Apoptosis
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2008-07-12T11:29:15Z
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[[Image:Apoptosis mouseliver.jpg|thumb|A section of mouse liver showing an apoptotic cell indicated by an arrow]]
'''Apoptosis''' (/̩æ.pəpˈtō.səs/<ref> [http://www.webster.com/dictionary/apoptosis Webster.com dictionary entry] </ref>) is a form of programmed [[Cell (biology)|cell]] death in multicellular organisms. It is one of the main types of [[programmed cell death]]s (PCD) and involves a series of biochemical events leading to a characteristic cell [[Morphology (biology)|morphology]] and death, in more specific terms, a series of biochemical events that lead to a variety of morphological changes, including [[Bleb (cell biology)|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 [[1,000,000,000 (number)|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]].
== Discovery and etymology ==
{{Main|History and highlights in apoptosis research}}
Cell deaths are 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 ([[Ancient Greek|Greek]]: ''apo'' - from, ''ptosis'' - falling; thus etymologically correct pronunciation is {{IPA|æpɒˈtəʊsɪs}}) 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]].<ref>{{cite journal|last=Kerr|first=JF.|year=1965|title=A histochemical study of hypertrophy and ischaemic injury of rat liver with special reference to changes in lysosomes.|journal=[[Journal of Pathology and Bacteriology]]|issue=90|pages=419–435|doi=10.1002/path.1700900210|volume=90}}</ref> Following publication of this paper, Kerr was invited to join Professor Alastair R Currie and [[Andrew Wyllie]], Currie's [[PhD]] student at the time,<ref name="AHW 1972">{{Cite web|url = http://www.a-star.edu.sg/astar/biomed/action/biomed_dvp_abstract.do?id=2901ddeb02dH |title=Prof Andrew H. Wyllie - Lecture Abstract|accessdate=2007-03-30|year=|author=Agency for Science, Technology and Research}}</ref> at the University of Aberdeen to continue his research. In 1972, the trio published a seminal article in the [[British Journal of Cancer]].<ref>{{cite journal|last = Kerr|first = JF|coauthors = Wyllie AH, Currie AR|title = Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics|journal = [[British Journal of Cancer]]|issue = 26|pages = 239–257|date = 1972}}</ref> 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]].<ref> [http://www.mja.com.au/public/issues/173_11_041200/orourke/orourke.html John Kerr and apoptosis] The Medical Journal of Australia, 2000; 173: 616-617 </ref>
In Greek, apoptosis means "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'' ({{pronEng|æpɒˈtəʊsɪs}}) and the ''p'' spelt out ({{pronEng|æpɒpˈtəʊsɪs}}),<ref name="aboutapop">{{Cite web|url=http://www.nih.gov/sigs/aig/Aboutapo.html|title=About apoptosis|accessdate=2006-12-15|year=1999|author=Apoptosis Interest Group}}</ref><ref> [http://www.webster.com/dictionary/apoptosis Webster.com dictionary entry]</ref> 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.
== Functions ==
=== Cell termination ===
Apoptosis can occur when a cell is damaged beyond repair, infected with a [[virus (biology)|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 [[TP53 (gene)|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.<ref name="pathogenesis">{{cite journal | author=Thompson, CB| title=Apoptosis in the pathogenesis and treatment of disease| journal=Science| year=1995| volume=267| issue=5203| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=DisplayFiltered&DB=pubmed| pages=1456–62| doi=10.1126/science.7878464| pmid=7878464}}</ref> 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.<ref name="damasio">{{cite book | title=The Feeling of What Happens| last=Damasio| first=Antonio| coauthors=(1999)| publisher=Harcourt Brace & Co.| location=New York}}</ref> 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 cells are dividing faster than they die, effectively developing a [[tumor]].
* The cells are dividing slower than they die, which results in a disorder of cell loss.
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 [[pancreas|pancreatic]] [[adenocarcinoma]] tissues.
