Programmed cell death

Programmed cell death (or PCD) is the death of a cell in any form, mediated by an intracellular program, and is also referred to as Cellular Suicide.[1][2][3] 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.[4]

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,[5] 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.[6]


The concept of "programmed cell-death" was used by Lockshin & Williams[7] in 1964 in relation to insect tissue development, around eight years before "apoptosis" was coined. Since then, PCD has become the more general of these two terms.

The first insight into the mechanism came from studying BCL2, the product of a putative oncogene activated by chromosome translocations often found in follicular lymphoma. Unlike other cancer genes, which promote cancer by stimulating cell proliferation, BCL2 promoted cancer by stopping lymphoma cells from being able to kill themselves.[8]

PCD has been the subject of increasing attention and research efforts. This trend has been highlighted with the award of the 2002 Nobel Prize in Physiology or Medicine to Sydney Brenner (United Kingdom), H. Robert Horvitz (US) and John E. Sulston (UK).[9]


Signal transduction pathways
Overview of signal transduction pathways involved in apoptosis.


Apoptosis is the process of programmed cell death (PCD) that may occur in multicellular organisms.[11] 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.[12]


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.


A critical regulator of autophagy induction is the kinase mTOR, which when activated, suppresses autophagy and when not activated promotes it. Three related serine/threonine kinases, UNC-51-like kinase -1, -2, and -3 (ULK1, ULK2, UKL3), which play a similar role as the yeast Atg1, act downstream of the mTOR complex. ULK1 and ULK2 form a large complex with the mammalian homolog of an autophagy-related (Atg) gene product (mAtg13) and the scaffold protein FIP200. Class III PI3K complex, containing hVps34, Beclin-1, p150 and Atg14-like protein or ultraviolet irradiation resistance-associated gene (UVRAG), is required for the induction of autophagy.

The ATG genes control the autophagosome formation through ATG12-ATG5 and LC3-II (ATG8-II) complexes. ATG12 is conjugated to ATG5 in a ubiquitin-like reaction that requires ATG7 and ATG10. The Atg12–Atg5 conjugate then interacts non-covalently with ATG16 to form a large complex. LC3/ATG8 is cleaved at its C terminus by ATG4 protease to generate the cytosolic LC3-I. LC3-I is conjugated to phosphatidylethanolamine (PE) also in a ubiquitin-like reaction that requires Atg7 and Atg3. The lipidated form of LC3, known as LC3-II, is attached to the autophagosome membrane.

Autophagy and apoptosis are connected both positively and negatively, and extensive crosstalk exists between the two. During nutrient deficiency, autophagy functions as a pro-survival mechanism, however, excessive autophagy may lead to cell death, a process morphologically distinct from apoptosis. Several pro-apoptotic signals, such as TNF, TRAIL, and FADD, also induce autophagy. Additionally, Bcl-2 inhibits Beclin-1-dependent autophagy, thereby functioning both as a pro-survival and as an anti-autophagic regulator.

Other types

Besides the above two types of PCD, other pathways have been discovered.[13] 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[14] and Wallerian degeneration.

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.

Eryptosis is a form of suicidal erythrocyte death.[15]

Aponecrosis is a hybrid of apoptosis and necrosis and refers to an incomplete apoptotic process that is completed by necrosis.[16]

NETosis is the process of cell-death generated by NETs.[17]

Paraptosis is another type of nonapoptotic cell death that is mediated by MAPK through the activation of IGF-1. It's characterized by the intracellular formation of vacuoles and swelling of mitochondria.[18]

Pyroptosis, an inflammatory type of cell death, is uniquely mediated by caspase 1, an enzyme not involved in apoptosis, in response to infection by certain microorganisms.[18]

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.

