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apoptosis

 
American Heritage Dictionary:

ap·op·to·sis

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(ăp'əp-tō'sĭs, ăp'ə-tō'-) pronunciation
n.
Disintegration of cells into membrane-bound particles that are then eliminated by phagocytosis or by shedding.


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Britannica Concise Encyclopedia:

apoptosis

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Mechanism that allows cells to self-destruct when stimulated by the appropriate trigger. It may be initiated when a cell is no longer needed, when a cell becomes a threat to the organism's health, or for other reasons. The aberrant inhibition or initiation of apoptosis contributes to many disease processes, including cancer. Though embryologists had long been familiar with the process of programmed cell death, not until 1972 was the mechanism's broader significance recognized. Apoptosis is distinguished from necrosis, a form of cell death that results from injury.

For more information on apoptosis, visit Britannica.com.

Word Overheard by Answers.com:

apoptosis

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Until now, normal cells committed suicide when they were finished being useful — a process called apoptosis — while cancer cells lived on and on. Now, researchers have found a way to trick cancer cells into bowing out gracefully:

"'We have identified a small, synthetic compound that directly activates procaspase-3 and induces apoptosis,' said lead author Paul J. Hergenrother, a professor of chemistry at the University of Illinois at Urbana-Champaign. 'By bypassing the broken pathway, we can use the cells' own machinery to destroy themselves.'"

Link: This Cancer Cell Will Self-Destruct In 5 Seconds

Posted August 29, 2006.

See our Word Overheard blog to see interesting uses of strange words.

Gale Genetics Encyclopedia:

Apoptosis

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Death is an inevitable fact of life for organisms. Increasingly, biologists have come to realize that death is also, in many cases, an important and predestined fate of individual cells of organisms. Apoptosis is a process by which cells in a multicellular organism commit suicide. While cells can die as a result of necrosis, apoptosis is a form of death that the cell itself initiates, regulates, and executes using an elaborate arsenal of cellular and molecular machinery. For this reason, the term apoptosis is often used interchangeably with the term "programmed cell death," or PCD (although technically, apoptosis is but one particular form of programmed cell death). There is some disagreement on the origins of the word. The word apoptosis has ancient Greek origins, referring to the falling of leaves, or possibly "dropping of scabs" or "falling off of bones." There is even less agreement on its proper pronunciation, and even specialists in the field seem to use every possible way to say the word. "A-pop-TOE-sis" and "AP-oh-TOE-sis" are both common.

Why Cells Commit Suicide

Why do cells commit apoptosis? There seem to be two major reasons. First, apoptosis is one means by which a developing organism shapes its tissues and organs. For instance, a human fetus has webbed hands and feet early on its development. Later, apoptosis removes skin cells, revealing individual fingers and toes. A fetus's eyelids form an opening by the process of apoptosis. During metamorphosis, tadpoles lose their tails through apoptosis. In young children, apoptosis is involved in the processes that literally shape the connections between brain cells, and in mature females, apoptosis of cells in the uterus causes the uterine lining to slough off at each menstrual cycle.

Cells may also commit suicide in times of distress, for the good of the organism as a whole. For example, in the case of a viral infection, certain cells of the immune system, called cytotoxic T lymphocytes, bind to infected cells and trigger them to undergo apoptosis. Also, cells that have suffered damage to their DNA, which can make them prone to becoming cancerous, are induced to commit apoptosis.

The Regulatory Mechanism

The cellular mechanisms that regulate and cause apoptosis were first elucidated by genetic studies of the roundworm, Caenorhabditis elegans. Normally, in the development of a C. elegans worm, one out of every eight body cells produced is eliminated by programmed cell death. By studying mutants in which either too many or too few cells died, worm geneticists identified many of the proteins that control apoptosis. Subsequently, the critical medical relevance of apoptosis became clear when biologists discovered that mammals contain many of the same genes that control apoptosis in worms. More strikingly, they found that many of these genes were mutated in tumors from cancer patients. Other genes often found to be mutated in cancers are those which regulate the cell cycle, which is the complex set of processes controlling how and when cells divide. These two findings led cancer researchers to recognize that cancer, a disease of uncontrolled cell proliferation, can result either from too much cell division or not enough apoptosis. Because of this important finding, apoptosis has become the subject of intense medical research, and molecules that regulate apoptosis are being studied as potential targets for anti-cancer drug therapies.

