Apoptosis
Apoptosis | |
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Identifiers | |
MeSH | D017209 |
Anatomical terminology |
Apoptosis (from
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 life cycle. 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 phagocytes 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.
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.[7]
Discovery and etymology
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 Kerr at the University of Queensland was able to distinguish apoptosis from traumatic cell death.[8] Following the publication of a paper describing the phenomenon, Kerr was invited to join Alastair Currie, as well as Andrew Wyllie, who was Currie's graduate student,[9] at the University of Aberdeen. In 1972, the trio published a seminal article in the British Journal of Cancer.[10] 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.[11]
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 the first component of the cell death control and effector mechanisms, and linkage of abnormalities in cell death to human disease, in particular cancer. This occurred in 1988 when it was shown that BCL2, the gene responsible for follicular lymphoma, encoded a protein that inhibited cell death.[12]
The 2002 Nobel Prize in Medicine was awarded to Sydney Brenner, H. Robert Horvitz and John 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.
In Greek, apoptosis translates to the "falling off" of leaves from a tree.[13] 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[14][15]) and the second p pronounced (/eɪpəpˈtoʊsɪs/).[14][16] 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,[10] 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
The initiation of apoptosis is tightly regulated by activation mechanisms, because once apoptosis has begun, it inevitably leads to the death of the cell.
A cell initiates intracellular apoptotic signaling in response to a stress,
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,[29] 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 intrinsic pathway is also known as the mitochondrial pathway. 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.[22][30] 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.[31] Nitric oxide has been implicated in initiating and inhibiting apoptosis through its possible action as a signal molecule of subsequent pathways that activate apoptosis.[32]
During apoptosis,
Mitochondria also release proteins known as SMACs (second mitochondria-derived activator of caspases) 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,[34] which carry out the degradation of the cell. Therefore, the actual degradation enzymes can be seen to be indirectly regulated by mitochondrial permeability.
Extrinsic pathway
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[35] coupled to extrinsic signals.
TNF pathway
Fas pathway
The
Common components
Following TNF-R1 and Fas activation in mammalian cells[
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 (caspases 2, 8, 9, 10, 11, and 12) and effector caspases (caspases 3, 6, and 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).[44]
Apoptosis model in amphibians
The frog
Negative regulators of apoptosis
Negative regulation of apoptosis inhibits cell death signaling pathways, helping tumors to evade cell death and developing
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
A cell undergoing apoptosis shows a series of characteristic morphological changes. Early alterations include:
- Cell shrinkage and rounding occur because of the retraction lamellipodia and the breakdown of the proteinaceous cytoskeleton by caspases.[53]
- The cytoplasm appears dense, and the organelles appear tightly packed.
- Chromatin undergoes condensation into compact patches against the
- 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.[56]
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.[57] Tests for DNA laddering differentiate apoptosis from ischemic or toxic cell death.[58]
Apoptotic cell disassembly
Before the apoptotic cell is disposed of, there is a process of disassembly. There are three recognized steps in apoptotic cell disassembly:[60]
- 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.[60] An important regulator of apoptotic cell membrane blebbing is ROCK1 (rho associated coiled-coil-containing protein kinase 1).[61][62]
- 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: Pannexin 1 is an important component of membrane channels involved in the formation of apoptopodia and beaded apoptopodia.[64]
- 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.[66] Dying cells that undergo the final stages of apoptosis display phagocytotic molecules, such as
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.[72] 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.[73] Apaf-1 is the protein that turns on caspase 9 by cleavage to begin the caspase cascade that leads to apoptosis.[74] 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.[75] 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.[76]
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[citation needed]. A caspase 8 knock-out leads to cardiac failure and thus embryonic lethality[citation needed]. 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[citation needed]. 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[citation needed]. 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 cells
Label-free
Implication in disease
Defective pathways
The many different types of apoptotic pathways contain a multitude of different biochemical components, many of them not yet understood.[83] 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
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.[86] 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.[87] 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, 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.[88] Pathological inactivation of apoptosis in cancer cells is correlated with frequent respiratory metabolic shifts toward glycolysis (an observation known as the "Warburg hypothesis".[89]
HeLa cell
Apoptosis in HeLa[b] cells is inhibited by proteins produced by the cell; these inhibitory proteins target retinoblastoma tumor-suppressing proteins.[90] These tumor-suppressing proteins regulate the cell cycle, but are rendered inactive when bound to an inhibitory protein.[90] 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.[91] HPV E6 causes p53, which regulates the cell cycle, to become inactive.[92] HPV E7 binds to retinoblastoma tumor suppressing proteins and limits its ability to control cell division.[92] These two inhibitory proteins are partially responsible for HeLa cells' immortality by inhibiting apoptosis to occur.[93]
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).
