8/20/2009 1 Mechanisms of Cell Death Carol M. Troy, MD PhD August 24, 2009 PHENOMENOLOGY OF CELL DEATH A. MORPHOGENESIS : SCULPTING/SHAPING STRUCTURES I. DEVELOPMENT CREATION OF CAVITIES AND TUBES FUSION OF TISSUE MASSES (PALATE/NEURAL TUBE) CREATION OF FORM (DIGITS) CELL DEATH AND FORMATION OF DIGITS CELL DEATH AND FORMATION OF DIGITS FROM: Chen and Zhao, J. Exp. Zool. 282:691 (1998). CELL DEATH AND FORMATION OF THE CELL DEATH AND FORMATION OF THE SEMICIRCULAR CANALS SEMICIRCULAR CANALS FROM: Fekete et al., Development 124: 2451 (1997) PHENOMENOLOGY OF CELL DEATH: DEVELOPMENT B. DELETION OF UNNEEDED STRUCTURES KIDNEY PRONEPHROS AND MESONEPHROS KIDNEY: PRONEPHROS AND MESONEPHROS UROGENITAL SYSTEM: WOLFFIAN AND MÜLLERIAN DUCTS BRAIN: CORTICAL SUBPLATE NEURONS PHENOMENOLOGY OF CELL DEATH: DEVELOPMENT C. ELIMINATION OF ECTOPIC, DAMAGED OR UNEEDED CELLS CELLS WITH DNA DAMAGE IMMUNE SYSTEM CELLS ECTOPIC CELLS
Transcript
8/20/2009
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Mechanisms of
Cell Death
Carol M. Troy, MD PhDAugust 24, 2009
PHENOMENOLOGY OF CELL DEATH
A. MORPHOGENESIS: SCULPTING/SHAPING STRUCTURES
I. DEVELOPMENT
CREATION OF CAVITIES AND TUBES
FUSION OF TISSUE MASSES (PALATE/NEURAL TUBE)
CREATION OF FORM (DIGITS)
CELL DEATH AND FORMATION OF DIGITSCELL DEATH AND FORMATION OF DIGITS
FROM: Chen and Zhao, J. Exp. Zool. 282:691 (1998).
CELL DEATH AND FORMATION OF THE CELL DEATH AND FORMATION OF THE SEMICIRCULAR CANALSSEMICIRCULAR CANALS
FROM: Fekete et al., Development 124: 2451 (1997)
PHENOMENOLOGY OF CELL DEATH: DEVELOPMENT
B. DELETION OF UNNEEDED STRUCTURES
KIDNEY PRONEPHROS AND MESONEPHROSKIDNEY: PRONEPHROS AND MESONEPHROS
UROGENITAL SYSTEM: WOLFFIAN AND MÜLLERIANDUCTS
BRAIN: CORTICAL SUBPLATE NEURONS
PHENOMENOLOGY OF CELL DEATH: DEVELOPMENT
C. ELIMINATION OF ECTOPIC, DAMAGED OR UNEEDEDCELLS
CELLS WITH DNA DAMAGE
IMMUNE SYSTEM CELLS
ECTOPIC CELLS
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D. CULLING: REGULATION OF CELL NUMBERS
NERVOUS SYSTEM:
PHENOMENOLOGY OF CELL DEATH: DEVELOPMENT
NERVOUS SYSTEM:
MATCHING NEURONS WITH TARGETS
MATCHING SCHWANN CELL AND OLIGODENDROCYTES WITH AXONS
15 000
20,000
25,000
IN C
HIC
K IO
N
NORMAL DEVELOPMENTAL NEURONAL DEATHIS REGULATED BY TARGET DERIVED TROPHIC FACTORS
0
5,000
10,000
15,000
36 38 40 42 44 46 P2 P4
NORMAL
ENUCLEATED
DEVELOPMENTAL STAGE
NEU
RO
N N
UM
BER
I
Clarke, Rogers & Cowan J. Comp. Neurol. 167: 125 (1976)
NEURONAL CULLING AS REGULATED BY COMPETITIONFOR TARGET-SUPPLIED TROPHIC FACTOR
NEURONAL CULLING AS REGULATED BY COMPETITIONFOR TARGET-SUPPLIED TROPHIC FACTOR
PHENOMENOLOGY OF CELL DEATH
II. ELIMINATION OF CELLS WITH DNA DAMAGE
III. DEFENSE FROM PATHOGENS
IV. REGULATION OF CELL NUMBERS
HOMEOSTASIS OF ORGAN/TISSUE SIZE
IMMUNE CELL NUMBERS
PREVENTION OF UNREGULATED CELL GROWTH
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Cell death maintains the mature organism
In the course of a year your body weight in cells should die.