A cell can be triggered to undergo apoptosis either by external signaling molecules, such as so-called "death activator" proteins, or through molecules that reside within the cell and monitor events that might commit the cell to suicide, such as damage to DNA. There are several biochemical pathways that lead to apoptosis. One of the major pathways involves inducing mitochondria to leak one of their proteins, cytochrome c, into the cystosol. This in turn activates a set of related proteases (enzymes that degrade proteins) called caspases. Ultimately, the caspases degrade proteins in the cell and activate enzymes that degrade other cell constituents, such as the DNA. Cells undergoing apoptosis exhibit characteristic morphological and biochemical traits, which can be recognized by microscopic examination or biochemical assays. Apoptosis can occur in as little as twenty minutes, after which the cell "corpse" typically becomes engulfed and completely degraded by neighboring phagocytic cells that are present in the tissue and attracted to the apoptotic cell.

Bibliography

Lodish, Harvey, et al. Molecular Cell Biology, 4th ed. New York: W. H. Freeman, 2000.

Nature 407, no. 12 (Oct., 2000). (Issue devoted to review articles on apoptosis).

Internet Resource

The WWW Virtual Library of Cell Biology. "Apoptosis." http://vlib.org/Science/Cell_Biology/apoptosis.shtml.

—Paul J. Muhlrad

Dictionary of Cultural Literacy: Science:

apoptosis

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(ap-uhp-toh-sis)

The programmed death of a cell. Scientists believe that this process is governed by chemical signals a given cell receives from its neighbors.

  • It is thought some forms of cancer may result when this process of cell death is somehow interrupted, allowing cells to grow unchecked, with the result being a cancerous tumor.

    • Oxford Dictionary of Biochemistry:

    apoptosis

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    or programmed cell death

    an intracellular controlled process characterized by cell shrinkage and detachment from the extracellular scaffolding, chromatin condensation and DNA fragmentation by activation of a calcium-dependent endonuclease, blebbing of plasma membrane, activation of caspases, and collapse of the cell into small membrane-enclosed fragments (called apoptotic bodies) that are removed by phagocytosis. There is no release of cell constituents and no inflammatory response. A cascade of caspases (which cleave at specific aspartic residues hence the name) is involved. In this cascade, caspases cleave procaspases to form additional caspases. Some of the caspases thus formed cleave other proteins, including deoxyribonucleases. Largely a phenomenon of multicellular organisms, apoptosis occurs under various physiological (e.g. during normal embryonal development, cell turnover) and pathological (nonlethal stress) conditions. It is distinguished from necrosis, in which the cell swells in response to lethal stress, bursts open and releases its contents into the surroundings, and elicits an inflammatory response.
    —apoptotic adj.; apoptotically adv. [From apo+ + Greek ptosis, falling.]

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    Saunders Veterinary Dictionary:

    apoptosis

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    Programmed cell death, a process including coagulative necrosis and shrinkage.

    Mosby's Dental Dictionary:

    apoptosis

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    n

    Cell reduction by fragmentation into membrane-bound particles that are phagocytosed by other cells.

    Wikipedia on Answers.com:

    Apoptosis

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    Apoptosis
    Hypertrophic Zone of Epiphyseal Plate.jpg
    Apoptosis increasing from normal cells (top) to apoptotic ones (bottom).

    Apoptosis (play /ˌæpəˈtoʊsɪs/)[1][2] is the process of programmed cell death (PCD) that may occur in multicellular organisms.[3] Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. (See also Apoptosis DNA fragmentation.) Unlike necrosis, apoptosis produces cell fragments called apoptotic bodies that phagocytic cells are able to engulf and quickly remove before the contents of the cell can spill out onto surrounding cells and cause damage.[4]

    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 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.[5]

    Research in and around 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 atrophy, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer.