=== Development ===
[[Image:Celldeath.jpg|thumb|200px|Incomplete differentiation in two toes ([[syndactyly]]) due to lack of apoptosis]]
Programmed cell death is an integral part of both plant and animal [[biological tissue|tissue]] [[developmental biology|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 (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 ([[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.<ref name="guerrero">{{cite journal | author=Guerrero I, Ruiz i Altaba A.| title=Development. Longing for ligand: patched, and cell death| journal=Science| year=2003| volume=301| issue=5634| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12907783| pages=774–776| doi=10.1126/science.1088625| pmid=12907783}}</ref><ref name="thibert">{{cite journal | author=Thibert C, Teillet MA, Lapointe F, Mazelin L, Le Douarin NM, Mehlen P.| title=Inhibition of neuroepithelial patched-induced apoptosis.| journal=Science| year=2003| volume=301| issue=5634| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12907805| pages=774–776| doi=10.1126/science.1085405| pmid=12907805}}</ref>
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 [[B cell#Development of B cells|development of B lymphocytes]] and the [[T cell#T cell development|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.<ref name="tcell">{{cite journal | author=Werlen G, ''et al.''| title=Signaling life and death in the thymus: timing is everything| journal=Science| year=2003| volume=299| issue=5614| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12649474| pages=1859–1863| doi=10.1126/science.1067833| pmid=12649474}}</ref>
[[Cytotoxic T-cell]]s 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.<ref name="robspath">{{cite book | title=Robbins Pathologic Basis of Disease| last=Cotran| coauthors=Kumar, Collins| publisher=W.B Saunders Company| location=Philadelphia| id=0-7216-7335-X}}</ref>
== Process ==
[[Image:Apoptosis.png|right]]
The process of apoptosis is controlled by a diverse range of [[cell signalling|cell signals]], which may originate either extracellularly (''extrinsic inducers'') or intracellularly (''intrinsic inducers''). Extracellular signals may include [[toxin]]s<ref>Popov SG, Villasmil R, Bernardi J, K Alibek, et al (2002), "Lethal toxin of Bacillus anthracis causes apoptosis of macrophages", Biochem Biophys Res Commun Apr 26;293(1):349-55, PMID: 12054607</ref>, [[hormone]]s, [[growth factor]]s, [[nitric oxide]]<ref name="NO">{{cite journal | author=Bernhard Brüne| title=Nitric oxide: NO apoptosis or turning it ON?| journal=Nature| year=2003| volume=10| issue=8| url=http://www.nature.com/cdd/journal/v10/n8/full/4401261a.html
| doi = 10.1038/sj.cdd.4401261 <!--Retrieved from url by DOI bot-->| pages=864–869}}</ref> or [[cytokine]]s, and therefore must either cross the plasma membrane or [[signal transduction|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 (medical)|hypoxia]] are all factors that can lead to the release of intracellular apoptotic signals by a damaged cell.<ref name="robspath"/> A number of cellular components, such as [[poly ADP ribose polymerase]], may also help regulate apoptosis.<ref name="parp1">{{cite journal | author=Chiarugi A, Moskowitz MA| title=PARP-1—a perpetrator of apoptotic cell death?| journal=Science| year=2002| volume=297| issue=5579| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12114611| pages=259–263| doi=10.1126/science.1074592| pmid=12114611}}</ref>
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 [[aerobic respiration|respire aerobically]] and quickly dies - a fact exploited by some apoptotic pathways. Apoptotic proteins that 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.<ref name="robspath"/> There is also a growing body of evidence that 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.<ref name="NO">{{cite journal | author=Bernhard Brüne| title=Nitric oxide: NO apoptosis or turning it ON?| journal=Nature| year=2003| volume=10| issue=8| url=http://www.nature.com/cdd/journal/v10/n8/full/4401261a.html
| doi = 10.1038/sj.cdd.4401261 <!--Retrieved from url by DOI bot-->| pages=864–869}}</ref>
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,<ref name="caspcontrol">{{cite journal | author=Fesik SW, Shi Y.| title=Controlling the caspases| journal=Science| year=2001| volume=294| issue=5546| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11711663| pages=1477–1478| doi=10.1126/science.1062236| pmid=11711663}}</ref> 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, [[mitochondrial apoptosis-induced channel|MAC]], in the outer mitochondrial membrane<ref name="knife">{{cite journal | author=Laurent M. Dejean, Sonia Martinez-Caballero, Kathleen W. Kinnally| title=Is MAC the knife that cuts cytochrome c from mitochondria during apoptosis? | journal=Cell Death and Differentiation| year=2006| volume=13| url=http://www.nature.com/cdd/journal/v13/n8/full/4401949a.html
