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Apoptosis

NOTE: COPE contains an Apoptosis Dictionary section listing all entries related to cell death.

Apoptosis (from a Greek word meaning the dropping of leaves from a tree) is a term referring to the cytologically observable changes associated with a process of cellular self-destruction observed in all eukaryotes. The term was introduced by Kerr (1971; Kerr et al, 1972) and the process was called shrinkage necrosis (see also: necrosis), which was the only type of cell death known at that time. This process of cell death has been termed also Programmed cell death (abbr. PCD) or active cell death (abbr. ACD) because it requires controlled gene expression, which is activated in response to a variety of external or internal stimuli or their absence. Many authors use the terms apoptosis and programmed cell death synonymously, while others consider programmed cell death a more general term that embraces different morphologies and biochemical processes. This type of cell death is often referred to also as Activation induced cell death (AICD) or activation induced apoptosis (AIA), AIPCD [activation induced programmed cell death], involving cell activation through the engagement of cell surface receptors and subsequent signaling processes initiated from these receptors (see also: death receptors, dependence receptors). The term cell autonomous death is used also synonymously (for mechanisms involving induction of apoptosis in bystander cells see also: fratricide, autocrine suicide, paracrine lysis).

Control of apoptosis is thought to be intimately linked with the progression of cells through the cell cycle and this process essentially guarantees a steady-state condition in which cell division is counterbalanced by cell death. Apoptosis allows selective elimination and swift clearance by phagocytosis of cells from a proliferating cell population and is an evolutionarily conserved process for killing unwanted cells in multicellular organisms. Apoptotic processes are observed, for example, during embryonal development, morphogenesis, metamorphosis, in endocrine tissue atrophy, during the normal turnover of tissues, and during tumor regression. Cellular self-destruction plays a decisive role in the elimination of self-recognizing T-lymphocytes in the thymus.

Many human diseases can be attributed directly or indirectly to a derangement of apoptosis (Fadeel and Orrenius, 2005). The disruption of normal processes leading to apoptosis results in illegitimate cell survival and can cause developmental abnormalities and facilitate cancer development Apoptosis contributes to the adaptation of an organism to the environment and constitutes a mechanism of safe clearance of unwanted cells during resolution of inflammation through the formation of apoptotic bodies in which potentially harmful cellular contents are prevented from being released and release pro-inflammatory mediators. At the same time, macrophages appear to be capable of ingesting apoptotic cells without releasing pro-inflammatory cytokines (Kurosaka et al, 2003). The removal of apoptotic cells is a complex process (see also: efferocytosis).

Apoptosis also provides a defense mechanism against viruses by reducing virus spread through the rapid death of virus-infected cells. Viruses often enhance their infectivity and/or evade immune responses by expressing proteins that inhibit apoptosis of their host cells (see also the Virulence Factors Dictionary section of this encyclopedia).

Cell death by apoptosis differs considerably from cell death by necrosis and other forms of cell death (see also: Oncosis, accidental cell death), which may be a consequence, for example, of injuries (see also: inflammation, wound healing), complement attacks, severe hypoxia, hypothermia, lytic virus infections, or exposure to a number of toxins and which eventually leads to cell lysis. Necrosis is a passive, catabolic process that represents a cellular response to extreme accidental or toxic insults and, unlike apoptosis, is always pathological. Distinct forms of cellular disintegration with some features of apoptosis or necrosis and features distinguishing it from both processes have been observed in various cell types. It has been suggested that classic apoptosis and necrosis may represent only two extremes of a continuum of intermediate forms of cell death (see: Aponecrosis, Abortosis, Necrapoptosis) and that the term necrosis should be used as a descriptive term for secondary processes taking place after a cell is dead, i.e., a characterization of dead cells rather than a description of a distinct form of cell death. Essentially, this implies that different morphologies are not necessarily the result of different and unique modes of cell death (Zeiss, 2003; Saraste and Pulkki, 2000).

Apoptosis is initiated when cells are given sufficient time to organize a number of intracellular events participating in their own destruction. Unlike necrosis, apoptosis initially requires a functional energy-producing system. Under nonphysiological conditions, both types of cell death can be the result of the same initial insult. The balance between death by apoptosis and by necrosis appears to depend upon the intensity of the injury and the level of available intracellular ATP.

The earliest indications of apoptotic cell death are morphological alterations of the cells such as chromatin condensation, disappearance of the nucleolus, and alterations of the cell surface, characterized by the occurrence of blebs. These signs are followed by a margination of the chromatin at the inner surface of the nuclear membrane. Eventually the activation of a variety of nucleases leads to the fragmentation of DNA. DNA degradation during apoptosis generally occurs at two levels: early as high molecular weight fragments and later on as fragments of the size of nucleosomes. This requires a number of specific DNases, which are activated specifically during apoptosis. DNA fragmentation can be used to identify apoptotic cells (see also: Apoptosis assays).

In contrast to cell death by necrosis, cells dying by apoptosis shrink and eventually break up into vesicles known as apoptotic bodies. Since intracellular contents are not released from apoptotic cells and their fragments this process is not accompanied by inflammation and the process, therefore, can be regarded as an injury-limiting mode of cell disposal.

Unlike necrosis, which is a passive process, the induction of apoptosis is an active genetically regulated process and, like other gene-directed processes such as differentiation, requires the co-ordinated expression of many genes. This process, once set in motion, is essentially irreversible.

