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TitleApoptosis - Physiology and Pathology - J. Reed, D. Green (Cambridge, 2011) WW
TagsMedical Physiology
LanguageEnglish
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Total Pages469
Table of Contents
                            Title
Copyright
Contents
Contributors
Part I General Principles of Cell Death
	1 Human Caspases – Apoptosis and Inflammation Signaling Proteases
		1. PROTEASE SIGNALING IN APOPTOSIS AND INFLAMMATION
			1.1. Apoptosis and limited proteolysis
			1.2. Caspase evolution
		2. ACTIVATION MECHANISMS
			2.1. Initiator caspases– activation by dimerization
			2.2. The activation platforms
			2.3. Executioner caspases– activation by cleavage
			2.4. Proteolytic maturation
		3. CASPASE SUBSTRATES
		4. REGULATION BY NATURAL INHIBITORS
		REFERENCES
	2 Inhibitor of Apoptosis Proteins
		1. THE BIR DOMAIN DEFINES MEMBERSHIP IN THE IAP FAMILY
		2. CELLULAR FUNCTIONS AND PHENOTYPES OF IAP
		3. IN VIVO FUNCTIONS OF IAP FAMILY PROTEINS
		4. SUBCELLULAR LOCATIONS OF IAP
		5. IAP AS CASPASE INHIBITORS
		6. IAP AS E3 LIGASES
		7. IAP AND SIGNAL TRANSDUCTION
		8. IAP–IAP INTERACTIONS
		9. POST-TRANSLATIONAL MODIFICATIONS OF BIR PROTEINS
		10. ENDOGENOUS ANTAGONISTS OF IAP
		11. IAPs AND DISEASE
		SUGGESTED READINGS
	3 Death Domain–Containing Receptors – Decisions between Suicide and Fire
		1. INTRODUCTION
		2. RECEPTOR-LIGAND SYSTEMS WITH PRIMARILY PROAPOPTOTIC FUNCTIONS
			2.1. The CD95 (Fas/APO-1)
system
				2.1.1. CD95 and CD95L: discovery of the first direct apoptosis-inducing receptor-ligand system
				2.1.2. Biochemistry of CD95 apoptosis signaling
			2.2. The TRAIL (Apo2L)
system
		3. DEATH RECEPTOR–LIGAND SYSTEMS WITH PRIMARILY IMMUNOSTIMULATORY, PROINFLAMMATORY ACTIVITY
			3.1. The TNF system
				3.1.1. Biochemistry of TNF signal transduction
				3.1.2. TNF and TNF blockers in the clinic
			3.2. The DR3 system
		4. THE DR6 SYSTEM
		5. FUNCTIONAL SPECIALIZATION BY SEQUENTIAL SIGNALING COMPLEX FORMATION IN DEATH RECEPTOR SIGNAL TRANSDUCTION
		6. CONCLUDING REMARKS AND OUTLOOK
		SUGGESTED READINGS
	4 Mitochondria and Cell Death
		1. INTRODUCTION
		2. MITOCHONDRIAL PHYSIOLOGY
		3. THE MITOCHONDRIAL PATHWAY OF APOPTOSIS
		4. MITOCHONDRIAL OUTER MEMBRANE PERMEABILIZATION
		5. MORPHOLOGICAL CHANGES IN MITOCHONDRIA DURING MOMP
		6. DOWNSTREAM OF MITOCHONDRIAL OUTER MEMBRANE PERMEABILIZATION
		7. MITOCHONDRIAL PERMEABILITY TRANSITION PORE AND NECROTIC CELL DEATH
		8. COMPARISON OF THE VERTEBRATE AND INVERTEBRATE PATHWAYS OF MITOCHONDRIAL CELL DEATH
		9. CONCLUSIONS
		SUGGESTED READINGS
	5 The Control of Mitochondrial Apoptosis by the BCL-2 Family
		1. INTRODUCTION
		2. ACTIVATING APOPTOSIS: BAX AND BAK AND THE ACTIVATOR BH3-ONLY PROTEINS
		3. INHIBITING APOPTOSIS
		4. INHIBITING THE INHIBITORS
		5. ACTIVATING THE ACTIVATORS – CONNECTING THE INSULT TO THE BCL-2 FAMILY
		6. THE BCL-2 FAMILY AND CANCER
		SUGGESTED READINGS
	6 Endoplasmic Reticulum Stress Response in Cell Death and Cell Survival
		1. INTRODUCTION
		2. THE ESR IN YEAST
		3. THE ESR IN MAMMALS
		4. THE ESR AND CELL DEATH
		5. THE ESR IN DEVELOPMENT AND TISSUE HOMEOSTASIS
		6. THE ESR IN HUMAN DISEASE
		7. CONCLUSION
	7 Autophagy – The Liaison between the Lysosomal System and Cell Death
		1. INTRODUCTION
		2. AUTOPHAGY
			2.1. Molecular dissection of autophagy
			2.2. Physiologic functions of autophagy
			2.3. Autophagy and human pathology
		3. AUTOPHAGY AND CELL DEATH
			3.1. Autophagy as anti–cell death mechanism
			3.2. Autophagy as a cell death mechanism
			3.3. Molecular players of the autophagy–cell death cross-talk
		4. AUTOPHAGY, CELLULAR DEATH, AND CANCER
		5. CONCLUDING REMARKS AND PENDING QUESTIONS
		SUGGESTED READINGS
	8 Cell Death in Response to Genotoxic Stress and DNA Damage
		1. TYPES OF DNA DAMAGE AND REPAIR SYSTEMS
		2. DNA DAMAGE RESPONSE
			2.1. Sensors
			2.2. Transducers
			2.3. Effectors
		3. INTEGRATION OF ATM AND ATR PATHWAYS
		4. CHROMATIN MODIFICATIONS
		5. CELL CYCLE CHECKPOINT REGULATION
		6. WHEN REPAIR FAILS: SENESCENCE VERSUS APOPTOSIS
			6.1. DNA damage response and the induction of apoptosis
			6.2. p53-independent mechanisms of apoptosis
			6.3. DNA damage response and senescence induction
		7. DNA DAMAGE FROM OXIDATIVE STRESS
		SUGGESTED READINGS
	9 Ceramide and Lipid Mediators in Apoptosis
		1. INTRODUCTION
		2. SPHINGOLIPID METABOLISM: CONSTITUENTS, COMPARTMENTALIZATION, AND KEY CONCEPTS