Atrophic factors

An atrophic factor is a force that causes a cell to die. Only natural forces on the cell are considered to be atrophic factors, whereas, for example, agents of mechanical or chemical abuse or lysis of the cell are considered not to be atrophic factors. Common types of atrophic factors are:[19]

  1. Decreased workload
  2. Loss of innervation
  3. Diminished blood supply
  4. Inadequate nutrition
  5. Loss of endocrine stimulation
  6. Senility
  7. Compression

Role in the development of the nervous system

Dying cells in the proliferative zone
Dying cells in the proliferate zone

The initial expansion of the developing nervous system is counterbalanced by the removal of neurons and their processes.[20] During the development of the nervous system almost 50% of developing neurons are naturally removed by programmed cell death (PCD).[21] PCD in the nervous system was first recognized in 1896 by John Beard.[22] Since then several theories were proposed to understand its biological significance during neural development.[23]

Role in neural development

PCD in the developing nervous system has been observed in proliferating as well as post-mitotic cells.[20] One theory suggests that PCD is an adaptive mechanism to regulate the number of progenitor cells. In humans, PCD in progenitor cells starts at gestational week 7 and remains until the first trimester.[24] This process of cell death has been identified in the germinal areas of the cerebral cortex, cerebellum, thalamus, brainstem, and spinal cord among other regions.[23] At gestational weeks 19-23, PCD is observed in post-mitotic cells.[25] The prevailing theory explaining this observation is the neurotrophic theory which states that PCD is required to optimize the connection between neurons and their afferent inputs and efferent targets.[23] Another theory proposes that developmental PCD in the nervous system occurs in order to correct for errors in neurons that have migrated ectopically, innervated incorrect targets, or have axons that have gone awry during path finding.[26] It is possible that PCD during the development of the nervous system serves different functions determined by the developmental stage, cell type, and even species.[23]

The neurotrophic theory

The neurotrophic theory is the leading hypothesis used to explain the role of programmed cell death in the developing nervous system. It postulates that in order to ensure optimal innervation of targets, a surplus of neurons is first produced which then compete for limited quantities of protective neurotrophic factors and only a fraction survive while others die by programmed cell death.[24] Furthermore, the theory states that predetermined factors regulate the amount of neurons that survive and the size of the innervating neuronal population directly correlates to the influence of their target field.[27]

The underlying idea that target cells secrete attractive or inducing factors and that their growth cones have a chemotactic sensitivity was first put forth by Santiago Ramon y Cajal in 1892.[28] Cajal presented the idea as an explanation for the “intelligent force” axons appear to take when finding their target but admitted that he had no empirical data.[28] The theory gained more attraction when experimental manipulation of axon targets yielded death of all innervating neurons. This developed the concept of target derived regulation which became the main tenet in the neurotrophic theory.[29][30] Experiments that further supported this theory led to the identification of the first neurotrophic factor, nerve growth factor (NGF).[31]

Peripheral versus central nervous system

Programmed cell death in the peripheral and central nervous system
Cell death in the peripheral vs central nervous system

Different mechanisms regulate PCD in the peripheral nervous system (PNS) versus the central nervous system (CNS). In the PNS, innervation of the target is proportional to the amount of the target-released neurotrophic factors NGF and NT3.[32][33] Expression of neurotrophin receptors, TrkA and TrkC, is sufficient to induce apoptosis in the absence of their ligands.[21] Therefore, it is speculated that PCD in the PNS is dependent on the release of neurotrophic factors and thus follows the concept of the neurotrophic theory.

Programmed cell death in the CNS is not dependent on external growth factors but instead relies on intrinsically derived cues. In the neocortex, a 4:1 ratio of excitatory to inhibitory interneurons is maintained by apoptotic machinery that appears to be independent of the environment.[33] Supporting evidence came from an experiment where interneuron progenitors were either transplanted into the mouse neocortex or cultured in vitro.[34] Transplanted cells died at the age of two weeks, the same age at which endogenous interneurons undergo apoptosis. Regardless of the size of the transplant, the fraction of cells undergoing apoptosis remained constant. Furthermore, disruption of TrkB, a receptor for brain derived neurotrophic factor (Bdnf), did not affect cell death. It has also been shown that in mice null for the proapoptotic factor Bax (Bcl-2-associated X protein) a larger percentage of interneurons survived compared to wild type mice.[34] Together these findings indicate that programmed cell death in the CNS partly exploits Bax-mediated signaling and is independent of BDNF and the environment. Apoptotic mechanisms in the CNS are still not well understood, yet it is thought that apoptosis of interneurons is a self-autonomous process.