DYSREGULATION OF CELL DEATH: DISEASEA. CANCER
B. HYPOXIC/ANOXIC CELL DEATH - Brain, heartC. NEURODEGENERATIVE DISORDERS - AD, PDD. ACUTE AND CHRONIC RENAL FAILUREE. VIRAL PATHOGENESIS
INITIATIONDEATH STIMULIDEATH STIMULI
PROPAGATION
SIGNALING EVENTSTRANSCRIPTIONALTRANSCRIPTIONAL
POST-TRANSCRIPTIONALPOST-TRANSLATIONAL
EXECUTION
CASPASES - DEATH PROTEASES
CELL DEATH
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Goldstein et al. Cell Death and Differentiation (2005) 12, 453–462.
cytochrome c-4CYS redphosphatidylserine, Bluehistone H2B coupled to GFP
APOPTOTIC DEATH vs NECROTIC DEATHPRESENT IN DEVELOPING TISSUES RESPONSE TO CELL INJURY, TOXINS
DNA DEGRADATION BY ENDONUCLEASES RANDOM DNA DEGRADATION(FORMATION OF DNA LADDER)
FORMATION OF MEMBRANE-LIMITED LOSS OF MEMBRANE INTEGRITYAPOPTOTIC BODIES & LOSS OF CYTOPLASMIC CONTENTS
PHAGOCYTOSIS OF APOPTOTIC BODIES
ABSENCE OF INFLAMMATORY RESPONSE INFLAMMATORY RESPONSE
Kerr, Wylie and Currie
CASPASES - 1: PROPERTIES
• EXECUTORS OF APOPTOTIC DEATH
• CYSTEINE PROTEASES
• CLEAVE AFTER ASP - ARE ASPARTASES
• DIFFERENT CASPASES DIFFER IN SPECIFICITY, MEANS OF ACTIVATION, AND SUBCELLULARCOMPARTMENTALIZATION
• WHEN ACTIVATED, CLEAVE CELLULARSUBSTRATES, LEADING TO APOPTOTIC DEATH
CASPASES - 2: EVIDENCE FOR ROLE IN APOPTOSIS
• OVER-EXPRESSION CAUSES APOPTOTIC DEATH
• ACTIVATED IN DYING CELLS
• CLEAVED FORMS DETECTABLE BY WESTERN & ANTIBODIES
• CAN MEASURE ACTIVITY IN DYING CELL EXTRACTS WITH SUBSTRATES
• BLOCK APOPTOTIC DEATH WITH CASPASE INHIBITORS
• NULL ANIMALS SHOW DEFECTIVE CELL DEATH
• REVERSIBLE AND IRREVERSIBLE PSEUDOSUBSTRATE PEPTIDES (zDEVD-FMK)
• VIRAL INHIBITORS: CRMA, p35 • IAPs
• MOLECULAR INHIBITION: ANTISENSE, siRNA
EMBRYOGENIC DEFECTS IN A MOUSE LACKING CASPASE-9
From: Kuida et al Cell:94: 325-337, 1998
CASPASES: HOW ARE THEY ACTIVATED?
