Apoptosis

Apoptosis (from Ancient Greek ἀπόπτωσις "falling off") is a form of programmed cell death that occurs in multicellular organisms.[2] Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation, and global mRNA decay. The average adult human loses between 50 and 70 billion cells each day due to apoptosis.[a] For an average human child between the ages of 8 to 14 year old approximately 20 to 30 billion cells die per day.[4]

In contrast to necrosis, which is a form of traumatic cell death that results from acute cellular injury, apoptosis is a highly regulated and controlled process that confers advantages during an organism's lifecycle. For example, the separation of fingers and toes in a developing human embryo occurs because cells between the digits undergo apoptosis. Unlike necrosis, apoptosis produces cell fragments called apoptotic bodies that phagocytic cells are able to engulf and remove before the contents of the cell can spill out onto surrounding cells and cause damage to them.[5]

Because apoptosis cannot stop once it has begun, it is a highly regulated process. Apoptosis can be initiated through one of two pathways. In the intrinsic pathway the cell kills itself because it senses cell stress, while in the extrinsic pathway the cell kills itself because of signals from other cells. Weak external signals may also activate the intrinsic pathway of apoptosis.[6] Both pathways induce cell death by activating caspases, which are proteases, or enzymes that degrade proteins. The two pathways both activate initiator caspases, which then activate executioner caspases, which then kill the cell by degrading proteins indiscriminately.

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 a wide variety of diseases. Excessive apoptosis causes atrophy, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer. Some factors like Fas receptors and caspases promote apoptosis, while some members of the Bcl-2 family of proteins inhibit apoptosis.

Apoptosis
Apoptosis DU145 cells mosaic
An etoposide-treated DU145 prostate cancer cell exploding into a cascade of apoptotic bodies. The sub images were extracted from a 61-hour time-lapse microscopy video, created using quantitative phase-contrast microscopy. The optical thickness is color-coded. With increasing thickness, color changes from gray to yellow, red, purple and finally black.[1]
See the video at The Cell: An Image Library
Identifiers
MeSHD017209
Anatomical terminology

Discovery and etymology

German scientist Karl 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 the University of Queensland was able to distinguish apoptosis from traumatic cell death.[7] 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,[8] at University of Aberdeen. In 1972, the trio published a seminal article in the British Journal of Cancer.[9] 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 H. Robert Horvitz.[10]

For many years, neither "apoptosis" nor "programmed cell death" was a highly cited term. Two discoveries brought cell death from obscurity to a major field of research: identification of components of the cell death control and effector mechanisms, and linkage of abnormalities in cell death to human disease, in particular cancer.

The 2002 Nobel Prize in Medicine was awarded to Sydney Brenner, Horvitz and John E. Sulston for their work identifying genes that control apoptosis. The genes were identified by studies in the nematode C. elegans and homologues of these genes function in humans to regulate apoptosis.

John Sulston
John E. Sulston won the Nobel Prize in Medicine in 2002, for his pioneering research on apoptosis.

In Greek, apoptosis translates to the "falling off" of leaves from a tree.[11] 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 (/æpəˈtoʊsɪs/ ap-ə-TOH-sis[12][13]) and the second p pronounced (/eɪpəpˈtoʊsɪs/),[12][14] 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, 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 & Currie paper,[9] 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" (ἀπόπτωσις) 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."

Activation mechanisms

Apoptosis
Control Of The Apoptosis Mecanisms.pdf
Control Of The Apoptotic Mechanisms

The initiation of apoptosis is tightly regulated by activation mechanisms, because once apoptosis has begun, it inevitably leads to the death of the cell.[15][16] The two best-understood activation mechanisms are the intrinsic pathway (also called the mitochondrial pathway) and the extrinsic pathway.[17] The intrinsic pathway is activated by intracellular signals generated when cells are stressed and depends on the release of proteins from the intermembrane space of mitochondria.[18] The extrinsic pathway is activated by extracellular ligands binding to cell-surface death receptors, which leads to the formation of the death-inducing signaling complex (DISC).[19]

A cell initiates intracellular apoptotic signaling in response to a stress, which may bring about cell suicide. The binding of nuclear receptors by glucocorticoids,[20] heat,[20] radiation,[20] nutrient deprivation,[20] viral infection,[20] hypoxia,[20] increased intracellular concentration of free fatty acids[21] and increased intracellular calcium concentration,[22][23] 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.[24] Single cell fluctuations have been observed in experimental studies of stress induced apoptosis.[25][26]

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 those 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: the targeting of mitochondria functionality,[27] or directly transducing the signal via adaptor proteins to the apoptotic mechanisms. An 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.

Intrinsic pathway

The mitochondria are essential to multicellular life. Without them, a cell ceases to respire aerobically and quickly dies. This fact forms the basis for 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.[20][28] They are very closely related to intrinsic pathway, and tumors arise more frequently through intrinsic pathway than the extrinsic pathway because of sensitivity.[29] 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.[30] Nitric oxide has been implicated in initiating and inhibiting apoptosis through its possible action as a signal molecule of subsequent pathways that activate apoptosis.[31]

Mitochondrial proteins known as SMACs (second mitochondria-derived activator of caspases) are released into the cell's cytosol following the increase in permeability of the mitochondria membranes. SMAC binds to proteins that inhibit apoptosis (IAPs) thereby deactivating them, and preventing the IAPs from arresting the process and therefore allowing apoptosis to proceed. IAP also normally suppresses the activity of a group of cysteine proteases called caspases,[32] 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,[33] and serves a regulatory function as it precedes morphological change associated with apoptosis.[20] 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 (not to be confused with the membrane attack complex formed by complement activation, also commonly denoted as 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.[34][35] 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.

Extrinsic pathway

Signal transduction pathways
Overview of signal transduction pathways.

Overview of TNF (left) and Fas (right) signalling in apoptosis, an example of direct signal transduction.

TFN-signalling
Fas-signalling

Two theories of the direct initiation of apoptotic mechanisms in mammals have been suggested: the TNF-induced (tumor necrosis factor) model and the Fas-Fas ligand-mediated model, both involving receptors of the TNF receptor (TNFR) family[36] coupled to extrinsic signals.

TNF path

TNF-alpha 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-alpha: TNFR1 and TNFR2. The binding of TNF-alpha to TNFR1 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). cIAP1/2 can inhibit TNF-α signaling by binding to TRAF2. FLIP inhibits the activation of caspase-8.[37] Binding of this receptor can also indirectly lead to the activation of transcription factors involved in cell survival and inflammatory responses.[38] However, signalling through TNFR1 might also induce apoptosis in a caspase-independent manner.[39] The link between TNF-alpha and apoptosis shows why an abnormal production of TNF-alpha plays a fundamental role in several human diseases, especially in autoimmune diseases.

Fas path

The fas receptor (First apoptosis signal) – (also known as Apo-1 or CD95) is a transmembrane protein of the TNF family which binds the Fas ligand (FasL).[36] 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 proapoptotic factors from mitochondria and the amplified activation of caspase-8.[40]

Common components

Following TNF-R1 and Fas activation in mammalian cells a balance between proapoptotic (BAX,[41] BID, BAK, or BAD) and anti-apoptotic (Bcl-Xl and Bcl-2) members of the Bcl-2 family are established. This balance is the proportion of proapoptotic homodimers that form in the outer-membrane of the mitochondrion. The proapoptotic homodimers are required to make the mitochondrial membrane permeable for the release of caspase activators such as cytochrome c and SMAC. Control of proapoptotic proteins under normal cell conditions of nonapoptotic 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

Caspases play the central role in the transduction of ER apoptotic signals. Caspases are proteins that are highly conserved, cysteine-dependent aspartate-specific proteases. There are two types of caspases: initiator caspases, caspase 2,8,9,10,11,12, and effector caspases, caspase 3,6,7. The activation of initiator caspases requires binding to specific oligomeric activator 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).[42]

Apoptosis model in amphibians

Amphibian frog Xenopus laevis serves as an ideal model system for the study of the mechanisms of apoptosis. In fact, iodine and thyroxine also stimulate the spectacular apoptosis of the cells of the larval gills, tail and fins in amphibians metamorphosis, and stimulate the evolution of their nervous system transforming the aquatic, vegetarian tadpole into the terrestrial, carnivorous frog.[43][44][45][46]

Negative regulators of apoptosis

Negative regulation of apoptosis inhibits cell death signaling pathways, helping tumors to evade cell death and developing drug resistance. Many families of proteins act as negative regulators categorized into either antiapoptotic factors, such as IAPs and Bcl-2 proteins or prosurvival factors like cFLIP, BNIP3, FADD, Akt, and NF-κB.[47]

Proteolytic caspase cascade: Killing the cell

Many pathways and signals lead to apoptosis, but these converge on a single mechanism that actually causes the death of the cell. After a cell receives stimulus, it undergoes organized degradation of cellular organelles by activated proteolytic caspases. In addition to the destruction of cellular organelles, mRNA is rapidly and globally degraded by a mechanism that is not yet fully characterized.[48] mRNA decay is triggered very early in apoptosis.

