BIO 5068Fundamentals of Molecular and Cell

Biology

ApoptosisDecember 1/6, 2005

Dr. Robert H. Archarch@wustl.eduphone 747-4681

The emergent integrated circuit of the cellThe emergent integrated circuit of the cell

2003 03230Hanahan and Weinberg (2000). Cell 100:57-70

The emergent integrated circuit of the cellThe emergent integrated circuit of the cell

2003 0330Hanahan and Weinberg (2000). Cell 100:57-70

2004 0481

Cell proliferation - apoptosis = homeostasisCell proliferation - apoptosis = homeostasis

proliferation apoptosis

disorders ofcell accumulation

disorders ofcell loss

homeostasis

time

Apoptosis: A basic biological phenomenon Apoptosis: A basic biological phenomenon with wide-ranging implications…with wide-ranging implications…

2003 0331

“The term apoptosis is proposed for a hitherto little recognized mechanism of controlled cell deletion, which appears to play a complementary but opposite role to mitosis in the regulation of animal cell populations. Its morphological features suggest that it is an active, inherently programmed phenomenon, and it has been shown that it can be initiated or inhibited by a variety of environmental stimuli, both physiological and pathological…”

Kerr, Wyllie, and Currie (1972). Br. J. Cancer 26:239-57

2003 0286

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Cell death-related publicationsCell death-related publications

Apoptosis (programmed cell death) – part IApoptosis (programmed cell death) – part II

2003 0329

first described by Kerr, Wyllie and Currie(Br. J. Cancer, 1972, 26:239)

Greek for “falling off” or “dropping off”

describes the molecular and morphological processes leading to controlled cellular self-destruction

stereotypical morphological changes: shrinkage, vacuoloation, loss of contact to ECM, chromatin condensation, fragmentation into apoptotic bodies

active and defined process that plays a crucial role in regulation of tissue homeostasis

2004 0477

Morphologic features ofMorphologic features ofnormal, apoptotic and necrotic cellsnormal, apoptotic and necrotic cells

1

6

3

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2

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Vitale et al. Purdue Cytometry CD-ROM Series, Vol. 4

necrosisnecrosis cell swelling nuclear disintegration

membrane dissolution annexin V+/PI+

2004 0478

Apoptosis vs. necrosisApoptosis vs. necrosis

apoptosisapoptosis cell shrinkage nuclear condensation,

apoptotic bodies cytoplasmic blebbing annexin V+/PIˉ single or few cells no inflammation

GITR crosslinking does not inhibitGITR crosslinking does not inhibitactivation-induced cell deathactivation-induced cell death

2004 0459

PI

annexV

0.00 mg/ml anti-CD3

0.02 mg/ml anti-CD3

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necrosisnecrosis cell swelling nuclear disintegration

membrane dissolution annexin V+/PI+

whole organs inflammation

2004 0478

Apoptosis vs. necrosisApoptosis vs. necrosis

apoptosisapoptosis cell shrinkage nuclear condensation,

apoptotic bodies cytoplasmic blebbing annexin V+/PIˉ single or few cells no inflammation

stimuli include signaling triggered by:cell surface receptors, growth factor withdrawal, hypoxia, heat shock, DNA damage, viral infection, chemotherapeutic agents

involved in many physiologic events:embryogenesis, differentiation, homeostasis, aging, removal of defect and/or harmful cells

cause for a variety of pathologic disorders:neurodegenerative disease, immunodeficiency,auto-immune disease, and cancer

stimuli include signaling triggered by:cell surface receptors, growth factor withdrawal, hypoxia, heat shock, DNA damage, viral infection, chemotherapeutic agents

involved in many physiologic events:embryogenesis, differentiation, homeostasis, aging, removal of defect and/or harmful cells

cause for a variety of pathologic disorders:neurodegenerative disease, immunodeficiency,auto-immune disease, and cancer

stimuli include signaling triggered by:cell surface receptors, growth factor withdrawal, hypoxia, heat shock, DNA damage, viral infection, chemotherapeutic agents

involved in many physiologic events:embryogenesis, differentiation, homeostasis, aging, removal of defect and/or harmful cells

cause for a variety of pathologic disorders:neurodegenerative disease, immunodeficiency,auto-immune disease, and cancer

stimuli include signaling triggered by:cell surface receptors, growth factor withdrawal, hypoxia, heat shock, DNA damage, viral infection, chemotherapeutic agents

involved in many physiologic events:embryogenesis, differentiation, homeostasis, aging, removal of defect and/or harmful cells

cause for a variety of pathologic disorders:neurodegenerative disease, immunodeficiency,auto-immune disease, and cancer