| doi = 10.1038/sj.cdd.4401949 <!--Retrieved from url by DOI bot-->| pages=1387–1395}}</ref>, and serves a regulatory function as it precedes morphological change associated with apoptosis.<ref name="robspath"/> Once cytochrome c is released it binds with ''[[Apaf-1]]'' and [[adenosine triphosphate|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, the Mitochondrial Apoptosis-Induced Channel|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 ''[[CED9 (gene)|ced-9]]'' gene found in ''[[C. elegans]]''.<ref name="knife2">{{cite journal | author=Laurent M. Dejean, Sonia Martinez-Caballero, Stephen Manon, Kathleen W. Kinnally| title=Regulation of the mitochondrial apoptosis-induced channel, MAC, by BCL-2 family proteins. | journal=Biochim Biophys Acta| year=2006| volume=1762| issue=2| url=http://www.ncbi.nlm.nih.gov/pubmed/16055309| pages=191–201}}</ref><ref name="lodish">{{cite book | title=Molecular Cell Biology| last=Lodish| first=Harvey| coauthors=''et al.''| date=2004| publisher=W.H. Freedman and Company| location=New York| id=0-7167-4366-3}}</ref> ''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.<ref name="robspath"/>
=== Direct signal transduction ===
[[Image:TFN-signalling.png|thumb|right|250px|Overview of TNF signalling in apoptosis, an example of direct signal transduction]]
[[Image:Fas-signalling.png|thumb|right|250px|Overview of Fas signalling in apoptosis, an example of 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) family<ref name="fas">{{cite journal | author=Wajant H| title=The Fas signaling pathway: more than a paradigm| journal=Science| year=2002| volume=296| issue=5573| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12040174| pages=1635–1636| doi=10.1126/science.1071553| pmid=12040174}}</ref> coupled to extrinsic signals.
TNF is a [[cytokine]] produced mainly by activated [[macrophage]]s, 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).<ref name="tnfr1">{{cite journal | author=Chen G, Goeddel DV| title=TNF-R1 signaling: a beautiful pathway| journal=Science| year=2002| volume=296| issue=5573| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12040173| pages=1634–1635| doi=10.1126/science.1071924| pmid=12040173}}</ref> Binding of this receptor can also indirectly lead to the activation of [[transcription factor]]s involved in cell survival and inflammatory responses.<ref name="tfnpathway">{{cite journal | author=Goeddel, DV ''et al''| title=Connection Map for Tumor Necrosis Factor Pathway| journal=Science| url=http://stke.sciencemag.org/cgi/cm/CMP_7107
| doi = 10.1126/stke.3822007tw132] <!--Retrieved from url by DOI bot-->}}</ref> 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|Fas ligand]] (FasL), a [[transmembrane protein]] part of the TNF family.<ref name="fas">{{cite journal | author=Wajant H| title=The Fas signaling pathway: more than a paradigm| journal=Science| year=2002| volume=296| issue=5573| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12040174| pages=1635–1636| doi=10.1126/science.1071553| pmid=12040174}}</ref> 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.<ref name="fassignal">{{cite journal | author=Wajant, H.| title=Connection Map for Fas Signaling Pathway| journal=Science| url=http://stke.sciencemag.org/cgi/cm/CMP_7966 | doi = 10.1126/stke.3802007tr1] <!--Retrieved from url by DOI bot-->}}</ref>
Following ''TNF-R1'' and ''Fas'' activation in mammalian cells a balance between pro-apoptotic ([[Bcl-2-associated X protein|BAX]],<ref name="bax">{{cite journal | author=Murphy, KM ''et al''| title=Bcl-2 inhibits Bax translocation from cytosol to mitochondria during drug-induced apoptosis of human tumor cells| journal=Cell Death and Differentiation| year=2000| volume=7| issue=1| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10713725| doi=10.1038/sj.cdd.4400597| pages=102}}</ref> [[BH3 interacting domain death agonist|BID]], [[Bcl-2 homologous antagonist killer|BAK]], or [[Bcl-2-associated death promoter|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.<ref name="VDAC2">{{cite journal | author=Cheng EH| title=VDAC2 inhibits BAK activation and mitochondrial apoptosis| journal=Science| year=2003| volume=301| issue=5632| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12881569| pages=513–517| doi=10.1126/science.1083995| pmid=12881569}}</ref> 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). For more information, see the article of the author Susin in Nature of 1999 and also reference 21 mentioned below.
