Mechanism that allows cells to self-destruct when stimulated by the appropriate trigger. It may be initiated when a cell is no longer needed, when a cell becomes a threat to the organism's health, or for other reasons. The aberrant inhibition or initiation of apoptosis contributes to many disease processes, including cancer. Though embryologists had long been familiar with the process of programmed cell death, not until 1972 was the mechanism's broader significance recognized. Apoptosis is distinguished from necrosis, a form of cell death that results from injury.
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Apoptosis () is a form of programmed cell death in multicellular organisms. It is one of the main types of programmed cell death (PCD) and involves a series of biochemical events leading to a characteristic cell morphology and death, in more specific terms, a series of biochemical events that lead to a variety of morphological changes, including blebbing, changes to the cell membrane such as loss of membrane asymmetry and attachment, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation (1-4). Processes of disposal of cellular debris whose results do not damage the organism differentiate apoptosis from necrosis.
In contrast to necrosis, which is a form of traumatic cell death that results from acute cellular injury, apoptosis, in general, confers advantages during an organism's life cycle. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose; the result is that the digits are separate. Between 50 billion and 70 billion cells die each day due to apoptosis in the average human adult. For an average child between the ages of 8 and 14, approximately 20 billion to 30 billion cells die a day. In a year, this amounts to the proliferation and subsequent destruction of a mass of cells equal to an individual's body weight.
Research on apoptosis has increased substantially since the early 1990s. In addition to its importance as a biological phenomenon, defective apoptotic processes have been implicated in an extensive variety of diseases. Excessive apoptosis causes hypotrophy, such as in ischemic damage, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer.
Cell death is a completely normal process in living organisms and was first discovered by scientists over 100 years ago. The German scientist Carl Vogt was first to describe the principle of apoptosis in 1842. In 1885, anatomist Walther Flemming delivered a more precise description of the process of programmed cell death. However, it was not until 1965 that the topic was resurrected. Apoptosis (Greek: apo - from, ptosis - falling) was distinguished from traumatic cell death by John Foxton Ross Kerr while he was studying tissues using electron microscopy at the University of Queensland Pathology Department in Brisbane. Following publication of this paper, Kerr was invited to join Professor Alastair R Currie and Andrew Wyllie, Currie's PhD student at the time, at the University of Aberdeen to continue his research. In 1972, the trio published a seminal article in the British Journal of Cancer. Kerr had originally used the term "programmed cell necrosis" to describe the phenomenon but in the 1972 article this process of natural cell death was called apoptosis. Kerr, Wylie and Currie credited Professor James Cormack (Department of Greek, University of Aberdeen) with suggesting the term apoptosis. John Foxton Ross Kerr, Emeritus Professor of Pathology at the University of Queensland, received the Paul Ehrlich and Ludwig Darmstaedter Prize on March 14, 2000, for his description of apoptosis. He shared the prize with Boston biologist Robert Horvitz.
In Greek, apoptosis translates to "dropping off" of petals or leaves from plants or trees. Cormack reintroduced the term for medical use as it had a medical meaning for the Greeks over two thousand years before. Hippocrates used the term to mean "the falling off of the bones". Galen extended its meaning to "the dropping of the scabs". Cormack was no doubt aware of this usage when he suggested the name. Debate continues over the correct pronunciation, with opinion divided between a pronunciation with a silent p and the p spelt out as in the original Greek. In English, the p of the Greek -pt- consonant cluster is typically silent at the beginning of a word (e.g. pterodactyl), but articulated when used in combining forms preceded by a vowel, as in helicopter or the orders of insects: diptera, lepidoptera, etc.
Apoptosis also plays a role in preventing cancer; if a cell is unable to undergo apoptosis, due to mutation or biochemical inhibition, it can continue dividing and develop into a tumour. For example, infection by papillomaviruses causes a viral gene to interfere with the cell's p53 protein, an important member of the apoptotic pathway. This interference in the apoptotic capability of the cell plays a critical role in the development of cervical cancer.
Homeostasis is achieved when the rate of mitosis (cell division) in the tissue is balanced by cell death. If this equilibrium is disturbed, one of two potentially fatal disorders occurs:
The organism must orchestrate a complex series of controls to keep homeostasis tightly controlled, a process that is ongoing for the life of the organism and involves many different types of cell signaling. Impairment of any one of these controls can lead to a diseased state; for example, dysregulation of signaling pathway has been implicated in several forms of cancer. The pathway, which conveys an anti-apoptotic signal, has been found to be activated in pancreatic adenocarcinoma tissues.
