Apoptosis and Cancer. Carol M. Troy, MD, PhD October 26, 2016

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1 Apoptosis and Cancer Carol M. Troy, MD, PhD October 26, 2016

2 PHENOMENOLOGY OF CELL DEATH -1 I. DEVELOPMENT A. MORPHOGENESIS: SCULPTING/SHAPING STRUCTURES FUSION OF TISSUE MASSES (PALATE/NEURAL TUBE) CREATION OF CAVITIES AND TUBES CREATION OF FORM (DIGITS)

3 CELL DEATH AND FORMATION OF DIGITS FROM: Chen and Zhao, J. Exp. Zool. 282:691 (1998).

4 PHENOMENOLOGY OF CELL DEATH -2 I. DEVELOPMENT B. REGULATION OF CELL MIGRATION AND PATTERNING C. DELETION OF UNNEEDED STRUCTURES UROGENITAL SYSTEM: WOLFFIAN AND MÜLLERIAN DUCTS D. CULLING: REGULATION OF CELL NUMBERS

5 NORMAL DEVELOPMENTAL NEURONAL DEATH IS REGULATED BY TARGET DERIVED TROPHIC FACTORS NEURON NUMBER IN CHICK ION 30,000 22,500 15,000 7,500 0 NORMAL ENUCLEATED P1P2P3P4 Clarke, Rogers & Cowan J. Comp. Neurol. 167: 125 (1976) DEVELOPMENTAL STAGE

6 PHENOMENOLOGY OF CELL DEATH -3 II. ELIMINATION OF CELLS WITH DNA DAMAGE III. DEFENSE FROM PATHOGENS IV. REGULATION OF CELL NUMBERS HOMEOSTASIS OF ORGAN/TISSUE SIZE PREVENTION OF UNREGULATED CELL GROWTH IMMUNE CELL NUMBERS

7 CELL DEATH MAINTAINS THE MATURE ORGANISM In the course of a year your body weight in cells should die.

8 DYSREGULATION OF CELL DEATH Tumors Cancer Alzheimers Disease Parkinson s Disease Stroke

9 INITIATION DEATH STIMULI

10 PROPAGATION SIGNALING EVENTS TRANSCRIPTIONAL POST-TRANSCRIPTIONAL POST-TRANSLATIONAL

11 EXECUTION CASPASES - DEATH PROTEASES

12 CELL DEATH

13 cytochrome c-4cys red phosphatidylserine, Blue histone H2B coupled to GFP Goldstein et al. Cell Death and Differentiation (2005) 12,

14 CASPASES - 1: PROPERTIES EXECUTORS OF APOPTOTIC DEATH CYSTEINE PROTEASES CLEAVE AFTER ASP - ARE ASPARTASES WHEN ACTIVATED, CLEAVE CELLULAR SUBSTRATES, LEADING TO APOPTOTIC DEATH DIFFERENT CASPASES DIFFER IN SPECIFICITY, MEANS OF ACTIVATION, AND SUBCELLULAR COMPARTMENTALIZATION

15 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 REVERSIBLE AND IRREVERSIBLE PSEUDOSUBSTRATE PEPTIDES (zdevd-fmk) MOLECULAR INHIBITION: ANTISENSE, sirna VIRAL INHIBITORS: CRMA, p35 IAPs NULL ANIMALS SHOW DEFECTIVE CELL DEATH

16 EMBRYOGENIC DEFECTS IN A MOUSE LACKING CASPASE-9 From: Kuida et al Cell:94: , 1998

17 From: Degterev A, Boyce M, Yuan J. A decade of caspases Oncogene (2003) 22,

18 CASPASE - DEPENDENT ACTIVATION OF THE CAD ENDONUCLEASE APOPTOTIC STIMULUS CASPASE CAD ICAD CAD

19 CASPASES: HOW ARE THEY ACTIVATED? CONSTITUTIVELY EXPRESSED IN CELLS AS INACTIVE PRO-FORMS TWO GENERAL CLASSES OF CASPASES: INITIATOR AND EFFECTOR OR EXECUTIONER CAPASES