Apoptosis (programmed cell death) – part IIApoptosis (programmed cell death) – part II

2003 0329

2004 0479

Apoptosis vs. ‘programmed cell death’Apoptosis vs. ‘programmed cell death’

‘programmed cell death’ and apoptosis are often used as synonyms, but the terms are not identical

‘programmed cell death’ is a genetically defined process during development of multicellular organisms, e.g., Caenorhabditis elegans:1090 cells are generated during development,exactly 131 of these cells undergo apoptosis

‘programmed cell death’ is mediated by apoptosis

2004 0480

Caenorhabditis elegansCaenorhabditis elegans::a model for apoptosis researcha model for apoptosis research

CED-9

CED-4

CED-3

EGL-1

apoptosis

2004 0491

The Nobel PrizeThe Nobel Prizein Physiology and Medicine 2002in Physiology and Medicine 2002

"for their discoveries concerning 'genetic regulation of organ development and programmed cell death'" 

                                                                                

Sydney Brenner H. Robert Horvitz John E. Sulston

    1/3 of the prize     1/3 of the prize     1/3 of the prize

United Kingdom USA United Kingdom

The Molecular Sciences Institute Berkeley, CA, USA

Massachusetts Institute of Technology (MIT) Cambridge, MA, USA

The Wellcome Trust Sanger Institute Cambridge, United Kingdom

b. 1927(in Union of South Africa)

b. 1947 b. 1942

http://nobelprize.org/medicine/laureates/2002/

Regulation of caspase activity:Regulation of caspase activity:C. elegans vs. higher eukaryotesC. elegans vs. higher eukaryotes

2001 0221

Ced-4

Ced-9

Ced-3

Apaf-1

Bcl-2Bcl-xL

cyto c

BaxBad

caspases

c-IAPsmodified from Arch and Thompson (1999).Ann. Rev. Cell Dev. Biol. 15:113-40

2004 0482

Biochemical features of apoptosisBiochemical features of apoptosis

proteolytic cleavage of cytoskeleton

proteolytic cleavage of nuclear proteins

endonucleolytic cleavage of genomic DNA

crosslinking of proteins by transglutaminase

exposure of phoshpatidyl serine on the cell surface

2004 0483

Proposed functions of biochemical Proposed functions of biochemical changes during apoptosischanges during apoptosis

changes of cytoskeleton and cell volume→ separation of cells from their environment

degradation of nuclear proteins and genomic DNA→ destruction of genetic material and interference

with DNA repair mechanisms

Transglutaminase activity→ packaging cell content

Plasma membrane changes→ activation of phagocytes

changes of cytoskeleton and cell volume→ separation of cells from their environment

degradation of nuclear proteins and genomic DNA→ destruction of genetic material and interference

with DNA repair mechanisms

Transglutaminase activity→ packaging cell content

Plasma membrane changes→ activation of phagocytes

changes of cytoskeleton and cell volume→ separation of cells from their environment

degradation of nuclear proteins and genomic DNA→ destruction of genetic material and interference

with DNA repair mechanisms

Transglutaminase activity→ packaging cell content

Plasma membrane changes→ activation of phagocytes

changes of cytoskeleton and cell volume→ separation of cells from their environment

degradation of nuclear proteins and genomic DNA→ destruction of genetic material and interference

with DNA repair mechanisms

Transglutaminase activity→ packaging cell content

Plasma membrane changes→ activation of phagocytes

changes of cytoskeleton and cell volume→ separation of cells from their environment

degradation of nuclear proteins and genomic DNA→ destruction of genetic material and interference

with DNA repair mechanisms

Transglutaminase activity→ packaging cell content

Plasma membrane changes→ activation of phagocytes

Cell-extrinsic and cell-intrinsicCell-extrinsic and cell-intrinsicapoptotic signaling pathwaysapoptotic signaling pathways

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TNFR signaling and apoptosisTNFR signaling and apoptosis

2003 0295

“death receptors” induce p53-independent apoptosis

TNF was identified as a tumoricidal serum compound (Carswell et al. 1975).

