Programmed Cell Death

Programmed cell death (PCD) is an evolutionarily conserved process in multicellular organisms that is important for morphogenesis during development and for the maintenance of tissue homeostasis in organs with ongoing cell proliferation.

From: Encyclopedia of Neuroscience, 2009

Chapters and Articles

Apoptosis

N. Cruickshanks, ... P. Dent, in Brenner's Encyclopedia of Genetics (Second Edition), 2013

Conclusions

Apoptosis is a complex series of protease pathways designed to kill cells in a selective manner. Apoptosis can simplistically be defined into linear pathways; however, each pathway is subject to fine control of its activity at multiple points. Other forms of cell survival regulation such as autophagy can impact on the outcome of a primary apoptosis signal. Alternatively, autophagy can be a primary signal that feeds into apoptosis resulting in cell killing. Thus, despite many years of investigation, there still remain many unanswered questions in the regulation of cell survival by apoptosis.

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Apoptosis

ARMIN HAUNSTETTER, SEIGO IZUMO, in Heart Physiology and Pathophysiology (Fourth Edition), 2001

I. INTRODUCTION

Apoptosis can be defined as cellular suicide involving specialized initiation and execution mechanisms within the cell. Literally, the term denotes the drop of leaves from trees in the fall season, reflecting the sporadic and gradual loss of cells in tissues. In recent years, apoptosis attracted increasing interest in the cardiology research community, essentially for two major reasons. First of all, in pathologic and experimental studies, apoptosis emerged as a widespread feature in several cardiac diseases, including ischemic heart disease and congestive heart failure. Second, apoptosis is a regulated form of cell death that may provide novel approaches for therapeutic intervention to prevent the loss of cardiac myocytes and thus prevent or slow the progression of cardiac disease. It is the scope of this chapter to summarize current knowledge of the morphological and molecular features of apoptosis in general. In addition, important aspects of apoptosis in cardiac disease will be addressed.

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Apoptosis

D.A. Brown, ... S.D. Ray, in Encyclopedia of Toxicology (Third Edition), 2014

Abstract

Apoptosis, known as programmed cell death, is a carefully controlled, energy-dependent process of cell death. Induction of apoptosis results in a cascade of characteristic biochemical events resulting in changes in cellular morphology and death. Cells undergoing apoptosis display blebbing, cell shrinkage, nuclear fragmentation, and DNA fragmentation. In contrast to necrosis, apoptotic cells form apoptotic bodies that are phagocytized by neighboring cells, without the release of cellular contents. Apoptosis plays important roles in physiology and pathology, and can be triggered by numerous stimuli, including ischemia, hypoxia, exposure to certain drugs and chemicals, immune reactions, infectious agents, high temperature, radiation, and various disease states.

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Cellular and Molecular Toxicology

S. Malladi, ... S.B. Bratton, in Comprehensive Toxicology, 2010

Apoptosis plays a critical role during normal development and homeostasis of adult tissues. Consequently, deregulation of apoptosis is commonly associated with diseases ranging from cancer to neurodegeneration. Toxicants also induce cell death via apoptosis, and in most cases this involves the activation of cysteinyl aspartate-specific proteases (caspases). In this chapter, we describe in biochemical and structural detail the mechanisms that mediate the activation of caspases within large multimeric complexes, including the death-inducing signaling complex (DISC) and the Apaf-1 apoptosome. In addition, we cover each of the factors known to directly or indirectly regulate the activation (or activity) of caspases, including inhibitor of apoptosis (IAP) and BCL-2 family members, as well as their antagonists.

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Programmed Cell Death

In Medical Cell Biology (Third Edition), 2008

SUMMARY

Apoptosis is a morphologically and biochemically distinct form of programmed cell death that plays an essential role during embryologic development, after birth, and during adulthood. However, deregulation of apoptosis is involved in the pathogenesis of a variety of human diseases. Since the late 1990s, the core components of the mammalian apoptotic machinery have been identified, and much information on how this complex machinery is regulated has been gathered. Current work is focused on completely unraveling the mechanisms regulating this process and using our knowledge in the development of therapies for a variety of human diseases.

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Programmed Cell Death

In Cell Biology (Third Edition), 2017

Excess Cells

Programmed cell death is also widely used for quality control during development. For example, in the brain, embryonic ganglia often have many more neurons than are required to enervate their target muscles. Production of excess cells is part of a Darwinian strategy to ensure that a sufficient number of axons reach their targets. Programmed cell death eliminates excess neurons that fail to make appropriate connections. Up to 80% of neurons in certain developing ganglia die in this way. Because of the importance of apoptosis during its development, the brain is often seriously affected in mice engineered to lack components of the apoptotic pathway.