20 PHYLOGENETIC RELATIONS OF CASPASES Cell Death and DifferentiationLamkanfi et al. (2002) 9:

21 CASPASE ACTIVATION

22 CASPASE REGULATION zymogen Diablo HtrA2

23 casp1/2

25 MEASURING CASPASE ACTIVATION AND ACTIVITY Pseudopeptide substrates: Not specific for targeted caspases (McStay et al, CDD 2008) Western blotting and cleavage specific antibodies: Good for effector activation but do not indicate activity. Initiators do not require cleavage. Caspase affinity ligand - bvadfmk- Irreversible general caspase inhibitor, specificity conferred by Western blotting, can detect active initiators.

26 IDENTIFYING ACTIVE CASPASES Caspase-3,-6,-7 Caspase-2,-8,-9 Pop C, Salvesen G S J. Biol. Chem. 2009;284: by American Society for Biochemistry and Molecular Biology bvadfmk

27 In vivo model of vasogenic edema and neuronal dysfunction Rat Transient Middle Cerebral Artery Occlusion (tmcao) Core Penumbra Pathology Vasogenic edema Neuronal process loss Neuronal death 2 hr Occlusion Reperfusion

28 ACTIVE CASPASE PRECIPITATION VAD biotin Convection Enhanced Delivery Bruce et al Ischemic Event VAD biotin Streptavidin Agarose Bead Precipitate & Boil Inactive Caspase Active Caspase bvad-caspase Complex (irreversible) Western Blot Adapted from Tu et al. Nature Cell Biol. 2006

29 INITIATOR CASPASE PRECIPITATION Rat Stroke Model bvad CED MCAo Reperfusion bvad CED -3hr -2hr 0hr 1hr 2hr 4hr 12hr 24hr 3d 7d 21d 1 hr 2-4 hr Active caspase-9 is a target for intervention in stroke Akpan et al. J Neurosci 2011

30 BCL2 PROTEINS

31 VERTEBRATE PRO-APOPTOTIC BCL2 FAMILY MEMBERS OVER-EXPRESSION OF PRO-APOPTOTIC FAMILY MEMBERS PROMOTES 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 FOR PRO-APOPTOTIC ACTIVITY

32 MITOCHONDRIA AND ACTIVATION OF CASPASE-9 IN MAMMALIAN CELLS APOPTOTIC STIMULI mitochondrion CYTOCHROME C APAF1 CASPASE-9 ACTIVATION CASPASE-9 CASP 3,6,7

33 MITOCHONDRIA AND ACTIVATION OF CASPASE-9 IN MAMMALIAN CELLS APOPTOTIC STIMULI mitochondrion WHERE DO PRO-AND ANTI-APOPTOTIC BCL2 MEMBERS FIT INTO THIS SCHEME?? CYTOCHROME C APAF1 (APOPTOSOME) CASPASE ACTIVATION CASPASE 9 CASP 3,6,7

34 THE BCL2 FAMILY AND CYTOCHROME C ARE RELEASED FROM MITOCHONDRIA ANTI-APOPTOTIC BCL2 MEMBERS ARE RESIDENT IN MITOCHONDRIA OVER-EXPRESSION OF ANTI-APOPTOTIC BCL2 MEMBERS (eg BCL2 AND BCLXL ) BLOCKS CYTOCHROME C RELEASE AND APOPTOSIS

35 MITOCHONDRIA AND APOPTOTIC DEATH -2 mitochondrion BCL2 BCL2 CYTOCHROME C APAF1 (APOPTOSOME) CASPASE 9 ACTIVATION CASPASE 3,6,7 ACTIVATION

36 HOW DO PRO-APOPTOTIC BCL2 FAMILY MEMBERS PROMOTE APOPTOSIS? THERE APPEARS TO BE A TWO STEP MECHANISM REQUIRING BOTH BAX FAMILY MEMBERS AND BH3-DOMAIN ONLY FAMILY MEMBERS