• CONSTITUTIVELY EXPRESSED IN CELLS ASINACTIVE PRO-FORMS
• TWO GENERAL CLASSES OF CASPASES: “INITIATOR” AND “EFFECTOR” OR“EXECUTIONER” CAPASES
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Phylogenetic Relations of Caspases
Cell Death and DifferentiationLamkanfi et al. (2002) 9: 358-361
CASPASES: ACTIVATION OF INITIATOR CASPASES BY INDUCED PROXIMITY
PRO DOMAIN P20 P10
(INACTIVE CED3, CASP 2,8,9,10)
CARD APOPTOTICSTIMULUS
Activatingplatform
CARDCARD
CARD
CARD
Activatingplatform (ACTIVE)
CARD
CARD
CARD
CARD
(ACTIVE)Autocleavage
CASPASES: ACTIVATION OF EFFECTOR CASPASES BY CLEAVAGE
PRO
APOPTOTIC
PRO DOMAIN P20 P10
(INACTIVE CASP 3,6,7)
(ACTIVE)
P10P20APOPTOTIC
STIMULUSINITIATORCASPASES
D1 D2
APOPTOTICSTIMULUS
CADICAD
CASPASE CAD
CASPASE - DEPENDENT ACTIVATION OF THE CAD ENDONUCLEASE
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zymogen
Caspase Regulation
Diablo
HtrA2
casp1/2
Bcl2 Proteins
VERTEBRATE PRO-APOPTOTIC BCL2 FAMILY MEMBERS
• OVER-EXPRESSION OF PRO-APOPTOTIC FAMILY MEMBERSPROMOTES APOPTOSIS
• CELLS OF ANIMALS NULL FOR PRO-APOPTOTIC MEMBERS SHOW LESS SUCEPTIBILITY TO APOPTOTIC DEATH
• CAN FORM HETERODIMERS WITH ANTI-APOPTOTIC FAMILY MEMBERS VIA BH DOMAINS AS WELL AS WITH ONE ANOTHER
• ABILITY TO BIND BCL2 FAMILY MEMBERS ESSENTIAL FORPRO-APOPTOTIC ACTIVITY
APOPTOTIC STIMULI
MITOCHONDRIA AND ACTIVATION OF APAF1 IN MAMMALIAN CELLS
CYTOCHROME C
mitochondrion
CASPASE-9 ACTIVATION
APAF1
CASPASE-9 CASP 3,6,7
APOPTOTIC STIMULI
MITOCHONDRIA AND ACTIVATION OF APAF1 IN MAMMALIAN CELLS
WHERE DO PRO-AND ANTI-APOPTOTIC BCL2 MEMBERSFIT INTO THIS SCHEME??
CYTOCHROME C
mitochondrion
CASPASE ACTIVATION
APAF1 (APOPTOSOME)
CASPASE 9 CASP 3,6,7
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THE BCL2 FAMILY AND CYTOCHROME C RELEASE FROM MITOCHONDRIA
• ANTI-APOPTOTIC BCL2 MEMBERS ARE RESIDENT INMITOCHONDRIA
• OVER-EXPRESSION OF ANTI-APOPTOTIC BCL2 MEMBERS(eg BCL2 AND BCLXL ) BLOCKS CYTOCHROME C RELEASE AND APOPTOSIS
MITOCHONDRIA AND APOPTOTIC DEATH -2
mitochondrion
CYTOCHROME C
CASPASE 9 ACTIVATION
APAF1 (APOPTOSOME)
CASPASE 3,6,7 ACTIVATION
mitochondrionBCL2BCL2
HOW DO PRO-APOPTOTIC BCL2 FAMILY MEMBERS PROMOTE APOPTOSIS?
THERE APPEARS TO BE A TWO STEP MECHANISM• THERE APPEARS TO BE A TWO STEP MECHANISM REQUIRING BOTH BAX FAMILY MEMBERS AND BH3-DOMAINONLY FAMILY MEMBERS
BOTH BAX AND BAK ARE REQUIRED FOR MITOCHONDRIALLY-DEPENDENT APOPTOSIS
BOTH ARE BH1 3 BAX FAMILY MEMBERS AND BOTH
• OVER-EXPRESSION OF PRO-APOPTOTIC BAX AND BAKMEMBERS CAUSES CYTOCHROME C RELEASE & DEATH
• BOTH ARE BH1-3 BAX FAMILY MEMBERS AND BOTH APPEAR TO BE REQUIRED FOR MANY CASES OF APOPTOSIS
• KNOCKOUT OF BAX AND BAK PROTECTS CELLS FROMDEATH
BAX AND BAK AND APOPTOTIC DEATH
mitochondrion BCL2
APOPTOTIC STIMULI
BAXBAX
CYTOCHROME C
CASPASE 9 ACTIVATION
APAF1 (APOPTOSOME)
CASPASE 3,6,7 ACTIVATION
mitochondrion BCL2BCL2BAXBAX BAKBAK
BAX BAX
HOW DO BH3-ONLY MOLECULES CONTRIBUTETO MITOCHONDRIAL-DEPENDENT APOPTOSIS?