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. Neurons that rely on mitochondrial respiration undergo apoptosis in neurodegenerative diseases such as Alzheimer's[95] and Parkinson's.[96] (an observation known as the "Inverse Warburg hypothesis"[88][97]). Moreover, there is an inverse epidemiological comorbidity between neurodegenerative diseases and cancer.[98] 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.[citation needed]
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
HIV progression
The progression of the
- 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.
- HIV may increase the level of cellular proteins that prompt Fas-mediated apoptosis.
- HIV proteins decrease the amount of CD4 glycoprotein marker present on the cell membrane.
- Released viral particles and proteins present in extracellular fluid are able to induce apoptosis in nearby "bystander" T helper cells.
- HIV decreases the production of molecules involved in marking the cell for apoptosis, giving the virus time to replicate and continue releasing apoptotic agents and virions into the surrounding tissue.
- The infected CD4+ cell may also receive the death signal from a cytotoxic T cell.
Cells may also die as direct consequences of viral infections. HIV-1 expression induces tubular cell G2/M arrest and apoptosis.[101] 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.[102]
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.[103]
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.[104] 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.[105]
The
OROV is a disease that is transmitted between humans by the biting midge (
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
With the use of
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.[107]
Many viruses encode proteins that can inhibit apoptosis.
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.[112] Prions can cause apoptosis in neurons.
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. Additionally, plants do not contain phagocytic cells, which are essential in the process of breaking down and removing apoptotic bodies.[114] 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.[115][116]
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.[117] 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
Explanatory footnotes
- ^ Note that the average human adult has more than 13 trillion cells (1.3×1013),[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.
- ^ 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 patient.
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General bibliography
- Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2015). Molecular Biology of the Cell (6th ed.). Garland Science. p. 2. ISBN 978-0815344322.
External links
- Apoptosis & cell surface[permanent dead link]
- Apoptosis & Caspase 3, The Proteolysis Map – animation
- Apoptosis & Caspase 8, The Proteolysis Map – animation
- Apoptosis & Caspase 7, The Proteolysis Map – animation
- Apoptosis MiniCOPE Dictionary – list of apoptosis terms and acronyms
- Apoptosis (Programmed Cell Death) – The Virtual Library of Biochemistry, Molecular Biology and Cell Biology Archived 2021-04-25 at the Wayback Machine
- Apoptosis Research Portal
- Apoptosis Info Apoptosis protocols, articles, news, and recent publications.
- Database of proteins involved in apoptosis
- Apoptosis Video
- Apoptosis Video (WEHI on YouTube )
- The Mechanisms of Apoptosis Archived 2018-03-09 at the Wayback Machine Kimball's Biology Pages. Simple explanation of the mechanisms of apoptosis triggered by internal signals (bcl-2), along the caspase-9, caspase-3 and caspase-7 pathway; and by external signals (FAS and TNF), along the caspase 8 pathway. Accessed 25 March 2007.
- WikiPathways – Apoptosis pathway Archived 2008-09-16 at the Wayback Machine
- "Finding Cancer's Self-Destruct Button". CR magazine (Spring 2007). Article on apoptosis and cancer.
- Xiaodong Wang's lecture: Introduction to Apoptosis Archived 2013-10-29 at the Wayback Machine
- Robert Horvitz's Short Clip: Discovering Programmed Cell Death
- The Bcl-2 Database Archived 2013-10-23 at the Wayback Machine
- DeathBase: a database of proteins involved in cell death, curated by experts
- European Cell Death Organization
- Apoptosis signaling pathway created by Cusabio