37 BOTH BAX AND BAK ARE REQUIRED FOR MITOCHONDRIALLY-DEPENDENT APOPTOSIS OVER-EXPRESSION OF PRO-APOPTOTIC BAX AND BAK MEMBERS 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 FROM DEATH

38 BAX AND BAK AND APOPTOTIC DEATH APOPTOTIC STIMULI BAX BAX mitochondrion BCL2 BAX BAK BCL2 BAX CYTOCHROME C APAF1 (APOPTOSOME) CASPASE 9 ACTIVATION CASPASE 3,6,7 ACTIVATION

39 HOW DO BAX/BAK INDUCE CYTOCHROME-C RELEASE AND APOPTOSIS? BAK APOPTOTIC STIMULI BAK BAK BAX BAK BAX BAK BAX BAX BAX BAK CYT- C BAX CYT- C PORE FORMATION IN MITOCHONDRIAL OUTER MEMBRANE RELEASE OF CYTOCHROME C

40 HOW DO BH3-ONLY MOLECULES CONTRIBUTE TO MITOCHONDRIAL-DEPENDENT APOPTOSIS? MITOCHONDRIAL-DEPENDENT APOPTOSIS REQUIRES BH3-ONLY PROTEINS AS WELL AS BAX/BAK OVER-EXPRESSION OF BH3-ONLY PROTEINS INDUCES APOPTOSIS, BUT NOT IN ABSENCE OF BAX OR BAK. SO THE LATTER APPEAR TO WORK DOWNSTREAM OF BH3 MOLECULES IN ABSENCE OF BH3-ONLY PROTEINS BAX AND BAK DO NOT CHANGE CONFORMATION AND FORM PORES THUS, APOPTOTIC DEATH VIA THE MITOCHONDRION REQUIRES BOTH BH3-ONLY PROTEINS AND BAX/BAK

41 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

42 HOW DO BH3-ONLY PROTEINS COOPERATE WITH BAX/BAK TO INDUCE CYTOCHROME-C RELEASE AND APOPTOSIS? BCL2 BAK APOPTOTIC STIMULI BAK BAX BAK BAX BAK BAK BCL2 BAX BH3-ONLY PROTEIN BCL2 BCL2 BAX BAX BAK CYT- C BAX CYT- C PORE FORMATION IN MITOCHONDRIAL OUTER MEMBRANE RELEASE OF CYTOCHROME C

43 THE RHEOSTAT MODEL OF CELL DEATH BCL2 BH3- BCL2ONLY BAK BCL2 BCL2 BCL2 BAX SURVIVAL BH3- BH3- ONLY BCL2ONLY BH3- ONLY BCL2 BH3- ONLY BCL2 BH3- BCL2 ONLY BCL2 BH3- ONLY BH3- ONLY BAX BAK DEATH

44 HOW ARE APOPTOTIC ACTIVITIES OF BH3 ONLY PROTEINS REGULATED? TRANSCRIPTIONAL CONTROL: EGL1, BIM, HRK, PUMA, NOXA PHOSPHORYLATION: BAD, BIM, BIK BAD AKT ON P BAD CYTOPLASMIC APOPTOTIC STIMULI AKT OFF BAD MITOCHONDRIAL TRANSLOCATION

45 REGULATION OF BH3 ONLY PROTEINS RELEVANT TO APOPTOSIS REGULATED SEQUESTRATION: BIM, Bmf Bmf Actin depolymerizing Conditions (Anoikis) Bmf MITOCHONDRIAL TRANSLOCATION DLC2 actin CLEAVAGE: BID Caspase 8,10 myr BID tbid MITOCHONDRIAL TRANSLOCATION