Programmed cell death is an integral part of both plant and animal tissue development. Development of an organ or tissue is often preceded by the extensive division and differentiation of a particular cell, the resultant mass is then "pruned" into the correct form by apoptosis. Unlike cellular death caused by injury, apoptosis results in cell shrinkage and fragmentation. This allows the cells to be efficiently phagocytosed and their components reused without releasing potentially harmful intracellular substances (such as hydrolytic enzymes, for example) into the surrounding tissue.
Research on chick embryos has suggested how selective cell proliferation, combined with selective apoptosis, sculpts developing tissues in vertebrates. During vertebrate embryo development, structures called the notochord and the floor plate secrete a gradient of the signaling molecule (Shh), and it is this gradient that directs cells to form patterns in the embryonic neural tube: cells that receive Shh in a receptor in their membranes called Patched1 (Ptc1) survive and proliferate; but, in the absence of Shh, one of the ends of this same Ptc1 receptor (the carboxyl-terminal, inside the membrane) is cleaved by caspase-3, an action that exposes an apoptosis-producing domain.
During development, apoptosis is tightly regulated and different tissues use different signals for inducing apoptosis. In birds, bone morphogenetic proteins (BMP) signaling is used to induce apoptosis in the interdigital tissue. In Drosophila flies, steroid hormones regulate cell death. Developmental cues can also induce apoptosis, such as the sex-specific cell death of hermaphrodite specific neurons in C. elegans males through low TRA-1 transcription factor activity (TRA-1 helps prevent cell death).
Cytotoxic T-cells are able to directly induce apoptosis in cells by opening up pores in the target's membrane and releasing chemicals that bypass the normal apoptotic pathway. The pores are created by the action of secreted perforin, and the granules contain granzyme B, a serine protease that activates a variety of caspases by cleaving aspartate residues.
The process of apoptosis is controlled by a diverse range of cell signals, which may originate either extracellularly (extrinsic inducers) or intracellularly (intrinsic inducers). Extracellular signals may include toxins, hormones, growth factors, nitric oxide or cytokines, and therefore must either cross the plasma membrane or transduce to effect a response. These signals may positively or negatively induce apoptosis; in this context the binding and subsequent initiation of apoptosis by a molecule is termed positive, whereas the active repression of apoptosis by a molecule is termed negative.
Intracellular apoptotic signalling is a response initiated by a cell in response to stress, and may ultimately result in cell suicide. The binding of nuclear receptors by glucocorticoids, heat, radiation, nutrient deprivation, viral infection, and hypoxia are all factors that can lead to the release of intracellular apoptotic signals by a damaged cell. A number of cellular components, such as poly ADP ribose polymerase, may also help regulate apoptosis.
Before the actual process of cell death is carried out by enzymes, apoptotic signals must be connected to the actual death pathway by way of regulatory proteins. This step allows apoptotic signals to either culminate in cell death, or be aborted should the cell no longer need to die. Several proteins are involved, however two main methods of achieving regulation have been identified; targeting mitochondria functionality, or directly transducing the signal via adapter proteins to the apoptotic mechanisms. The whole preparation process requires energy and functioning cell machinery.
Mitochondrial proteins known as SMACs (second mitochondria-derived activator of caspases) are released into the cytosol following an increase in permeability. SMAC binds to inhibitor of apoptosis proteins (IAPs) and deactivates them, preventing the IAPs from arresting the apoptotic process and therefore allowing apoptosis to proceed. IAP also normally suppresses the activity of a group of cysteine proteases called caspases, which carry out the degradation of the cell, therefore the actual degradation enzymes can be seen to be indirectly regulated by mitochondrial permeability.
Cytochrome c is also released from mitochondria due to formation of a channel, MAC, in the outer mitochondrial membrane, and serves a regulatory function as it precedes morphological change associated with apoptosis. Once cytochrome c is released it binds with Apaf-1 and ATP, which then bind to pro-caspase-9 to create a protein complex known as an apoptosome. The apoptosome cleaves the pro-caspase to its active form of caspase-9, which in turn activates the effector caspase-3.
MAC is itself subject to regulation by various proteins, such as those encoded by the mammalian Bcl-2 family of anti-apoptopic genes, the homologs of the ced-9 gene found in C. elegans. Bcl-2 proteins are able to promote or inhibit apoptosis either by direct action on MAC or indirectly through other proteins. It is important to note that the actions of some Bcl-2 proteins are able to halt apoptosis even if cytochrome c has been released by the mitochondria.