=== Execution ===
Although many pathways and signals lead to apoptosis, there is only one mechanism that 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 organized degradation of cellular organelles by activated [[proteolytic]] [[caspase]]s. 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.<ref name="nuclearapopt">{{cite journal | author=Santos A. Susin, ''et al.''| title=Two Distinct Pathways Leading to Nuclear Apoptosis| journal=Journal of Experimental Medicine| year=2000| volume=192| issue=4| url=http://www.jem.org/cgi/content/abstract/192/4/571
| doi = 10.1073/pnas.191208598v1 <!--Retrieved from url by DOI bot-->| pages=571–580| pmid=10952727}}</ref><ref name="chromatindegrad">{{cite journal | author=Madeleine Kihlmark, ''et al.''| title=Sequential degradation of proteins from the nuclear envelope during apoptosis| journal=Journal of Cell Science| year=2001| issue=114| url=http://jcs.biologists.org/cgi/content/full/114/20/3643| pages=3643–3653| pmid=11707516}}</ref>
# 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.<ref name="nuclearfrag">{{cite journal | author=Nagata S| title=Apoptotic DNA fragmentation| journal=Experimental Cell Research| year=2000| volume=256| issue=1| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10739646| pages=12–8| doi=10.1006/excr.2000.4834}}</ref>
# The cell membrane shows irregular buds known as [[bleb (cell biology)|bleb]]s.
# The cell breaks apart into several [[vesicle (biology)|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 [[Ischemia|ischemic]] or toxic cell death.<ref name=Iwata>{{cite web|title= An evaluation of renal tubular DNA laddering in response to oxygen deprivation and oxidant injury|author=M Iwata, D Myerson, B Torok-Storb and RA Zager |url=http://jasn.asnjournals.org/cgi/content/abstract/5/6/1307|year=1996| accessdate = 2006-04-17}}</ref>
=== Removal of dead cells ===
Dying cells that undergo the final stages of apoptosis display phagocytotic molecules, such as [[phosphatidylserine]], on their cell surface.<ref name="Phosphatidylserine">{{cite journal | author=Li MO, ''et al.'''| title=Phosphatidylserine receptor is required for clearance of apoptotic cells| journal=Science| year=2003| volume=302| issue=5650| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14645847| pages=1560–1563| doi=10.1126/science.1087621| pmid=14645847}}</ref> 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]].<ref name="phago2">{{cite journal | author=Wang X, ''et al.''| title=Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12| journal=Science| year=2003| volume=302| issue=5650| pages=1563–1566| doi=10.1126/science.1087641| pmid=14645848}}</ref> These molecules mark the cell for [[phagocytosis]] by cells possessing the appropriate receptors, such as macrophages.<ref name="phago1">{{cite journal | author=Savill J, Gregory C, Haslett C.| title=Eat me or die| journal=Science| year=2003| volume=302| issue=5650| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14645835| pages=1516–1517| doi=10.1126/science.1092533| pmid=14645835}}</ref> 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]].
== Implication in disease ==
[[Image:Apoptosis multi mouseliver.jpg|thumb|right|220px|A section of mouse liver showing several apoptotic cells, indicated by arrows]]
[[Image:Apoptosis stained.jpg|thumb|right|220px|A section of mouse liver [[Staining (biology)|stained]] to show cells undergoing apoptosis (orange)]]
=== Defective apoptotic pathways ===
The many different types of apoptotic pathways contain a multitude of different biochemical components, many of them not yet understood.<ref name="pathogenesis">{{cite journal | author=Thompson, CB| title=Apoptosis in the pathogenesis and treatment of disease| journal=Science| year=1995| volume=267| issue=5203| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=DisplayFiltered&DB=pubmed| pages=1456–62| doi=10.1126/science.7878464| pmid=7878464}}</ref> As a pathway is more or less sequential in nature it is a victim of causality; removing or modifying one component leads to an effect in another. In a living organism this can have disastrous effects, often in the form of disease or disorder. A discussion of every disease caused by modification of the various apoptotic pathways would be impractical, but the concept overlying each one is the same: the normal functioning of the pathway has been disrupted in such a way as to impair the ability of the cell to undergo normal apoptosis. This results in a cell that lives past its "use-by-date" and is able to replicate and pass on any faulty machinery to its progeny, increasing the likelihood of the cell becoming cancerous or diseased.