46 ADDITIONAL REGULATORS OF CELL DEATH IAPS - INHIBITOR OF APOPTOSIS PROTEINS

47 INHIBITOR OF APOPTOSIS PROTEINS Verhagen et al. Genome Biol. 2: , 2001

48 IAPS FAMILY OF PROTEINS THAT INHIBIT SELECT CASPASES (3,7,9) MULTIPLE FAMILY MEMBERS IN MAMMALS. ALSO PRESENT 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 OF CASPASES AND OTHER PRO-APOPTOTIC MOLECULES

49 IAPS MAY FUNCTION AS A CHECK POINT BEFORE THE LAST IRREVERSIBLE STAGE OF DEATH LEVELS CAN BE UP-REGULATED BY GROWTH FACTORS (EG., GDNF) OR DOWN-REGULATED BY APOPTOTIC SIGNALS OVER-EXPRESSED IN SOME TUMORS - SO POTENTIAL CLINICAL TARGET

50 IAPS INHIBIT CASPASES AND APOPTOTIC DEATH APOPTOTIC STIMULI BIM BCL2 mitochondrion BIM BCL2 BAX BAX CYTOCHROME C APAF1 CASPASE 9 ACTIVATION CASPASE 3,7 ACTIVATION X XIAP ciap1,2

51 INTERACTIONS OF XIAP Bax BIRC4 XIAP BIR1 BIR2 BIR3 RING COOH Caspase-3, -7 Caspase-9 Rho-GDI vxiap binds to and inhibits caspases-3,-7 via the BIR2-linker domain vxiap binds to and inhibits caspase-9 via the BIR3 domain vxiap binds to Rho-GDI via the RING domain vxiap binds to and oligomerizes Bax via the RING domain

52 IAP LEVELS VARY IN MESOTHELIOMA CELL LINES AND AFFECT SENSITIVITY TO CHEMOTHERAPEUTICS Gordon, G. J. et al. Carcinogenesis : ;

53 ADDITIONAL REGULATORS OF CELL DEATH SMAC/DIABLO - INHIBITORS OF IAPS

54 SMAC/DIABLO INHIBITS IAPS APOPTOTIC STIMULI BIM BIM BCL2 mitochondrion BCL2 BAX BAX SMAC/DIABLO CYTOCHROME C APAF1 CASPASE 9 ACTIVATION CASPASE 3, 7 ACTIVATION X IAPs

55 SMAC DISPLACES IAPS FROM CASPASES XIAP BIR3 N-TERMINAL TETRA-PEPTIDE OF SMAC N-TERMINAL TETRA-PEPTIDE OF CASPASE 9 SMALL SUBUNIT

56 SMAC/DIABLO RELEASED FROM MITOCHONDRIA BY APOPTOTIC STIMULI BLOCKS IAPS FROM INHIBITING CASPASES: PRO-APOPTOTIC REQUIRED FOR DEATH IN AT LEAST SOME PARADIGMS. IN OTHERS, IT MAKES CELLS MORE SUCEPTIBLE TO DEATH

57 OMI/HTRA2 INHIBITS IAPS APOPTOTIC STIMULI BIM BIM mitochondrion BCL2 BAX BCL2 BAX OMI/HTRA2 CYTOCHROME C APAF1 CASPASE 9 ACTIVATION CASPASE 3,7 ACTIVATION X IAPs SER/THR PROTEASE

58 OMI/HTRA2 RELEASED FROM MITOCHONDRIA BY APOPTOTIC STIMULI IS A SERINE/THREONINE PROTEASE DEGRADES IAPS: PRO-APOPTOTIC MAKES CELLS MORE SUSCEPTIBLE TO DEATH UP-REGULATED BY p53

59 DEATH BY MURDER - RECEPTOR MEDIATED IN ADDITION TO SUICIDE (THE INTRINSIC APOPTOTIC MECHANISM), THERE IS ALSO A MAMMALIAN MECHANISM FOR MURDERING CELLS (THE EXTRINSIC APOPTOTIC PATHWAY) THE EXTRINSIC APOPTOTIC PATHWAY IS REGULATED BY A SERIES OF SPECIFIC DEATH-PROMOTING RECEPTORS AND LIGANDS. OCCUPATION OF THESE RECEPTORS BRINGS ABOUT ACTIVATION OF PATHWAYS THAT CULMINATE IN CELL DEATH.