A cell undergoing apoptosis shows a series of characteristic morphological changes. Early alterations include:

  1. Cell shrinkage and rounding occur because of the retraction lamellipodia and the breakdown of the proteinaceous cytoskeleton by caspases.[49]
  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.[50][51]
  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.[52]

Apoptosis progresses quickly and its products are quickly removed, making it difficult to detect or visualize on classical histology sections. During karyorrhexis, endonuclease activation leaves short DNA fragments, regularly spaced in size. These give a characteristic "laddered" appearance on agar gel after electrophoresis.[53] Tests for DNA laddering differentiate apoptosis from ischemic or toxic cell death.[54]

Apoptotic cell disassembly

Apoptotic cell disassembly
Different steps in apoptotic cell disassembly.[55]

Before the apoptotic cell is disposed of, there is a process of disassembly. There are three recognized steps in apoptotic cell disassembly:[56]

  1. Membrane blebbing: The cell membrane shows irregular buds known as blebs. Initially these are smaller surface blebs. Later these can grow into larger so-called dynamic membrane blebs.[56] An important regulator of apoptotic cell membrane blebbing is ROCK1 (rho associated coiled-coil-containing protein kinase 1).[57][58]
  2. Formation of membrane protrusions: Some cell types, under specific conditions, may develop different types of long, thin extensions of the cell membrane called membrane protrusions. Three types have been described: microtubule spikes, apoptopodia (feet of death), and beaded apoptopodia (the latter having a beads-on-a-string appearance).[59][60][61] Pannexin 1 is an important component of membrane channels involved in the formation of apoptopodia and beaded apoptopodia.[60]
  3. Fragmentation: The cell breaks apart into multiple vesicles called apoptotic bodies, which undergo phagocytosis. The plasma membrane protrusions may help bring apoptotic bodies closer to phagocytes.

Removal of dead cells

The removal of dead cells by neighboring phagocytic cells has been termed efferocytosis.[62] Dying cells that undergo the final stages of apoptosis display phagocytotic molecules, such as phosphatidylserine, on their cell surface.[63] Phosphatidylserine is normally found on the inner leaflet surface of the plasma membrane, but is redistributed during apoptosis to the extracellular surface by a protein known as scramblase.[64] These molecules mark the cell for phagocytosis by cells possessing the appropriate receptors, such as macrophages.[65] The removal of dying cells by phagocytes occurs in an orderly manner without eliciting an inflammatory response.[66] During apoptosis cellular RNA and DNA are separated from each other and sorted to different apoptotic bodies; separation of RNA is initiated as nucleolar segregation.[67]

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 APAF1 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. In addition, after embryonic day 12.5, the brain of the embryos showed several structural changes. 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. 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 other organs developed normally and some cell types were still sensitive to apoptotic stimuli suggesting that unknown proapoptotic pathways exist.

Methods for distinguishing apoptotic from necrotic (necroptotic) cells

In order to perform analysis of apoptotic versus necrotic (necroptotic) cells, one can do analysis of morphology by time-lapse microscopy, flow fluorocytometry, and transmission electron microscopy. There are also various biochemical techniques for analysis of cell surface markers (phosphatidylserine exposure versus cell permeability by flow cytometry), cellular markers such as DNA fragmentation[68] (flow cytometry),[69] caspase activation, Bid cleavage, and cytochrome c release (Western blotting). It is important to know how primary and secondary necrotic cells can be distinguished by analysis of supernatant for caspases, HMGB1, and release of cytokeratin 18. However, no distinct surface or biochemical markers of necrotic cell death have been identified yet, and only negative markers are available. These include absence of apoptotic markers (caspase activation, cytochrome c release, and oligonucleosomal DNA fragmentation) and differential kinetics of cell death markers (phosphatidylserine exposure and cell membrane permeabilization). A selection of techniques that can be used to distinguish apoptosis from necroptotic cells could be found in these references.[70][71][72][73]

Implication in disease

Apoptosis multi mouseliver
A section of mouse liver showing several apoptotic cells, indicated by arrows
Apoptosis stained
A section of mouse liver stained to show cells undergoing apoptosis (orange)
Apoptosis
Neonatal cardiomyocytes ultrastructure after anoxia-reoxygenation.

Defective pathways

The many different types of apoptotic pathways contain a multitude of different biochemical components, many of them not yet understood.[74] As a pathway is more or less sequential in nature, 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's 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.[75] 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 proapoptotic agonists. As a consequence, the balance of anti-apoptotic and proapoptotic effectors is upset in favour of the former, and the damaged cells continue to replicate despite being directed to die. Defects in regulation of apoptosis in cancer cells occur often at the level of control of transcription factors. As a particular example, defects in molecules that control transcription factor NF-κB in cancer change the mode of transcriptional regulation and the response to apoptotic signals, to curtail dependence on the tissue that the cell belongs. This degree of independence from external survival signals, can enable cancer metastasis.[76]

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, resulting in the increase of p53 protein level and enhancement of cancer cell-apoptosis.[77] 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.[78] Any disruption to the regulation of the p53 or interferon genes will result in impaired apoptosis and the possible formation of tumors.

Inhibition

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. Some apoptotic factors are vital during mitochondrial respiration e.g. cytochrome C.[79] Pathological inactivation of apoptosis in cancer cells is correlated with frequent respiratory metabolic shifts toward glycolysis (an observation known as the “Warburg hypothesis”.[80]

HeLa cell

Apoptosis in HeLa[b] cells is inhibited by proteins produced by the cell; these inhibitory proteins target retinoblastoma tumor-suppressing proteins.[81] These tumor-suppressing proteins regulate the cell cycle, but are rendered inactive when bound to an inhibitory protein.[81] HPV E6 and E7 are inhibitory proteins expressed by the human papillomavirus, HPV being responsible for the formation of the cervical tumor from which HeLa cells are derived.[82] HPV E6 causes p53, which regulates the cell cycle, to become inactive.[83] HPV E7 binds to retinoblastoma tumor suppressing proteins and limits its ability to control cell division.[83] These two inhibitory proteins are partially responsible for HeLa cells' immortality by inhibiting apoptosis to occur.[84] CDV (Canine Distemper Virus) is able to induce apoptosis despite the presence of these inhibitory proteins. This is an important oncolytic property of CDV: this virus is capable of killing canine lymphoma cells. Oncoproteins E6 and E7 still leave p53 inactive, but they are not able to avoid the activation of caspases induced from the stress of viral infection. These oncolytic properties provided a promising link between CDV and lymphoma apoptosis, which can lead to development of alternative treatment methods for both canine lymphoma and human non-Hodgkin lymphoma. Defects in the cell cycle are thought to be responsible for the resistance to chemotherapy or radiation by certain tumor cells, so a virus that can induce apoptosis despite defects in the cell cycle is useful for cancer treatment.[84]

Treatments

The main method of treatment for potential death from 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 either to stimulate or to inhibit apoptosis in various places along the death signaling pathway.[85]

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.