		3. SPHINGOLIPIDS AS MEDIATORS OF APOPTOTIC SIGNALING
			3.1. Basic cell signaling often involves small molecules
			3.2. Sphingolipids are cell-signaling molecules
				3.2.1. Ceramide induces apoptosis
				3.2.2. Ceramide accumulates during programmed cell death
				3.2.3. Inhibition of ceramide production alters cell death signaling
		4. CERAMIDE MEDIATES APOPTOTIC CELL DEATH: ROLE OF PARTICULAR ENZYME SYSTEMS
			4.1. Ceramide is generated through SM hydrolysis
			4.2. aSMase is activated after activation of extracellular receptors to promote apoptosis
			4.3. aSMase can be activated independently of extracellular receptors to regulate apoptosis
			4.4. Controversial aspects of the role of aSMase in apoptosis
			4.5. De novo ceramide synthesis regulates programmed cell death
			4.6. p53 and Bcl-2–like proteins are connected to de novo ceramide synthesis
			4.7. The role and regulation of de novo synthesis in ceramide-mediated cell death is poorly understood
		5. CONCLUDING REMARKS AND FUTURE DIRECTIONS
			5.1. Who? (Which enzyme?)
			5.2. What? (Which ceramide?)
			5.3. Where? (Which compartment?)
			5.4. When? (At what steps?)
			5.5. How? (Through what mechanisms?)
			5.6. What purpose?
		6. SUMMARY
		SUGGESTED READINGS
	10 Cytotoxic Granules House Potent Proapoptotic Toxins Critical for Antiviral Responses and Immune Homeostasis
		1. General Introduction
			1.1. Cytotoxic lymphocytes and apoptosis
		2. CYTOTOXIC GRANULES AND GRANULE EXOCYTOSIS
			2.1. Synthesis and loading of the cytotoxic granule proteins into the secretory granules
			2.2. The immunological synapse
			2.3. Secretion of granule proteins
			2.4. Uptake of proapoptotic proteins into the target cell
			2.5. Activation of death pathways by granzymes
		3. GRANULE-BOUND CYTOTOXIC PROTEINS
			3.1. Perforin
			3.2. Granulysin
			3.3. Granzymes
				3.3.1. GrB-mediated apoptosis
				3.3.2. GrA-mediated cell death
				3.3.3. Orphan granzyme-mediated cell death
		4. A ROLE FOR GRANULE PROTEINS IN VIRAL RESPONSE, IMMUNE SURVEILLANCE, AND IMMUNE HOMEOSTASIS
		5. CONCLUSIONS
		REFERENCES
Part II Cell Death in Tissues and Organs
	11 Cell Death in Nervous System Development and Neurological Disease
		1. NATURALLY OCCURRING NEURONAL CELL DEATH DURING DEVELOPMENT WHEN NEURONS ARE ESTABLISHING THEIR TARGETING CONNECTIONS
			1.1. Death by trophic factor deprivation
			1.2. Key molecules regulating neuronal apoptosis during development
				1.2.1. Roles of caspases and Apaf-1 in neuronal cell death
				1.2.2. Role of Bcl-2 family members in neuronal cell death
			1.3. Signal transduction from neurotrophins and neurotrophin receptors
				1.3.1. Signals for survival
				1.3.2. Signals for death
		2. PATHOLOGIC NEURONAL CELL DEATH IN THE ADULT BRAIN
		2.1. Apoptosis in neurodegenerative diseases
			2.1.1. Alzheimers disease
			2.1.2. Parkinsons disease
			2.1.3. Huntingtons disease
			2.1.4. Amyotrophic lateral sclerosis
				2.2. Necrotic cell death in neurodegenerative diseases
				2.2.1. Calpains
				2.2.2. Cathepsins
		3. CONCLUSIONS
		ACKNOWLEDGMENT
		SUGGESTED READINGS
	12 Role of Programmed Cell Death in Neurodegenerative Disease
		1. INTRODUCTION: PROGRAMMED CELL DEATH, CELL DEATH SIGNALING, AND NEURODEGENERATIVE DISEASE
		2. MECHANISTIC TAXONOMY OF CELL DEATH: HOW MANY TYPES OF PROGRAMMED CELL DEATH CAN BE DISTINGUISHED?
		3. PROGRAMMED CELL DEATH SIGNALING IN NEURODEGENERATION
		4. APOPTOSIS INDUCED BY MISFOLDED, UNFOLDED, OR ALTERNATIVELY FOLDED PROTEINS
		5. TROPHIC FACTORS AND CELLULAR DEPENDENCE IN NEURODEGENERATIVE DISEASE
		ACKNOWLEDGMENT
		SUGGESTED READINGS
	13 Implications of Nitrosative Stress-Induced Protein Misfolding in Neurodegeneration
		1. INTRODUCTION
		2. PROTEIN MISFOLDING AND AGGREGATION IN NEURODEGENERATIVE DISEASES
		3. NMDA RECEPTOR-MEDIATED GLUTAMATERGIC SIGNALING PATHWAYS INDUCE Ca2+ INFLUX AND GENERATION OF RNS/ROS
		4. PROTEIN S-NITROSYLATION AND NEURONAL CELL DEATH
		5. S-NITROSYLATION OF PARKIN
		6. S-NITROSYLATION OF PDI MEDIATES PROTEIN MISFOLDING AND NEUROTOXICITY IN CELL MODELS OF PD OR AD
		7. POTENTIAL TREATMENT OF EXCESSIVE NMDA-INDUCED Ca2+ INFLUX AND FREE RADICAL GENERATION
		8. FUTURE THERAPEUTICS: NITROMEMANTINES
		9. CONCLUSIONS
		Acknowledgments
		SUGGESTED READINGS
	14 Mitochondrial Mechanisms of Neural Cell Death in Cerebral Ischemia
		1. CELL DEATH AFTER CEREBRAL ISCHEMIA AND REPERFUSION
		2. MITOCHONDRIA MEDIATE BOTH NECROTIC AND APOPTOTIC CELL DEATH
