- •Contents
- •Contributors
- •Part I General Principles of Cell Death
- •1 Human Caspases – Apoptosis and Inflammation Signaling Proteases
- •1.1. Apoptosis and limited proteolysis
- •1.2. Caspase evolution
- •2. ACTIVATION MECHANISMS
- •2.2. The activation platforms
- •2.4. Proteolytic maturation
- •3. CASPASE SUBSTRATES
- •4. REGULATION BY NATURAL INHIBITORS
- •REFERENCES
- •2 Inhibitor of Apoptosis Proteins
- •2. CELLULAR FUNCTIONS AND PHENOTYPES OF IAP
- •3. IN VIVO FUNCTIONS OF IAP FAMILY PROTEINS
- •4. SUBCELLULAR LOCATIONS OF IAP
- •8. IAP–IAP INTERACTIONS
- •10. ENDOGENOUS ANTAGONISTS OF IAP
- •11. IAPs AND DISEASE
- •SUGGESTED READINGS
- •1. INTRODUCTION
- •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
- •3.1. 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
- •6. CONCLUDING REMARKS AND OUTLOOK
- •SUGGESTED READINGS
- •4 Mitochondria and Cell Death
- •1. INTRODUCTION
- •2. MITOCHONDRIAL PHYSIOLOGY
- •3. THE MITOCHONDRIAL PATHWAY OF APOPTOSIS
- •9. CONCLUSIONS
- •SUGGESTED READINGS
- •1. INTRODUCTION
- •3. INHIBITING APOPTOSIS
- •4. INHIBITING THE INHIBITORS
- •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
- •2.2. 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
- •2.2. Transducers
- •2.3. Effectors
- •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
- •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
- •4.1. Ceramide is generated through SM hydrolysis
- •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
- •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
- •5. CONCLUSIONS
- •REFERENCES
- •Part II Cell Death in Tissues and Organs
- •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
- •2.1. Apoptosis in neurodegenerative diseases
- •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
- •ACKNOWLEDGMENT
- •SUGGESTED READINGS
- •1. INTRODUCTION
- •5. S-NITROSYLATION OF PARKIN
- •7. POTENTIAL TREATMENT OF EXCESSIVE NMDA-INDUCED Ca2+ INFLUX AND FREE RADICAL GENERATION
- •8. FUTURE THERAPEUTICS: NITROMEMANTINES
- •9. CONCLUSIONS
- •Acknowledgments
- •SUGGESTED READINGS
- •3. MITOCHONDRIAL PERMEABILITY TRANSITION ACTIVATED BY Ca2+ AND OXIDATIVE STRESS
- •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
- •1. INTRODUCTION
- •2. HISTORICAL ANTECEDENTS
- •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
- •1.1. Lens
- •1.2. Retina
- •2. ROLE OF APOPTOSIS IN DISEASES OF THE EYE
- •2.1. Glaucoma
- •2.2. Age-related macular degeneration
- •4. APOPTOSIS AND OCULAR IMMUNE PRIVILEGE
- •5. CONCLUSIONS
- •SUGGESTED READINGS
- •17 Cell Death in the Inner Ear
- •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
- •REFERENCES
- •1. Introduction
- •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
- •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
- •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
- •1. INTRODUCTION
- •2. APOPTOSIS IN THE NORMAL BREAST
- •2.1. Occurrence and role of apoptosis in the developing breast
- •2.2.2. Death ligands and death receptor 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
- •5. CONCLUSION
- •SUGGESTED READINGS
- •1. INTRODUCTION
- •2. DETECTING CELL DEATH IN THE FEMALE GONADS
- •4. APOPTOSIS AND FEMALE REPRODUCTIVE AGING
- •6. CONCLUDING REMARKS
- •REFERENCES
- •25 Apoptotic Signaling in Male Germ Cells
- •1. INTRODUCTION
- •3.1. Murine models
- •3.2. Primate models
- •3.3. Pathways of caspase activation and apoptosis
- •3.4. Apoptotic signaling in male germ cells
- •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
- •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
- •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
- •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
- •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
- •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
- •4.1. 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
- •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
- •1. PHENOTYPE AND ASSAYS OF YEAST APOPTOSIS
- •2.1. Pheromone-induced cell death
- •2.1.1. Colony growth
- •2.1.2. Killer-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
- •2. DROSOPHILA CASPASES AND PROXIMAL REGULATORS
- •6. CLOSING COMMENTS
- •SUGGESTED READINGS
- •36 Analysis of Cell Death in Zebrafish
- •1. INTRODUCTION
- •2. WHY USE ZEBRAFISH TO STUDY CELL DEATH?