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. It is of interest to note that neurons that rely on mitochondrial respiration undergo apoptosis in neurodegenerative diseases such as Alzheimer’s [86] and Parkinson’s [87] (an observation known as the “Inverse Warburg hypothesis” [88][79] ). Moreover, there is an inverse epidemiological comorbidity between neurodegenerative diseases and cancer.[89] 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. At the molecular level, hyperactive apoptosis can be caused by defects in signaling pathways that regulate the Bcl-2 family proteins. Increased expression of apoptotic proteins such as BIM, or their decreased proteolysis, leads to cell death, and can cause a number of pathologies, depending on the cells where excessive activity of BIM occurs. Cancer cells can escape apoptosis through mechanisms that suppress BIM expression or by increased proteolysis of BIM.[90]

Treatments

Treatments aiming to inhibit works to block specific caspases. Finally, the Akt protein kinase promotes cell survival through two pathways. Akt phosphorylates and inhibits Bad (a Bcl-2 family member), causing Bad 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 a proapoptotic role depending on the stimuli utilized and the cell type.[91]

HIV progression

The progression of the human immunodeficiency virus infection into AIDS is due primarily 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:[92]

  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 proapoptotic procaspase-8, which does directly activate the mitochondrial events of apoptosis.
  2. HIV may increase the level of cellular proteins that 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 direct consequences of viral infections. HIV-1 expression induces tubular cell G2/M arrest and apoptosis.[93] The progression from HIV to AIDS is not immediate or even necessarily rapid; HIV's cytotoxic activity toward CD4+ lymphocytes is classified as AIDS once a given patient's CD4+ cell count falls below 200.[94]

Researchers from Kumamoto University in Japan have developed a new method to eradicate HIV in viral reservoir cells, named "Lock-in and apoptosis." Using the synthesized compound Heptanoylphosphatidyl L-Inositol Pentakisphophate (or L-Hippo) to bind strongly to the HIV protein PR55Gag, they were able to suppress viral budding. By suppressing viral budding, the researchers were able to trap the HIV virus in the cell and allow for the cell to undergo apoptosis (natural cell death). Associate Professor Mikako Fujita has stated that the approach is not yet available to HIV patients because the research team has to conduct further research on combining the drug therapy that currently exists with this "Lock-in and apoptosis" approach to lead to complete recovery from HIV.[95]

Viral infection

Viral induction of apoptosis occurs when one or several cells of a living organism are infected with a virus, leading to cell death. Cell death in organisms is necessary for the normal development of cells and the cell cycle maturation.[96] It is also important in maintaining the regular functions and activities of cells.

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.[97]

Canine distemper virus (CDV) is known to cause apoptosis in central nervous system and lymphoid tissue of infected dogs in vivo and in vitro.[98] Apoptosis caused by CDV is typically induced via the extrinsic pathway, which activates caspases that disrupt cellular function and eventually leads to the cells death.[81] In normal cells, CDV activates caspase-8 first, which works as the initiator protein followed by the executioner protein caspase-3.[81] However, apoptosis induced by CDV in HeLa cells does not involve the initiator protein caspase-8. HeLa cell apoptosis caused by CDV follows a different mechanism than that in vero cell lines.[81] This change in the caspase cascade suggests CDV induces apoptosis via the intrinsic pathway, excluding the need for the initiator caspase-8. The executioner protein is instead activated by the internal stimuli caused by viral infection not a caspase cascade.[81]

The Oropouche virus (OROV) is found in the family Bunyaviridae. The study of apoptosis brought on by Bunyaviridae was initiated in 1996, when it was observed that apoptosis was induced by the La Crosse virus into the kidney cells of baby hamsters and into the brains of baby mice.[99]

OROV is a disease that is transmitted between humans by the biting midge (Culicoides paraensis).[100] It is referred to as a zoonotic arbovirus and causes febrile illness, characterized by the onset of a sudden fever known as Oropouche fever.[101]

The Oropouche virus also causes disruption in cultured cells – cells that are cultivated in distinct and specific conditions. An example of this can be seen in HeLa cells, whereby the cells begin to degenerate shortly after they are infected.[99]

With the use of gel electrophoresis, it can be observed that OROV causes DNA fragmentation in HeLa cells. It can be interpreted by counting, measuring, and analyzing the cells of the Sub/G1 cell population.[99] When HeLA cells are infected with OROV, the cytochrome C is released from the membrane of the mitochondria, into the cytosol of the cells. This type of interaction shows that apoptosis is activated via an intrinsic pathway.[96]

In order for apoptosis to occur within OROV, viral uncoating, viral internalization, along with the replication of cells is necessary. Apoptosis in some viruses is activated by extracellular stimuli. However, studies have demonstrated that the OROV infection causes apoptosis to be activated through intracellular stimuli and involves the mitochondria.[99]

Many viruses encode proteins that can inhibit apoptosis.[102] Several viruses encode viral homologs of Bcl-2. These homologs can inhibit proapoptotic 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.[103] 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.[104] Furthermore, many viruses express p53 inhibitors that can bind p53 and inhibit its transcriptional transactivation activity. As a consequence, p53 cannot induce apoptosis, since it cannot induce the expression of proapoptotic proteins. The adenovirus E1B-55K protein and the hepatitis B virus HBx protein are examples of viral proteins that can perform such a function.[105]

Viruses can remain intact from apoptosis in particular 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.[104]

Plants

Programmed cell death in plants has a number of molecular similarities to that of animal apoptosis, but it also has differences, notable ones being the presence of a cell wall and the lack of an immune system that 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 that 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.[106]

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.[107] 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.

See also

Footnotes

  1. ^ Note that the average human adult has more than 13 trillion cells (1013),[3] of which at most only 70 billion (7.0×1010) die per day. That is, about 5 out of every 1,000 cells (0.5%) die each day due to apoptosis.
  2. ^ HeLa cells are an immortalized cancer cell line used frequently in research. The cell line was established by removing cells directly from Henrietta Lacks, a cancer patent