TNFR was identified years later(Rubin et al. 1985, Kull et al. 1985).

TNF and TNFR belong to superfamilies(Aggarwal et al. 1985).

TNFR superfamily can be divided based on the presence of a death domain in some of the receptors.

2003 0344

Ashkenazi (2002). Nature Reviews Cancer Vol 2:420-30

TNFR and TNF superfamiliesTNFR and TNF superfamilies

Signaling triggered by TNFR family membersSignaling triggered by TNFR family members

2005 0529mod

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Therapeutic strategies utilizing death receptorsTherapeutic strategies utilizing death receptors

2003 0278Ash

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Death receptor-induced signalingDeath receptor-induced signaling

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Targeting of the FADD geneTargeting of the FADD gene

2003 0268Yeh et al. (1998). Science 279:1954-8

Defective apoptotic pathwaysDefective apoptotic pathwaysin FADDin FADD-/--/- MEFs MEFs

2003 0296Yeh et al. (1998). Science 279:1954-8

Apoptotic pathways in FADDApoptotic pathways in FADD-/--/- fibroblasts fibroblasts

2003 0297Yeh et al. (1998). Science 279:1954-8

10 ng TNF- + chx c-myc adenovirus c-myc adenovirus

adriamycinE1B-neg adenovirus

● FADD+/+

■ FADD-/-

Death receptor-induced signalingDeath receptor-induced signaling

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Caspases (part I)Caspases (part I)

2003 0301

cysteine proteases with specificity for aspartic acid.

related to Caenorhabditis elegans gene ced-3.

constitutively and ubiquitously expressed as catalytically inactive pro-enzymes (zymogens).

N-terminal pro-domain, large and small subunit.

activation requires proteolysis of the zymogen at specific Asp residues resulting in removal of thepro-domain and formation of heterodimers

active caspases are tetramers composed of two heterodimers

2004 0484

Mechanism of caspase activationMechanism of caspase activation

catalytic domain requires amino acids from large and small subunits

zymogen

active caspase

prodomain smalllarge

prodomainautoproteolysis,other caspases

Asp Asp

Caspases (part II)Caspases (part II)

2003 0301

differences in length and sequence of pro-domain:long pro-domain [casp 1, 2, 4, 5, 8, 9, 10, 11, 12, 13]short pro-domain [casp 3, 6, 7, 14]

long pro-domains mediate protein-protein interaction:death effector domain (DED) mediates interactionwith death receptors [casp 8, 10]casp recruitment domain (CARD) also found in Ced-4, Apaf-1 and RAIDD [casp 1, 2, 4, 5, 9, 11, 12, 13]

arranged in proteolytic cascades that amplify signals.

initiator caspases (instigators) cleaveeffector caspases (terminators).

Caspase-3, -8, and -9 knockoutsCaspase-3, -8, and -9 knockouts

2003 0320

caspase-8: embryonically lethal (>E11.5)death receptor (Fas, TNFR, DR3) pathway

caspase-9: perinatally lethal<2% survive and develop normallyneuroepithelial progenitors; mitochondrial pathways (dexamethasone, staurosporin, etoposide, -irradiation)

caspase-3: perinatally lethaldepends on genetic backgroundneuroepithelial progenitors; lack of or delayed morphological changes and DNA fragmentation

Apoptotic signaling pathwaysApoptotic signaling pathways

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Apoptotic pathways in caspase-3Apoptotic pathways in caspase-3-/--/- ES cells ES cells

2003 0317Woo et al. (1998). Genes Dev. 12:806-19

Some examples of caspase substratesSome examples of caspase substratesCategory Substrate Caspase Effect proposed role in apoptosis

Structural Nuclear Lamins 6 Degraded Disassembly of nuclear matrix

FAK 7,6 Inactivated Disassembly of focal adhesionsGelsolin 3 Activated Disassembly of actin filaments,

blebbing, DNA cleavageActin 3,1 Degraded Disassembly of actin filamentsb-catenin 3 Degraded Disassembly of cell-cell contacts

Signaling MEKK1 3 Activated Activation of SAPKAkt-1 ? Inactivated Inhibition of survival pathway

