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Apoptosis is a process of Suicide by a Cell in a Multicellular Organism . It is one of the main types of Programmed Cell Death (PCD), and involves an orchestrated series of biochemical events leading to a characteristic cell Morphology and death. The apoptotic process is executed in such a way as to safely dispose of cellular debris. In contrast to Necrosis , which is a form of traumatic cell death that results from acute cellular injury, apoptosis is carried out in an orderly process that generally confers advantages during an organism's life cycle. For example, the differentiation of fingers and toes in a developing human Embryo requires cells between the fingers to initiate apoptosis so that the digits can 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 to 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 , such as in Ischemic damage, whereas an insufficient amount results in uncontrolled cell proliferation, such as Cancer . DISCOVERY AND ETYMOLOGY See Also: History and highlights in apoptosis research Apoptosis ( 1 was so impressed with Kerr's findings that he invited Kerr to join him at his own University of Aberdeen to continue his research. Wyllie's PhD student, Alastair R Currie was also added to the team. In 1972, the trio published a seminal article in the British Journal of Cancer (Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239-257.). Kerr had originally used the term "cell shrinkage" 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 the term apoptosis as it was Cormack who had suggested it. In Greek, apoptosis means “dropping off” of petals or leaves from plants or trees. It is now apparent that this is, however, a re-introduction of the term for medical use. The phrase had a medical meaning to the Greeks over two thousand of years ago. Hippocrates of Cos (460-370 BC) used the term to mean “the falling off of the bones” and Galen extended its meaning to “the dropping of the scabs”. Of course, Professor Cormack may well have been aware of this usage when he suggested the word. Debate remains over the correct pronunciation, with opinion divided between a pronunciation with a silent p (a-PO-tosis), and the p spelt out (a-POP-tosis). 2 Webster.com dictionary entry John Foxton Ross Kerr, Emeritus Professor of Pathology at the University Of Queensland , received the Paul Ehrlich and Ludwig Darmstaedter Prize on 14 March 2000, for his description of apoptosis. He shared the prize with Boston biologist Robert Horvitz . John Kerr and apoptosis The Medical Journal of Australia, 2000; 173: 616-617 FUNCTIONS Cell termination Apoptosis can occur when a cell is damaged beyond repair, infected with a Virus , or undergoing stress conditions such as starvation. DNA damage from Ionizing Radiation or toxic chemicals can also induce apoptosis via the actions of the tumour-suppressing gene '' P53 ''. The "decision" for apoptosis can come from the cell itself, from the surrounding tissue, or from a cell that is part of the Immune System . In these cases apoptosis functions to remove the damaged cell, preventing it from sapping further nutrients from the organism, or to prevent the spread of viral infection. 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 Papillomavirus es 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 In the adult organism, the number of cells is kept relatively constant through cell death and division. Cells must be replaced when they become diseased or malfunctioning; but proliferation must be compensated by cell death.3 This balancing process is part of the Homeostasis required by living organisms to maintain their internal states within certain limits. Some scientists have suggested ''homeodynamics'' as a more accurate term.4 The related term '' Allostasis '' reflects a balance of a more complex nature by the body. 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 which is ongoing for the life of the organism and involves many different types of has been implicated in several forms of cancer. The hedgehog pathway, which conveys an anti-apoptotic signal, has been found to be activated in Pancreatic Adenocarcinoma tissues. Development ) due to lack of apoptosis]] 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 Phagocytose d and their components reused without releasing potentially harmful intracellular substances 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 Sonic Hedgehog (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.56 During development, apoptosis is tightly regulated and different tissues use different signals for inducing apoptosis. In birds, Bone Morphogenetic Protein s (BMP) signaling is used to induce apoptosis in the interdigital tissue. In '' Drosophila '' flies, Steroid Hormone s 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). Lymphocyte interactions The Development Of B Lymphocytes and the Development Of T Lymphocytes in the human body is a complex process that effectively creates a large pool of diverse cells to begin with, then weeds out those potentially damaging to