- •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
- •3.1. 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
278 |
KAISA SELESNIEMI AND JONATHAN L. TILLY |
Over the past few years, the wealth of information obtained from nearly 10 years of work with rodent models demonstrating the efficacy of S1P in preserving ovarian function and fertility of adult females exposed to conventional cancer treatments36,39,98,99,100,101 has served as a basis for testing the translational feasibility of using S1P as a fertility preservation agent in primates. This work is important for two principal reasons. The first and foremost is related to the very real possibility that the outcomes obtained with drug studies using rodent models will not be observed in primates as a result of species differences in drug bioactivity, metabolism, and the like. The second hurdle is one of an anatomical nature because primate ovaries are not enclosed within bursal sacs, as is the case with rodent ovaries. This is a key aspect in determining the potential utility of any antiapoptotic compound for the purpose of protecting the ovaries, because systemic availability of the compound could also protect the tumor targeted for destruction. In mice and rats this can be, and in fact was, circumvented by direct intrabursal injection of S1P before irradiation.36,98 Without a bursa, primate ovaries are not amenable to this type of localized drug delivery. However, using an intraovarian catheter-osmotic minipump system developed specifically for this purpose, very recent studies have reported that direct and controlled long-term delivery of S1P or the long-acting S1P mimetic FTY720 to the ovaries of adult female primates can be successfully achieved. Moreover, this approach was reported to protect monkey ovaries from the damaging effects of radiotherapy, leading to a maintenance of natural fertility and birth of offspring free of anatomical or cytogenetic defects.102 These encouraging findings provide important translational proof-of-concept that targeted antiapoptotic therapies can be used to preserve ovarian function and fertility in primates exposed to devastating cancer treatments.
6. CONCLUDING REMARKS
For many years, the field of apoptosis flourished by virtue of the fact that new regulatory genes and pathways were discovered on almost a daily basis. Many additional years have been spent attempting to integrate all of this information into a working generic blueprint for how apoptosis is activated and executed in various cell types and how these events are influenced by the surrounding environmental cues being constantly interpreted by the cell.103,104,105,106,107 With the assembly of this blueprint nearing completion, the new challenge faced by those in this field revolves around addressing
the question of how this information could actually be used for combating diseases and improving organ or tissue function in humans.108,109,110 Our goals here were to concisely summarize a few of the highlights of cell death research in the field of female reproduction, and in particular ovarian biology, over the past 20 years and to provide examples of how scientists in this field are attempting the meet the challenge of translating basic science findings to clinical medicine. Although some of these examples are clearly early stage, the progression of work to validate S1P as an ovarian protectant and fertility preservation agent for female cancer patients undergoing cytotoxic treatments clearly shows that such translational work with antiapoptotic compounds is feasible. Although the true measure of success of this approach awaits the final outcome of a future clinical trial in humans, as little as 10 years ago this line of thinking was viewed by many as not likely to succeed. However, the importance of the goal – improving the quality of life for female cancer survivors – far outweighed any resistance met, eventually leading the field of reproductive medicine to a point never before reached: protection of primate ovaries from 15 Gy of radiation using a small antiapoptotic molecule.102 So, does a delay of age-related ovarian failure and menopause, which has considerable ramifications for improving the quality of life in aging women, really seem that unattainable? If history is our best teacher, then the answer is no, especially considering the striking observations already made with aging Bax-deficient female mice.29,68 The challenge will be how to take what has been learned from these types of rodent studies and devise clinically amenable strategies for sustaining the oocyte and follicle pool in women as they age.
REFERENCES
1.Oktem, O., and Oktay, K. (2008). The ovary: anatomy and function throughout human life. Ann N Y Acad Sci. 1127, 1–9.