Comparison of cell death by necrosis and apoptosis. The two processes differ in various aspects. Cellular necrosis is usually caused by cell damage and does not require further gene activity. The membrane is the major site of damage and, among other things, loses its ability to regulate osmotic pressure. Eventually cell contents are released and elicit inflammatory reactions. Apoptotic cell death requires gene activity. It can be prevented by increased expression of some genes or by external signals. Apoptotic cells eventually break up into apoptotic cell bodies. Cell contents are not released and there is no inflammation.

Being an active process requiring controlled gene expression, apoptotic cell death can be regarded as a differentiation event. Apoptotic processes involve the coordinated activity of a plethora of proteins that can be separated into activators, effectors, and negative regulators (see also: Apoptosis MiniCOPE Dictionary). Note, however, that any kind of protein implicated specifically in apoptosis may have vital functions unrelated to cell death (Galluzzi et al, 2008).

The apoptotic process can be inhibited by inhibitors of RNA and protein synthesis, suggesting that a number of specific proteins are required for its initiation and progression. The genetic analysis of some genes of the nematode Caenorhabditis elegans has revealed the existence of a variety of genes and proteins involved in the control of apoptosis. The expression of these genes is subject to very complex regulatory circuits. Similar genes have been identified in other species, including Drosophila melanogaster and humans, and some of these proteins encoded by them are highly conserved. Especially the reported interactions of proteins from other species with human proteins or their ability to functionally replace each other suggest strong evolutionary conservation of the main components of the mammalian apoptosis machinery throughout metazoan evolution.

Cell death can be triggered by a variety of stimuli, including gamma irradiation, cytotoxic lymphocytes, glucocorticoids, and various cytolytic cytokines, for example, TNF-alpha. In thymocytes apoptosis can be induced by treatment with glucocorticoids or irradiation. In certain hematopoietic cell types the growth of which depends on the continuous presence of growth factors, growth factor withdrawal also leads to apoptotic cell death rather than a cessation of cell growth (see also: Factor-dependent cell lines). Many growth factors and cytokines act as cellular survival factors by preventing apoptosis. They are said to have anti-apoptotic activities. Other factors, said to have pro-apoptotic activities, promote cell death by apoptosis. Apoptosis can be initiated also by cross-linking or engagement of one of several death receptor surface antigens. Some cell types such as neutrophils or eosinophils are constitutively programmed to undergo cell death by apoptosis.

At the molecular level, two prinicpal pathways of apoptotic cell death have been described (Twomey and McCarthy, 2005). The pathway of apoptosis often referred to as extrinsic apoptosis, type 1 apoptosis, or mitochondria-independent apoptosis, involves interactions of membrane receptors belonging to the TNF family of proteins, their ligands, and signaling molecules. Many of the proteins involved utilize at least two types of sequence motifs. One motif is known as death domain and the other motif as death effector domain. Protein-protein interactions between proteins by means of these domains are instrumental in the assembly of large protein complexes that are required to recruit and activate members of the aspartate-specific proteases known as caspases. Caspases form an enzyme cascade with some of these enzymes, referred to as initiator caspases initiating the process (initiator caspases, activator caspases, upstream caspases), and others acting as downstream caspases involved in the execution of cell death (executioner caspases, effector caspases) (Taylor et al, 2008).

The pathway of apoptosis referred to as intrinsic apoptosis (also referred to as mitochondrial apoptosis, mitochondria-dependent apoptosis, type 2 apoptosis) is characterized by the participation of mitochondria, which release proteins that also activate the cascade of caspases. Both apoptosis pathways are not isolated from each other but cross-talk exists between these two pathways. Uncoupling of mitochondrial oxidative phosphorylation as a consequence of the loss of mitochondrial membrane potential and disruption of electron transport as a consequence of cytochrome-C release would greatly affect ATP production. Ultimately, dropping ATP levels would increase necrotic cell death because apoptosis requires functional apoptosomes, which, in turn, depends on ATP (Nicotera et al, 1998; Eguchi et al, 1999) (see also: aponecrosis, necrapoptosis). Latta et al (2000) have reported that metabolically induced alterations of ATP levels prevents mitochondrial cytochrome C release, loss of mitochondrial membrane potential, activation of type 2 caspases, DNA fragmentation, and cell lysis after exposure to TNF-alpha and controls receptor-mediated apoptosis in vitro and in vivo. Cell death mediated by TNF-alpha is blocked completely in ATP-depleted cultures of hepatocytes. Apoptosis mediated by CD95 is enhanced. The extent of apoptosis inhibition correlates with the severity of ATP depletion, and TNF-induced apoptosis can be restored when ATP is repleted by increasing the extracellular phosphate concentration.

Apoptosis requires a plethora of intracellular protein-protein interactions between the participating death proteins. These proteins frequently interact with each other through a death domain, a DED sequence or a CARD domain. The process takes place in macromolecular assemblies referred to as DISC (death-inducing signaling complex) and the apoptosome. In many instances the exact interplay between the proteins forming these complexes still remains to be elucidated. It appears, however, that there are several independent pathways by which apoptosis can be initiated or prevented and the outcome of the death differentiation programme may depend critically upon the relative amounts of death-promoting and death-inhibiting proteins. Expression of these proteins may depend on the kinds of stimuli received by the cell. Negative regulators of apoptosis (cell death suppressors) include BCL2 and related family members (see also: BCL2 homology domains), members of the IAP (inhibitor of apoptosis) family of proteins, and also virus-encoded proteins (see, for example: Epstein Bar virus BHRF-1, crmA, baculovirus p35 protein). The study of these viral proteins has revealed ways in which viruses subvert normal biological processes and evade protective host defense mechanisms.

Galluzzi et al (2009) have reviewed methods of standardization of experimental procedures used to identify and quantify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios.

LAST MODIFIED: August 2009

See REFERENCES for entry Apoptosis

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