Nervous system development in its absence

Programmed cell death can be reduced or eliminated in the developing nervous system by the targeted deletion of pro-apoptotic genes or by the overexpression of anti-apoptotic genes. The absence or reduction of PCD can cause serious anatomical malformations but can also result in minimal consequences depending on the gene targeted, neuronal population, and stage of development.[23] Excess progenitor cell proliferation that leads to gross brain abnormalities is often lethal, as seen in caspase-3 or caspase-9 knockout mice which develop exencephaly in the forebrain.[35][36] The brainstem, spinal cord, and peripheral ganglia of these mice develop normally, however, suggesting that the involvement of caspases in PCD during development depends on the brain region and cell type.[37] Knockout or inhibition of apoptotic protease activating factor 1 (APAF1), also results in malformations and increased embryonic lethality.[38][39][40] Manipulation of apoptosis regulator proteins Bcl-2 and Bax (overexpression of Bcl-2 or deletion of Bax) produces an increase in the number of neurons in certain regions of the nervous system such as the retina, trigeminal nucleus, cerebellum, and spinal cord.[41][42][43][44][45][46][47] However, PCD of neurons due to Bax deletion or Bcl-2 overexpression does not result in prominent morphological or behavioral abnormalities in mice. For example, mice overexpressing Bcl-2 have generally normal motor skills and vision and only show impairment in complex behaviors such as learning and anxiety.[48][49][50] The normal behavioral phenotypes of these mice suggest that an adaptive mechanism may be involved to compensate for the excess neurons.[23]

Invertebrates and vertebrates

A conserved apoptotic pathway in nematodes, mammals and fruitflies
A conserved apoptotic pathway in nematodes, mammals and fruitflies

Learning about PCD in various species is essential in understanding the evolutionary basis and reason for apoptosis in development of the nervous system. During the development of the invertebrate nervous system, PCD plays different roles in different species. The similarity of the asymmetric cell death mechanism in the nematode and the leech indicates that PCD may have an evolutionary significance in the development of the nervous system.[51] In the nematode, PCD occurs in the first hour of development leading to the elimination of 12% of non-gonadal cells including neuronal lineages.[52] Cell death in arthropods occurs first in the nervous system when ectoderm cells differentiate and one daughter cell becomes a neuroblast and the other undergoes apoptosis.[53] Furthermore, sex targeted cell death leads to different neuronal innervation of specific organs in males and females.[54] In Drosophila, PCD is essential in segmentation and specification during development.

In contrast to invertebrates, the mechanism of programmed cell death is found to be more conserved in vertebrates. Extensive studies performed on various vertebrates show that PCD of neurons and glia occurs in most parts of the nervous system during development. It has been observed before and during synaptogenesis in the central nervous system as well as the peripheral nervous system.[23] However, there are a few differences between vertebrate species. For example, mammals exhibit extensive arborization followed by PCD in the retina while birds do not.[55] Although synaptic refinement in vertebrate systems is largely dependent on PCD, other evolutionary mechanisms also play a role.[23]

In plant tissue

Programmed cell death in plants has a number of molecular similarities to animal apoptosis, but it also has differences, the most obvious 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.[56]

In "APL regulates vascular tissue identity in Arabidopsis",[57] Martin Bonke and his colleagues had stated that one of the two long-distance transport systems in vascular plants, xylem, consists of several cell-types "the differentiation of which involves deposition of elaborate cell-wall thickenings and programmed cell-death." The authors emphasize that the products of plant PCD play an important structural role.