2.Gougeon, A. (2004). Dynamics of human follicular growth: morphologic, dynamic and functional aspects. In: The Ovary, P. C. K. Leung and E. Y. Adashi (eds.). San Diego: Elsevier Academic Press; pp. 25–43.
3.Hirshfield, A. N. (1991). Development of follicles in the mammalian ovary. Int Rev Cytol. 124, 43–101.
4.Gougeon, A. (1986). Dynamics of follicular growth in the human: a model from preliminary results. Hum Reprod. 1, 81–7.
5.Tilly, J. L. (1993). Ovarian follicular atresia: a model to study the mechanisms of physiological cell death. Endocr J. 1, 67–72.
THERAPEUTIC TARGETING APOPTOSIS IN FEMALE REPRODUCTIVE BIOLOGY |
279 |
6.Tilly, J. L. (1996). Apoptosis and ovarian function. Rev Reprod. 1, 162–72.
7.Morita, Y., and Tilly, J. L. (1999). Oocyte apoptosis: like sand through an hourglass. Dev Biol. 213, 1–17.
8.Tilly, J. L. (2001). Commuting the death sentence: how oocytes strive to survive. Nat Rev Mol Cell Biol. 2, 838–48.
9.Tilly, J. L., Pru, J. K., and Rueda B. R. (2004). Apoptosis in ovarian development, function and failure. In: The Ovary, P. C. K. Leung and E. Y. Adashi (eds.). San Diego: Elsevier Academic Press; pp. 321–52.
10.Byskov, A. G. (1986). Differentiation of the mammalian embryonic gonad. Physiol Rev. 66, 71–117.
11.Pinkerton, J. H. M., McKay, D. G., Adams, E. C., and Hertig, T. A. (1961). Development of the human ovary: a study using histochemical techniques. Obstet Gynecol. 18, 152– 81.
12.Baker, T. G. (1963). A quantitative and cytological study of germ cells in human ovaries. Proc R Soc London (B). 158, 417–33.
13.Forabosco, A., Sforza, C., De Pol, A., Vizzotto, L., Marzona, L., and Ferrario, V. F. (1991). Morphometric study of the human neonatal ovary. Anat Rec. 231, 201–8.
14.Pesce, M., and De Felici, M. (1994). Apoptosis in mouse primordial germ cells: a study by transmission and scanning electron microscope. Anat Embryol. 189, 435–40.
15.De Pol, A., Vaccina, F., Forabosco, A., Cavazzuti, E., Marzona, L. (1997). Apoptosis of germ cells during human prenatal oogenesis. Hum Reprod. 12, 2235–41.
16.Manabe, N., Inoue, N., Miyano, T., Sakamaki, K., Sugimoto, M., and Miyamoto, H. (2004). Follicle selection in mammalian ovaries: regulatory mechanisms of granulosa cell apoptosis during follicular atresia. In: The Ovary, P. C. K. Leung and E. Y. Adashi (eds.). San Diego: Elsevier Academic Press; pp. 369–85.
17.Richardson, S. J., Senikas, V., and Nelson, J. F. (1987). Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin
Endocrinol Metab. 65, 1231–7.
¨
18. Flemming, W. (1885). Uber die bildung von richtungsfiguren in saugethiereiern¨ beim untergang Graaf’scher follikel. Arch Anat Entwickelungsgeschichte (Arch Anat Physiol). 221–44.
19. Kerr, J. F. R., Wyllie, A. H., and Currie, A. R. (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26, 239–57.
20. Tilly, J. L., Kowalski, K. I., Johnson, A. L., and Hsueh, A. J. W. (1991). Involvement of apoptosis in ovarian follicular atresia and postovulatory regression. Endocrinology. 129, 2799–801.
21. Hughes, F. M. Jr., and Gorospe, W. C. (1991). Biochemical identification of apoptosis (programmed cell death) in granulosa cells: evidence for a potential mechanism underlying follicular atresia. Endocrinology. 129, 2415–22.
22. Coucouvanis, E. C., Sherwood, S. W., Carswell-Crumpton, C., Spack, E. G., and Jones, P. P. (1993). Evidence that the
mechanism of prenatal germ cell death in the mouse is apoptosis. Exp Cell Res. 209, 238–47.