Two important examples of the direct initiation of apoptotic mechanisms in mammals include the TNF-induced (tumour necrosis factor) model and the Fas-Fas ligand-mediated model, both involving receptors of the TNF receptor (TNFR) family coupled to extrinsic signals.
TNF is a cytokine produced mainly by activated macrophages, and is the major extrinsic mediator of apoptosis. Most cells in the human body have two receptors for TNF: TNF-R1 and TNF-R2. The binding of TNF to TNF-R1 has been shown to initiate the pathway that leads to caspase activation via the intermediate membrane proteins TNF receptor-associated death domain (TRADD) and Fas-associated death domain protein (FADD). Binding of this receptor can also indirectly lead to the activation of transcription factors involved in cell survival and inflammatory responses. The link between TNF and apoptosis shows why an abnormal production of TNF plays a fundamental role in several human diseases, especially in autoimmune diseases.
The Fas receptor (also known as Apo-1 or CD95) binds the Fas ligand (FasL), a transmembrane protein part of the TNF family. The interaction between Fas and FasL results in the formation of the death-inducing signaling complex (DISC), which contains the FADD, caspase-8 and caspase-10. In some types of cells (type I), processed caspase-8 directly activates other members of the caspase family, and triggers the execution of apoptosis. In other types of cells (type II), the Fas-DISC starts a feedback loop that spirals into increasing release of pro-apoptotic factors from mitochondria and the amplified activation of caspase-8.
Following TNF-R1 and Fas activation in mammalian cells a balance between pro-apoptotic (BAX, BID, BAK, or BAD) and anti-apoptotic (Bcl-Xl and Bcl-2) members of the Bcl-2 family is established. This balance is the proportion of pro-apoptotic homodimers that form in the outer-membrane of the mitochondrion. The pro-apoptotic homodimers are required to make the mitochondrial membrane permeable for the release of caspase activators such as cytochrome c and SMAC. Control of pro-apoptotic proteins under normal cell conditions of non-apoptotic cells is incompletely understood, but it has been found that a mitochondrial outer-membrane protein, VDAC2, interacts with BAK to keep this potentially-lethal apoptotic effector under control. When the death signal is received, products of the activation cascade displace VDAC2 and BAK is able to be activated.
There also exists a caspase-independent apoptotic pathway that is mediated by AIF (apoptosis-inducing factor).
Apoptosis progresses quickly and its products are quickly removed, making it difficult to detect or visualize. During karyorrhexis, endonuclease activation leaves short DNA fragments, regularly spaced in size. These give a characteristic "laddered" appearance on agar gel after electrophoresis. Tests for DNA laddering differentiate apoptosis from ischemic or toxic cell death.
A recently-described example of this concept in action can be seen in the development of a lung cancer called NCI-H460. The X-linked inhibitor of apoptosis protein (XIAP) is overexpressed in cells of the H460 cell line. XIAPs bind to the processed form of caspase-9, and suppress the activity of apoptotic activator cytochrome c, therefore overexpression leads to a decrease in the amount of pro-apoptotic agonists. As a consequence, the balance of anti-apoptotic and pro-apoptotic effectors is upset in favour of the former, and the damaged cells continue to replicate despite being directed to die.
In addition to apoptosis, infected cells may also die as a direct consequence of the viral infection.
Most viruses encode proteins that can inhibit apoptosis. Several viruses encode viral homologs of Bcl-2. These homologs can inhibit pro-apoptotic proteins such as BAX and BAK, which are essential for the activation of apoptosis. Examples of viral Bcl-2 proteins include the Epstein-Barr virus BHRF1 protein and the adenovirus E1B 19K protein. Some viruses express caspase inhibitors that inhibit caspase activity and an example is the CrmA protein of cowpox viruses. Whilst a number of viruses can block the effects of TNF and Fas. For example the M-T2 protein of myxoma viruses can bind TNF preventing it from binding the TNF receptor and inducing a response. Furthermore, many viruses express p53 inhibitors that can bind p53 and inhibit its transcriptional transactivation activity. Consequently p53 cannot induce apoptosis since it cannot induce the expression of pro-apoptotic proteins. The adenovirus E1B-55K protein and the hepatitis B virus HBx protein are examples of viral proteins that can perform such a function.
Interestingly, viruses can remain intact from apoptosis particularly in the latter stages of infection. They can be exported in the apoptotic bodies that pinch off from the surface of the dying cell and the fact that they are engulfed by phagocytes prevents the initiation of a host response. This favours the spread of the virus.