Cell cycle DNA replication complex C

3 Inactivated Inhibition of DNA replication

mdm2 3 Altered Inhibition of p53Rb 3 Inactivated Release of E2F-1

DNA repair /damage

PARP 3 Inactivated DNA nicks not recognized

iCAD 3 Inactivated Degradation of genomic DNADNA-PK 3 Inactivated Inhibition of DNA repair

2004 0485

DNA fragmentation in apoptosisDNA fragmentation in apoptosis

DNA fragmentation

chromatin

DNA

core histonenucleosome

180bp

endonucleolytic

agarose gel electrophoresis

Abnormal chromatin condensation andAbnormal chromatin condensation andlack of DNA degradation in caspase-3lack of DNA degradation in caspase-3-/--/- cells cells

2003 0318Woo et al. (1998). Genes Dev. 12:806-19

Abnormal chromatin condensationAbnormal chromatin condensationin caspase-3in caspase-3-/--/- MEFs MEFs

2003 0319Woo et al. (1998). Genes Dev. 12:806-19

Lethal effect of anti-Fas mAbLethal effect of anti-Fas mAbin caspase-deficient animalsin caspase-deficient animals

2003 0321Zheng et al. (2000). Nature Med. 6:1241-7

Apoptotic signaling pathwaysApoptotic signaling pathways

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Cytochrome c release, Bid translocation and Cytochrome c release, Bid translocation and caspase activation triggered by anti-Fas mAbcaspase activation triggered by anti-Fas mAb

2003 0322Zheng et al. (2000). Nature Med. 6:1241-7

*

I +Bcl-2Bcl-xL

BaxBakBadtBid

cytochrome cSmac/DIABLO

Interactions betweenInteractions betweenprocaspase-9, Apaf-1, and cytochrome cprocaspase-9, Apaf-1, and cytochrome c

2003 0325Zou et al. (1999). J. Biol. Chem. 274:11549-56

*

I +Bcl-2Bcl-xL

BaxBakBadtBid

cytochrome cSmac/DIABLO

The apoptosomeThe apoptosome

2003 0324Zou et al. (1999). J. Biol. Chem. 274:11549-56

Phenotypes of Apaf1Phenotypes of Apaf1-/--/- embryos embryos

2003 0302Yoshida et al. (1998). Cell 94:739-50

Apaf-1-/-

Apaf-1+/+

Apoptotic pathways in Apaf1Apoptotic pathways in Apaf1-/--/- ES and EF cells ES and EF cells

2003 0303Yoshida et al. (1998). Cell 94:739-50

ES cells EF cells

cellular IAPscellular IAPs – family of cytoplasmic proteins that interfere with caspase activation but are also involved in receptor-induced signal transduction pathways.

Bcl-2/Bcl-xBcl-2/Bcl-xLL – family of pro- and anti-apoptotic proteins that act as sensor for cellular damage or stress.

p53 – transcription factor that senses DNA damage and regulates cell proliferation and apoptosis.

PI-3K and Akt/PKBPI-3K and Akt/PKB – lipid and protein kinases that integrate signals from growth factor receptor to regulate multiple pathways of cell survival and apoptosis.

cellular IAPscellular IAPs – family of cytoplasmic proteins that interfere with caspase activation but are also involved in receptor-induced signal transduction pathways.

Bcl-2/Bcl-xBcl-2/Bcl-xLL – family of pro- and anti-apoptotic proteins that act as sensor for cellular damage or stress.

p53 – transcription factor that senses DNA damage and regulates cell proliferation and apoptosis.

PI-3K and Akt/PKBPI-3K and Akt/PKB – lipid and protein kinases that integrate signals from growth factor receptor to regulate multiple pathways of cell survival and apoptosis.

cellular IAPscellular IAPs – family of cytoplasmic proteins that interfere with caspase activation but are also involved in receptor-induced signal transduction pathways.

Bcl-2/Bcl-xBcl-2/Bcl-xLL – family of pro- and anti-apoptotic proteins that act as sensor for cellular damage or stress.

p53 – transcription factor that senses DNA damage and regulates cell proliferation and apoptosis.

PI-3K and Akt/PKBPI-3K and Akt/PKB – lipid and protein kinases that integrate signals from growth factor receptor to regulate multiple pathways of cell survival and apoptosis.

cellular IAPscellular IAPs – family of cytoplasmic proteins that interfere with caspase activation but are also involved in receptor-induced signal transduction pathways.