Basic morphological and biochemical features of PCD have been conserved in both plant and animal kingdoms.[58] Specific types of plant cells carry out unique cell-death programs. These have common features with animal apoptosis—for instance, nuclear DNA degradation—but they also have their own peculiarities, such as nuclear degradation triggered by the collapse of the vacuole in tracheary elements of the xylem.[59]

Janneke Balk and Christopher J. Leaver, of the Department of Plant Sciences, University of Oxford, carried out research on mutations in the mitochondrial genome of sun-flower cells. Results of this research suggest that mitochondria play the same key role in vascular plant PCD as in other eukaryotic cells.[60]

PCD in pollen prevents inbreeding

During pollination, plants enforce self-incompatibility (SI) as an important means to prevent self-fertilization. Research on the corn poppy (Papaver rhoeas) has revealed that proteins in the pistil on which the pollen lands, interact with pollen and trigger PCD in incompatible (i.e., self) pollen. The researchers, Steven G. Thomas and Veronica E. Franklin-Tong, also found that the response involves rapid inhibition of pollen-tube growth, followed by PCD.[61]

In slime molds

The social slime mold Dictyostelium discoideum has the peculiarity of either adopting a predatory amoeba-like behavior in its unicellular form or coalescing into a mobile slug-like form when dispersing the spores that will give birth to the next generation.[62]

The stalk is composed of dead cells that have undergone a type of PCD that shares many features of an autophagic cell-death: massive vacuoles forming inside cells, a degree of chromatin condensation, but no DNA fragmentation.[63] The structural role of the residues left by the dead cells is reminiscent of the products of PCD in plant tissue.

D. discoideum is a slime mold, part of a branch that might have emerged from eukaryotic ancestors about a billion years before the present. It seems that they emerged after the ancestors of green plants and the ancestors of fungi and animals had differentiated. But, in addition to their place in the evolutionary tree, the fact that PCD has been observed in the humble, simple, six-chromosome D. discoideum has additional significance: It permits the study of a developmental PCD path that does not depend on caspases characteristic of apoptosis.[64]

Evolutionary origin of mitochondrial apoptosis

The occurrence of programmed cell death in protists is possible,[65][66] but it remains controversial. Some categorize death in those organisms as unregulated apoptosis-like cell death.[67][68]

Biologists had long suspected that mitochondria originated from bacteria that had been incorporated as endosymbionts ("living together inside") of larger eukaryotic cells. It was Lynn Margulis who from 1967 on championed this theory, which has since become widely accepted.[69] The most convincing evidence for this theory is the fact that mitochondria possess their own DNA and are equipped with genes and replication apparatus.

This evolutionary step would have been risky for the primitive eukaryotic cells, which began to engulf the energy-producing bacteria, as well as a perilous step for the ancestors of mitochondria, which began to invade their proto-eukaryotic hosts. This process is still evident today, between human white blood cells and bacteria. Most of the time, invading bacteria are destroyed by the white blood cells; however, it is not uncommon for the chemical warfare waged by prokaryotes to succeed, with the consequence known as infection by its resulting damage.

One of these rare evolutionary events, about two billion years before the present, made it possible for certain eukaryotes and energy-producing prokaryotes to coexist and mutually benefit from their symbiosis.[70]

Mitochondriate eukaryotic cells live poised between life and death, because mitochondria still retain their repertoire of molecules that can trigger cell suicide.[71] It is not clear why apoptotic machinery is maintained in the extant unicellular organisms. This process has now been evolved to happen only when programmed.[72] to cells (such as feedback from neighbors, stress or DNA damage), mitochondria release caspase activators that trigger the cell-death-inducing biochemical cascade. As such, the cell suicide mechanism is now crucial to all of our lives.