References

  1. ^ "Quantitative phase contrast microscopy — label-free live cell imaging and quantification". Phase Holographic Imaging AB.
  2. ^ Green, Douglas (2011). Means to an End: Apoptosis and other Cell Death Mechanisms. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press. ISBN 978-0-87969-888-1.
  3. ^ Alberts, p. 2.
  4. ^ Karam, Jose A. (2009). Apoptosis in Carcinogenesis and Chemotherapy. Netherlands: Springer. ISBN 978-1-4020-9597-9.
  5. ^ Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2008). "Chapter 18 Apoptosis: Programmed Cell Death Eliminates Unwanted Cells". Molecular Biology of the Cell (textbook) (5th ed.). Garland Science. p. 1115. ISBN 978-0-8153-4105-5.
  6. ^ Raychaudhuri S (August 2010). "A minimal model of signaling network elucidates cell-to-cell stochastic variability in apoptosis". PLOS One. 5 (8): e11930. doi:10.1371/journal.pone.0011930. PMC 2920308. PMID 20711445.
  7. ^ Kerr JF (October 1965). "A histochemical study of hypertrophy and ischaemic injury of rat liver with special reference to changes in lysosomes". The Journal of Pathology and Bacteriology. 90 (2): 419–35. doi:10.1002/path.1700900210. PMID 5849603.
  8. ^ Agency for Science, Technology and Research. "Prof Andrew H. Wyllie – Lecture Abstract". Archived from the original on 2007-11-13. Retrieved 2007-03-30.CS1 maint: Uses authors parameter (link)
  9. ^ a b Kerr JF, Wyllie AH, Currie AR (August 1972). "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics". British Journal of Cancer. 26 (4): 239–57. doi:10.1038/bjc.1972.33. PMC 2008650. PMID 4561027.
  10. ^ O'Rourke MG, Ellem KA (2000). "John Kerr and apoptosis". The Medical Journal of Australia. 173 (11–12): 616–7. PMID 11379508.
  11. ^ Alberts, p. 1021.
  12. ^ a b American Heritage Dictionary Archived June 30, 2008, at the Wayback Machine
  13. ^ Apoptosis Interest Group (1999). "About apoptosis". Archived from the original on 28 December 2006. Retrieved 2006-12-15.
  14. ^ "Definition of APOPTOSIS". www.webster.com.
  15. ^ Alberts, p. 1029.
  16. ^ Böhm I, Schild H (2003). "Apoptosis: the complex scenario for a silent cell death". Molecular Imaging and Biology. 5 (1): 2–14. doi:10.1016/S1536-1632(03)00024-6. PMID 14499155.
  17. ^ Alberts, p. 1023.
  18. ^ Alberts, p. 1032.
  19. ^ Alberts, p. 1024.
  20. ^ a b c d e f g h Cotran RS, Kumar C (1998). Robbins Pathologic Basis of Disease. Philadelphia: W.B Saunders Company. ISBN 978-0-7216-7335-6.
  21. ^ Hardy S, El-Assaad W, Przybytkowski E, Joly E, Prentki M, Langelier Y (August 2003). "Saturated fatty acid-induced apoptosis in MDA-MB-231 breast cancer cells. A role for cardiolipin". The Journal of Biological Chemistry. 278 (34): 31861–70. doi:10.1074/jbc.m300190200. PMID 12805375.
  22. ^ Mattson MP, Chan SL (December 2003). "Calcium orchestrates apoptosis". Nature Cell Biology. 5 (12): 1041–3. doi:10.1038/ncb1203-1041. PMID 14647298.
  23. ^ Uğuz AC, Naziroğlu M, Espino J, Bejarano I, González D, Rodríguez AB, Pariente JA (December 2009). "Selenium modulates oxidative stress-induced cell apoptosis in human myeloid HL-60 cells through regulation of calcium release and caspase-3 and -9 activities". The Journal of Membrane Biology. 232 (1–3): 15–23. doi:10.1007/s00232-009-9212-2. PMID 19898892.
  24. ^ Chiarugi A, Moskowitz MA (July 2002). "Cell biology. PARP-1--a perpetrator of apoptotic cell death?". Science. 297 (5579): 200–1. doi:10.1126/science.1074592. PMID 12114611.
  25. ^ Goldstein JC, Waterhouse NJ, Juin P, Evan GI, Green DR (March 2000). "The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant". Nature Cell Biology. 2 (3): 156–62. doi:10.1038/35004029. PMID 10707086.
  26. ^ Lee JK, Lu S, Madhukar A (October 2010). "Real-Time dynamics of Ca2+, caspase-3/7, and morphological changes in retinal ganglion cell apoptosis under elevated pressure". PLOS One. 5 (10): e13437. doi:10.1371/journal.pone.0013437. PMC 2956638. PMID 20976135.
  27. ^ Bejarano I, Espino J, González-Flores D, Casado JG, Redondo PC, Rosado JA, Barriga C, Pariente JA, Rodríguez AB (September 2009). "Role of Calcium Signals on Hydrogen Peroxide-Induced Apoptosis in Human Myeloid HL-60 Cells". International Journal of Biomedical Science. 5 (3): 246–56. PMC 3614781. PMID 23675144.
  28. ^ D. González, I. Bejarano, C. Barriga, A.B. Rodríguez, J.A. Pariente (2010). "Oxidative Stress-Induced Caspases are Regulated in Human Myeloid HL-60 Cells by Calcium Signal". Current Signal Transduction Therapy 5: 181–186. doi:[10.2174/157436210791112172]
  29. ^ Mohan S, Abdul AB, Abdelwahab SI, Al-Zubairi AS, Sukari MA, Abdullah R, Elhassan Taha MM, Ibrahim MY, Syam S (October 2010). "Typhonium flagelliforme induces apoptosis in CEMss cells via activation of caspase-9, PARP cleavage and cytochrome c release: its activation coupled with G0/G1 phase cell cycle arrest". Journal of Ethnopharmacology. 131 (3): 592–600. doi:10.1016/j.jep.2010.07.043. PMID 20673794.
  30. ^ Brüne B (August 2003). "Nitric oxide: NO apoptosis or turning it ON?". Cell Death and Differentiation. 10 (8): 864–9. doi:10.1038/sj.cdd.4401261. PMID 12867993.
  31. ^ Brüne B, von Knethen A, Sandau KB (October 1999). "Nitric oxide (NO): an effector of apoptosis". Cell Death and Differentiation. 6 (10): 969–75. doi:10.1038/sj.cdd.4400582. PMID 10556974.
  32. ^ Fesik SW, Shi Y (November 2001). "Structural biology. Controlling the caspases". Science. 294 (5546): 1477–8. doi:10.1126/science.1062236. PMID 11711663.
  33. ^ Dejean LM, Martinez-Caballero S, Kinnally KW (August 2006). "Is MAC the knife that cuts cytochrome c from mitochondria during apoptosis?". Cell Death and Differentiation. 13 (8): 1387–95. doi:10.1038/sj.cdd.4401949. PMID 16676005.
  34. ^ Dejean LM, Martinez-Caballero S, Manon S, Kinnally KW (February 2006). "Regulation of the mitochondrial apoptosis-induced channel, MAC, by BCL-2 family proteins". Biochimica et Biophysica Acta. 1762 (2): 191–201. doi:10.1016/j.bbadis.2005.07.002. PMID 16055309.
  35. ^ Lodish, Harvey; et al. (2004). Molecular Cell Biology. New York: W.H. Freedman and Company. ISBN 978-0-7167-4366-8.
  36. ^ a b Wajant H (May 2002). "The Fas signaling pathway: more than a paradigm". Science. 296 (5573): 1635–6. doi:10.1126/science.1071553. PMID 12040174.
  37. ^ Chen G, Goeddel DV (May 2002). "TNF-R1 signaling: a beautiful pathway". Science. 296 (5573): 1634–5. doi:10.1126/science.1071924. PMID 12040173.
  38. ^ Goeddel, DV (2007). "Connection Map for Tumor Necrosis Factor Pathway". Science's STKE. 2007 (382): tw132. doi:10.1126/stke.3822007tw132.
  39. ^ Chen W, Li N, Chen T, Han Y, Li C, Wang Y, He W, Zhang L, Wan T, Cao X (December 2005). "The lysosome-associated apoptosis-inducing protein containing the pleckstrin homology (PH) and FYVE domains (LAPF), representative of a novel family of PH and FYVE domain-containing proteins, induces caspase-independent apoptosis via the lysosomal-mitochondrial pathway". The Journal of Biological Chemistry. 280 (49): 40985–95. doi:10.1074/jbc.M502190200. PMID 16188880.
  40. ^ Wajant H (2007). "Connection Map for Fas Signaling Pathway". Science's STKE. 2007 (380): tr1. doi:10.1126/stke.3802007tr1.
  41. ^ Murphy KM, Ranganathan V, Farnsworth ML, Kavallaris M, Lock RB (January 2000). "Bcl-2 inhibits Bax translocation from cytosol to mitochondria during drug-induced apoptosis of human tumor cells". Cell Death and Differentiation. 7 (1): 102–11. doi:10.1038/sj.cdd.4400597. PMID 10713725.
  42. ^ Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G (February 1999). "Molecular characterization of mitochondrial apoptosis-inducing factor". Nature. 397 (6718): 441–6. doi:10.1038/17135. PMID 9989411.