    Contents

    Discovery and etymology

    Main article: History and highlights in apoptosis research

    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. While studying tissues using electron microscopy, John Foxton Ross Kerr at University of Queensland was able to distinguish apoptosis (Greek: apo - from/off/without, ptosis - falling) from traumatic cell death.[6] Following the publication of a paper describing the phenomenon, Kerr was invited to join Alastair R Currie, as well as Andrew Wyllie, who was Currie's graduate student,[7] at University of Aberdeen. In 1972, the trio published a seminal article in the British Journal of Cancer.[8] Kerr had initially used the term programmed cell necrosis, but in the article, the process of natural cell death was called apoptosis. Kerr, Wyllie and Currie credited James Cormack, a professor of Greek language at University of Aberdeen, with suggesting the term apoptosis. Kerr 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.[9] The 2002 Nobel Prize in Medicine was awarded to Sydney Brenner, Horvitz and John E. Sulston for their work regarding apoptosis.

    Apoptosis is a multi-step, multi-pathway cell-death programme that is inherent in every cell of the body. In cancer, the apoptosis cell-division ratio is altered. Cancer treatment by chemotherapy and irradiation kills target cells primarily by inducing apoptosis.

    In Greek, apoptosis translates to the "dropping off" of petals or leaves from plants or trees. Cormack, professor of Greek language, 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 the second p silent (/æpəˈtoʊsɨs/ ap-ə-toh-sis[1][10]) and the second p pronounced (/æpəpˈtoʊsɨs/),[1][11] as in the original Greek.[citation needed] In English, the p of the Greek -pt- consonant cluster is typically silent at the beginning of a word (e.g. pterodactyl, Ptolemy), but articulated when used in combining forms preceded by a vowel, as in helicopter or the orders of insects: diptera, lepidoptera, etc.

    In the original Kerr Wyllie and Currie paper, British Journal of Cancer, 1972 Aug;26(4):239-57, there is a footnote regarding the pronunciation:

    "We are most grateful to Professor James Cormack of the Department of Greek, University of Aberdeen, for suggesting this term. The word "apoptosis" (ἁπόπτωσισ) is used in Greek to describe the "dropping off" or "falling off" of petals from flowers, or leaves from trees. To show the derivation clearly, we propose that the stress should be on the penultimate syllable, the second half of the word being pronounced like "ptosis" (with the "p" silent), which comes from the same root "to fall", and is already used to describe the drooping of the upper eyelid."

    Process

    Apoptosis.png
    Control Of The Apoptotic hai Mechanisms
    Control Of The Apoptotic Mechanisms

    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,[12] hormones, growth factors, nitric oxide[13] or cytokines, that must either cross the plasma membrane or transduce to effect a response. These signals may positively (i.e., trigger) or negatively (i.e., repress, inhibit, or dampen) affect apoptosis. (Binding and subsequent trigger of apoptosis by a molecule is termed positive induction, whereas the active repression or inhibition of apoptosis by a molecule is termed negative induction.)

    A cell initiates intracellular apoptotic signaling in response to a stress, which may bring about cell suicide. The binding of nuclear receptors by glucocorticoids,[14] heat,[14] radiation,[14] nutrient deprivation,[14] viral infection,[14] hypoxia[14] and increased intracellular calcium concentration,[15] for example, by damage to the membrane, can all trigger 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.[16]

    Before the actual process of cell death is precipitated by enzymes, apoptotic signals must cause regulatory proteins to initiate the apoptosis pathway. This step allows apoptotic signals to cause cell death, or the process to be stopped, should the cell no longer need to die. Several proteins are involved, but two main methods of regulation have been identified: targeting mitochondria functionality, or directly transducing the signal via adaptor proteins to the apoptotic mechanisms. Another extrinsic pathway for initiation identified in several toxin studies is an increase in calcium concentration within a cell caused by drug activity, which also can cause apoptosis via a calcium binding protease calpain.

    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.[14]  These are very closely related to intrinsic pathway, and tumors arise more frequently through intrinsic pathway than the extrinsic pathway because of sensitivity.[17] There is also a growing body of evidence indicating that nitric oxide is able to induce apoptosis by helping to dissipate the membrane potential of mitochondria and therefore make it more permeable.[13] A research done in 1999 exhibits how Nitric Oxide can both initiate and inhibit apoptosis due to the cellular variables. [18]

    Mitochondrial proteins known as SMACs (small 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,[19] 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, the mitochondrial apoptosis-induced channel (MAC), in the outer mitochondrial membrane,[20] and serves a regulatory function as it precedes morphological change associated with apoptosis.[14]  Once cytochrome c is released it binds with Apoptotic protease activating factor - 1 (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, also called "Mitochondrial Outer Membrane Permeabilization Pore" is regulated 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.[21][22]  Bcl-2 proteins are able to promote or inhibit apoptosis by direct action on MAC/MOMPP.  Bax and/or Bak form the pore, while Bcl-2, Bcl-xL or Mcl-1 inhibit its formation.