		3. MITOCHONDRIAL PERMEABILITY TRANSITION ACTIVATED BY Ca2+ AND OXIDATIVE STRESS
		4. MITOCHONDRIAL MECHANISMS OF APOPTOTIC DEATH AFTER CEREBRAL ISCHEMIA
			4.1. Mitochondrial apoptotic pathways
			4.2. Bcl-2 family proteins
			4.3. Caspase-dependent apoptosis
			4.4. Caspase-independent apoptosis
			4.5. Calpains in ischemic neural cell death
		5. SUMMARY
		ACKNOWLEDGMENTS
		SUGGESTED READINGS
	15 Cell Death in Spinal Cord Injury – An Evolving Taxonomy with Therapeutic Promise
		1. INTRODUCTION
		2. HISTORICAL ANTECEDENTS
		3. CELL DEATH IN THE ACUTE PHASE OF SCI: BEYOND THE APOPTOSIS AND NECROSIS DICHOTOMY
		4. INTRINSIC MEDIATORS OF ACUTE CELL DEATH: EXCITOTOXICITY VERSUS HIF OR JUN
		5. EXECUTIONER CASPASES IN THE ACUTE PHASE OF SPINAL CORD INJURY
		6. MITOCHONDRIA AS A TARGET OF SPINAL CORD PROTECTION
		7. SUBACUTE PHASE: EXTRINSIC PATHWAYS TO DEATH IN NEURONS AND OLIGODENDROCYTES
			7.1. Activation of p21 waf1/cip1: Targeting extrinsic and intrinsic pathways to death
		8. CONCLUSION
		ACKNOWLEDGMENTS
		REFERENCES
	16 Apoptosis and Homeostasis in the Eye
		1. APOPTOSIS AND APOPTOSIS-LIKE PROCESSES THAT SHAPE THE DEVELOPMENT OF THE MAMMALIAN EYE
			1.1. Lens
			1.2. Retina
		2. ROLE OF APOPTOSIS IN DISEASES OF THE EYE
			2.1. Glaucoma
			2.2. Age-related macular degeneration
		3. APOPTOSIS AND SURVEILLANCE OF INTRAOCULAR TUMORS
		4. APOPTOSIS AND OCULAR IMMUNE PRIVILEGE
		5. CONCLUSIONS
		SUGGESTED READINGS
	17 Cell Death in the Inner Ear
		1. HAIR CELLS ARE THE SENSORY RECEPTOR CELLS IN THE HEARING AND BALANCE ORGANS OF THE INNER EAR
		2. HAIR CELLS SYNAPSE WITH VESTIBULAR GANGLION NEURONS AND SPIRAL GANGLION NEURONS
		3. THE COCHLEA IS THE HEARING ORGAN
			3.1. Ototoxic hair cell death
			3.2. Aminoglycoside-induced hair cell death
			3.3. Cisplatin-induced hair cell death
			3.4. Therapeutic strategies to prevent hair cell death
			3.5. Challenges to studies of hair cell death
		4. SPIRAL GANGLION NEURON DEATH
			4.1. Neurotrophic support from sensory hair cells and supporting cells
			4.2. Afferent activity from hair cells
			4.3. Molecular manifestations of spiral ganglion neuron death
			4.4. Therapeutic interventions to prevent SGN death
		ACKNOWLEDGMENTS
		SUGGESTED READINGS
	18 Cell Death in the Olfactory System
		1. Introduction
		2. Anatomical Aspects
		3. Life and Death in the Olfactory System
			3.1. Olfactory epithelium
			3.2. Olfactory bulb
		4. Olfaction in Aging and Neurodegenerative Disease
		REFERENCES
	19 Contribution of Apoptosis to Physiologic Remodeling of the Endocrine Pancreas and Pathophysiology of Diabetes
		1. Introduction
		2. APOPTOSIS IN PHYSIOLOGIC CONTROL OF BETA CELL MASS
		3. CONTRIBUTION OF APOPTOSIS TO BETA CELL MASS INADEQUACIES IN DIABETES
			3.1. Beta cell death in the development of T1D
			3.2. Mechanisms of beta cell death in type 1 diabetes
				3.2.1. Apoptosis signaling pathways downstream of death receptors and inflammatory cytokines
				3.2.2. Oxidative stress
			3.3. Mechanisms of beta cell death in type 2 diabetes
				3.3.1. Glucolipitoxicity
				3.3.2. Endoplasmic reticulum stress
		4. BETA CELL APOPTOSIS AND ISLET TRANSPLANTATION THERAPY
		5. SUMMARY
		Acknowledgments
		REFERENCES
	20 Apoptosis in the Physiology and Diseases of the Respiratory Tract
		1. APOPTOSIS IN LUNG DEVELOPMENT
		2. APOPTOSIS IN LUNG PATHOPHYSIOLOGY
			2.1. Apoptosis in pulmonary inflammation
			2.2. Apoptosis in acute lung injury
			2.3. Apoptosis in chronic obstructive pulmonary disease
			2.4. Apoptosis in interstitial lung diseases
			2.5. Apoptosis in pulmonary arterial hypertension
			2.6. Apoptosis in lung cancer
			SUGGESTED READINGS
	21 Regulation of Cell Death in the Gastrointestinal Tract
		1. INTRODUCTION
		2. ESOPHAGUS
		3. STOMACH
		4. SMALL AND LARGE INTESTINE
		5. LIVER
		6. PANCREAS
		7. SUMMARY AND CONCLUDING REMARKS
		SUGGESTED READINGS
	22 Apoptosis in the Kidney
		1. NORMAL KIDNEY STRUCTURE AND FUNCTION
		2. APOPTOSIS IN KIDNEY DEVELOPMENT AND CONGENITAL KIDNEY DISEASES
		3. APOPTOSIS IN ADULT KIDNEY DISEASE
		4. REGULATION OF APOPTOSIS IN KIDNEY CELLS
			4.1. Survival factors
			4.2. Lethal factors
				4.2.1. TNF superfamily cytokines
				4.2.2. Other cytokines
				4.2.3. Glucose
				4.2.4. Drugs and xenobiotics
				4.2.5. Ischemia-reperfusion and sepsis
		5. THERAPEUTIC APPROACHES
		SUGGESTED READINGS
	23 Physiologic and Pathological Cell Death in the Mammary Gland
		1. INTRODUCTION