• OVER-EXPRESSION OF BH3-ONLY PROTEINS INDUCESAPOPTOSIS BUT NOT IN ABSENCE OF BAX OR BAK
• MITOCHONDRIAL-DEPENDENT APOPTOSIS REQUIRESBH3-ONLY PROTEINS AS WELL AS BAX/BAK
APOPTOSIS, BUT NOT IN ABSENCE OF BAX OR BAK. SO THE LATTER APPEAR TO WORK DOWNSTREAM OF BH3 MOLECULES
• THUS, APOPTOTIC DEATH VIA THE MITOCHONDRIONREQUIRES BOTH BH3-ONLY PROTEINS AND BAX/BAK
• IN ABSENCE OF BH3-ONLY PROTEINS BAX AND BAK DONOT CHANGE CONFORMATION AND FORM PORES
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HOW DO BAX/BAK AND BH3-ONLY PROTEINS COOPERATE TO
INDUCE CYTOCHROME-C RELEASE AND APOPTOSIS?
• 1) BH3-ONLY PROTEINS DISPLACE BAX/BAK FROM BCL2
AND OTHER ANTI-APOPTOTIC FAMILY MEMBERS
HOW DO BH3-ONLY PROTEINS COOPERATE WITH BAX/BAK
TO INDUCE CYTOCHROME-C RELEASE AND APOPTOSIS?
BAK BAKAPOPTOTICSTIMULI
BAKBAX BAX
BAK BAK
BCL2
BAX BAX BAX BAXBAK
PORE FORMATION IN MITOCHONDRIAL OUTER MEMBRANE
CYT-CCYT-C
RELEASE OF CYTOCHROME C
BCL2 BH3-ONLY
PROTEIN
BCL2BCL2
BCL2BAK BAX
BH3-ONLY
BCL2
BCL2BCL2
BCL2SURVIVAL
THE RHEOSTAT MODEL OF CELL DEATH
BH3-ONLY
BH3-ONLY
BCL2 BAK
BAXBH3-ONLY
BCL2
BCL2BCL2
BH3-ONLY
BH3-ONLY BH3-
ONLYBCL2
BH3-ONLY
DEATH
ADDITIONAL REGULATORS OF CELL DEATH
• IAPS - INHIBITOR OF APOPTOSIS PROTEINS
Inhibitor of Apoptosis Proteins
Verhagen et al. Genome Biol. 2:3009.1-10, 2001
IAPS
• FAMILY OF PROTEINS THAT INHIBIT CASPASES (3,7,9)
• MULTIPLE FAMILY MEMBERS IN MAMMALS. ALSOPRESENT IN INSECTS AND VIRUSES.
• ALL HAVE “BIR” (BACULOVIRAL IAP REPEAT) DOMAINS THAT ARE REQUIRED FOR BINDING AND INHIBITING CASPASES
• SEVERAL (IAP1,2 AND XIAP) HAVE RING FINGERS AND E3 LIGASE ACTIVITY AND CAN LEAD TO DEGRADATION OFCASPASES AND OTHER PRO-APOPTOTIC MOLECULES
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IAPS
• LEVELS CAN BE UP-REGULATED BY GROWTH FACTORS(EG GDNF) OR DOWN REGULATED BY APOPTOTIC SIGNALS
• MAY FUNCTION AS A CHECK POINT BEFORE THE LAST IRREVERSIBLE STAGE OF DEATH
• OVER-EXPRESSED IN SOME TUMORS - SO POTENTIALCLINICAL TARGET
(EG., GDNF) OR DOWN-REGULATED BY APOPTOTIC SIGNALS
IAPS INHIBIT CASPASES AND APOPTOTIC DEATH
APOPTOTIC STIMULI
mitochondrionBCL2BCL2 BAXBIM
BAXBIM
CASPASE 9 ACTIVATION
APAF1
CASPASE 3,7 ACTIVATION
CYTOCHROME C
IAPs cIAP1,2XIAP
X
ADDITIONAL REGULATORS OF CELL DEATH
• SMAC/DIABLO - INHIBITORS OF IAPS
SMAC/DIABLO INHIBITS IAPS
APOPTOTIC STIMULI
mitochondrionBCL2BCL2 BAXBIM
BAXBIM SMAC/DIABLO
CASPASE 9 ACTIVATION
APAF1
CASPASE 3, 7 ACTIVATION
CYTOCHROME C
IAPs
X
N-TERMINAL TETRA-PEPTIDEOF SMAC
SMAC DISPLACES IAPS FROM CASPASES
XIAPBIR3
N-TERMINAL TETRA-PEPTIDEOF CASPASE 9 SMALL SUBUNIT
SMAC/DIABLO
• RELEASED FROM MITOCHONDRIA BY APOPTOTIC STIMULI
