Apoptosis

Apoptosis (IPA-en|ˌæpəpˈtoʊsəs [ [http://www.webster.com/dictionary/apoptosis Webster.com dictionary entry] ] ) 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.

Discovery and etymology

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. [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=419–35|doi=10.1002/path.1700900210|volume=90] Following publication of this paper, Kerr was invited to join Professor Alastair R Currie and Andrew Wyllie, Currie's PhD student at the time,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] at the University of Aberdeen to continue his research. In 1972, the trio published a seminal article in the British Journal of Cancer. [cite journal |author=Kerr JF, Wyllie AH, Currie AR |title=Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics |journal=Br. J. Cancer |volume=26 |issue=4 |pages=239–57 |year=1972 |month=Aug |pmid=4561027 |doi= |url=] 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. [cite journal |author=O'Rourke MG, Ellem KA |title=John Kerr and apoptosis |journal=Med. J. Aust. |volume=173 |issue=11-12 |pages=616–7 |year=2000 |pmid=11379508 |doi= |url=http://www.mja.com.au/public/issues/173_11_041200/orourke/orourke.html]

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" (pronEng|æpɒˈtəʊsɪs) and the "p" spelt out (pronEng|æpɒpˈtəʊsɪs),Cite web|url=http://www.nih.gov/sigs/aig/Aboutapo.html|title=About apoptosis|accessdate=2006-12-15|year=1999|author=Apoptosis Interest Group] [ [http://www.webster.com/dictionary/apoptosis Webster.com dictionary entry] ] 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, 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 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

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.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.sciencemag.org/cgi/pmidlookup?view=long&pmid=7878464 | pages=1456–62| doi=10.1126/science.7878464| pmid=7878464] 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.cite book | title=The Feeling of What Happens| last=Damasio| first=Antonio| coauthors=(1999)| publisher=Harcourt Brace & Co.| location=New York] 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 pancreatic adenocarcinoma tissues.

Development

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.cite journal |author=Guerrero I, Ruiz i Altaba A |title=Development. Longing for ligand: hedgehog, patched, and cell death |journal=Science (journal) |volume=301 |issue=5634 |pages=774–6 |year=2003 |month=Aug |pmid=12907783 |doi=10.1126/science.1088625 |url=] cite journal |author=Thibert C, Teillet MA, Lapointe F, Mazelin L, Le Douarin NM, Mehlen P |title=Inhibition of neuroepithelial patched-induced apoptosis by sonic hedgehog |journal=Science (journal) |volume=301 |issue=5634 |pages=843–6 |year=2003 |month=Aug |pmid=12907805 |doi=10.1126/science.1085405 |url=]

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).

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.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| pages=1859–63| doi=10.1126/science.1067833| pmid=12649474]

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.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]

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 toxins [cite journal |author=Popov SG, Villasmil R, Bernardi J, "et al" |title=Lethal toxin of Bacillus anthracis causes apoptosis of macrophages |journal=Biochem. Biophys. Res. Commun. |volume=293 |issue=1 |pages=349–55 |year=2002 |month=Apr |pmid=12054607 |doi=10.1016/S0006-291X(02)00227-9 |url=] , hormones, growth factors, nitric oxidecite journal |author=Brüne B |title=Nitric oxide: NO apoptosis or turning it ON? |journal=Cell Death Differ. |volume=10 |issue=8 |pages=864–9 |year=2003 |month=Aug |pmid=12867993 |doi=10.1038/sj.cdd.4401261 |url=] 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.cite journal | author=Chiarugi A, Moskowitz MA| title=PARP-1—a perpetrator of apoptotic cell death?| journal=Science| year=2002| volume=297| issue=5579| pages=259–63| doi=10.1126/science.1074592| pmid=12114611]

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 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. 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.

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,cite journal | author=Fesik SW, Shi Y.| title=Controlling the caspases| journal=Science| year=2001| volume=294| issue=5546| pages=1477–8| doi=10.1126/science.1062236| pmid=11711663] 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 membranecite 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 | pages=1387–5] , 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".cite journal |author=Dejean LM, Martinez-Caballero S, Manon S, Kinnally KW |title=Regulation of the mitochondrial apoptosis-induced channel, MAC, by BCL-2 family proteins |journal=Biochim. Biophys. Acta |volume=1762 |issue=2 |pages=191–201 |year=2006 |month=Feb |pmid=16055309 |doi=10.1016/j.bbadis.2005.07.002 |url=] 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] "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.