  43. ^ Jewhurst K, Levin M, McLaughlin KA (2014). "Optogenetic Control of Apoptosis in Targeted Tissues of Xenopus laevis Embryos". Journal of Cell Death. 7: 25–31. doi:10.4137/JCD.S18368. PMC 4213186. PMID 25374461.
  44. ^ Venturi S (2011). "Evolutionary Significance of Iodine". Current Chemical Biology. 5 (3): 155–162. doi:10.2174/187231311796765012.
  45. ^ Venturi, Sebastiano (2014). "Iodine, PUFAs and Iodolipids in Health and Disease: An Evolutionary Perspective". Human Evolution-. 29 (1–3): 185–205. ISSN 0393-9375.
  46. ^ Tamura K, Takayama S, Ishii T, Mawaribuchi S, Takamatsu N, Ito M (June 2015). "Apoptosis and differentiation of Xenopus tail-derived myoblasts by thyroid hormone". Journal of Molecular Endocrinology. 54 (3): 185–92. doi:10.1530/JME-14-0327. PMID 25791374.
  47. ^ Razaghi A, Heimann K, Schaeffer PM, Gibson SB (February 2018). "Negative regulators of cell death pathways in cancer: perspective on biomarkers and targeted therapies". Apoptosis. 23 (2): 93–112. doi:10.1007/s10495-018-1440-4. PMID 29322476.
  48. ^ Thomas MP, Liu X, Whangbo J, McCrossan G, Sanborn KB, Basar E, Walch M, Lieberman J (May 2015). "Apoptosis Triggers Specific, Rapid, and Global mRNA Decay with 3' Uridylated Intermediates Degraded by DIS3L2". Cell Reports. 11 (7): 1079–89. doi:10.1016/j.celrep.2015.04.026. PMC 4862650. PMID 25959823.
  49. ^ Böhm I (2003). "Disruption of the cytoskeleton after apoptosis induction by autoantibodies". Autoimmunity. 36 (3): 183–189. doi:10.1080/0891693031000105617.
  50. ^ Susin SA, Daugas E, Ravagnan L, Samejima K, Zamzami N, Loeffler M, Costantini P, Ferri KF, et al. (August 2000). "Two distinct pathways leading to nuclear apoptosis". The Journal of Experimental Medicine. 192 (4): 571–80. doi:10.1084/jem.192.4.571. PMC 2193229. PMID 10952727.
  51. ^ Kihlmark M, Imreh G, Hallberg E (October 2001). "Sequential degradation of proteins from the nuclear envelope during apoptosis". Journal of Cell Science. 114 (Pt 20): 3643–53. PMID 11707516.
  52. ^ Nagata S (April 2000). "Apoptotic DNA fragmentation". Experimental Cell Research. 256 (1): 12–8. doi:10.1006/excr.2000.4834. PMID 10739646.
  53. ^ Gong J, Traganos F, Darzynkiewicz Z (May 1994). "A selective procedure for DNA extraction from apoptotic cells applicable for gel electrophoresis and flow cytometry". Analytical Biochemistry. 218 (2): 314–9. doi:10.1006/abio.1994.1184. PMID 8074286.
  54. ^ Iwata M, Myerson D, Torok-Storb B, Zager RA (December 1994). "An evaluation of renal tubular DNA laddering in response to oxygen deprivation and oxidant injury". Journal of the American Society of Nephrology : JASN. 5 (6): 1307–13. PMID 7893995.
  55. ^ Smith A, Parkes MA, Atkin-Smith GK, Tixeira R, Poon IK (2017). "Cell disassembly during apoptosis". WikiJournal of Medicine. 4 (1). doi:10.15347/wjm/2017.008.
  56. ^ a b Tixeira R, Caruso S, Paone S, Baxter AA, Atkin-Smith GK, Hulett MD, Poon IK (March 2017). "Defining the morphologic features and products of cell disassembly during apoptosis". Apoptosis. 22 (3): 475–477. doi:10.1007/s10495-017-1345-7. PMID 28102458.
  57. ^ Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF (April 2001). "Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I". Nature Cell Biology. 3 (4): 339–45. doi:10.1038/35070009. PMID 11283606.
  58. ^ Sebbagh M, Renvoizé C, Hamelin J, Riché N, Bertoglio J, Bréard J (April 2001). "Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing". Nature Cell Biology. 3 (4): 346–52. doi:10.1038/35070019. PMID 11283607.
  59. ^ Moss DK, Betin VM, Malesinski SD, Lane JD (June 2006). "A novel role for microtubules in apoptotic chromatin dynamics and cellular fragmentation". Journal of Cell Science. 119 (Pt 11): 2362–74. doi:10.1242/jcs.02959. PMC 1592606. PMID 16723742.
  60. ^ a b Poon IK, Chiu YH, Armstrong AJ, Kinchen JM, Juncadella IJ, Bayliss DA, Ravichandran KS (March 2014). "Unexpected link between an antibiotic, pannexin channels and apoptosis". Nature. 507 (7492): 329–34. doi:10.1038/nature13147. PMC 4078991. PMID 24646995.
  61. ^ Atkin-Smith GK, Tixeira R, Paone S, Mathivanan S, Collins C, Liem M, Goodall KJ, Ravichandran KS, Hulett MD, Poon IK (June 2015). "A novel mechanism of generating extracellular vesicles during apoptosis via a beads-on-a-string membrane structure". Nature Communications. 6: 7439. doi:10.1038/ncomms8439. PMC 4490561. PMID 26074490.
  62. ^ Vandivier RW, Henson PM, Douglas IS (June 2006). "Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease". Chest. 129 (6): 1673–82. doi:10.1378/chest.129.6.1673. PMID 16778289.
  63. ^ Li MO, Sarkisian MR, Mehal WZ, Rakic P, Flavell RA (November 2003). "Phosphatidylserine receptor is required for clearance of apoptotic cells". Science. 302 (5650): 1560–3. doi:10.1126/science.1087621. PMID 14645847.
  64. ^ Wang X, Wu YC, Fadok VA, Lee MC, Gengyo-Ando K, Cheng LC, Ledwich D, Hsu PK, et al. (November 2003). "Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12". Science. 302 (5650): 1563–6. doi:10.1126/science.1087641. PMID 14645848.
  65. ^ Savill J, Gregory C, Haslett C (November 2003). "Cell biology. Eat me or die". Science. 302 (5650): 1516–7. doi:10.1126/science.1092533. PMID 14645835.
  66. ^ Krysko DV, Vandenabeele P (2009-01-14). Phagocytosis of dying cells: from molecular mechanisms to human diseases. ISBN 978-1-4020-9292-3.
  67. ^ Halicka HD, Bedner E, Darzynkiewicz Z (November 2000). "Segregation of RNA and separate packaging of DNA and RNA in apoptotic bodies during apoptosis". Experimental Cell Research. 260 (2): 248–56. doi:10.1006/excr.2000.5027. PMID 11035919.
  68. ^ Lozano GM, Bejarano I, Espino J, González D, Ortiz A, García JF, Rodríguez AB, Pariente JA (2009). "Density gradient capacitation is the most suitable method to improve fertilization and to reduce DNA fragmentation positive spermatozoa of infertile men". Anatolian Journal of Obstetrics & Gynecology. 3 (1): 1–7.
  69. ^ Darzynkiewicz Z, Juan G, Li X, Gorczyca W, Murakami T, Traganos F (January 1997). "Cytometry in cell necrobiology: analysis of apoptosis and accidental cell death (necrosis)". Cytometry. 27 (1): 1–20. doi:10.1002/(sici)1097-0320(19970101)27:1<1::aid-cyto2>3.3.co;2-x. PMID 9000580.
  70. ^ Krysko DV, Vanden Berghe T, Parthoens E, D'Herde K, Vandenabeele P (2008). Methods for distinguishing apoptotic from necrotic cells and measuring their clearance. Methods in Enzymology. 442. pp. 307–41. doi:10.1016/S0076-6879(08)01416-X. ISBN 9780123743121. PMID 18662577.
  71. ^ Krysko DV, Vanden Berghe T, D'Herde K, Vandenabeele P (March 2008). "Apoptosis and necrosis: detection, discrimination and phagocytosis". Methods. 44 (3): 205–21. doi:10.1016/j.ymeth.2007.12.001. PMID 18314051.
  72. ^ Vanden Berghe T, Grootjans S, Goossens V, Dondelinger Y, Krysko DV, Takahashi N, Vandenabeele P (June 2013). "Determination of apoptotic and necrotic cell death in vitro and in vivo". Methods. 61 (2): 117–29. doi:10.1016/j.ymeth.2013.02.011. PMID 23473780.
  73. ^ Wlodkowic D, Telford W, Skommer J, Darzynkiewicz Z (2011). Apoptosis and beyond: cytometry in studies of programmed cell death. Methods in Cell Biology. 103. pp. 55–98. doi:10.1016/B978-0-12-385493-3.00004-8. ISBN 9780123854933. PMC 3263828. PMID 21722800.
  74. ^ Thompson CB (March 1995). "Apoptosis in the pathogenesis and treatment of disease". Science. 267 (5203): 1456–62. doi:10.1126/science.7878464. PMID 7878464.
  75. ^ Yang L, Mashima T, Sato S, Mochizuki M, Sakamoto H, Yamori T, Oh-Hara T, Tsuruo T (February 2003). "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". Cancer Research. 63 (4): 831–7. PMID 12591734.