		2. APOPTOSIS IN THE NORMAL BREAST
			2.1. Occurrence and role of apoptosis in the developing breast
			Molecular regulation ofapoptosis in the normal breast
				2.2.1. Autocrine/paracrine regulation by growth factors, death ligands, and other cytokines
				2.2.2. Death ligands and death receptor pathway
				2.2.3. TGF3 proapoptotic pathway
				2.2.4. LIF-STAT3 proapoptotic signaling
				2.2.5. IGF survival signaling
				2.2.6. Regulation by adhesion
				2.2.7. PI3K/AKT pathway: molecular hub for survival signals
				2.2.8. Downstream regulators of apoptosis: the BCL-2 family members
		3. APOPTOSIS IN BREAST CANCER
			3.1. Apoptosis in breast tumorigenesis and cancer progression
			3.2. Molecular dysregulation of apoptosis in breast cancer
				3.2.1. Altered expression of death ligands and their receptors in breast cancer
				3.2.2. Deregulation of prosurvival growth factors and their receptors
				3.2.3. Alterations in cell adhesion and resistance to anoikis
				3.2.4. Enhanced activation of the PI3K/AKT pathway in breast cancer
				3.2.5. p53 inactivation in breast cancer
				3.2.6. Altered expression of BCL-2 family of proteins in breast cancer
		4. NONAPOPTOTIC TYPES OF CELL DEATH IN NORMAL AND NEOPLASTIC BREAST
		5. CONCLUSION
		SUGGESTED READINGS
	24 Therapeutic Targeting Apoptosis in Female Reproductive Biology
		1. INTRODUCTION
		2. DETECTING CELL DEATH IN THE FEMALE GONADS
		3. OCCURRENCE AND REGULATION OF CELL DEATH IN THE OVARIES
		4. APOPTOSIS AND FEMALE REPRODUCTIVE AGING
		5. ANTIAPOPTOTIC AGENTS AND FERTILITY PRESERVATION FOR CANCER SURVIVORS
		6. CONCLUDING REMARKS
		REFERENCES
	25 Apoptotic Signaling in Male Germ Cells
		1. INTRODUCTION
		2. TESTICULAR GERM CELL APOPTOSIS HAS MANY UNIQUE REGULATORY GENES
		3. MODELS TO STUDY TESTICULAR GERM CELL APOPTOSIS
			3.1. Murine models
			3.2. Primate models
			3.3. Pathways of caspase activation and apoptosis
			3.4. Apoptotic signaling in male germ cells
		4. THE FAS SIGNALING SYSTEM DOES NOT CONTRIBUTE TO HEAT- OR HORMONE DEPRIVATION–INDUCED MALE GERM CELL APOPTOSIS
		5. P38 MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) AND NITRIC OXIDE (NO)–MEDIATED INTRINSIC PATHWAY SIGNALING CONSTITUTES A CRITICAL COMPONENT OF APOPTOTIC SIGNALING IN MALE GERM CELLS AFTER HORMONE DEPRIVATION
		6. P38 MAPK PATHWAY IS ALSO THE KEY PATHWAY FOR HEAT-INDUCED MALE GERM CELL APOPTOSIS
		7. CASPASE-2 IS AN UPSTREAM ACTIVATOR OF P38 MAPK AND NO-MEDIATED INTRINSIC PATHWAY SIGNALING
		8. SIGNALING PATHWAYS FOR TESTICULAR GERM CELL DEATH IN NONHUMAN PRIMATES
		9. SIGNALING PATHWAYS FOR TESTICULAR GERM CELL DEATH IN HUMAN
		10. COMPLETE REVERSIBILITY OF SPERMATOGENESIS AFTER DISCONTINUATION OF SUPPRESSION OF GONADOTROPINS BY EXPERIMENTAL CONTRACEPTIVES
		11. CONCLUSIONS AND PERSPECTIVES
		REFERENCES
	26 Cell Death in the Cardiovascular System
		1. INTRODUCTION
		2. CELL DEATH IN THE VASCULATURE
			2.1. Apoptosis in the developing blood vessels
			2.2. Apoptosis in atherosclerosis
				2.2.1. Vascular smooth muscle cells
				2.2.2. Macrophages
				2.2.3. Regulation of apoptosis in atherosclerosis
				2.2.4. Necrosis and autophagy in atherosclerosis
		3. CELL DEATH IN THE MYOCARDIUM
			3.1. Cell death in myocardial infarction
				3.1.1. Apoptosis in myocardial infarction
				3.1.2. Necrosis in myocardial infarction
				3.1.3. Autophagy in myocardial infarction
			3.2. Cell death in heart failure
				3.2.1. Apoptosis in heart failure
				3.2.2. Necrosis in heart failure
				3.2.3. Autophagy in heart failure
		4. CONCLUDING REMARKS
		ACKNOWLEDGMENTS
		REFERENCES
	27 Cell Death Regulation in Muscle
		1. INTRODUCTION TO MUSCLE
			1.1. Skeletal muscle adaptation to endurance training
			1.2. Myonuclear domains
		2. MITOCHONDRIALLY MEDIATED APOPTOSIS IN MUSCLE
			2.1. Skeletal muscle apoptotic susceptibility
		3. EVIDENCE OF APOPTOSIS DURINGMUSCLE DISUSE
			3.1. Mitochondrially mediatedapoptosis during chronicmuscle disuse
		4. APOPTOSIS IN MUSCLE DURING AGING AND DISEASE
			4.1. Aging
			4.2. Type 2 diabetes mellitus
			4.3. Cancer cachexia
			4.4. Chronic heart failure
		5. EFFECT OF ENDURANCE EXERCISE/CHRONIC CONTRACTILE ACTIVITY ON APOPTOSIS
		6. CONCLUSION
		SUGGESTED READINGS
	28 Cell Death in the Skin
		1. INTRODUCTION
		2. CELL DEATH IN SKIN HOMEOSTASIS
			2.1. Cornification and apoptosis
			2.2. Death receptors in the skin
		3. CELL DEATH IN SKIN PATHOLOGY
			3.1. Sunburn
			3.2. Skin cancer
			3.3. Necrolysis