23.Pru, J. K., and Tilly J. L. (2001). Programmed cell death in the ovary: insights and future prospects using genetic technologies. Mol Endocrinol. 15, 845–53.
24.Buckler, H. (2005). The menopause transition: endocrine changes and clinical symptoms. J Br Menopause Soc. 11, 61–5.
25.Klein, J., and Sauer, M. V. (2001). Assessing fertility in women of advanced reproductive age. Am J Obstet Gynecol. 185, 758–70.
26.Navot, D., Bergh, P. A., Williams, M. A., Garrisi, G. J., Guzman, I., Sandler, B., and Grunfeld, L. (1991). Poor oocyte quality rather than implantation failure as a cause of agerelated decline in female fertility. Lancet. 337, 1375–7.
27.Ventura, S. J. (1989). Trends and variations in first births to older women, United States, 1970–86. Vital Health Stat. 47, 1–27.
28.Ventura, S. J., Abma, J. C., Mosher, W. D., and Henshaw,
S.(2004). Estimated pregnancy rates for the United States, 1990–2000: an update. Natl Vital Stat Rep. 52, 1–9.
29.Perez, G. I., Robles, R., Knudson C. M., Flaws J. A., Korsmeyer S. J., and Tilly J. L. (1999). Prolongation of ovarian lifespan into advanced chronological age by Baxdeficiency. Nat Genet. 21, 200–3.
30.Meirow, D., and Nugent, D. (2001). The effects of radiotherapy and chemotherapy on female reproduction. Hum Reprod Update. 7, 535–43.
31.Tilly, J. L. (2004). Pharmacological protection of female fertility. In: Preservation of Fertility, T. Tulandi and R. G. Gosden (eds.). London: Taylor & Francis: pp. 65–75.
32.Salooja, N., Reddy, N., and Apperley, J. (2004). Vulnerability of the reproductive system to radiotherapy and chemotherapy. In: Preservation of Fertility, T. Tulandi and
R.G. Gosden (eds.). London: Taylor & Francis; pp. 39–64.
33.Sharara, F. I., Beatse, S. N., Leonardi, M. R., Navot, D., and Scott, R. T. Jr. (1994). Cigarette smoking accelerates the development of diminished ovarian reserve as evidence by the clomiphene citrate challenge test. Fertil Steril. 62, 257–62.
34.Freour, T., Masson, D., Mirallie, S., Jean, M., Bach, K., Dejoie, T., and Barriere, P. (2008). Active smoking compromises IVF outcome and affects ovarian reserve. Reprod Biomed Online. 16, 96–102.
35.Bishop, J. B., Morris, R. W., Seely, J. C., Hughes, L. A., Cain,
K.T., and Generoso, W. M. (1997). Alterations in the reproductive patterns of female mice exposed to xenobiotics.
Fundam Appl Toxicol. 40, 191–204.
36.Perez, G. I., Knudson, C. M., Leykin, L., Korsmeyer, S. J., and Tilly, J.L. (1997). Apoptosis-associated signaling pathways are required for chemotherapy-mediated female germ cell destruction. Nat Med. 3, 1228–32.
37.Bergeron, L., Perez, G. I., Macdonald, G., Shi, L., Sun, Y., Jurisicova, A., Varmuza, S., Latham, K. E., Flaws, J. A., Salter, J. C., Hara, H., Moskowitz, M. A., Li, E., Greenberg, A., Tilly,
280 |
KAISA SELESNIEMI AND JONATHAN L. TILLY |
J.L., and Yuan, J. (1998). Defects in regulation of apoptosis in caspase-2-deficient mice. Genes Dev. 12, 1304–14.
38.Morita, Y., Perez, G. I., Maravei, D. V., Tilly, K. I., and Tilly,
J.L. (1999). Targeted expression of Bcl-2 in mouse oocytes inhibits ovarian follicle atresia and prevents spontaneous and chemotherapy-induced oocyte apoptosis in vitro. Mol Endocrinol. 13, 841–50.