60 THE RECEPTOR-MEDIATED PATHWAY OF APOPTOTIC DEATH DEATH DOMAIN TRAIL-R1 TRAIL-R2 CELL INTERIOR

61 DEATH PROMOTING RECEPTORS AND LIGANDS LIGAND TNFα FAS ligand TRAIL RECEPTOR TNFαR1 FAS TRAIL-R(DR-4 & DR-5)

62 THE RECEPTOR-MEDIATED PATHWAY OF APOPTOTIC DEATH = DD TNFα = DED TNFR1 FADD CASPASES 8,10 BID BAX e to ente tbid MITOCHONDRIAL PATHWAY CASPASE 3

63 CELLULAR ANTAGONISTS OF THE EXTRINSIC APOPTOTIC PATHWAY

64 ANTAGONISTS OF THE RECEPTOR-MEDIATED PATHWAY OF APOPTOTIC DEATH = DD = DED SODD TNFα TNFR FADD TNFα DECOY R (DcR3. TRID) c-flip X X BID Typ e to ente r text BAX tbid MITOCHONDRIAL PATHWAY CASPASE 3

65 ANTAGONISTS OF THE RECEPTOR-MEDIATED PATHWAY OF APOPTOTIC DEATH = DD TNFα TNFα = DED SODD TNFR FADD DECOY R (DcR3. TRID) c-flip X X BID tbid BAX MITOCHONDRIAL PATHWAY CASPASE 3

66 DEATH PROMOTING RECEPTORS AND LIGANDS-2 THE EXTRINSIC DEATH PATHWAY BEGINS WITH RECEPTOR-MEDIATED ACTIVATION OF INITIATOR CASPASES 8 AND/0R 10 THE PATHWAY CAN EITHER BYPASS MITOCHONDRIAL INVOLVEMENT IN DEATH OR CAN INVOLVE MITOCHONDRIA AS A MEANS OF AMPLIFICATION THE SAME CELL CAN EXPRESS BOTH DEATH RECEPTOR AND DEATH LIGAND SUSCEPTIBILITY IS SUBJECT TO REGULATION BY PATHWAY ANTAGONISTS

67 FLIP DOWN-REGULATION SENSITIZES SKBR3 BREAST CANCER CELL LINE TO TRAIL-INDUCED DEATH FROM Zang F, et al., BBRC 450: , 2014

68 PATHWAYS MEDIATING SENSITIZATION TO TRAIL BY DOWN-REGULATION OF MCL-1 Kim S et al. Cancer Res 2008;68: by American Association for Cancer Research

69 DEATH PROMOTING RECEPTORS AND LIGANDS-3 THE EXTRINSIC PATHWAY CONTRIBUTES TO DEATH IN A VARIETY OF CONTEXTS MANY TUMOR CELLS EXPRESS EXTRINSIC PATHWAY RECEPTORS, BUT ALSO OVER-EXPRESS PATHWAY ANTAGONISTS (50% of colon cancers have amplified DcR3 gene) EXPRESSION OF LIGAND AND RECEPTORS AS WELL AS OF PATHWAY ANTAGONISTS IS SUBJECT TO REGULATION

70 ROLE OF TRANSCRIPTION IN APOPTOSIS IN MANY, BUT NOT ALL PARADIGMS OF APOPTOTIC DEATH CELLS MUST SYNTHESIZE SPECIFIC GENES TO DIE THE PATHWAYS THAT REGULATE SUCH DEATH-ASSOCIATED GENES APPEAR TO BE ACTIVATED BY MECHANISMS THAT ARE INDEPENDENT OF MITOCHONDRIA. THE GENE PRODUCTS OF THESE PATHWAYS CAN ACT BOTH UPSTREAM AND DOWNSTREAM OF MITOCHONDRIA BH3-DOMAIN ONLY MOLECULES SEEM TO BE COMMON GENE TARGETS (eg. BIM IS REGULATED BY JUN, E2F, AND FORKHEAD)