    Direct signal transduction

    Overview of signal transduction pathways.
    Overview of TNF signalling in apoptosis, an example of direct signal transduction
    Overview of Fas signalling in apoptosis, an example of direct signal transduction

    Two theories of the direct initiation of apoptotic mechanisms in mammals have been suggested: the TNF-induced (tumour necrosis factor) model and the Fas-Fas ligand-mediated model, both involving receptors of the TNF receptor (TNFR) family[23] coupled to extrinsic signals.

    TNF path

    TNF is a cytokine produced mainly by activated macrophages, and is the major extrinsic mediator of binary hipaloptic 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).[24] Binding of this receptor can also indirectly lead to the activation of transcription factors involved in cell survival and inflammatory responses.[25] 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.

    Fas path

    The Fas receptor (also known as Apo-1 or CD95) binds the Fas ligand (FasL), a transmembrane protein part of the TNF family.[23] 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 of the cell. 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.[26]

    Common components

    Following TNF-R1 and Fas activation in mammalian cells a balance between pro-apoptotic (BAX,[27] 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 in general, Bax or Bak are activated by the activation of BH3-only proteins, part of the Bcl-2 family.

    Caspases

    Caspase play the central role in the transduction of DR apoptotic signals. Caspases are proteins that are highly conserved, cysteine-dependent aspartate-specific proteases. There are two types of caspases: initiator caspases, caspase 8,10,9,2, and effector caspases, caspase 3,7,6. The activation of initiator caspases requires binding to specific oligomeric adaptor protein. Effector caspases are then activated by these active initiator caspases through proteolytic cleavage. The active effector caspases then proteolytically degrade a host of intracellular proteins to carry out the cell death program.

    Caspase-independent apoptotic pathway

    There also exists a caspase-independent apoptotic pathway that is mediated by AIF (apoptosis-inducing factor).[28]

    Execution

    Histologic cross section of embryonic foot of mouse (Mus musculus) in 15.5 day of its development. There are still cells between fingers. (Full development of mouse lasts 27 days.) (Compare this image with image of leg of mouse.)

    Many pathways and signals lead to apoptosis, but there is only one mechanism that actually causes the death of a cell.[citation needed] After a cell receives stimulus, it undergoes organized degradation of cellular organelles by activated proteolytic caspases. A cell undergoing apoptosis shows a characteristic morphology:

    1. Cell shrinkage and rounding are shown because of the breakdown of the proteinaceous cytoskeleton by caspases.
    2. The cytoplasm appears dense, and the organelles appear tightly packed.
    3. Chromatin undergoes condensation into compact patches against the nuclear envelope (also known as the perinuclear envelope) in a process known as pyknosis, a hallmark of apoptosis.[29][30]
    4. 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.[31]
    5. The cell membrane shows irregular buds known as blebs.
    6. 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.[32]

    Removal of dead cells

    The removal of dead cells by neighboring phagocytic cells has been termed efferocytosis.[33] Dying cells that undergo the final stages of apoptosis display phagocytotic molecules, such as phosphatidylserine, on their cell surface.[34] 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.[35] These molecules mark the cell for phagocytosis by cells possessing the appropriate receptors, such as macrophages.[36] 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.