the body. Apoptosis is the mechanism by which the body removes both the ineffective and the potentially damaging immature cells, and in T-cells is initiated by the withdrawal of survival signals.7 Cytotoxic T-cell s are able to directly induce apoptosis in cells by opening up pores in the target's membrane and releasing chemicals which bypass the normal apoptotic pathway. The pores are created by the action of secreted Perforin , and the granules contain Granzyme B , a Serine Protease which activates a variety of caspases by cleaving Aspartate residues.8 PROCESS 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 Hormone s, Growth Factor s, Nitric Oxide 9 or Cytokine s, 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 Glucocorticoid s, heat, radiation, nutrient deprivation, viral infection and Hypoxia are all factors which 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.10 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 regulation The mitochondria are essential to multicellular life, without them a cell ceases to Respire Aerobically and quickly dies - a fact exploited by some apoptotic pathways. Apoptotic proteins which target mitochondria affect them in different ways; they may cause mitochondrial swelling through the formation of membrane pores, or they may increase the permeability of the mitochondrial membrane and cause apoptotic effectors to leak out. There is also a growing body of evidence which indicates that nitric oxide (NO) is able to induce apoptosis by helping to dissipate the membrane potential of mitochondria and therefore make it more permeable.11 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 Protease s called Caspase s,12 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 increased permeability of 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''. The mitochondrial permeability 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 ''.13 ''Bcl-2'' proteins are able to promote or inhibit apoptosis by either direct action on mitochondrial permeability, or indirectly through other proteins. Importantly, the actions of some ''Bcl-2'' proteins are able to halt apoptosis even if cytochrome c has been released by the mitochondria. Direct signal transduction 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) family14 coupled to extrinsic signals. TNF is a s involved in cell survival and inflammatory responses.16 The link between TNF and apoptosis shows why an abnormal production of TNF plays a fundamental role in several human diseases, especially in Autoimmune Disease s. The Fas Receptor (also known as ''Apo-1'' or ''CD95'') binds the Fas Ligand (FasL), a Transmembrane Protein part of the TNF family.17 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-8.18 Following ''TNF-R1'' and ''Fas'' activation in mammalian cells a balance between pro-apoptotic ( BAX ,19 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 Homodimer s 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.20 When the death signal is received, products of the activation cascade displace VDAC2 and BAK is able to be activated. Execution Although many pathways and signals lead to apoptosis, there is only one mechanism which actually causes the death of the cell in this process; after the appropriate stimulus has been received by the cell and the necessary controls exerted, a cell will undergo the organised degradation of cellular organelles by activated Proteolytic caspases. A cell undergoing apoptosis shows a characteristic morphology that can be observed with a Microscope : # Cell shrinkage and rounding due to the breakdown of the proteinaceous cytoskeleton by caspases. # The cytoplasm appears dense, and the organelles appear tightly packed. # Chromatin undergoes condensation into compact patches against the Nuclear Envelope in a process known as Pyknosis , a hallmark of apoptosis.2122 # The nuclear envelope becomes discontinuous and the DNA inside it is fragmented in a process referred to as Karyorrhexis . The nucleus breaks into several discrete ''chromatin bodies'' or ''nucleosomal units'' due to the degradation of DNA.23 # The cell membrane shows irregular buds known as Bleb s. # The cell breaks apart into several Vesicles called ''apoptotic bodies'', which are then phagocytosed. 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.24 Removal of dead cells Dying cells that undergo the final stages of apoptosis display phagocytotic molecules, such as Phosphatidylserine , on their cell surface.25 Phosphatidylserine is normally found on the cytosolic surface of the plasma membrane, but is redistributed during apoptosis to the extracellular surface by a hypothetical protein known as Scramblase .26 These molecules mark the cell for Phagocytosis by cells possessing the appropriate receptors, such as macrophages.27 Upon recognition, the phagocyte reorganizes its cytoskeleton for engulfment of the cell. The removal of dying cells by phagocytes occurs in an orderly manner without eliciting an Inflammatory Response . SEE ALSO REFERENCES In fiction
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