			3.4. Pemphigus
			3.5. Eczema
			3.6. Graft-versus-host disease
		4. CONCLUDING REMARKS AND PERSPECTIVES
		ACKNOWLEDGMENTS
		SUGGESTED READINGS
	29 Apoptosis and Cell Survival in the Immune System
		1. TWO APOPTOTIC PATHWAYS CONVERGE IN CASPASE ACTIVATION
		2. APOPTOSIS AND SURVIVAL IN THE DEVELOPMENT AND HOMEOSTASIS OF THE IMMUNE SYSTEM
			2.1. Survival of early hematopoietic progenitors
			2.2. Sizing of the T-cell population
				2.2.1. Establishing central tolerance
				2.2.2. Peripheral tolerance
				2.2.3. Memory T cells
			2.3. Control of apoptosis in B-cell development
				2.3.1. Early B-cell development
				2.3.2. Deletion of autoreactive B cells
				2.3.3. Survival and death of activated B cells
		3. IMPAIRED APOPTOSIS AND LEUKEMOGENESIS
		4. CONCLUSIONS
		ACKNOWLEDGMENTS
		REFERENCES
	30 Cell Death Regulation in the Hematopoietic System
		1. INTRODUCTION
		2. HEMATOPOIETIC STEM CELLS
		3. HEMATOPOIETIC PROGENITOR EXPANSION AND LINEAGE DETERMINATION
		4. ERYTHROPOIESIS
		5. MEGAKARYOPOIESIS
		6. GRANULOPOIESIS
		7. MONOPOIESIS
		8. CONCLUSION
		ACKNOWLEDGMENTS
		REFERENCES
	31 Apoptotic Cell Death in Sepsis
		1. INTRODUCTION
		2. HOST INFLAMMATORY RESPONSE TO SEPSIS
		3. CLINICAL OBSERVATIONS OF CELL DEATH IN SEPSIS
			3.1. Sepsis-induced apoptosis
			3.2. Necrotic cell death in sepsis
		4. THE DEVELOPMENT OF CLINICALLY RELEVANT ANIMAL MODELS OF SEPSIS
			4.1. Central role of apoptosis in sepsis mortality: immune effector cells and gut epithelium
			4.2. Apoptotic pathways in sepsis-induced immune cell death
			4.3. Investigations implicating the extrinsic apoptotic pathway in sepsis
			4.4. Investigations implicating the intrinsic apoptotic pathway in sepsis
		5. THE EFFECT OF APOPTOSIS ON THE IMMUNE SYSTEM
			5.1. Cellular effects of an increased apoptotic burdens
			5.2. Network effects of selective loss of immune cell types
			5.3. Studies of immunomodulation by apoptotic cells in other fields
		6. DEVELOPING THERAPIES TO AMELIORATE SEPSIS-INDUCED LYMPHOCYTE APOPTOSIS
		7. CONCLUSION
		REFERENCES
	32 Host–Pathogen Interactions
		1. INTRODUCTION
		2. FROM THE PATHOGEN PERSPECTIVE
			2.1. Commensals versus pathogens
			2.2. Pathogen strategies to infect the host
		3. HOST DEFENSE
			3.1. Antimicrobial peptides
			3.2. PRRs and inflammation
				3.2.1. TLRs
				3.2.2. NLRs
				3.2.3. The Nod signalosome
				3.2.4. The inflammasome
			3.3. Cell death
				3.3.1. Apoptosis and pathogen clearance
				3.3.2. Pyroptosis
				3.2.3. Caspase-independent cell death
				3.2.4. Autophagy and autophagic cell death
		4. CONCLUSIONS
		REFERENCES
	Part III Cell Death in Nonmammalian Organisms
		33 Programmed Cell Death in the Yeast Saccharomyces cerevisiae
			1. PHENOTYPE AND ASSAYS OF YEAST APOPTOSIS
			2. PHYSIOLOGIC CONDITIONS THAT INDUCE APOPTOSIS IN YEAST
				2.1. Pheromone-induced cell death
			3. EXTERNAL STIMULI THAT INDUCE APOPTOSIS IN YEAST
			4. THE GENETICS OF YEAST APOPTOSIS
			5. PROGRAMMED AND ALTRUISTIC AGING
				SUGGESTED READINGS
	34 Caenorhabditis elegans and Apoptosis
		1. Overview
		2. KILLING
		3. SPECIFICATION
		4. EXECUTION
			4.1. DNA degradation
			4.2. Mitochondrial elimination
			4.3. Engulfment
		5. SUMMARY
		SUGGESTED READINGS
	35 Apoptotic Cell Death in Drosophila
		1. CORE MOLECULES SPECIFYING APOPTOTIC CELL DEATH ARE CONSERVED
		2. DROSOPHILA CASPASES AND PROXIMAL REGULATORS
		3. IAP PARTICIPATE IN CASPASE-DEPENDENT CELL DEATH
		4. RPR PROTEINS ARE IAP ANTAGONISTS WITH CONSERVED BINDING PROPERTIES
		5. DROSOPHILA: WHAT IS UPSTREAM OF THE APOPTOSOME?
		6. CLOSING COMMENTS
		SUGGESTED READINGS
	36 Analysis of Cell Death in Zebrafish
		1. INTRODUCTION
		2. WHY USE ZEBRAFISH TO STUDY CELL DEATH?
			2.1. The zebrafish life cycle
			2.2. Molecular techniques to rapidly assess gene function in embryos
				2.2.1. Studies of gene function using microinjections into early embryos
				2.2.2. In situ hybridization and immunohistochemistry
			2.3. Forward genetic screening
			2.4. Drug and small-molecule screening
			2.5. Transgenesis
			2.6. Targeted knockouts
		3. THE ZEBRAFISH MODEL ORGANISM IN CELL DEATH RESEARCH
			3.1. Intrinsic apoptosis
			3.2. Extrinsic apoptosis
			3.3. Chk-1 suppressed apoptosis
			3.4. Anoikis
			3.5. Autophagy
			3.6. Necrosis
		4. DEVELOPMENTAL CELL DEATH IN ZEBRAFISH EMBRYOS
		5. THE P53 PATHWAY
		6. PERSPECTIVES AND FUTURE DIRECTIONS
		SUGGESTED READING
Color Plates
                        