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Apoptosis

Margaret A. Shield, Philip E. Mirkes, in Handbook of Developmental Neurotoxicology, 1998

A Developmental Events Involving Apoptosis

PCD occurs in a wide range of developing tissues (Jacobson et al., 1997). Among the critical developmental roles of PCD are the sculpting of tissues, the removal of embryonic structures that are unnecessary in the adult, and the controlled removal of excess, non-functional, or misplaced cells. Formation of the digits during limb development demonstrates the importance of PCD in sculpting tissues. The distal portion of the limb bud differentiates into digits as a result of dramatic cell death in the interidgital mesoderm (Garcia-Martinez et al., 1993; Hurle et al., 1995). In this situation, the PCD is so rapid and localized that a dense region of apoptotic bodies is visible between the developing digits. Genetic defects or teratogenic exposures that result in the formation of webbed fingers or toes result from incomplete cell death in the interdigital region.

PCD plays a critical role in normal development of the vertebrate nervous system because the number of both neurons and oligodendrocytes formed at early embryonic stages is in great excess of the number required in the mature organism. Fifty percent or more of sensory neurons and motoneurons formed during development undergo PCD (Oppenheim, 1991; Johnson and Deck-werth, 1993; Raff et al., 1993). This massive amount of cell death begins as axons connect to their target tissues during embyrogenesis and continues postnatally (Nar-use and Keino, 1995). Most of the PCD occurring during nervous system development appears to be apoptotic cell death.

The current mechanistic model explaining this PCD, called the neurotrophic theory, is that the survival of neurons is dependent on specific neurotrophic factors that are secreted by the synaptic target cells (Oppenheim, 1991; Yuen et al., 1996). Neurons that fail to reach appropriate targets also fail to receive the appropriate growth factor stimuli and subsequently die by apoptosis. Other factors related to proper matching of neuron to target, such as electrical activity, afferent stimulation, and cell-cell interactions, may also influence this PCD. Thus cell death matches the number of neurons to the number of target cells and guards against inappropriate connections. Oligodendrocytes are also initially in excess, but undergo PCD until their number matches that of the axons they myelinate. Although it is now well accepted that cells in the nervous system die in large numbers during development, the rationale for this developmental process is still not understood. Does an overproduction of neurons offer organisms a greater variety of options for innervation of target tissues? Or does the PCD of neurons correct a lack of regulation in the early stages of neurogenesis?

The critical neurotrophic factor for sensory and sympathetic neurons is nerve growth factor (NGF), although these neurons are also responsive to other neurotrophins (Yuen et al., 1996). Exogenously supplemented NGF blocks neuronal PCD, whereas removal of NGF in vivo results in an increase in neuronal PCD (Johnson and Deckwerth, 1993). Cultured neuronal cells exhibit a similar requirement for NGF. Motoneurons do not respond to NGF, but are responsive to a larger array of survival factors including fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), and insulin and insulin-like growth factors (Oppenheim, 1996; Yuen et al., 1996).

PCD is also observed during the joining of epithelial sheets to form tubular structures in the embryo, such as during the closure of the neural tube (Naruse and Keino, 1995). Developing chick embryos exposed to peptide inhibitors of the apoptotic caspases exhibit less PCD in the developing neural tube and the neural tube fails to close (Weil et al., 1997). These results suggest that apoptosis is required for correct formation of the neural tube.

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Apoptosis

Derek Le Roith, Michael Karas, in Encyclopedia of Hormones, 2003

I Cellular events in apoptosis

Apoptotic cell death is crucial for both normal development and homeostasis of multicellular organisms. During embryonic development, apoptosis counteracts proliferation by removing unnecessary cells to ensure proper organogenesis. In the adult, apoptosis is important mainly in counteracting unrestricted (i.e., neoplastic) proliferation and in the cyclic involution of many endocrine-dependent tissues. Apoptosis is distinct from necrotic death in that (1) characteristic and specific morphological changes occur and (2) energy synthesis and protein synthesis are required in the dying apoptotic cell, to regulate specific genes and biochemical pathways.

The morphology of apoptosis involves changes within the nucleus, within specific organelles (most notably, the mitochondria), and within the plasma membrane. In what was once considered to be the hallmark of apoptosis, the chromatin condenses within the nucleus, as DNA is degraded first into large 30 to 50 kb fragments and then into smaller nucleosomal fragments of 180–200 bp. These nuclear alterations, however, are not a sine qua non of apoptosis, as their inhibition fails to block cell death.