39.Morita, Y., Perez, G. I., Paris, F., Miranda, S. R., Ehleiter, D., Haimovitz-Friedman, A., Fuks, Z., Xie, Z., Reed, J. C., Schuchman, E. H., Kolesnick, R. N., and Tilly, J. L. (2000). Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate therapy. Nat Med. 6, 1109–14.
40.Matikainen, T., Perez, G. I., Jurisicova, A., Schlezinger, J. J., Ryu, H.-Y., Pru, J. K., Sakai, T., Korsmeyer, S. J., Casper, R. F., Sherr. D. H., and Tilly, J. L. (2001). Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nat Genet. 28, 355–60.
41.Matikainen, T. M., Moriyama, T., Morita, Y., Perez, G. I., Korsmeyer, S. J., Sherr, D. H., and Tilly JL. (2002). Ligand activation of the aromatic hydrocarbon receptor transcription factor drives Bax-dependent apoptosis in developing fetal ovarian germ cells. Endocrinology. 143, 615–20.
42.Van Blerkom, J., and Davis, P. W. (1998). DNA strand breaks and phosphatidylserine redistribution in newly ovulated and cultured mouse and human oocytes: occurrence and relationship to apoptosis. Hum Reprod. 13, 1317–24.
43.Perez, G. I., Tao, X.-J., and Tilly, J. L. (1999). Fragmentation and death (a.k.a. apoptosis) of ovulated oocytes. Mol Hum Reprod. 5, 414–20.
44.Ghafari, F., Gutierre, C. G., and Hartshorne, G. M. (2007). Apoptosis in mouse fetal and neonatal oocytes during meiotic prophase one. BMC Dev Biol. 7, 87.
45.Reynaud, K., and Driancourt, M. A. (2000). Oocyte attrition.
Mol Cell Endocrinol. 163, 101–8.
46.Matikainen, T., Perez, G. I., Zheng, T. S., Kluzak, T. R., Rueda, B. R., Flavell, R. A., and Tilly, J. L. (2001). Caspase- 3 gene knockout defines cell lineage specificity for programmed cell death signaling in the ovary. Endocrinology
142, 2468–80.
47.Vaskivuo, T. E., Anttonen, M., Herva, R., Billig, H., Dorland, M., te Velde, E. R., Stenback,¨ F., Heikinheimo, M., and Tapanainen, J. S. (2001). Survival of human ovarian follicles from fetal to adult life: apoptosis, apoptosis-related proteins, and transcription factor GATA-4. J Clin Endocrinol Metab. 86, 3421–9.
48.Kim, M. R., and Tilly, J. L. (2004). Current concepts in Bcl- 2 family member regulation of female germ cell development and survival. Biochim Biophys Acta. 1644, 205–10.
49.Takai, Y., Matikainen, T., Jurisicova, A., Kim, M. R., Trbovich, A. M., Fujita, E., Nakagawa, T., Lemmers, B., Flavell, R. A., Hakem, R., Momoi, T., Yuan, J., Tilly, J. L., and Perez, G. I. (2007). Caspase-12 compensates for lack of caspase-2 and caspase-3 in female germ cells. Apoptosis. 12, 791–800.
50.Krysko, D. V., Diez-Fraile, A., Criel, G., Svistunov, A. A., Vandenabeele, P., and D’Herde, K. (2008). Life and death of female gametes during oogenesis and folliculogenesis.
Apoptosis. 13, 1065–87.
51.Ginsburg, M., Snow, M. H., and McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation.
Development. 110, 521–8.
52.Chiquoine, A. D. (1954). The identification, origin and migration of the primordial germ cells of the mouse embryo. Anal Rec. 118, 135–46.
53.Anderson, R., Copeland, T., Scholer,¨ H., Heasman, J., and Wylie, C. (2000). The onset of germ cell migration in the mouse embryo. Mech Dev. 91, 61–8.
54.Molyneaux, K., Stallock, J., Schaible, K., and Wylie, C. (2001). Time-lapse analysis of living germ cell migration.
Dev Biol. 240, 488–98.
55.Stallock, J., Molyneaux, K., Schaible, K., Knudson, C. M., and Wylie, C. (2003). The pro-apoptotic gene Bax is required for the death of ectopic primordial germ cells during their migration in the mouse embryo. Development.
130, 6589–97.