    Apoptosis pathway knock-outs

    Many knock-outs have been made in the apoptosis pathways to test the function of each of the proteins.  Several caspases, in addition to APAF-1 and FADD, have been mutated to determine the new phenotype.  In order to create a tumor necrosis factor (TNF) knockout, an exon containing the nucleotides 3704-5364 was removed from the gene.  This exon encodes a portion of the mature TNF domain, as well as the leader sequence which is a highly conserved region necessary for proper intracellular processing.  TNF-/- mice develop normally and have no gross structural or morphological abnormalities.  However, upon immunization with SRBC (sheep red blood cells), these mice demonstrated a deficiency in the maturation of an antibody response; they were able to generate normal levels of IgM, but could not develop specific IgG levels.  Apaf-1 is the protein that turns on caspase 9 by cleavage to begin the caspase cascade that leads to apoptosis.  Since a -/- mutation in the APAF-1 gene is embryonic lethal, a gene trap strategy was used in order to generate an APAF-1 -/- mouse.  This assay is used to disrupt gene function by creating an intragenic gene fusion.  When an APAF-1 gene trap is introduced into cells, many morphological changes occur, such as spina bifida, the persistence of interdigital webs, and open brain.  Additionally, after embryonic day 12.5, the brain of the embryos showed several structural changes.  Interestingly, APAF-1 cells are protected from apoptosis stimuli such as irradiation.  A BAX-1 knock-out mouse exhibits normal forebrain formation and a decreased programmed cell death in some neuronal populations and in the spinal cord, leading to an increase in motor neurons.

    The caspase proteins are integral parts of the apoptosis pathway, so it follows that knock-outs made have varying damaging results.  A caspase 9 knock-out leads to a severe brain malformation.  A caspase 8 knock-out leads to cardiac failure and thus embryonic lethality.  However, with the use of cre-lox technology, a caspase 8 knock-out has been created that exhibits an increase in peripheral T cells, an impaired T cell response, and a defect in neural tube closure.  Interestingly, these mice were found to be resistant to apoptosis mediated by CD95, TNFR, etc. but not resistant to apoptosis caused by UV irradiation, chemotherapeutic drugs, and other stimuli.  Finally, a caspase 3 knock-out was characterized by ectopic cell masses in the brain and abnormal apoptotic features such as membrane blebbing or nuclear fragmentation.  A remarkable feature of these KO mice is that they have a very restricted phenotype: Casp3, 9, APAF-1 KO mice have deformations of neural tissue and FADD and Casp 8 KO showed defective heart development, however in both types of KO others organs developed normally and some cell types were still sensitive to apoptotic stimuli suggesting that unknown pro-apoptotic pathways exist.

    Implication in disease

    A section of mouse liver showing several apoptotic cells, indicated by arrows
    A section of mouse liver 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.[37] 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.[38] 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.

    Dysregulation of p53

    The tumor-suppressor protein p53 accumulates when DNA is damaged due to a chain of biochemical factors. 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.[39] 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.

    Inhibition of apoptosis

    Inhibition of apoptosis can result in a number of cancers, autoimmune diseases, inflammatory diseases, and viral infections. It was originally believed that the associated accumulation of cells was due to an increase in cellular proliferation, but it is now known that it is also due to a decrease in cell death. The most common of these diseases is cancer, the disease of excessive cellular proliferation, which is often characterized by an overexpression of IAP family members. As a result, the malignant cells experience an abnormal response to apoptosis induction: cycle regulating genes (such as p53, ras or c-myc) are mutated or inactivated in diseased cells, and further genes (such as bcl-2) also modify their expression in tumors.

    Treatments

    The main method of treatment for death signaling-related diseases involves either increasing or decreasing the susceptibility of apoptosis in diseased cells, depending on whether the disease is caused by either the inhibition of or excess apoptosis. For instance, treatments aim to restore apoptosis to treat diseases with deficient cell death, and to increase the apoptotic threshold to treat diseases involved with excessive cell death. To stimulate apoptosis, one can increase the number of death receptor ligands (such as TNF or TRAIL), antagonize the anti-apoptotic Bcl-2 pathway, or introduce Smac mimetics to inhibit the inhibitor (IAPs). The addition of agents such as Herceptin, Iressa or Gleevec works to stop cells from cycling and causes apoptosis activation by blocking growth and survival signaling further upstream. Finally, adding p53-MDM2 complexes displaces p53 and activates the p53 pathway, leading to cell cycle arrest and apoptosis. Many different methods can be used to stimulate apoptosis in various places along the death signaling pathway.

    Hyperactive apoptosis

    On the other hand, loss of control of cell death (resulting in excess apoptosis) can lead to neurodegenerative diseases, hematologic diseases, and tissue damage. The progression of HIV is directly linked to excess, unregulated apoptosis. In a healthy individual, the number of CD4+ lymphocytes is in balance with the cells generated by the bone marrow; however, in HIV-positive patients, this balance is lost due to an inability of the bone marrow to regenerate CD4+ cells. In the case of HIV, CD4+ lymphocytes die at an accelerated rate through uncontrolled apoptosis, when stimulated.