Clinical significance


The BCR-ABL oncogene has been found to be involved in the development of cancer in humans.[73]


c-Myc is involved in the regulation of apoptosis via its role in downregulating the Bcl-2 gene. Its role the disordered growth of tissue.[73]


A molecular characteristic of metastatic cells is their altered expression of several apoptotic genes.[73]

See also

Notes and references

  • Srivastava, R. E. in Molecular Mechanisms (Humana Press, 2007).
  • Kierszenbaum, A. L. & Tres, L. L. (ed Madelene Hyde) (ELSEVIER SAUNDERS, Philadelphia, 2012).
  1. ^ "Suicide".
  2. ^ Engelberg-Kulka H, Amitai S, Kolodkin-Gal I, Hazan R (2006). "Bacterial Programmed Cell Death and Multicellular Behavior in Bacteria". PLoS Genetics. 2 (10): e135. doi:10.1371/journal.pgen.0020135. PMC 1626106. PMID 17069462.
  3. ^ Green, Douglas (2011). Means To An End. New York: Cold Spring Harbor Laboratory Press. ISBN 978-0-87969-887-4.
  4. ^ Kierszenbaum, Abraham (2012). Histology and Cell Biology - An Introduction to Pathology. Philadelphia: ELSEVIER SAUNDERS.
  5. ^ Degterev, Alexei; Huang, Zhihong; Boyce, Michael; Li, Yaqiao; Jagtap, Prakash; Mizushima, Noboru; Cuny, Gregory D.; Mitchison, Timothy J.; Moskowitz, Michael A. (2005-07-01). "Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury". Nature Chemical Biology. 1 (2): 112–119. doi:10.1038/nchembio711. ISSN 1552-4450. PMID 16408008.
  6. ^ Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P (2014). "Regulated necrosis: the expanding network of non-apoptotic cell death pathways". Nat Rev Mol Cell Biol. 15 (2): 135–147. doi:10.1038/nrm3737. PMID 24452471.
  7. ^ Lockshin RA, Williams CM (1964). "Programmed cell death—II. Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths". Journal of Insect Physiology. 10 (4): 643–649. doi:10.1016/0022-1910(64)90034-4. Archived from the original on 2009-02-28.
  8. ^ Vaux DL, Cory S, Adams JM (September 1988). "Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells". Nature. 335 (6189): 440–2. doi:10.1038/335440a0. PMID 3262202.
  9. ^ "The Nobel Prize in Physiology or Medicine 2002". The Nobel Foundation. 2002. Retrieved 2009-06-21.
  10. ^ Schwartz LM, Smith SW, Jones ME, Osborne BA (1993). "Do all programmed cell deaths occur via apoptosis?". PNAS. 90 (3): 980–4. doi:10.1073/pnas.90.3.980. PMC 45794. PMID 8430112.;and, for a more recent view, see Bursch W, Ellinger A, Gerner C, Fröhwein U, Schulte-Hermann R (2000). "Programmed cell death (PCD). Apoptosis, autophagic PCD, or others?". Annals of the New York Academy of Sciences. 926: 1–12. doi:10.1111/j.1749-6632.2000.tb05594.x. PMID 11193023.
  11. ^ Green, Douglas (2011). Means To An End. New York: Cold Spring Harbor Laboratory Press. ISBN 978-0-87969-888-1.
  12. ^ D. Bowen, Ivor (1993). "Cell Biology International 17". Cell Biology International. 17 (4): 365–380. doi:10.1006/cbir.1993.1075. PMID 8318948. Archived from the original on 2014-03-12. Retrieved 2012-10-03.
  13. ^ Kroemer G, Martin SJ (2005). "Caspase-independent cell death". Nature Medicine. 11 (7): 725–30. doi:10.1038/nm1263. PMID 16015365.
  14. ^ Dixon Scott J.; Lemberg Kathryn M.; Lamprecht Michael R.; Skouta Rachid; Zaitsev Eleina M.; Gleason Caroline E.; Patel Darpan N.; Bauer Andras J.; Cantley Alexandra M.; et al. (2012). "Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death". Cell. 149 (5): 1060–1072. doi:10.1016/j.cell.2012.03.042. PMID 22632970.