56.Russell, E. S. (1957). Gene-induced embryological modifications of primordial germ cells in the mouse. J Exp Zool. 134, 207–37.
57.Godin, I., Deed, R., Cooke, J., Zsebo, K., Dexter, M., and Wylie C. C. (1991). Effects of the Steel gene product on mouse primordial germ cells in culture. Nature. 352, 807–9.
58.Pesce, M., Farrace, M. G., Piacentini, M., Dolci, S., and De Felici, M.,(1993). Stem cell factor and leukemia inhibitory factor promote primordial germ cell survival by suppressing programmed cell death (apoptosis). Development. 118, 1089–94.
59.Runyan, C., Schaible, K., Molyneaux, K., Wang, Z., Levin, L., and Wylie, C. (2006). Steel factor controls midline cell death of primordial germ cells and is essential for their nor-
mal proliferation and migration. Development. 133, 861– 9.
60. Morita, Y., Manganaro, T. F., Tao, X. J., Martimbeau, S., Donahoe, P. K., and Tilly, J. L. (1999). Requirement for phosphatidylinositol-3 -kinase in cytokine-mediated germ cell survival during fetal oogenesis in the mouse.
Endocrinology. 140, 941–9.
61.Maravei, D. V., Morita, Y., Kuida, K., and Tilly, J. L. (1999). Preand postnatal ovarian apoptosis defects in caspase-9- deficient mice. Mol Biol Cell. 10 (Suppl.), 352.
62.Morita, Y., Maravei, D. V., Bergeron, L., Wang, S., Perez, G. I., Tsutsumi, O., Taketani, Y., Asano, M., Horai, R., Korsmeyer, S. J., Iwakura, Y., Yuan, J., and Tilly, J. L. (2001). Caspase- 2 deficiency rescues female germ cells from death due to
cytokine insufficiency but not meiotic defects caused by ataxia telangiectasia-mutated (Atm) gene inactivation. Cell Death Differ. 8, 614–20.
63.Pepling, M. E., de Cuevas, M., and Spradling, A. C. (1999). Germline cysts: a conserved phase of germ cell development? Trends Cell Biol. 9, 257–62.
THERAPEUTIC TARGETING APOPTOSIS IN FEMALE REPRODUCTIVE BIOLOGY |
281 |
64.Pepling, M. E., and Spradling, A. C. (2001). Mouse ovarian germ cell cysts undergo programmed breakdown to form primordial follicles. Dev Biol. 234, 339–51.
65.Gougeon, A. (1996). Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr Rev. 17, 121–55.
66.Knudson, C. M., Tung, K. S., Tourtellotte, W. G., Brown, G. A., Korsmeyer, S. J. (1995). Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science. 270, 96–9.
67.Gosden, R. G., Laing, S. C., Felicio, L. S., Nelson, J. F., and Finch, C. E. (1983). Imminent oocyte exhaustion and reduced follicular recruitment mark the transition to acyclicity in aging C57BL/6J mice. Biol Reprod. 28, 255–60.
68.Perez, G. I., Jurisicova, A., Wise, L., Lipina, T., Kanisek, M., Bechard, A., Takai, Y., Hunt, P., Roder, J., Grynpas, M., and Tilly, J. L. (2007). Absence of the proapoptotic Bax protein extends fertility and alleviates age-related health complications in female mice. Proc Natl Acad Sci USA. 104, 5229– 34.
69.Zuckerman, S. (1951). The number of oocytes in the mature ovary. Rec Prog Horm Res. 6, 63–108.
70.Johnson, J., Canning, J., Kaneko, T., Pru, J. K., and Tilly
J.L. (2004). Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. 428, 145– 50.
71.Johnson, J., Bagley, J., Skaznik-Wikiel, M., Lee, H.-J., Adams, G. B., Niikura, Y., Tschudy, K. S., Tilly, J. C., Cortes,
M.L., Forkert, R., Spitzer,T., Iacomini, J., Scadden, D. T., Tilly, J. L. (2005). Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell. 122, 303–15.
72.Kerr, J. B., Duckett, R., Myers, M., Britt, K. L., Mladenovska, T., and Findlay, J. K. (2006). Quantification of healthy follicles in the neonatal and adult mouse ovary: evidence for maintenance of primordial follicle supply. Reproduction. 132, 95–109.