BLOCKS IAPS FROM INHIBITING CASPASES PRO APOPTOTIC• BLOCKS IAPS FROM INHIBITING CASPASES: PRO-APOPTOTIC
• REQUIRED FOR DEATH IN AT LEAST SOME PARADIGMS. IN OTHERS, IT MAKES CELLS MORE SUCEPTIBLE TO DEATH
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OMI/HTRA2 INHIBITS IAPS
APOPTOTIC STIMULI
mitochondrionBCL2BCL2 BAXBIM
BAXBIM OMI/HTRA2
CASPASE 9 ACTIVATION
APAF1
CASPASE 3,7 ACTIVATION
CYTOCHROME C
IAPs
XSER/THR PROTEASE
OMI/HTRA2
• RELEASED FROM MITOCHONDRIA BY APOPTOTIC STIMULI
• IS A SERINE/THREONINE PROTEASE
• DEGRADES IAPS: PRO-APOPTOTIC
• MAKES CELLS MORE SUCEPTIBLE TO DEATH
IS A SERINE/THREONINE PROTEASE
• UP-REGULATED BY P53
DEATH BY MURDER - RECEPTOR MEDIATED
• IN ADDITION TO SUICIDE (THE INTRINSIC APOPTOTICMECHANISM), THERE IS ALSO A MAMMALIAN MECHANISM FOR MURDERING CELLS (THE EXTRINSIC APOPTOTIC PATHWAY)
• THE EXTRINSIC APOPTOTIC PATHWAY IS REGULATEDBY A SERIES OF SPECIFIC DEATH-PROMOTING RECEPTORSAND LIGANDS. OCCUPATION OF THESE RECEPTORS BRINGSABOUT ACTIVATION OF PATHWAYS THAT CULMINATE INCELL DEATH.
THE RECEPTOR-MEDIATED PATHWAY OF APOPTOTIC DEATH
DEATHDOMAIN
TRAIL-R1
TRAIL-R2
CELL INTERIOR
DEATH PROMOTING RECEPTORS AND LIGANDS
LIGAND RECEPTOR
TNFα TNFαR1TNFα TNFαR1
FAS ligand FAS
TRAIL TRAIL-R(DR-4 & DR-5)
TNFTNFαα
TNFR1
FADD
CASPASES 8,10 BID
= DD
= DED
THE RECEPTOR-MEDIATED PATHWAY OF APOPTOTIC DEATH
,
BAX
MITOCHONDRIAL PATHWAY
CASPASE 3
BID
tBID
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DEATH PROMOTING RECEPTORS AND LIGANDS-2
• THE PATHWAY CAN EITHER BYPASS MITOCHONDRIAL INVOLVEMENT IN DEATH OR CAN INVOLVE MITOCHONDRIA AS A MEANS OF AMPLIFICATION
• THE EXTRINSIC DEATH PATHWAY BEGINS WITH RECEPTOR-MEDIATED ACTIVATION OF INITIATOR CASPASES 8 AND/0R 10
AS A MEANS OF AMPLIFICATION
• THE SAME CELL CAN EXPRESS BOTH DEATH RECEPTOR AND DEATH LIGAND
• SUSCEPTIBILITY IS SUBJECT TO REGULATION BY PATHWAY ANTAGONISTS
DEATH PROMOTING RECEPTORS AND LIGANDS-3
• MANY TUMOR CELLS EXPRESS EXTRINSIC PATHWAY RECEPTORS BUT ALSO OVER EXPRESS PATHWAY
• THE EXTRINSIC PATHWAY CONTRIBUTES TO DEATH IN A VARIETY OF CONTEXTS
• EXPRESSION OF LIGAND AND RECEPTORS AS WELL AS OF PATHWAY ANTAGONISTS IS SUBJECT TO REGULATION
RECEPTORS, BUT ALSO OVER-EXPRESS PATHWAY ANTAGONISTS (50% of colon cancers have amplified DcR3 gene)
ROLE OF TRANSCRIPTION IN APOPTOSIS
• IN MANY, BUT NOT ALL PARADIGMS OF APOPTOTIC DEATHCELLS MUST SYNTHESIZE SPECIFIC GENES TO DIE
• THE PATHWAYS THAT REGULATE SUCH DEATH-ASSOCIATED THE PATHWAYS THAT REGULATE SUCH DEATH ASSOCIATEDGENES APPEAR TO BE ACTIVATED BY MECHANISMS THAT AREINDEPENDENT OF MITOCHONDRIA.