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) familycite journal | author=Wajant H| title=The Fas signaling pathway: more than a paradigm| journal=Science| year=2002| volume=296| issue=5573| pages=1635–6| doi=10.1126/science.1071553| pmid=12040174] 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).cite journal | author=Chen G, Goeddel DV| title=TNF-R1 signaling: a beautiful pathway| journal=Science| year=2002| volume=296| issue=5573| pages=1634–5| doi=10.1126/science.1071924| pmid=12040173] Binding of this receptor can also indirectly lead to the activation of transcription factors involved in cell survival and inflammatory responses.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] ] 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.cite journal | author=Wajant H| title=The Fas signaling pathway: more than a paradigm| journal=Science| year=2002| volume=296| issue=5573| pages=1635–6| doi=10.1126/science.1071553| pmid=12040174] 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.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] ]

Following "TNF-R1" and "Fas" activation in mammalian cells a balance between pro-apoptotic (BAX,cite journal |author=Murphy KM, Ranganathan V, Farnsworth ML, Kavallaris M, Lock RB |title=Bcl-2 inhibits Bax translocation from cytosol to mitochondria during drug-induced apoptosis of human tumor cells |journal=Cell Death Differ. |volume=7 |issue=1 |pages=102–11 |year=2000 |month=Jan |pmid=10713725 |doi=10.1038/sj.cdd.4400597 |url=] 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.cite journal | author=Cheng EH| title=VDAC2 inhibits BAK activation and mitochondrial apoptosis| journal=Science| year=2003| volume=301| issue=5632| pages=513–7| doi=10.1126/science.1083995| pmid=12881569] 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).cite journal |author=Susin SA, Lorenzo HK, Zamzami N, "et al" |title=Molecular characterization of mitochondrial apoptosis-inducing factor |journal=Nature |volume=397 |issue=6718 |pages=441–6 |year=1999 |month=February |pmid=9989411 |doi=10.1038/17135 |url=http://dx.doi.org/10.1038/17135]

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 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.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 | pages=571–80| pmid=10952727] 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=3643–53| pmid=11707516]
# 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.cite journal |author=Nagata S |title=Apoptotic DNA fragmentation |journal=Exp. Cell Res. |volume=256 |issue=1 |pages=12–8 |year=2000 |month=Apr |pmid=10739646 |doi=10.1006/excr.2000.4834 |url=]
# The cell membrane shows irregular buds known as blebs.
# 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.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]

Removal of dead cells

Dying cells that undergo the final stages of apoptosis display phagocytotic molecules, such as phosphatidylserine, on their cell surface.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| pages=1560–3| doi=10.1126/science.1087621| pmid=14645847] 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.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] These molecules mark the cell for phagocytosis by cells possessing the appropriate receptors, such as macrophages.cite journal | author=Savill J, Gregory C, Haslett C.| title=Eat me or die| journal=Science| year=2003| volume=302| issue=5650| pages=1516–7| doi=10.1126/science.1092533| pmid=14645835] 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

Defective apoptotic pathways

The many different types of apoptotic pathways contain a multitude of different biochemical components, many of them not yet understood.cite journal | author=Thompson, CB| title=Apoptosis in the pathogenesis and treatment of disease| journal=Science| year=1995| volume=267| issue=5203| pages=1456–62| doi=10.1126/science.7878464| pmid=7878464] 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.cite journal |author=Yang L, Mashima T, Sato S, "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 Res. |volume=63 |issue=4 |pages=831–7 |year=2003 |month=Feb |pmid=12591734 |doi= |url=http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12591734] 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.

"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.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| pmid=12872134| pages=516–23| doi=10.1038/nature01850] 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 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: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 | pages=1649–61| pmid=12810858]
# 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.cite journal | author=Everett, H. and McFadden, G. | title=Apoptosis: an innate immune response to virus infection | journal=Trends Microbiol | year=1999 | pages=160–5 | volume=7 | issue=4 | pmid= 10217831 | doi=10.1016/S0966-842X(99)01487-0] Most viruses encode proteins that can inhibit apoptosis.cite journal | author=Teodoro, J.G. Branton, P.E. | title=Regulation of apoptosis by viral gene products | journal=J Virol | year=1997 | pages=1739–46 | volume=71 | issue=3 | pmid= 9032302] 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.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=211–27 | volume=1644 | issue=2–3 | pmid= 14996505 | doi=10.1016/j.bbamcr.2003.11.001] 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.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=1547–64 | volume=83 | issue= | pmid= 12075073] 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.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=6012–6 | volume=55 | issue=24 | pmid= 8521383]

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.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=1547–64 | volume=83 | issue= | pmid= 12075073]

ee also

* Anoikis
* Apaf-1
* Autolysis
* Autophagy
* Autophagy network
* Necrosis
* Immunology
* Apo2.7
* Apoptosis DNA Fragmentation
* Cisplatin

References

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.