  76. ^ Vlahopoulos SA (August 2017). "Aberrant control of NF-κB in cancer permits transcriptional and phenotypic plasticity, to curtail dependence on host tissue: molecular mode". Cancer Biology & Medicine. 14 (3): 254–270. doi:10.20892/j.issn.2095-3941.2017.0029. PMC 5570602. PMID 28884042.
  77. ^ Takaoka A, Hayakawa S, Yanai H, Stoiber D, Negishi H, Kikuchi H, Sasaki S, Imai K, et al. (July 2003). "Integration of interferon-alpha/beta signalling to p53 responses in tumour suppression and antiviral defence". Nature. 424 (6948): 516–23. doi:10.1038/nature01850. PMID 12872134.
  78. ^ Bernstein C, Bernstein H, Payne CM, Garewal H (June 2002). "DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis". Mutation Research. 511 (2): 145–78. doi:10.1016/S1383-5742(02)00009-1. PMID 12052432.
  79. ^ a b Kaczanowski, S. Apoptosis: its origin, history, maintenance and the medical implications for cancer and aging. Phys Biol 13, 031001 http://iopscience.iop.org/article/10.1088/1478-3975/13/3/031001
  80. ^ Warburg O (February 1956). "On the origin of cancer cells". Science. 123 (3191): 309–14. doi:10.1126/science.123.3191.309. PMID 13298683.
  81. ^ a b c d e f Del Puerto HL, Martins AS, Milsted A, Souza-Fagundes EM, Braz GF, Hissa B, Andrade LO, Alves F, Rajão DS, Leite RC, Vasconcelos AC (June 2011). "Canine distemper virus induces apoptosis in cervical tumor derived cell lines". Virology Journal. 8 (1): 334. doi:10.1186/1743-422X-8-334. PMC 3141686. PMID 21718481.
  82. ^ Liu HC, Chen GG, Vlantis AC, Tse GM, Chan AT, van Hasselt CA (March 2008). "Inhibition of apoptosis in human laryngeal cancer cells by E6 and E7 oncoproteins of human papillomavirus 16". Journal of Cellular Biochemistry. 103 (4): 1125–43. doi:10.1002/jcb.21490. PMID 17668439.
  83. ^ a b Niu XY, Peng ZL, Duan WQ, Wang H, Wang P (2006). "Inhibition of HPV 16 E6 oncogene expression by RNA interference in vitro and in vivo". International Journal of Gynecological Cancer. 16 (2): 743–51. doi:10.1111/j.1525-1438.2006.00384.x. PMID 16681755.
  84. ^ a b Liu Y, McKalip A, Herman B (May 2000). "Human papillomavirus type 16 E6 and HPV-16 E6/E7 sensitize human keratinocytes to apoptosis induced by chemotherapeutic agents: roles of p53 and caspase activation". Journal of Cellular Biochemistry. 78 (2): 334–49. doi:10.1002/(sici)1097-4644(20000801)78:2<334::aid-jcb15>3.3.co;2-6. PMID 10842327.
  85. ^ Boehm I (June 2006). "Apoptosis in physiological and pathological skin: implications for therapy". Current Molecular Medicine. 6 (4): 375–94. doi:10.2174/156652406777435390. PMID 16900661.
  86. ^ LaFerla, F. M., Tinkle, B. T., Bieberich, C. J., Haudenschild, C. C. & Jay, G. The Alzheimer's A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nat Genet 9, 21–30, doi:10.1038/ng0195-21 (1995).
  87. ^ Mochizuki, H., Goto, K., Mori, H. & Mizuno, Y. Histochemical detection of apoptosis in Parkinson's disease. J Neurol Sci 137, 120–123 (1996)
  88. ^ Demetrius, L. A., Magistretti, P. J. & Pellerin, L. Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect. Front Physiol 5, 522, doi:10.3389/fphys.2014.00522 (2014).
  89. ^ Musicco, M. et al. Inverse occurrence of cancer and Alzheimer disease: a population-based incidence study. Neurology 81, 322–328, doi:10.1212/WNL.0b013e31829c5ec1 (2013).
  90. ^ Sionov RV, Vlahopoulos SA, Granot Z (September 2015). "Regulation of Bim in Health and Disease". Oncotarget. 6 (27): 23058–134. doi:10.18632/oncotarget.5492. PMC 4695108. PMID 26405162.
  91. ^ Farhana, Lulu. "Apoptosis Induction by a Novel Retinoid-Related Molecule Requires Nuclear Factor- κB Activation" (PDF). American Association of Cancer Research (AACR). Retrieved 2012-01-24.
  92. ^ Alimonti JB, Ball TB, Fowke KR (July 2003). "Mechanisms of CD4+ T lymphocyte cell death in human immunodeficiency virus infection and AIDS". The Journal of General Virology. 84 (Pt 7): 1649–61. doi:10.1099/vir.0.19110-0. PMID 12810858. Archived from the original on 2007-01-13. Retrieved 2006-12-18.
  93. ^ Vashistha H, Husain M, Kumar D, Yadav A, Arora S, Singhal PC. (2008) Ren Fail. 2008;30(6):655–64.
  94. ^ Indiana University Health. "AIDS Defining Criteria | Riley". IU Health. Archived from the original on 2013-05-26. Retrieved 2013-01-20.
  95. ^ Tateishi H, Monde K, Anraku K, Koga R, Hayashi Y, Ciftci HI, DeMirci H, Higashi T, Motoyama K, Arima H, Otsuka M, Fujita M (August 2017). "A clue to unprecedented strategy to HIV eradication: "Lock-in and apoptosis"". Scientific Reports. 7 (1): 8957. doi:10.1038/s41598-017-09129-w. PMC 5567282. PMID 28827668.
  96. ^ a b Indran IR, Tufo G, Pervaiz S, Brenner C (June 2011). "Recent advances in apoptosis, mitochondria and drug resistance in cancer cells". Biochimica et Biophysica Acta. 1807 (6): 735–45. doi:10.1016/j.bbabio.2011.03.010. PMID 21453675.
  97. ^ Everett H, McFadden G (April 1999). "Apoptosis: an innate immune response to virus infection". Trends in Microbiology. 7 (4): 160–5. doi:10.1016/S0966-842X(99)01487-0. PMID 10217831.
  98. ^ Nishi T, Tsukiyama-Kohara K, Togashi K, Kohriyama N, Kai C (November 2004). "Involvement of apoptosis in syncytial cell death induced by canine distemper virus". Comparative Immunology, Microbiology and Infectious Diseases. 27 (6): 445–55. doi:10.1016/j.cimid.2004.01.007. PMID 15325517.
  99. ^ a b c d Acrani GO, Gomes R, Proença-Módena JL, da Silva AF, Carminati PO, Silva ML, Santos RI, Arruda E (April 2010). "Apoptosis induced by Oropouche virus infection in HeLa cells is dependent on virus protein expression". Virus Research. 149 (1): 56–63. doi:10.1016/j.virusres.2009.12.013. PMID 20080135.
  100. ^ Azevedo RS, Nunes MR, Chiang JO, Bensabath G, Vasconcelos HB, Pinto AY, Martins LC, Monteiro HA, Rodrigues SG, Vasconcelos PF (June 2007). "Reemergence of Oropouche fever, northern Brazil". Emerging Infectious Diseases. 13 (6): 912–5. doi:10.3201/eid1306.061114. PMC 2792853. PMID 17553235.
  101. ^ Santos RI, Rodrigues AH, Silva ML, Mortara RA, Rossi MA, Jamur MC, Oliver C, Arruda E (December 2008). "Oropouche virus entry into HeLa cells involves clathrin and requires endosomal acidification". Virus Research. 138 (1–2): 139–43. doi:10.1016/j.virusres.2008.08.016. PMID 18840482.
  102. ^ Teodoro JG, Branton PE (March 1997). "Regulation of apoptosis by viral gene products". Journal of Virology. 71 (3): 1739–46. PMC 191242. PMID 9032302.
  103. ^ Polster BM, Pevsner J, Hardwick JM (March 2004). "Viral Bcl-2 homologs and their role in virus replication and associated diseases". Biochimica et Biophysica Acta. 1644 (2–3): 211–27. doi:10.1016/j.bbamcr.2003.11.001. PMID 14996505.
  104. ^ a b Hay S, Kannourakis G (July 2002). "A time to kill: viral manipulation of the cell death program". The Journal of General Virology. 83 (Pt 7): 1547–64. CiteSeerX 10.1.1.322.6923. doi:10.1099/0022-1317-83-7-1547. PMID 12075073.
  105. ^ Wang XW, Gibson MK, Vermeulen W, Yeh H, Forrester K, Stürzbecher HW, Hoeijmakers JH, Harris CC (December 1995). "Abrogation of p53-induced apoptosis by the hepatitis B virus X gene". Cancer Research. 55 (24): 6012–6. PMID 8521383.
  106. ^ Collazo C, Chacón O, Borrás O (2006). "Programmed cell death in plants resembles apoptosis of animals" (PDF). Biotecnología Aplicada. 23: 1–10. Archived from the original (PDF) on 2009-03-03.
  107. ^ Xiang J, Chao DT, Korsmeyer SJ (December 1996). "BAX-induced cell death may not require interleukin 1 beta-converting enzyme-like proteases". Proceedings of the National Academy of Sciences of the United States of America. 93 (25): 14559–63. doi:10.1073/pnas.93.25.14559. PMC 26172. PMID 8962091.
  108. ^ "Atromentin-Induced Apoptosis in Human Leukemia U937 Cells". Kim Jin Hee and Choong Hwan Lee, Journal of Microbiology and Biotechnology, 2009, vol. 19, no. 9, pages 946–950, INIST:21945937