73.Lee, H.-J., Selesniemi, K., Niikura, Y., Niikura, T., Klein, R., Dombkowski, D. M., and Tilly, J. L. (2007). Bone marrow transplantation generates immature oocytes and rescues long-term fertility in a preclinical mouse model of chemotherapy-induced premature ovarian failure. J Clin Oncol. 25, 3198–204.
74.Virant-Klun, I., Zech, N., Roman, P., Vogler, A., Cvjetianin, B., Klemenc, P., Maliev, E., and Meden-Vrtovec, H. (2008). Putative stem cells with an embryonic character isolated from the ovarian surface epithelium of women with no naturally present follicles and oocytes. Differentiation. 76, 843–56.
75.Virant-Klun, I., Roman, P., Cvjetianin, B., Vrtacnik-Bokal, E., Novakovic, S., Ruelicke, T. (2009). Parthenogenetic embryo-like structures in the human ovarian surface epithelium cell culture in postmenopausal women with no naturally occurring follicles and oocytes. Stem Cells Dev. 18, 137–49.
76.Selesniemi, K., Lee, H.-J., Niikura, T., and Tilly, J. L. (2009). Young adult donor bone marrow infusions into female mice postpone age-related reproductive failure and improve offspring survival. Aging. 1, 49–57.
77.Tilly, J. L., and Rueda, B. R. (2008). Minireview: stem cell contribution to ovarian development, function, and disease. Endocrinology. 149, 4307–11.
78.Tilly, J. L., Niikura, Y., and Rueda, B. R. (2009). The current status of evidence for and against postnatal oogenesis in mammals: a case of ovarian optimism versus pessimism?
Biol Reprod. 80, 2–12.
79.Osborne, T. B., Mendel, L. B., Ferry, E. L. (1917). The effect of retardation of growth upon the breeding period and duration of life of rats. Science. 45, 294–5.
80.Ball, Z. B., Barnes, R. H., and Visscher, M. B. (1947). The effects of dietary caloric restriction on maturity and senescence, with particular reference to fertility and longevity. Am J Physiol. 150, 511–19.
81.Masoro, E. J. (2003). Subfield history: caloric restriction, slowing aging, and extending life. Sci Aging Knowledge Environ. 2003, re2.
82.Selesniemi, K., Lee, H.-J., and Tilly, J. L. (2008). Moder-
ate caloric restriction initiated in rodents during adulthood sustains function of the female reproductive axis into advanced chronological age. Aging Cell. 7, 622– 9.
83.Ingram, D. K., Anson, R. M., de Cabo, R., Mamczarz, J., Zhu, M., Mattison, J., Lane, M. A., and Roth, G. S. (2004). Development of calorie restriction mimetics as a prolongevity strategy. Ann N Y Acad Sci. 1019, 412–23.
84.Baur, J. A., and Sinclair, D. A. (2006). Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 5, 493–506.
85.Ingram, D. K., Zhu, M., Mamczarz, J., Zou, S., Lane, M. A., Roth, G. S., de Cabo, R. (2007). Calorie restriction mimetics: an emerging research field. Aging Cell. 5, 97–108.
86.Austad, S. N. (2007). Vertebrate aging research 2006. Aging Cell. 6, 135–8.
87.Chen, D., Guarente, L. (2007). SIR2: a potential target for calorie restriction mimetics. Trends Mol Med. 13, 64–71.
88.Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., Murray, T., and Thun, M. J. (2008). Cancer statistics, 2008. CA Cancer J Clin. 58, 71–96.
89.Partridge, A. H., Bunnell, C. A., and Winer, E. P. (2001). Quality of life issues among women undergoing high-dose chemotherapy for breast cancer. Breast Dis. 14, 41–50.
90.Wenzel, L., Dogan-Ates, A., Habbal, R., Berkowitz, R., Goldstein, D. P., Bernstein, M., Kluhsman, B. C., Osann, K., Newlands, E., Seckl, M. J., Hancock, B., and Cella, D. (2005). Defining and measuring reproductive concerns of female cancer survivors. J Natl Cancer Inst Monogr. 34, 94–8.