Apoptosis leads to uncoupling of electron transport from ATP synthesis in the mitochondria, thereby leading to an increase in reactive oxygen species (ROS) and a decrease in transmembrane potential. These changes precede the nuclear changes described above and can occur in the absence of nuclear changes in apoptotic cells. Different members of the bcl-2 family of proteins oppose or promote cell survival under apoptotic conditions, as described in more detail below. The identification of bcl-2 family members in mitochondrial membranes suggests that mitochondrial changes are not merely the end result of apoptosis but are involved in the apoptotic cascade itself.

Changes in the plasma membrane and cytoskeleton lead to cell shrinkage and to the formation of membrane protuberances or “blebs.” As apoptosis proceeds, these blebs of membrane enclosing cellular debris detach and become “apoptotic bodies,” which are then engulfed by neighboring phagocytic cells. These changes are relatively easy to observe with light microscopy. However, the rapid time course of the apoptotic process, which is complete within a few hours, makes it difficult to identify a significant number of apoptotic cells at any given time. This problem is further compounded in vivo, where apoptotic rates are probably even slower than under experimental conditions in vitro and where the close proximity of phagocytic cells within normal tissue facilitates the rapid clearance of apoptotic cells. The loss of membrane asymmetry causes translocation of the phospholipid phosphatidyl serine from the internal leaflet to the outer surface, where it serves as a recognition marker for apoptotic cells by phagocytes.

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Apoptosis

Erika Darrah BS, Antony Rosen MD, in Systemic Lupus Erythematosus, 2007

SLE AUTOANTIGENS CLUSTER INTO CELL SURFACE BLEBS DURING APOPTOSIS

Apoptosis is a form of programmed cell death in which a highly specific and orderly set of biochemical changes underlie the unique morphologic changes and the ultimate disposition of the dying cell and its contents. Apoptotic cells undergo a striking, orderly fragmentation and disassembly, and are strong inducers of immune tolerance (see below). Several specific biochemical pathways form the apoptotic framework. In addition to a specialized signaling apparatus (which transduces proapoptotic signals from a variety of subcellular domains), apoptosis is mediated through the activation of a proteolytic caspase cascade, in which a restricted subset of cellular targets are cleaved after aspartic acid residues. Substrates include proteins whose fragments function directly in generating the apoptotic phenotype, as well as a variety of molecules in which cleavage abolishes critical, antiapoptotic functions.3

Reorganization of multiple cellular components occurs during apoptosis, with clustering of a variety of otherwise intracellular molecules in blebs at the surface of the apoptotic cell.4 Prior to nuclear fragmentation, DNA, RNA, ribosomes, and ER components such as Ro can be found clustered at the surface of apoptotic blebs.4–6 Redistribution of histones to the surface of apoptotic blebs and release from the nucleus early in apoptosis has also been documented.5,6 More than a decade ago, it was noted that many of these redistributed intracellular components are autoantigens in lupus and other systemic autoimmune diseases, suggesting that apoptotic blebs might be an important source of autoantigens for both tolerance induction and systemic autoimmunity.

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Apoptosis

Antonio Blanco, Gustavo Blanco, in Medical Biochemistry, 2017

Intrinsic or mitochondrial pathway

Apoptosis can be activated by stimuli coming within the cell, including cell stressors, such as hypoxia or lack of nutrients, and agents that cause damage of DNA or other cell structures. In vertebrates this pathway is initiated by the release of apoptosis mediators from the mitochondrial intermembrane space, when certain intracellular signals permeabilize the outer membrane of the mitochondria.

A major protein in this process is cytochrome c, component of the electron transport chain on the external face of the inner mitochondrial membrane. When released into the cytosol, cytochrome c binds to APAF-1, which oligomerizes to form a complex or apoptosome. Once formed this complex, comprising APAF-1–cytochrome c–procaspase 9, triggers the activation of procaspase 9 to caspase 9. This initiator protease starts the hydrolytic cascade that stimulates the effector caspases (3, 6, and 7).

In addition to cytochrome c, other molecules are released from mitochondria. These include Diablo or second mitochondria-derived activator of caspases (SMAC), which by blocking inhibitor of apoptosis proteins induces programmed cell death; Omi, which is a stress-regulated endoprotease that activates caspases; and endonuclease G, which is responsible for DNA degradation, chromatin condensation, and DNA fragmentation.

Other apoptotic pathways. A third pathway leading to apoptosis is specific of cytotoxic T lymphocytes (CTL) and natural killer cells (NK) (Chapter 30). A serine protease designated granzyme B (Gra-B) functions as caspases, hydrolyzing peptide bonds at aspartate residues. Gra-B enters the cells through channels formed by perforin. Gra-B also activates procaspases 3 and 10 and can stimulate the mitochondrial pathway.