Bibliography

  • Alberts B, Johnson A, Lewis J, Morgan D, Raff M, Roberts K, Walter P (2015). Molecular Biology of the Cell (6th ed.). Garland Science. p. 2. ISBN 978-0815344322.

External links

ASK1

Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5) is a member of MAP kinase kinase kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. ASK1 has been found to be involved in cancer, diabetes, cardiovascular and neurodegenerative diseases.MAP3K5 gene coding for the protein is located on chromosome 6 at locus 6q22.33. and the transcribed protein contains 1,374 amino acids with 11 kinase subdomains. Northern blot analysis shows that MAP3K5 transcript is abundant in human heart and pancreas.

Apoptosis-antagonizing transcription factor

Protein AATF is a protein that in humans is encoded by the AATF gene.

Bcl-2

Bcl-2 (B-cell lymphoma 2), encoded in humans by the BCL2 gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inducing (pro-apoptotic) or inhibiting (anti-apoptotic) apoptosis.Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in follicular lymphomas. Orthologs (such as Bcl2 in mice) have been identified in numerous mammals for which complete genome data are available.

Like BCL3, BCL5, BCL6, BCL7A, BCL9, and BCL10, it has clinical significance in lymphoma.

Caspase

Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death (including apoptosis, pyroptosis and necroptosis) and inflammation. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 11 or 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

The role of these enzymes in programmed cell death was first identified in 1993, with their functions in apoptosis well characterised. This is a form of programmed cell death, occurring widely during development, and throughout life to maintain cell homeostasis. Activation of Caspases ensures that the cellular components are degraded in a controlled manner, carrying out cell death with minimal effect on surrounding tissues.Caspases have other identified roles in programmed cell death such as pyroptosis and necroptosis. These forms of cell death are important for protecting an organism from stress signals and pathogenic attack. Caspases also have a role in inflammation, whereby it directly processes pro-inflammatory cytokines such as pro-IL1β. These are signalling molecules that allow recruitment of immune cells to an infected cell or tissue. There are other identified roles of caspases such as cell proliferation, tumour suppression, cell differentiation, neural development and axon guidance and ageing.Caspase deficiency has been identified as a cause of tumour development. Tumour growth can occur by a combination of factors, including a mutation in a cell cycle gene which removes the restraints on cell growth, combined with mutations in apoptopic proteins such as Caspases that would respond by inducing cell death in abnormally growing cells. Conversely, over-activation of some caspases such as caspase-3 can lead to excessive programmed cell death. This is seen in several neurodegenerative diseases where neural cells are lost, such as Alzheimer's disease. Caspases involved with processing inflammatory signals are also implicated in disease. Insufficient activation of these caspases can increase an organism's susceptibility to infection, as an appropriate immune response may not be activated. The integral role caspases play in cell death and disease has led to research on using caspases as a drug target. For example, inflammatory caspase-1 has been implicated in causing autoimmune diseases; drugs blocking the activation of Caspase-1 have been used to improve the health of patients. Additionally, scientists have used caspases as cancer therapy to kill unwanted cells in tumours.

Cell death

Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, or may result from such factors as disease, localized injury, or the death of the organism of which the cells are part. Kinds of cell death include the following:

Programmed cell death (or PCD) is cell death mediated by an intracellular program. PCD is carried out in a regulated process, which usually confers advantage 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. PCD serves fundamental functions during both plant and metazoa (multicellular animals) tissue development.

Apoptosis or Type I cell-death, and autophagy or Type II cell-death are both forms of programmed cell death, while necrosis is a non-physiological process that occurs as a result of infection or injury. Necrosis is cell death caused by external factors such as trauma or infection, and occurs in several different forms. Recently a form of programmed necrosis, called necroptosis, has been recognized as an alternative form of programmed cell death. It is hypothesized that necroptosis can serve as a cell-death backup to apoptosis when the apoptosis signaling is blocked by endogenous or exogenous factors such as viruses or mutations.

Mitotic catastrophe is a mode of cell death that is due to premature or inappropriate entry of cells into mitosis. It is the most common mode of cell death in cancer cells exposed to ionizing radiation and many other anti-cancer treatments.Autophagy is cytoplasmic, characterized by the formation of large vacuoles that eat away organelles in a specific sequence prior to the destruction of the nucleus.Apoptosis is the process of programmed cell death (PCD) that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. It is now thought that – in a developmental context – cells are induced to positively commit suicide whilst in a homeostatic context; the absence of certain survival factors may provide the impetus for suicide. There appears to be some variation in the morphology and indeed the biochemistry of these suicide pathways; some treading the path of "apoptosis", others following a more generalized pathway to deletion, but both usually being genetically and synthetically motivated. There is some evidence that certain symptoms of "apoptosis" such as endonuclease activation can be spuriously induced without engaging a genetic cascade, however, presumably true apoptosis and programmed cell death must be genetically mediated. It is also becoming clear that mitosis and apoptosis are toggled or linked in some way and that the balance achieved depends on signals received from appropriate growth or survival factors.Macroautophagy, often referred to as autophagy, is a catabolic process that results in the autophagosomic-lysosomal degradation of bulk cytoplasmic contents, abnormal protein aggregates, and excess or damaged organelles. Autophagy is generally activated by conditions of nutrient deprivation but has also been associated with physiological as well as pathological processes such as development, differentiation, neurodegenerative diseases, stress, infection and cancer.

Other pathways of programmed cell death have been discovered.

Called "non-apoptotic programmed cell-death" (or "caspase-independent programmed cell-death" or "necroptosis"), these alternative routes to death are as efficient as apoptosis and can function as either backup mechanisms or the main type of PCD.

Other forms of programmed cell death include anoikis, almost identical to apoptosis except in its induction; cornification, a form of cell death exclusive to the eyes; excitotoxicity; ferroptosis, an iron-dependent form of cell death and Wallerian degeneration.

Plant cells undergo particular processes of PCD similar to autophagic cell death. However, some common features of PCD are highly conserved in both plants and metazoa.

Activation-induced cell death (AICD) is a programmed cell death caused by the interaction of Fas receptor (Fas, CD95)and Fas ligand (FasL, CD95 ligand). It occurs as a result of repeated stimulation of specific T-cell receptors (TCR) and it helps to maintain the periphery immune tolerance. Therefore, an alteration of the process may lead to autoimmune diseases. In the other words AICD is the negative regulator of activated T-lymphocytes.

Ischemic cell death, or oncosis, is a form of accidental, or passive cell death that is often considered a lethal injury. The process is characterized by mitochondrial swelling, cytoplasm vacuolization, and swelling of the nucleus and cytoplasm.Immunogenic cell death or immunogenic apoptosis is a form of cell death caused by some cytostatic agents such as anthracyclines, oxaliplatin and bortezomib, or radiotherapy and photodynamic therapy (PDT).Pyroptosis is a highly inflammatory form of programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response in myeloid cells.

The term "cell necrobiology" has been used to describe the life processes associated with morphological, biochemical, and molecular changes which predispose, precede, and accompany cell death, as well as the consequences and tissue response to cell death. The word is derived from the Greek νεκρό meaning "death", βìο meaning "life", and λόγος meaning "the study of". The term was initially coined to broadly define investigations of the changes that accompany cell death, detected and measured by multiparameter flow- and laser scanning- cytometry. It has been used to describe the real-time changes during cell death, detected by flow cytometry

Cytochrome c

The cytochrome complex, or cyt c is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is highly water-soluble, unlike other cytochromes, and is an essential component of the electron transport chain, where it carries one electron. It is capable of undergoing oxidation and reduction, but does not bind oxygen. It transfers electrons between Complexes III (Coenzyme Q – Cyt C reductase) and IV (Cyt C oxidase). In humans, cytochrome c is encoded by the CYCS gene.

Death receptor 4

Death receptor 4 (DR4), also known as TRAIL receptor 1 (TRAILR1) and tumor necrosis factor receptor superfamily member 10A (TNFRSF10A), is a cell surface receptor of the TNF-receptor superfamily that binds TRAIL and mediates apoptosis.