Bcl-2/Bcl-xBcl-2/Bcl-xLL – family of pro- and anti-apoptotic proteins that act as sensor for cellular damage or stress.

p53 – transcription factor that senses DNA damage and regulates cell proliferation and apoptosis.

PI-3K and Akt/PKBPI-3K and Akt/PKB – lipid and protein kinases that integrate signals from growth factor receptor to regulate multiple pathways of cell survival and apoptosis.

cellular IAPscellular IAPs – family of cytoplasmic proteins that interfere with caspase activation but are also involved in receptor-induced signal transduction pathways.

Bcl-2/Bcl-xBcl-2/Bcl-xLL – family of pro- and anti-apoptotic proteins that act as sensor for cellular damage or stress.

p53 – transcription factor that senses DNA damage and regulates cell proliferation and apoptosis.

PI-3K and Akt/PKBPI-3K and Akt/PKB – lipid and protein kinases that integrate signals from growth factor receptor to regulate multiple pathways of cell survival and apoptosis.

Regulators of apoptosisRegulators of apoptosis

2004 0494

2004 0486

Bcl-2 proteins as regulators of Bcl-2 proteins as regulators of apoptosisapoptosis

inner membraneintermembranespace

outer membrane

Cytochrome crelease

caspaseactivation

*I +Bcl-2Bcl-xL

BaxBak BadtBid

Smac/DIABLOrelease

X-IAPinhibition

Smac/DIABLO deficiencySmac/DIABLO deficiencyimpairs caspase 3 cleavage impairs caspase 3 cleavage in vitroin vitro

2003 0311Okada et al. (2002). Mol. Cell. Biol. 22:3509-17

*

I +Bcl-2Bcl-xL

BaxBakBadtBid

cytochrome cSmac/DIABLO

2004 0500

Role of X-IAP in exogenous and endogenous Role of X-IAP in exogenous and endogenous cell death pathwayscell death pathways

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Bcl-2 family membersBcl-2 family members

Chan and Yu (2004). Clin. Exp. Pharm. Phys. 31:119-28

Bcl-2 inhibits cytochrome c release and Bcl-2 inhibits cytochrome c release and apoptotic changes in a cell-free systemapoptotic changes in a cell-free system

2003 03256Kluck et al. (1997). Science 275:1132-6

*

I +Bcl-2Bcl-xL

BaxBak BadtBid

cytochrome cSmac/DIABLO

Cytochrome c bypassesCytochrome c bypassesthe inhibitory effects of Bcl-2 on apoptosisthe inhibitory effects of Bcl-2 on apoptosis

2003 03258

*

I +Bcl-2Bcl-xL

BaxBakBadtBid

cytochrome cSmac/DIABLO

Kluck et al. (1997). Science 275:1132-6

2004 0497

Interactions of Bcl-2 family membersInteractions of Bcl-2 family members

Chan and Yu (2004). Clin. Exp. Pharm. Phys. 31:119-28

Gross Anatomical PhenotypesGross Anatomical Phenotypesof bax-/- bak-/- miceof bax-/- bak-/- mice

2003 0306

*

I +Bcl-2Bcl-xL

BaxBakBadtBid

cytochrome cSmac/DIABLO

Lindsten et al. (2000). Molecular Cell 6:1389-99

Lymphoid abnormalitiesLymphoid abnormalitiesof bax-/- bak-/- miceof bax-/- bak-/- mice

2003 0307Lindsten et al. (2000). Molecular Cell 6:1389-99

*

I +Bcl-2Bcl-xL

BaxBak BadtBid

cytochrome cSmac/DIABLO

2004 0498

Role of p53 in cell survival and apoptosisRole of p53 in cell survival and apoptosis

p53

DNA damage

cell cycle arrest

DNA repair

other mechanisms

Fas

Bax

Bcl-2

2005 0538

Functional domains of p53Functional domains of p53

Yee and Vousden (2005). Carcinogenesis 26:1317-22

2005 0540

Transcriptional targets of p53Transcriptional targets of p53mediate its different biological outcomesmediate its different biological outcomes