A fourth pathway for caspase activation is triggered by cell organelle–mediated cell death. Apoptosis can be initiated by stressors that affect the integrity of the nucleus, endoplasmic reticulum, Golgi, and lysosomes.

Regulation of apoptosis. Due to the irreversible consequence of apoptosis, both the intrinsic and extrinsic pathways are under tight control. The major regulator of apoptosis is the Bcl (from B cell lymphoma) family of proteins. The members of this group of proteins include proapoptotic and antiapoptotic agents, which control the release of cytochrome c and other mitochondrial proteins to the cytosol, regulating downstream caspase activation. The Bcl family of proteins have BH (Bcl-2 homology) domains, which gave them the designation BH1234. Bcl-2 has four BH domains and was initially identified as a protein encoded by the oncogene that stimulates the development of B cells lymphomas. Unlike other oncogenes, such as Ras, that stimulate cell proliferation, Bcl-2 is an inhibitor of programmed cell death, promoting the survival of cancer cells, which continue their uncontrolled growth. Other Bcl proteins with antiapoptotic function are Bcl-xL, Bcl-W, and other proteins that contain BH1234 homologous domains.

Not all the members of the Bcl family of proteins are antiapoptotic. Bcl-2 associated X protein (Bax) and Bcl-2 antagonist killer (Bak) have three BH domains instead of four (designated BH123). They promote programmed cell death. When the intrinsic pathway is activated, Bax and Bak form oligomers on the cytosolic side of the outer mitochondrial membrane, creating pores that permeabilize the mitochondrial membrane, allowing the release of cytochrome c and other intermembrane proapoptotic proteins, including Diablo and Omi, to the cytosol.

The fate of a cell depends on the balance between pro- and antiapoptotic proteins, which antagonize each other. Bcl-2 interferes with Bax and Bak proteins, disrupting the balance in favor of cell survival.

The intrinsic and extrinsic pathways are both regulated by the apoptosis inhibitor protein (IAP). IAP directly interacts with caspases and suppresses apoptosis either by inhibiting them, or labeling them for ubiquitination and subsequent degradation in the proteasome (p. 368). The Diablo and Omi proteins released from the intermembrane space, are proapoptotic. Diablo opposes to Bcl and Omi stimulates caspase activity by interfering the action of AIP. Fig. 32.1 is a scheme of the factors involved in apoptosis.

Figure 32.1. Scheme of the factors involved in the apoptotic process.

APAF-1, Apoptosis protease activator factor-1; Bak, Bcl-associated antagonist killer; Bax, Bcl-associated X protein; Bcl-2, B cell lymphoma-2; DD, death domain; DED, death effector domain; IAP, inhibitor apoptosis protein; TNFR, tumor necrosis factor receptor; TRADD, TNFR-associated death domain.

An important function of programmed cell death is the elimination of damaged cells, especially those that have undergone changes in their DNA. These cells are dangerous as they can accumulate mutations and become carcinogenic. Many neoplastic cells show an upregulation of the expression of antiapoptotic members of the Bcl-2 family. In mammalian cells there are mechanisms that prevent malignant transformation of cells. In response to DNA damage, these mechanisms are mediated by the transcription factor of p53 (tumor suppressor protein) that induces expression of cyclin inhibitors and stops cell cycle progression. In addition to this action, p53 also triggers apoptosis by inducing expression of protein BH3 of the intrinsic pathway.

Medical importance. Many diseases are associated with disturbances in the regulation of apoptosis. For example, in Alzheimer’s disease and other neurodegenerative diseases, abnormal apoptosis leads to exacerbated neuronal destruction in specific regions of the brain. There is also increased apoptotic activity in T lymphocytes in the acquired immunodeficiency syndrome (AIDS).

Other examples of increased cell destruction are heart attacks and strokes. In these cases, the necrosis resulting from the lack of oxygen supply predominates, but some cells affected by hypoxia undergo apoptosis. It is expected that the development of caspase inhibitor drugs will be useful in these conditions.

Mutations in the genes encoding factors associated with programmed cell death result in serious alterations. A failure of the gene that directs the synthesis of Fas death receptors, reduces cell removal, leading to cell accumulation in spleen and lymph nodes, which is a cause of autoimmune diseases.

Elimination of unwanted cells is impaired in some types of tumors. In lymphoma, there is a chromosomal translocation that determines excessive production of Bcl-2 protein and inhibition of apoptosis. In 50% of human cancers, mutations in the p53 gene have been shown. Some of the drugs used in the treatment of neoplasias induce apoptosis and cell cycle arrest by a mechanism dependent on p53. In cases in which the p53 gene is mutated, the cancer cells are not sensitive to chemotherapy.

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