91.Oktem, O., and Oktay, K. (2007). Quantitative assessment of the impact of chemotherapy on ovarian follicle reserve and stromal function. Cancer. 110, 2222–9.
282 |
KAISA SELESNIEMI AND JONATHAN L. TILLY |
92.Wallace, W. H., Thomson, A. B., and Kelsey, T. W. (2003). Radiosensitivity of the human oocyte. Hum Reprod. 18,
117–21.
93. Lee, S. J., Schover, L. R., Partridge, A. H., Patrizio, P., Wallace, W. H., Hagerty, K., Beck, L.N., Brennan, L.V., and Oktay, K. (2006). American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol. 24, 2917–31.
94.Roberts, J. E., Oktay, K. (2005). Fertility preservation: a comprehensive approach to the young woman with cancer. J Natl Cancer Inst Monogr. 34, 57–9.
95.Scorrano, L., and Korsmeyer, S. J. (2003). Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem Biophys Res Commun. 304, 437–44.
96.Hannun, Y. A. (1996). Functions of ceramide in coordinating cellular responses to stress. Science. 274, 1855–9.
97.Cuvillier, O., Pirianov, G., Kleuser, B., Vanek, P. G., Coso,
O.A., Gutkind, S., and Spiegel, S. (1996). Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature. 381, 800–3.
98.Paris, F., Perez, G. I., Haimovitz-Friedman, A., Nguyen, H., Fuks, Z., Bose, M., Ilagan, A., Hunt, P. A., Morgan, W. F., Tilly,
J.L., and Kolesnick, R. (2002). Sphingosine-1-phosphate preserves fertility in irradiated female mice without propagating genomic damage in offspring. Nat Med. 8, 901–2.
99.Jurisicova, A., Lee, H. J., D’Estaing, S. G., Tilly, J., Perez, G. I. (2006). Molecular requirements for doxorubicin-mediated death in murine oocytes. Cell Death Differ. 13, 1466–74.
100.Hancke, K., Strauch, O., Kissel, C., Gobel,¨ H., Schafer,¨ W., and Denschlag, D. (2007). Sphingosine 1-phosphate protects ovaries from chemotherapy-induced damage in vivo.
Fertil Steril. 87, 172–7.
101.Kaya, H., Desdicioglu, R., Sezik, M., Ulukaya, E., Ozkaya, O., Yilmaztepe, A., and Demirci, M. (2008). Does sphingo- sine-1-phosphate have a protective effect on cyclophosphamideand irradiation-induced ovarian damage in the rat model? Fertil Steril. 89, 732–25.
102.Zelinski, M. B., Murphy, M. K., Lawson, M. S., Jurisicova, A., Pau, K. Y. F., Toscano, N. P., Jacob, D. S., Fanton, J. K., Casper, R. F., Dertinger, S. D., Tilly, J. L. (2011). In-vivo delivery of FTY720 prevents radiation-induced ovarian failure and infertility in adult female non-human primates. Fertil Steril doi: 10.1016/j.fertnstert.2011.01.012 (released online 10 February 2011).
103.Reed, J. C. (1998). Bcl-2 family proteins. Oncogene. 17, 3225–36.
104.Zimmerman, K. C., Bonzon, C., and Green, D. R. (2001). The machinery of programmed cell death. Pharmacol Ther. 92, 57–70.
105.Danial, N. N., and Korsmeyer, S. J. (2004). Cell death: critical control points. Cell. 116, 205–19.
106.Jiang, X., and Wang, X. (2004). Cytochrome C-mediated apoptosis. Annu Rev Biochem. 73, 87–106.
107.Yan, N., and Shi, Y. (2005). Mechanisms of apoptosis through structural biology. Annu Rev Cell Dev Biol. 21, 35– 56.
108.Green, D. R., and Kroemer, G. (2005). Pharmacological manipulation of cell death: clinical applications in sight?
J Clin Invest. 115, 2610–17.
109.Reed, J. C. (2006). Proapoptotic multidomain Bcl-2/Bax- family proteins: mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ. 13, 1378–86.
110.Kim, I., Xu, W., and Reed, J. C. (2008). Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 7, 1013–30.