• THE GENE PRODUCTS OF THESE PATHWAYS CAN ACT BOTHUPSTREAM AND DOWNSTREAM OF MITOCHONDRIA
• BH3-DOMAIN ONLY MOLECULES SEEM TO BE COMMON GENETARGETS (eg. BIM IS REGULATED BY JUN, E2F, AND FORKHEAD)
APOPTOTIC STIMULI (DNA DAMAGE)
p53 MAPKPAC1SIAH
TRANSCRIPTIONAL TARGETS OF P53 IN APOPTOSIS
E2F
P53 PHOSPHORYLATION AND STABILIZATION
JNK/JUN BAXBIDPUMANOXA
CASPASE 6
APAF-1
Cell specificStimulus specific
BIM
FAS AND THE TRANSCRIPTIONAL REGULATION OF EXTRINSIC DEATH PATHWAY
APOPTOTIC STIMULI
p53 cJun FKH E2F NFKB FAS
FAS-L
CASPASE 9 ACTIVATION
APAF1
CASPASE 3,7 ACTIVATION
CYTOCHROME CAIF
mitochondrionBCL2BCL2 BAXBIM
BAXBIM
IAPs
SMAC/DIABLO
WHAT SIGNALS KEEP CELL FROM DYING?ACTIVATION OF AKT/PKB
Growth factor
P-
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AKT BLOCKS DEATH AT MULTIPLE LEVELS OF THE APOPTOTIC MECHANISM
A. CANCERB. HYPOXIC/ANOXIC CELL DEATH - Brain, heart
C. NEURODEGENERATIVE DISORDERS - AD, PD
D. ACUTE AND CHRONIC RENAL FAILUREE. VIRAL PATHOGENESIS
MECHANISMS OF APOPTOSIS RESISTANCE-1
• MUTATIONS OF CASPASES
-MCF7 BREAST CA HAS NO CASPASE-3 EXPRESSION
-DECREASED CASPASE-7 EXPRESSION IN COLON CA
• LOSS OF APAF-1 EXPRESSION IN MELANOMA
-HYPERMETHYLATION OF CASPASE-8 PROMOTER
MECHANISMS OF APOPTOSIS RESISTANCE-2
• INCREASED EXPRESSION OF IAPS
-SURVIVIN IN NEUROBLASTOMA
-cIAP1/2 IN LUNG CAcIAP1/2 IN LUNG CA
-cIAP1 IN ESOPHAGEAL SQUAMOUS CELL CA
-cIAP1 INCREASES RESISTANCE TO CHEMOTHERAPY
-XIAP IN OVARIAN CA
MECHANISMS OF APOPTOSIS RESISTANCE-3
• INCREASED EXPRESSION OF BCL2 IN ALL, AML, CLL,MULTIPLE MYELOMA, PROSTATE CA, NEUROBLASTOMA
• DECREASED EXPRESSION OF BAX IN COLON CA, BREAST CA
STRATEGIES FOR TARGETING CANCER
• INHIBITION OF OVEREXPRESSED ANTI-APOPTOTIC MOLECULES -e.g. BCL2, BH3 PROTEINS, SURVIVIN, OTHER IAPS
• ENHANCE PRO-APOPTOTIC PATHWAYS-small molecule mimetic of SMAC/Diablo
• ENHANCE RECEPTOR MEDIATED DEATHVIA TRAIL-R
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MAINTENANCE OF HOMEOSTASIS
• TIGHT REGULATION OF DEATH PATHWAYSAT SEVERAL LEVELS IS ESSENTIAL
• A BETTER UNDERSTANDING OF THE MOLECULAR MECHANISM(S) OFMOLECULAR MECHANISM(S) OF APOPTOSIS WILL ENABLE DESIGN OF TARGETED THERAPIES FOR DISORDERS WITH DYSREGULATED CELL DEATH.