Document Text Contents
Page 2

APOPTOSIS

Apoptosis, or cell death, can be pathological, a sign of disease and damage, or physiologic, a
process essential for normal health. This pathological dysregulation of cell death can be charac-
terized by either too much loss of essential cells in the heart, brain, and other tissues with little
regenerative capacity or too little cell turnover in self-renewing tissues, giving rise to cancer
and other maladies. This is a process of fundamental importance for development and normal
health, which is altered in many disease conditions. This book, with contributions from experts
in the field, provides a timely compilation of reviews of mechanisms of apoptosis. The book is
organized into three convenient sections. The first section explores the different processes of
cell death and how they relate to each other. The second section focuses on organ-specific
apoptosis-related diseases. The third section explores cell death in nonmammalian organisms
that have served as popular models for research. This comprehensive text is a must-read for all
researchers and scholars interested in apoptosis and cell death.

John C. Reed is Chief Executive Officer of the Sanford-Burnham Medical Research Institute.
Dr. Reed is also Professor and Donald Bren Executive Chair at Sanford-Burnham, with adjunct
professor appointments at several universities. Dr. Reed and his research team have con-
tributed more than 800 research publications to the literature. Their work is among the most
highly cited in all of science worldwide. Dr. Reed is the recipient of numerous awards and
honors and has been awarded more than eighty research grants for his work. He is a named
inventor for nearly 100 patents and the founder or cofounder of four biotechnology companies.
Dr. Reed has served on the editorial boards of numerous journals; as an advisor to numerous
public, private, and governmental organizations; and on the boards of directors of several pub-
lic and private biotechnology companies and life-sciences organizations.

Douglas R. Green is Chair of the Department of Immunology at St. Jude Children’s Research
Hospital, where he also holds the Peter Doherty Endowed Chair. Dr. Green came to St. Jude in
2005, prior to which he was Head of the Division of Cellular Immunology at the La Jolla Institute
of Allergy and Immunology. Dr. Green serves as an editor for a number of leading journals and
is Editor-in-Chief of the journal Oncogene.

Page 234

CONTRIBUTION OF APOPTOSIS TO PHYSIOLOGIC REMODELING OF THE ENDOCRINE PANCREAS 219

236. Castelnau, P., et al. Wolcott-Rallison syndrome: a case with

endocrine and exocrine pancreatic deficiency and pancre-

atic hypotrophy. Eur J Pediatr 159, 631–633 (2000).

237. Delepine, M., et al. EIF2AK3, encoding translation initia-

tion factor 2-alpha kinase 3, is mutated in patients with

Wolcott-Rallison syndrome. Nat Genet 25, 406–9 (2000).

238. Thornton, C.M., Carson, D.J. & Stewart, F.J. Autopsy find-

ings in the Wolcott-Rallison syndrome. Pediatr Pathol Lab

Med 17, 487–96 (1997).

239. Meex, S.J., et al. Activating transcription factor 6 polymor-

phisms and haplotypes are associated with impaired glu-

cose homeostasis and type 2 diabetes in Dutch Caucasians.

J Clin Endocrinol Metab 92, 2720–5 (2007).

240. Thameem, F., Farook, V.S., Bogardus, C. & Prochazka, M.

Association of amino acid variants in the activating tran-

scription factor 6 gene (ATF6) on 1q21-q23 with type 2 dia-

betes in Pima Indians. Diabetes 55, 839–42 (2006).

241. Seino, S. S20G mutation of the amylin gene is associated

with Type II diabetes in Japanese. Study group of com-

prehensive analysis of genetic factors in diabetes mellitus.

Diabetologia 44, 906–9 (2001).

242. McCullough, K.D., Martindale, J.L., Klotz, L.O., Aw, T.Y.

& Holbrook, N.J. Gadd153 sensitizes cells to endoplasmic

reticulum stress by down-regulating Bcl2 and perturbing

the cellular redox state. Mol Cell Biol 21, 1249–59 (2001).

243. Puthalakath, H., et al. ER stress triggers apoptosis by acti-

vating BH3-only protein Bim. Cell 129, 1337–49 (2007).

244. Futami, T., Miyagishi, M. & Taira, K. Identification of a net-

work involved in thapsigargin-induced apoptosis using a

library of small interfering RNA expression vectors. J Biol

Chem 280, 826–31 (2005).

245. Li, J., Lee, B. & Lee, A.S. Endoplasmic reticulum stress-

induced apoptosis: multiple pathways and activation of

p53-up-regulated modulator of apoptosis (PUMA) and

NOXA by p53. J Biol Chem 281, 7260–70 (2006).

246. Yamaguchi, H. & Wang, H.G. CHOP is involved in endo-

plasmic reticulum stress-induced apoptosis by enhancing

DR5 expression in human carcinoma cells. J Biol Chem 279,

45495–502 (2004).

247. Zhang, S., Liu, H., Yu, H. & Cooper, G.J. Fas-associated

death receptor signaling evoked by human amylin in islet

beta-cells. Diabetes 57, 348–56 (2008).

248. Ohoka, N., Yoshii, S., Hattori, T., Onozaki, K. & Hayashi,

H. TRB3, a novel ER stress-inducible gene, is induced via

ATF4-CHOP pathway and is involved in cell death. EMBO J

24, 1243–55 (2005).

249. Oyadomari, S., et al. Targeted disruption of the Chop gene

delays endoplasmic reticulum stress-mediated diabetes.

J Clin Invest 109, 525–32 (2002).

250. Oyadomari, S., et al. Nitric oxide-induced apoptosis in

pancreatic beta cells is mediated by the endoplasmic retic-

ulum stress pathway. Proc Natl Acad Sci U S A 98, 10845–50

(2001).

251. Huang, C.J., et al. Induction of endoplasmic reticu-

lum stress-induced beta-cell apoptosis and accumula-

tion of polyubiquitinated proteins by human islet amyloid

polypeptide. Am J Physiol Endocrinol Metab 293, E1656–62

(2007).

252. Urano, F., et al. Coupling of stress in the ER to activation

of JNK protein kinases by transmembrane protein kinase

IRE1. Science 287, 664–6 (2000).

253. Nishitoh, H., et al. ASK1 is essential for endoplasmic

reticulum stress-induced neuronal cell death triggered by

expanded polyglutamine repeats. Genes Dev 16, 1345–55

(2002).

254. Bassik, M.C., Scorrano, L., Oakes, S.A., Pozzan, T. &

Korsmeyer, S.J. Phosphorylation of BCL-2 regulates ER

Ca2+ homeostasis and apoptosis. EMBO J 23, 1207–16
(2004).

255. Rong, Y. & Distelhorst, C.W. Bcl-2 protein family members:

versatile regulators of calcium signaling in cell survival and

apoptosis. Annu Rev Physiol 70, 73–91 (2008).

256. Hetz, C., et al. Bax channel inhibitors prevent mito-

chondrion-mediated apoptosis and protect neurons in a

model of global brain ischemia. J Biol Chem 280, 42960–70

(2005).

257. Halban, P.A. Cellular sources of new pancreatic beta cells

and therapeutic implications for regenerative medicine.

Nat Cell Biol 6, 1021–25 (2004).

258. Limbert, C., Path, G., Jakob, F. & Seufert, J. Beta-cell

replacement and regeneration: Strategies of cell-based

therapy for type 1 diabetes mellitus. Diabetes Res Clin Pract

79, 389–99 (2008).