Har

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908

2005 0539

Models p53 function as BH3-only proteinModels p53 function as BH3-only protein

Yee and Vousden (2005). Carcinogenesis 26:1317-22

Bad

2004 0499

Role of PKB/Akt in apoptosisRole of PKB/Akt in apoptosis

P P

P P P PP

P PP

P PPPI-3K

PKBPDK1

growthfactor

activatedtyrosine kinase

PI(4,5)P2 PI(3,4,5)P3

P P

P PP

14-3-3

Bcl-2

P

IKKFKHRL1caspase 9

ICAD/CADp53

PARP

MAPK

AP-1

NF-B

tBid

caspase-3

Fas DR5TNFR-I DR4DR3 DR6

FADDTRADD

caspase-8

2004 0487

Regulators of apoptosisRegulators of apoptosis

c-IAPs

Akt/PKB

cytochrome cSmac/DIABLO

Bcl-xL

BadBcl-2

Bax

caspase-9

APAF-1

Bak

AIFendo-G

granzymes

extrinsic

intrinsic

2004 0488

Apoptosis in developmentApoptosis in developmentElimination of unwanted or supernumerary cellsElimination of unwanted or supernumerary cells

active C. elegans: neurons through induction of Egl-1 Drosophila: through ectdysone induction of rpr vertebrate: interdigital webs, cells in wrong organs,

infected cells, transformed cellspassive

vertebrate: T cells with no self-recognition

Enforced selection of appropriate cellsEnforced selection of appropriate cellsactive

positive selection of lymphocytes XBP1 required for plasma cell development

passive role of Bcl-xL in hematopoiesis role of IL-7 in early thymocyte development

Apoptosis in the adult organismApoptosis in the adult organism

2004 0492

EyeEye – the lens of the eye, which forms during embryonic development consist of apoptotic cells that have replaced their content with the clear protein crystallin.

IntestineIntestine – cells composing the finger-like projections of the intestinal wall arise at the bottom of the crypts, travel to the tips, undergo apoptosis and are sloughed off.

SkinSkin – cells migrating from the deepest layers to the epithelial layer undergo apoptosis and form the protective epithelium.

ThymusThymus – most developing T cells undergo apoptosis because they lack a functional T cell receptor or are autoreactive.

UterusUterus – cells of the uterine wall undergo apoptosis and are sloughed off during menstruation.

OtherOther – virally infected and transformed cells undergo apoptosis; deregulation of the process often causes cancer.

2004 0490

Apoptosis in inflammatory responsesApoptosis in inflammatory responsesPathogens inhibit apoptosisPathogens inhibit apoptosis

E1B-19k bcl-2 homologuep35 IAPcrm A caspase inhibitor

Release of inflammatory mediatorsRelease of inflammatory mediators

IL-1, IL-1b, and IL-18 lack secretory sequences

IL-1b and IL-18 must be activated by caspase 1

GranzymesGranzymesserine proteaseseffectively released into target cells by lymphocytesdirectly activate caspases or substrates (granzyme B)Initiate bcl-2 family-independent mitochondrial lesion

2004 0489

Apoptosis in cancerApoptosis in cancerInitiation and selectionInitiation and selection

overexpression of anti-apoptotic genes (bcl-2, IAPs)loss of anchorage-dependent growth (PTEN, PI-3K, PKB/Akt)failure to suppress pro-apoptotic genes (PKB/Akt)suppression of Apaf-1 (melanoma and leukemia)suppression of caspase 8 (neuroblastoma)TRAIL-R1 and TRAIL-R2 mutations in breast cancer

Resistance to chemotherapyResistance to chemotherapychemotherapy damages genome or cytoskeletonchemotherapy activates intrinsic and extrinsic pathwaysp53 mutations allow escape of damaged cellsmutations suppress responses

Apoptosis: A basic biological phenomenon Apoptosis: A basic biological phenomenon with wide-ranging implications…with wide-ranging implications…

2003 0331

“The term apoptosis is proposed for a hitherto little recognized mechanism of controlled cell deletion, which appears to play a complementary but opposite role to mitosis in the regulation of animal cell populations. Its morphological features suggest that it is an active, inherently programmed phenomenon, and it has been shown that it can be initiated or inhibited by a variety of environmental stimuli, both physiological and pathological…”

Kerr, Wyllie, and Currie (1972). Br. J. Cancer 26:239-57