    Treatments

    Treatments aiming to inhibit apoptosis work to simultaneously inhibit the expression of pro-apoptotic factors and promote the expression of anti-apoptotic factors. Fas-induced apoptosis can be blocked by use of FLIPs (FLICE-inhibitory proteins, which inhibit caspases-8 and -10), Bcl-2 (which prevents cytochrome c release and the subsequent activation of caspase 9), and CrmA (Cytokine response modifier A). Increasing the concentration of IAPs works to block specific caspases. Finally, the Akt protein kinase promotes cell survival through two pathways. Akt phosphorylates and inhibits Bas (a Bcl-2 family member), causing Bas to interact with the 14-3-3 scaffold, resulting in Bcl dissociation and thus cell survival. Akt also activates IKKα, which leads to NF-κB activation and cell survival. Active NF-κB induces the expression of anti-apoptotic genes such as Bcl-2, resulting in inhibition of apoptosis. NF-κB has been found to play both an antiapoptotic role and proapoptotic role depending on the stimuli utilized and the cell type. [40]

    HIV progression

    The progression of the human immunodeficiency virus infection into AIDS is primarily due to the depletion of CD4+ T-helper lymphocytes in a manner that is too rapid for the body's bone marrow to replenish the cells, leading to a compromised immune system. One of the mechanisms by which T-helper cells are depleted is apoptosis, which results from a series of biochemical pathways:[41]

    1. HIV enzymes deactivate anti-apoptotic Bcl-2 This does not directly cause cell death, but primes the cell for apoptosis should the appropriate signal be received. In parallel, these enzymes activate pro-apoptotic procaspase-8, which does directly activate the mitochondrial events of apoptosis.
    2. HIV may increase the level of cellular proteins which prompt Fas-mediated apoptosis.
    3. HIV proteins decrease the amount of CD4 glycoprotein marker present on the cell membrane.
    4. Released viral particles and proteins present in extracellular fluid are able to induce apoptosis in nearby "bystander" T helper cells.
    5. 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.
    6. The infected CD4+ cell may also receive the death signal from a cytotoxic T cell.

    Cells may also die as a direct consequence of viral infection. HIV-1 expression induces tubular cell G2/M arrest and apoptosis.[42] The progression from HIV to AIDS is not immediate or even necessarily rapid; HIV's cytotoxic activity towards CD4+ lymphocytes is classified as AIDS once a given patient's CD4+ cell count falls below 200.[43]

    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.[44]

    Most viruses encode proteins that can inhibit apoptosis.[45] 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.[46] 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.[47] 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.[48]

    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.[47]

    Apoptosis in plants

    Programmed cell death in plants has a number of molecular similarities to animal apoptosis, but it also has differences, notably the presence of a cell wall and the lack of an immune system which removes the pieces of the dead cell. Instead of an immune response, the dying cell synthesizes substances to break itself down and places them in a vacuole which ruptures as the cell dies. Whether this whole process resembles animal apoptosis closely enough to warrant using the name apoptosis (as opposed to the more general programmed cell death) is unclear.[49]

    Caspase independent apoptosis

    The characterization of the caspases allowed the development of caspase inhibitors which can be used to determine whether a cellular process involves active caspases. Using these inhibitors it was discovered that cells can die while displaying a morphology similar to apoptosis without caspase activation [50]. Later studies linked this phenomenon to the release of AIF (apoptosis inducing factor) from the mitochondria and its translocation into the nucleus mediated by its NLS (nuclear localization signal). Inside the mitochondria, AIF is anchored to the inner membrane. In order to be released the protein is cleaved by a calcium-dependent calpain protease.

    Apoptosis protein subcellular location prediction

    In 2003, a method was developed for predicting subcellular location of apoptosis proteins [51] Subsequently, various modes of Chou's pseudo amino acid composition were developed for improving the quality of predicting subcellular localization of apoptosis proteins based on their sequence information alone. [52] [53] [54] [55]

    See also

    References

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    External links
    Cyclin
    A (A1, A2) · B (B1, B2, B3) · D (D1, D2, D3) · E (E1, E2)
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    Apoptosis · G0 phase · Meiosis
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