A recently-described example of this concept in action can be seen in the development of a lung cancer called NCI-H460.<ref name="h460">{{cite journal | author=Yang, L. ''et al.''| title=Predominant suppression of apoptosome by inhibitor of apoptosis protein in non-small cell lung cancer H460 cells: therapeutic effect of a novel polyarginine-conjugated Smac peptide.| journal=Cancer Research| year=2003| volume=63| issue=4| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12591734| pages=831–837}}</ref> The ''X-linked inhibitor of apoptosis protein'' ([[XIAP]]) is [[Gene expression|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.
=== ''p53'' disregulation ===
The tumor-suppressor protein [[p53]] accumulates when DNA is damaged due to a chain of biochemical reactions. Part of this pathway includes alpha-[[interferon]] and beta-interferon, which induce transcription of the ''p53'' gene and result in the increase of p53 protein level and enhancement of cancer cell-apoptosis.<ref name="takaoka">{{cite journal | author=Takaoka A, ''et al.''| title=Integration of interferon-alpha/beta signalling to p53 responses in tumour suppression and antiviral defence.| journal=Nature| year=2003| volume=424| issue=6948| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12872134| pages=516–523| doi=10.1038/nature01850}}</ref> p53 prevents the cell from replicating by stopping the [[cell cycle]] at G1, or interphase, to give the cell time to repair, however it will induce apoptosis if damage is extensive and repair efforts fail. Any disruption to the regulation of the ''p53'' or interferon genes will result in impaired apoptosis and the possible formation of tumors.
=== HIV progression ===
The progression of the [[human immunodeficiency virus]] (HIV) to [[AIDS]] is primarily due to the depletion of [[T helper cell|CD4+ T-helper lymphocytes]], which leads to a compromised immune system. One of the mechanisms by which T-helper cells are depleted is apoptosis, which can be the end-product of multiple biochemical pathways:<ref name="Judie">{{cite journal | author=Judie B. Alimonti, T. Blake Ball, Keith R. Fowke| title=Mechanisms of CD4+ T lymphocyte cell death in human immunodeficiency virus infection and AIDS| journal=J Gen Virology| year=2003| issue=84| url=http://vir.sgmjournals.org/cgi/content/full/84/7/1649
| doi = 10.1099/vir.0.19110-0 <!--Retrieved from url by DOI bot-->| pages=1649–1661| pmid=12810858}}</ref>
# HIV enzymes inactivate anti-apoptotic ''Bcl-2'' and simultaneously activate pro-apoptotic ''procaspase-8''. This does not directly cause cell death but primes the cell for apoptosis should the appropriate signal be received.
# HIV products may increase levels of cellular proteins which have a promotive effect on Fas-mediated apoptosis.
# HIV proteins decrease the amount of [[CD4]] glycoprotein marker present on the cell membrane.
# Released viral particles and proteins present in extracellular fluid are able to induce apoptosis in nearby "bystander" T-helper cells.
# HIV decreases the production of molecules involved in marking the cell for apoptosis, giving the virus time to replicate and continue releasing apoptotic agents and virions into the surrounding tissue.
# The infected CD4+ cell may also receive the death signal from a cytotoxic T cell, leading to apoptosis.
In addition to apoptosis, infected cells may also die as a direct consequence of the viral infection.
===Viral infection===
Viruses can trigger apoptosis of infected cells via a range of mechanisms including:
*Receptor binding.
*Activation of [[protein kinase R]] (PKR).
*Interaction with p53.