  15. ^ Lang, F; Lang, KS; Lang, PA; Huber, SM; Wieder, T (2006). "Mechanisms and significance of eryptosis". Antioxidants & Redox Signaling. 8 (7–8): 1183–92. doi:10.1089/ars.2006.8.1183. PMID 16910766.
  16. ^ Formigli, L; et al. (2000). "aponecrosis: morphological and biochemical exploration of a syncretic process of cell death sharing apoptosis and necrosis". Journal of Cellular Physiology. 182 (1): 41–49. doi:10.1002/(sici)1097-4652(200001)182:1<41::aid-jcp5>;2-7.
  17. ^ Fadini, GP; Menegazzo, L; Scattolini, V; Gintoli, M; Albiero, M; Avogaro, A (25 November 2015). "A perspective on NETosis in diabetes and cardiometabolic disorders". Nutrition, Metabolism, and Cardiovascular Diseases : NMCD. 26 (1): 1–8. doi:10.1016/j.numecd.2015.11.008. PMID 26719220.
  18. ^ a b Ross, Michael (2016). Histology: A Text and Atlas (7th ed.). p. 94. ISBN 978-1451187427.
  19. ^ Chapter 10: All the Players on One Stage from
  20. ^ a b Tau, GZ (2009). "Normal development of brain circuits". Neuropsychopharmacology. 35 (1): 147–168. doi:10.1038/npp.2009.115. PMC 3055433. PMID 19794405.
  21. ^ a b Dekkers, MP (2013). "Death of developing neurons: new insights and implications for connectivity". Journal of Cell Biology. 203 (3): 385–393. doi:10.1083/jcb.201306136. PMC 3824005. PMID 24217616.
  22. ^ Oppenheim, RW (1981). Neuronal cell death and some related regressive phenomena during neurogenesis: a selective historical review and progress report. In Studies in Developmental Neurobiology: Essays in Honor of Viktor Hamburger: Oxford University Press. pp. 74–133.
  23. ^ a b c d e f g h Buss, RR (2006). "Adaptive roles of programmed cell death during nervous system development". Annual Review of Neuroscience. 29: 1–35. doi:10.1146/annurev.neuro.29.051605.112800. PMID 16776578.
  24. ^ a b De la Rosa, EJ; De Pablo, F (October 23, 2000). "Cell death in early neural development: beyond the neurotrophic theory". Trends in Neurosciences. 23 (10): 454–458. doi:10.1016/s0166-2236(00)01628-3.
  25. ^ Lossi, L; Merighi, A (April 2003). "In vivo cellular and molecular mechanisms of neuronal apoptosis in the mammalian CNS". Progress in Neurobiology. 69 (5): 287–312. doi:10.1016/s0301-0082(03)00051-0. PMID 12787572.
  26. ^ Finlay, BL (1989). "Control of cell number in the developing mammalian visual system". Progress in Neurobiology. 32 (3): 207–234. doi:10.1016/0301-0082(89)90017-8.
  27. ^ Rubenstein, John; Pasko Rakic (2013). "Regulation of Neuronal Survival by Neurotrophins in the Developing Peripheral Nervous System". Patterning and Cell Type Specification in the Developing CNS and PNS: Comprehensive Developmental Neuroscience. Academic Press. ISBN 978-0-12-397348-1.
  28. ^ a b Constantino, Sotelo (2002). The chemotactic hypothesis of Cajal: a century behind. Progress in Brain Research. 136. pp. 11–20. doi:10.1016/s0079-6123(02)36004-7. ISBN 9780444508157. PMID 12143376.
  29. ^ Oppenheim, Ronald (1989). "The neurotrophic theory and naturally occurring motorneuron death". Trends in Neurosciences. 12 (7): 252–255. doi:10.1016/0166-2236(89)90021-0.
  30. ^ Dekkers, MP; Nikoletopoulou, V; Barde, YA (November 11, 2013). "Cell biology in neuroscience: Death of developing neurons: new insights and implications for connectivity". J Cell Biol. 203 (3): 385–393. doi:10.1083/jcb.201306136. PMC 3824005. PMID 24217616.