259. Carlsson, P.O., Palm, F., Andersson, A. & Liss, P. Markedly

decreased oxygen tension in transplanted rat pancreatic

islets irrespective of the implantation site. Diabetes 50,

489–495 (2001).

260. Carlsson, P.O., Palm, F. & Mattsson, G. Low revascular-

ization of experimentally transplanted human pancreatic

islets. J Clin Endocrinol Metab 87, 5418–23 (2002).

261. He, H., Stone, J.R. & Perkins, D.L. Analysis of robust

innate immune response after transplantation in the

absence of adaptive immunity. Transplantation 73, 853–61

(2002).

262. Mandrup-Poulsen, T. beta-cell apoptosis: stimuli and sig-

naling. Diabetes 50 Suppl 1, S58–63 (2001).

263. Biarnes, M., et al. Beta-cell death and mass in syngene-

ically transplanted islets exposed to short- and long-term

hyperglycemia. Diabetes 51, 66–72 (2002).

264. Davalli, A.M., et al. Vulnerability of islets in the immediate

posttransplantation period. Dynamic changes in structure

and function. Diabetes 45, 1161–7 (1996).

265. Ryan, E.A., et al. Successful islet transplantation: contin-

ued insulin reserve provides long-term glycemic control.

Diabetes 51, 2148–57 (2002).

266. Emamaullee, J.A. & Shapiro, A.M. Interventional strate-

gies to prevent beta-cell apoptosis in islet transplantation.

Diabetes 55, 1907–14 (2006).

267. Mysore, T.B., et al. Overexpression of glutathione peroxi-

dase with two isoforms of superoxide dismutase protects

mouse islets from oxidative injury and improves islet graft

function. Diabetes 54, 2109–16 (2005).

Page 235

220 NIKA N. DANIAL

268. Gysemans, C., et al. Prevention of primary non-function

of islet xenografts in autoimmune diabetic NOD mice

by anti-inflammatory agents. Diabetologia 46, 1115–23

(2003).

269. Sandberg, J.O., Eizirik, D.L., Sandler, S., Tracey, D.E. &

Andersson, A. Treatment with an interleukin-1 receptor

antagonist protein prolongs mouse islet allograft survival.

Diabetes 42, 1845–51 (1993).

270. Tellez, N., et al. Adenoviral overproduction of interleukin-

1 receptor antagonist increases beta cell replication and

mass in syngeneically transplanted islets, and improves

metabolic outcome. Diabetologia 50, 602–11 (2007).

271. Ronn, S.G., et al. Suppressor of cytokine signalling-3

expression inhibits cytokine-mediated destruction of pri-

mary mouse and rat pancreatic islets and delays allograft

rejection. Diabetologia 51, 1873–82 (2008).

272. Emamaullee, J., Liston, P., Korneluk, R.G., Shapiro, A.M. &

Elliott, J.F. XIAP overexpression in islet beta-cells enhances

engraftment and minimizes hypoxia-reperfusion injury.

Am J Transplant 5, 1297–305 (2005).

273. Emamaullee, J.A., et al. XIAP overexpression in human

islets prevents early posttransplant apoptosis and reduces

the islet mass needed to treat diabetes. Diabetes 54, 2541–8

(2005).

274. Hui, H., et al. Adenovirus-mediated XIAP gene transfer

reverses the negative effects of immunosuppressive drugs

on insulin secretion and cell viability of isolated human

islets. Diabetes 54, 424–33 (2005).

275. Plesner, A., Liston, P., Tan, R., Korneluk, R.G. & Verchere,

C.B. The X-linked inhibitor of apoptosis protein enhances

survival of murine islet allografts. Diabetes 54, 2533–40

(2005).

276. Dohi, T., et al. Inhibition of apoptosis by survivin improves

transplantation of pancreatic islets for treatment of dia-

betes in mice. EMBO Rep 7, 438–43 (2006).

277. Montolio, M., Tellez, N., Biarnes, M., Soler, J. & Mon-

tanya, E. Short-term culture with the caspase inhibitor z-

VAD.fmk reduces beta cell apoptosis in transplanted islets

and improves the metabolic outcome of the graft. Cell

Transplant 14, 59–65 (2005).

278. Dupraz, P., et al. Lentivirus-mediated Bcl-2 expression

in betaTC-tet cells improves resistance to hypoxia and

cytokine-induced apoptosis while preserving in vitro and

in vivo control of insulin secretion. Gene Ther 6, 1160–9

(1999).

279. Klein, D., et al. Delivery of Bcl-XL or its BH4 domain by

protein transduction inhibits apoptosis in human islets.

Biochem Biophys Res Commun 323, 473–8 (2004).

280. Contreras, J.L., et al. Cytoprotection of pancreatic islets

before and soon after transplantation by gene transfer of

the anti-apoptotic Bcl-2 gene. Transplantation 71, 1015–23

(2001).

281. Pinton, P. & Rizzuto, R. Bcl-2 and Ca2+ homeostasis in
the endoplasmic reticulum. Cell Death Differ 13, 1409–18

(2006).

282. Zhou, Y.P., et al. Overexpression of Bcl-x(L) in beta-cells

prevents cell death but impairs mitochondrial signal for

insulin secretion. Am J Physiol Endocrinol Metab 278,

E340–51 (2000).

283. Danial, N.N., et al. BAD and glucokinase reside in a mito-

chondrial complex that integrates glycolysis and apopto-

sis. Nature 424, 952–6 (2003).

284. Terauchi, Y., et al. Glucokinase and IRS-2 are required for

compensatory beta cell hyperplasia in response to high-

fat diet-induced insulin resistance. J Clin Invest 117, 246–

57 (2007).

285. Bose, A.K., Mocanu, M.M., Carr, R.D., Brand, C.L. & Yellon,

D.M. Glucagon-like peptide 1 can directly protect the heart

against ischemia/reperfusion injury. Diabetes 54, 146–51

(2005).

286. Baggio, L.L. & Drucker, D.J. Biology of incretins: GLP-1 and

GIP. Gastroenterology 132, 2131–57 (2007).

287. De Leon, D.D., Crutchlow, M.F., Ham, J.Y. & Stoffers, D.A.

Role of glucagon-like peptide-1 in the pathogenesis and

treatment of diabetes mellitus. Int J Biochem Cell Biol 38,

845–59 (2006).