71 TRANSCRIPTIONAL TARGETS OF P53 IN APOPTOSIS APOPTOTIC STIMULI (DNA DAMAGE) P53 PHOSPHORYLATION AND STABILIZATION E2F SIAH p53 PAC1 MAPK JNK/JUN BIM BAX BID PUMA NOXA APAF-1 Cell specific Stimulus specific CASPASE 6

72 POST-TRANSCRIPTIONAL REGULATION OF APOPTOSIS BY mirnas (APOPTOMIRS) Andrea Vecchione, and Carlo M Croce Endocr Relat Cancer 2010;17:F37-F Society for Endocrinology

73 WHAT SIGNALS KEEP CELL FROM DYING? ACTIVATION OF AKT/PKB & MAPK RAS RAF MEK SURVIVAL ERK Brazil DP, Hemmings BA.Trends Biochem Sci Nov;26(11):

74 EXAMPLES OF HOW AKT PROMOTES SURVIVAL BAD AKT P- BAD (cytoplasmic) mitochondria FKHR AKT P-FKHR (cytoplasmic) SURVIVAL nucleus MDM2 AKT P- MDM2 + p53 p53 inactive active p53

75 EXAMPLES OF HOW AKT PROMOTES SURVIVAL HEXOKINASE AKT P- HK PTP (mitochondria) Cytoplasm SURVIVAL IAP AKT TRANSCRIPTIONAL ACTIVATION IAP

76 EXAMPLES OF HOW RAF/ERKS PROMOTE SURVIVAL BAD RAF/ERKS P- BAD (cytoplasmic) mitochondria SURVIVAL BIM RAF/ERKS BIM INDUCTION Non-induced & destablized

77 MECHANISMS OF APOPTOSIS RESISTANCE-1 MUTATIONS OF CASPASES -MCF7 BREAST CA HAS NO CASPASE-3 EXPRESSION -DECREASED CASPASE-7 EXPRESSION IN COLON CA -HYPERMETHYLATION OF CASPASE-8 PROMOTER LOSS OF APAF-1 EXPRESSION IN MELANOMA

78 MECHANISMS OF APOPTOSIS RESISTANCE-2 INCREASED EXPRESSION OF IAPS -SURVIVIN IN NEUROBLASTOMA -ciap1/2 IN LUNG CA -ciap1 IN ESOPHAGEAL SQUAMOUS CELL CA -ciap1 INCREASES RESISTANCE TO CHEMOTHERAPY -XIAP IN OVARIAN CA

79 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 INCREASED EXPRESSION OF cflip IN BREAST CA

80 STRATEGIES FOR TARGETING CANCER INHIBITION OF OVEREXPRESSED ANTI- APOPTOTIC MOLECULES -e.g. BCL2, BH3 PROTEINS, SURVIVIN, OTHER IAPS ENHANCE RECEPTOR MEDIATED DEATH VIA TRAIL-R ENHANCE PRO-APOPTOTIC PATHWAYS -small molecule mimetic of SMAC/Diablo - stapled Bim TARGETING CANCER SPECIFIC APOPTOMIRS

81 MAINTENANCE OF HOMEOSTASIS TIGHT REGULATION OF DEATH PATHWAYS AT SEVERAL LEVELS IS ESSENTIAL A BETTER UNDERSTANDING OF THE MOLECULAR MECHANISM(S) OF ANTI- APOPTOSIS FOR A PARTICULAR TUMOR WILL ENABLE DESIGN OF TARGETED THERAPIES

Mechanisms of Cell Death

Mechanisms of Cell Death CELL DEATH AND FORMATION OF THE SEMICIRCULAR CANALS Carol M. Troy, MD PhD August 24, 2009 FROM: Fekete et al., Development 124: 2451 (1997) PHENOMENOLOGY OF CELL DEATH I. DEVELOPMENT