  31. ^ Cowan, WN (2001). "Viktor Hamburger and Rita Levi-Montalcini: the path to the discovery of nerve growth factor". Annual Review of Neuroscience. 24: 551–600. doi:10.1146/annurev.neuro.24.1.551. PMID 11283321.
  32. ^ Weltman, JK (February 8, 1987). "The 1986 Nobel Prize for Physiology or Medicine awarded for discovery of growth factors: Rita Levi-Montalcini, M.D., and Stanley Cohen, Ph.D.". New England Regional Allergy Proceedings. 8 (1): 47–8. doi:10.2500/108854187779045385. PMID 3302667.
  33. ^ a b Dekkers, M (April 5, 2013). "Programmed Cell Death in Neuronal Development". Science. 340 (6128): 39–41. doi:10.1126/science.1236152. PMID 23559240.
  34. ^ a b Southwell, D.G. (November 2012). "Intrinsically determined cell death of developing cortical interneurons". Nature. 491 (7422): 109–115. doi:10.1038/nature11523. PMC 3726009. PMID 23041929.
  35. ^ Kuida, K (1998). "Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9". Cell. 94 (3): 325–337. doi:10.1016/s0092-8674(00)81476-2. PMID 9708735.
  36. ^ Kuida, K (1996). "Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice". Nature. 384 (6607): 368–372. doi:10.1038/384368a0. PMID 8934524.
  37. ^ Oppenheim, RW (2001). "Programmed cell death of developing mammalian neurons after genetic deletion of caspases". Journal of Neuroscience. 21 (13): 4752–4760. doi:10.1523/JNEUROSCI.21-13-04752.2001.
  38. ^ Cecconi, F (1998). "Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development". Cell. 94 (6): 727–737. doi:10.1016/s0092-8674(00)81732-8. PMID 9753320.
  39. ^ Hao, Z (2005). "Specific ablation of the apoptotic functions of cytochrome c reveals a differential requirement for cytochrome c and Apaf-1 in apoptosis". Cell. 121 (4): 579–591. doi:10.1016/j.cell.2005.03.016. PMID 15907471.
  40. ^ Yoshida, H (1998). "Apaf1 is required for mitochondrial pathways of apoptosis and brain development". Cell. 94 (6): 739–750. doi:10.1016/s0092-8674(00)81733-x.
  41. ^ Bonfanti, L (1996). "Protection of retinal ganglion cells from natural and axotomy-induced cell death in neonatal transgenic mice overexpressing bcl-2". Journal of Neuroscience. 16 (13): 4186–4194. doi:10.1523/JNEUROSCI.16-13-04186.1996.
  42. ^ Martinou, JC (1994). "Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia". Neuron. 13 (4): 1017–1030. doi:10.1016/0896-6273(94)90266-6.
  43. ^ Zanjani, HS (1996). "Increased cerebellar Purkinje cell numbers in mice overexpressing a human bcl-2 transgene". Journal of Computational Neurology. 374 (3): 332–341. doi:10.1002/(sici)1096-9861(19961021)374:3<332::aid-cne2>;2-2.
  44. ^ Zup, SL (2003). "Overexpression of bcl-2 reduces sex differences in neuron number in the brain and spinal cord". Journal of Neuroscience. 23 (6): 2357–2362. doi:10.1523/JNEUROSCI.23-06-02357.2003.
  45. ^ Fan, H (2001). "Elimination of Bax expression in mice increases cerebellar Purkinje cell numbers but not the number of granule cells". Journal of Computational Neurology. 436: 82–91. doi:10.1002/cne.1055.abs.
  46. ^ Mosinger, Ogilvie (1998). "Suppression of developmental retinal cell death but not of photoreceptor degeneration in Bax-deficient mice". Investigative Ophthalmology & Visual Science. 39: 1713–1720.
  47. ^ White, FA (1998). "Widespread elimination of naturally occurring neuronal death in Bax-deficient mice". Journal of Neuroscience. 18 (4): 1428–1439. doi:10.1523/JNEUROSCI.18-04-01428.1998.