288. Froud, T., et al. The use of exenatide in islet transplant

recipients with chronic allograft dysfunction: safety, effi-

cacy, and metabolic effects. Transplantation 86, 36–45

(2008).

289. King, P.J. The hypothalamus and obesity. Current Drug Tar-

gets 6, 225–40 (2005).

290. Philipson, L.H. & Roe, M.W. When BAD is good for beta

cells. Cell Metab 7, 280–1 (2008).

Page 468

ANALYSIS OF CELL DEATH IN ZEBRAFISH 421

morpholino loss-of-function studies, and it also hinted

at a new mechanism for p53 activation by injection

of foreign nucleic acids. Though the molecular mech-

anism(s) for this activation are still unclear, the work

suggests that cells have an internal p53-dependent sen-

sor for detecting the presence of morpholino oligonu-

cleotide stress and eliminating cells as a result. Of course,

if researchers are studying an antiapoptotic molecule

whose specific knockdown actually does trigger p53 acti-

vation, other types of controls such as phenotypic rescue

or development of a stable genetic mutant become criti-

cal for establishing the validity of the observed effects.

6. PERSPECTIVES AND FUTURE DIRECTIONS

In this chapter, we have reviewed studies demonstrat-

ing that the zebrafish is a very useful model system for

studying cell death processes that are relevant to human

development and disease. Although the zebrafish model

has been primarily used for studies of vertebrate devel-

opmental processes, this system is increasingly being

used for studies of disease mechanisms. Technologies

such as those employed in the articles we have high-

lighted are allowing researchers to quickly and effectively

attack pressing questions in the field of cell death, and

future approaches should further enhance the useful-

ness of this model system for rapidly assessing drug effi-

cacy and the essential functions of cell death regulators.

Zebrafish thus combine the strengths of flies and worms

in genetic analysis based on phenotype assessment with

the strengths of the mammalian mouse model in its rele-

vance to human disease processes. From a muddy fresh-

water river in India, the zebrafish has begun to show its

stripes as a premier animal model for studying verte-

brate cell death pathways.

SUGGESTED READING

Berghmans S, Murphey RD, Wienholds E, Neuberg D, Kutok JL,

Fletcher CD, Morris JP, Liu TX, Schulte-Merker S, Kanki JP,

Plasterk R, Zon LI, Look AT. tp53 mutant zebrafish develop

malignant peripheral nerve sheath tumors. Proc Natl Acad Sci

U S A. 2005 Jan 11;102(2):407–12.

Cole LK, Ross LS. Apoptosis in the developing zebrafish embryo.

Dev Biol. 2001 Dec 1;240(1):123–42.

Eimon PM, Kratz E, Varfolomeev E, Hymowitz SG, Stern H,

Zha J, Ashkenazi A. Delineation of the cell-extrinsic apop-

tosis pathway in the zebrafish. Cell Death Differ. 2006

Oct;13(10):1619–30.

Feng H, Stachura DL, White RM, Gutierrez A, Zhang L, Sanda

T, Jette CA, Testa JR, Neuberg DS, Langenau DM, Kutok

JL, Zon LI, Traver D, Fleming MD, Kanki JP, Look AT. T-

lymphoblastic lymphoma cells express high levels of BCL2,

S1P1, and ICAM1, leading to a blockade of tumor cell intrava-

sation. Cancer Cell. 2010 Oct 19;18(4):353–66.

Inohara N and Nunez G. Genes with homology to mammalian

apoptosis regulators identified in zebrafish. Cell Death Differ.

2000 May;7(5):509–10.

Jette CA, Flanagan AM, Ryan J, Pyati UJ, Carbonneau S, Stew-

art RA, Langenau DM, Look AT, Letai A. BIM and other BCL-

2 family proteins exhibit cross-species conservation of func-

tion between zebrafish and mammals. Cell Death Differ. 2008

Jun;15(6):1063–72.

Kratz E, Eimon PM, Mukhyala K, Stern H, Zha J, Strasser

A, Hart R, Ashkenazi A. Functional characterization of the

Bcl-2 gene family in the zebrafish. Cell Death Differ. 2006

Oct;13(10):1631–40.

Kwan TT, Liang R, Verfaillie CM, Ekker SC, Chan LC, Lin S,

Leung AY. Regulation of primitive hematopoiesis in zebrafish

embryos by the death receptor gene. Exp Hematol. 2006

Jan;34(1):27-34.

McNeill MS, Paulsen J, Bonde G, Burnight E, Hsu MY, Cornell

RA. Cell death of melanophores in zebrafish trpm7 mutant

embryos depends on melanin synthesis. J Invest Dermatol.

2007 Aug;127(8):2020–30.

Nowak M, Köster C, Hammerschmidt M. Perp is required for

tissue-specific cell survival during zebrafish development.

Cell Death Differ. 2005 Jan;12(1):52–64.

Peri F, Nüsslein-Volhard C. Live imaging of neuronal degrada-

tion by microglia reveals a role for v0-ATPase a1 in phagoso-

mal fusion in vivo. Cell. 2008 May 30;133(5):916–27.

Reyes R, Haendel M, Grant D, Melancon E, Eisen JS. Slow

degeneration of zebrafish Rohon-Beard neurons during pro-

grammed cell death. Dev Dyn. 2004 Jan;229(1):30–41.

Robu ME, Larson JD, Nasevicius A, Beiraghi S, Brenner C, Far-

ber SA, Ekker SC. p53 activation by knockdown technologies.

PLoS Genet. 2007 May 25;3(5):e78.

Santoro MM, Samuel T, Mitchell T, Reed JC, Stainier DY. Birc2

(cIap1) regulates endothelial cell integrity and blood vessel

homeostasis. Nat Genet. 2007 Nov;39(11):1397–402.

Sidi S, Sanda T, Kennedy RD, Hagen AT, Jette CA, Hoffmans

R, Pascual J, Imamura S, Kishi S, Amatruda JF, Kanki JP,

Green DR, D’Andrea AA, Look AT. Chk1 suppresses a caspase-

2 apoptotic response to DNA damage that bypasses p53, Bcl-

2, and caspase-3. Cell. 2008 May 30;133(5):864–77.

Swaim LE, Connolly LE, Volkman HE, Humbert O, Born DE,

Ramakrishnan L. Mycobacterium marinum infection of adult

zebrafish causes caseating granulomatous tuberculosis and

is moderated by adaptive immunity. Infect Immun. 2006

Nov;74(11):6108–17.

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