Fas ligand

Fas ligand (FasL or CD95L) is a type-II transmembrane protein that belongs to the tumor necrosis factor (TNF) family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.

Fas receptor

Fas or FasR, also known as apoptosis antigen 1 (APO-1 or APT), cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6) is a protein that in humans is encoded by the FAS gene.The Fas receptor is a death receptor on the surface of cells that leads to programmed cell death (apoptosis). It is one of two apoptosis pathways, the other being the mitochondrial pathway. FasR is located on chromosome 10 in humans and 19 in mice. Similar sequences related by evolution (orthologs) are found in most mammals.

Inhibitor of apoptosis

Apoptosis, or programmed cell death, is a highly regulated process used by many multicellular organisms. Like any regulated process, apoptosis is subject to either activation or inhibition by a variety of chemical factors. Apoptosis can be triggered through two main pathways; extrinsic and intrinsic. The extrinsic pathway mostly involves extracellular signals triggering intracellular apoptosis mechanisms by binding to receptors in the cell membrane and sending signals from the outside of the cell. Intrinsic pathways involved internal cell signaling primarily through the mitochondria. Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death, which can frequently lead to cancer or other effects for the cell if mutated or improperly regulated. Many of these inhibitors act to block caspases, a family of cysteine proteases that play an integral role in apoptosis. Some of these inhibitors include the Bcl-2 family, viral inhibitor crmA, and IAP's.

Intrinsic apoptosis

Apoptosis is a programmed form of cell death involving the degradation of cellular constituents by a group of cysteine proteases called caspases. The caspases can be activated through either the intrinsic (mitochondrial mediated) or extrinsic (death receptor mediated) apoptotic pathways.

The intrinsic apoptotic pathway is characterized by permeabilisation of the mitochondria and release of cytochrome c into the cytoplasm. Cytochrome c then forms a multi-protein complex known as the "apoptosome" and initiates activation of the caspase cascade through caspase 9.

Ischemic cell death

"Ischemic cell death", or "Oncosis", is a form of accidental cell death. The process is characterized by an ATP depletion within the cell leading to impairment of ionic pumps, cell swelling, clearing of the cytosol, dilation of the Endoplasmic Reticulum and Golgi, mitochondrial condensation, chromatin clumping, and cytoplasmic bleb formation. Oncosis refers to a series of cellular reactions following injury that precedes cell death. The process of oncosis is divided into three stages. First, the cell becomes committed to oncosis as a result of damage incurred to the plasma membrane through toxicity or ischemia, resulting in the leak of ions and water due to ATP depletion. The ionic imbalance that occurs subsequently causes the cell to swell without a concurrent change in membrane permeability to reverse the swelling. Stage two the reversibility threshold for the cell is passed and it becomes committed to cell death. During this stage the membrane becomes abnormally permeable to trypan blue and propidium iodide, indicating membrane compromise. The final stage is cell death and removal of the cell via phagocytosis mediated by an inflammatory response.

Karyorrhexis

Karyorrhexis (from Greek κάρυον karyon, "kernel, seed or nucleus", and ῥῆξις rhexis, "bursting") is the destructive fragmentation of the nucleus of a dying cell whereby its chromatin is distributed irregularly throughout the cytoplasm. It is usually preceded by pyknosis and can occur as a result of either programmed cell death (apoptosis), senescence, or necrosis.

In apoptosis, the cleavage of DNA is done by Ca2+ and Mg2+ -dependent endonucleases.

Necroptosis

Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding defense pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication. In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.The signaling pathway responsible for carrying out necroptosis is generally understood. TNFα leads to stimulation of its receptor TNFR1. TNFR1 binding protein TNFR-associated death protein TRADD and TNF receptor-associated factor 2 TRAF2 signals to RIPK1 which recruits RIPK3 forming the necrosome also named ripoptosome. Phosphorylation of MLKL by the ripoptosome drives oligomerization of MLKL, allowing MLKL to insert into and permeabilize plasma membranes and organelles. Integration of MLKL leads to the inflammatory phenotype and release of damage-associated molecular patterns (DAMPs), which elicit immune responses.

Necrosis

Necrosis (from the Greek νέκρωσις "death, the stage of dying, the act of killing" from νεκρός "dead") is a form of cell injury which results in the premature death of cells in living tissue by autolysis.Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma which result in the unregulated digestion of cell components.

In contrast, apoptosis is a naturally occurring programmed and targeted cause of cellular death.

While apoptosis often provides beneficial effects to the organism, necrosis is almost always detrimental and can be fatal.Cellular death due to necrosis does not follow the apoptotic signal transduction pathway, but rather various receptors are activated, and result in the loss of cell membrane integrity and an uncontrolled release of products of cell death into the extracellular space.This initiates in the surrounding tissue an inflammatory response which attracts leukocytes and nearby phagocytes which eliminate the dead cells by phagocytosis. However, microbial damaging substances released by leukocytes would create collateral damage to surrounding tissues. This excess collateral damage inhibits the healing process. Thus, untreated necrosis results in a build-up of decomposing dead tissue and cell debris at or near the site of the cell death. A classic example is gangrene. For this reason, it is often necessary to remove necrotic tissue surgically, a procedure known as debridement.

Oncogene

An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.Most normal cells will undergo a programmed form of rapid cell death (apoptosis) when critical functions are altered and malfunctioning. Activated oncogenes can cause those cells designated for apoptosis to survive and proliferate instead. Most oncogenes began as proto-oncogenes, normal genes involved in cell growth and proliferation or inhibition of apoptosis. If normal genes promoting cellular growth, through mutation, are up-regulated, (gain of function mutation) they will predispose the cell to cancer and are thus termed oncogenes. Usually multiple oncogenes, along with mutated apoptotic or tumor suppressor genes will all act in concert to cause cancer. Since the 1970s, dozens of oncogenes have been identified in human cancer. Many cancer drugs target the proteins encoded by oncogenes.

Programmed cell death

Programmed cell death (or PCD) is the death of a cell in any form, mediated by an intracellular program. PCD is carried out in a biological process, which usually confers advantage 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. PCD serves fundamental functions during both plant and animal tissue development.

Apoptosis and autophagy, both are the forms of programmed cell death, but necrosis was long seen as a non-physiological process that occurs as a result of infection or injury.Necrosis is the death of a cell caused by external factors such as trauma or infection and occurs in several different forms. Recently a form of programmed necrosis, called necroptosis, has been recognized as an alternative form of programmed cell death. It is hypothesized that necroptosis can serve as a cell-death backup to apoptosis when the apoptosis signaling is blocked by endogenous or exogenous factors such as viruses or mutations. Most recently, other types of regulated necrosis have been discovered as well, which share several signaling events with necroptosis and apoptosis.

Pseudoapoptosis

Pseudoapoptosis can be defined from multiple viewpoints, with an underlying premise of the differences in cellular processes and states relating to apoptosis. Pseudoapoptosis can be referred to as an apoptotic-like cellular state that can be readily reversed, or as a process that induces rapid apoptosis through the introduction of drugs such as bleomycin.Pseudoapoptosis has been used to define a cellular state closely resembling the initial stages of apoptosis, but asserts a readily reversible state of which a cell can resume normal cellular function. Chemical and morphological changes a cell may undergo associated with pseudoapoptosis include blebbing, plasma membrane lipid asymmetry, cytoskeleton alterations, changes in mitochondrial function, and increased concentration of cytosolic calcium. Regardless of these cellular alterations, pseudoapoptotic cells reverse these changes to resume normal cellular process.Pseudoapoptosis has also been used in some instances when describing an accelerated, drug induced apoptotic pathway by bleomycin. Cell death occurs as it would in apoptosis, but certain apoptotic mechanisms are not utilized when in the presence of bleomycin.

TRAIL

In the field of cell biology, TNF-related apoptosis-inducing ligand (TRAIL), is a protein functioning as a ligand that induces the process of cell death called apoptosis.TRAIL is a cytokine that is produced and secreted by most normal tissue cells. It causes apoptosis primarily in tumor cells, by binding to certain death receptors. TRAIL and its receptors have been used as the targets of several anti-cancer therapeutics since the mid-1990s, such as Mapatumumab. However, as of 2013, these have not shown significant survival benefit. TRAIL has also been implicated as a pathogenic or protective factor in various pulmonary diseases, particularly pulmonary arterial hypertension.TRAIL has also been designated CD253 (cluster of differentiation 253) and TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10).

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