*Expression of viral proteins coupled to MHC proteins on the surface of the infected cell, allowing recognition by cells of the immune system (such as Natural Killer and cytotoxic T cells) that then induce the infected cell to undergo apoptosis.<ref name=Everett>{{cite journal | author=Everett, H. and McFadden, G. | title=Apoptosis: an innate immune response to virus infection | journal=Trends Microbiol | year=1999 | pages=160–165 | volume=7 | issue=4 | pmid= 10217831 | doi=10.1016/S0966-842X(99)01487-0}}</ref>
Most viruses encode proteins that can inhibit apoptosis.<ref name=Teodora>{{cite journal | author=Teodoro, J.G. Branton, P.E. | title=Regulation of apoptosis by viral gene products | journal=J Virol | year=1997 | pages=1739–1746 | volume=71 | issue=3 | pmid= 9032302}}</ref> 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.<ref name=Polster>{{cite journal | author=Polster, B.M. Pevsner, J. and Hardwick, J.M. | title=Viral Bcl-2 homologs and their role in virus replication and associated diseases | journal=Biochim Biophys Acta | year=2004 | pages=211–227 | volume=1644 | issue=2–3 | pmid= 14996505 | doi=10.1016/j.bbamcr.2003.11.001}}</ref> 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.<ref name=Hay>{{cite journal
| author=Hay, S. and Kannourakis, G. | title=A time to kill: viral manipulation of the cell death program | journal=J Gen Virol | year=2002 | pages=1547–1564 | volume=83 | issue= | pmid= 12075073}}</ref> 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.<ref name=Wang>{{cite journal | author=Wang, X.W. Gibson, M.K. Vermeulen, W. Yeh, H. Forrester, K. Sturzbecher, H.W. Hoeijmakers, J.H. and Harris, C.C. | title=Abrogation of p53-induced Apoptosis by the Hepatitis B Virus X Gene | journal=Cancer Res | year=1995 | pages=6012–6016 | volume=55 | issue=24 | pmid= 8521383}}</ref>
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.<ref name=Hay>{{cite journal | author=Hay, S. and Kannourakis, G. | title=A time to kill: viral manipulation of the cell death program | journal=J Gen Virol | year=2002 | pages=1547–1564 | volume=83 | issue= | pmid= 12075073}}</ref>
==See also==
<div class="references-small" style="-moz-column-count:3; column-count:3;">
*[[Anoikis]]
*[[Apaf-1]]
*[[Autolysis (biology)|Autolysis]]
*[[Autophagy]]
*[[Autophagy network]]
*[[Necrosis]]
*[[Immunology]]
*[[Apo2.7]]
*[[Apoptosis DNA Fragmentation]]
</div>
==References==
{{reflist|2}}
<div class="references-small">
* {{cite book | title=Molecular Biology of the Cell| url=http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=cell.TOC| last=Alberts| first=Bruce| coauthors=''et al.''| publisher=Garland Publishing}}
* {{cite book | title=Cancer Medicine, 5th edn| url=http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=cmed.TOC&depth=2| last=Bast| first=Robert C. Jr| coauthors=''et al.'', (2000)| publisher=B.C. Decker}}
* {{cite journal | author=Alfons Lawen| title=Apoptosis - an introduction| journal=BioEssays| year=2003| volume=25| issue=9| url=http://www3.interscience.wiley.com/cgi-bin/abstract/104552885/ABSTRACT| pages=888–896| doi=10.1002/bies.10329}}
* {{cite journal | author=Α. Afantitis, G. Melagraki, H. Sarimveis, P.A. Koutentis, J. Markopoulos and O. Igglessi – Markopoulou | title=A Novel QSAR Model for Modeling and Predicting Induction of Apoptosis by 4-Aryl-4H-chromenes| journal=Bioorganic and Medicinal Chemistry | year=2006| volume=14 | url=http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=16782350&ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum| pages=6686–6694 | doi=10.1016/j.bmc.2006.05.061}}
</div>
== External links ==
*[http://www.biochemweb.org/apoptosis.shtml Apoptosis (Programmed Cell Death) - The Virtual Library of Biochemistry and Cell Biology]
*[http://www.caspases.org Apoptosis Research Portal]
*[http://www.apoptosisinfo.com Apoptosis Info] Apoptosis protocols, articles, news, and recent publications.
*[http://www.apoptosis-db.org/welcome.html Database of proteins involved in apoptosis]
*[http://stke.sciencemag.org/content/vol2007/issue380/images/data/tr1/DC1/Apoptosis_WEHI.mov Apoptosis Video]
*[http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Apoptosis.html#The_Mechanisms_of_Apoptosis The Mechanisms of Apoptosis] Kimball's Biology Pages. Simple explanation of the mechanisms of apoptosis triggered by internal signals (bcl-2), along the caspase-9, caspase-3 and caspase-7 pathway; and by external signals (FAS and TNF), along the caspase 8 pathway. Accessed [[25 March]] [[2007]].
*WikiPathways - [http://www.wikipathways.org/index.php/Pathway:Homo_sapiens:Apoptosis Apoptosis pathway]
*[http://www.crmagazine.org/home/magazine/spring-2007.aspx?d=746 Finding Cancer’s Self-Destruct Button] CR magazine (Spring 2007). Article on apoptosis and cancer.
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[[Category:Programmed cell death]]
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