43. Pathogen-induced host cell death. See Figure 32-11 for details.

Plate 44. The four male-speciﬁc chemosensory (CEM) neurons located in the cephalic region of the animal undergo programmed cell death in hermaphrodites. See Figure 34-3 for details.

12.5 Gy

acridine orange

TUNEL

p53 +/+

non-injected

chk1 MO

p53e7/e7

non-injected

chk1 MO

Plate 45. A rapid morpholino loss-of-function screen identiﬁes chk1 knockdown as a caspase-3–independent radiation sensitizer in p53 mutant embryos. See Figure 36-3 for details.

Regions of developmental cell death

Brain

Spinal cord

Ear

Eye

Plate 46. Cell death zones in developing zebraﬁsh embryos. See Figure 36-5 for details.

Germ cells

Excretory system

Tail bud

Plate 47. Images of microglia consuming dying neurons by phagocytosis in wild-type and atpv0a1 morphant larvae. See Figure 36-6 for details.

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