  48. ^ Gianfranceschi, L (1999). "Behavioral visual acuity of wild type and bcl2 transgenic mouse". Vision Research. 39 (3): 569–574. doi:10.1016/s0042-6989(98)00169-2.
  49. ^ Rondi-Reig, L (2002). "To die or not to die, does it change the function? Behavior of transgenic mice reveals a role for developmental cell death". Brain Research Bulletin. 57: 85–91. doi:10.1016/s0361-9230(01)00639-6.
  50. ^ Rondi-Reig, L (2001). "Transgenic mice with neuronal overexpression of bcl-2 gene present navigation disabilities in a water task". Neuroscience. 104: 207–215. doi:10.1016/s0306-4522(01)00050-1.
  51. ^ Sulston, JE (1980). "The Caenorhabditis elegans male: postembryonic development of nongonadal structures". Developmental Biology. 78 (2): 542–576. doi:10.1016/0012-1606(80)90352-8.
  52. ^ Sulston2, JE (1983). "The embryonic cell lineage of the nematode Caenorhabditis elegans". Developmental Biology. 100 (1): 64–119. doi:10.1016/0012-1606(83)90201-4. PMID 6684600.
  53. ^ Doe, Cq (1985). "Development and segmental differences in the pattern of neuronal precursor cells". Journal of Developmental Biology. 111: 193–205. doi:10.1016/0012-1606(85)90445-2.
  54. ^ Giebultowicz, JM (1984). "Sexual differentiation in the terminal ganglion of the moth Manduca sexta: role of sex-specific neuronal death". Journal of Comparative Neurology. 226: 87–95. doi:10.1002/cne.902260107. PMID 6736297.
  55. ^ Cook, B (1998). "Developmental neuronal death is not a universal phenomenon among cell types in the chick embryo retina". Journal of Comparative Neurology. 396: 12–19. doi:10.1002/(sici)1096-9861(19980622)396:1<12::aid-cne2>;2-l.
  56. ^ 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 2012-03-14.
  57. ^ Bonke M, Thitamadee S, Mähönen AP, Hauser MT, Helariutta Y (2003). "APL regulates vascular tissue identity in Arabidopsis". Nature. 426 (6963): 181–6. doi:10.1038/nature02100. PMID 14614507.
  58. ^ Solomon M, Belenghi B, Delledonne M, Menachem E, Levine A (1999). "The involvement of cysteine proteases and protease inhibitor genes in the regulation of programmed cell death in plants". The Plant Cell. 11 (3): 431–44. doi:10.2307/3870871. JSTOR 3870871. PMC 144188. PMID 10072402. See also related articles in The Plant Cell Online
  59. ^ Ito J, Fukuda H (2002). "ZEN1 Is a Key Enzyme in the Degradation of Nuclear DNA during Programmed Cell Death of Tracheary Elements". The Plant Cell. 14 (12): 3201–11. doi:10.1105/tpc.006411. PMC 151212. PMID 12468737.
  60. ^ Balk J, Leaver CJ (2001). "The PET1-CMS Mitochondrial Mutation in Sunflower Is Associated with Premature Programmed Cell Death and Cytochrome c Release". The Plant Cell. 13 (8): 1803–18. doi:10.1105/tpc.13.8.1803. PMC 139137. PMID 11487694.
  61. ^ Thomas SG, Franklin-Tong VE (2004). "Self-incompatibility triggers programmed cell death in Papaver pollen". Nature. 429 (6989): 305–9. doi:10.1038/nature02540. PMID 15152254.
  62. ^ Crespi B, Springer S (2003). "Ecology. Social slime molds meet their match". Science. 299 (5603): 56–7. doi:10.1126/science.1080776. PMID 12511635.
  63. ^ Levraud JP, Adam M, Luciani MF, de Chastellier C, Blanton RL, Golstein P (2003). "Dictyostelium cell death: early emergence and demise of highly polarized paddle cells". Journal of Cell Biology. 160 (7): 1105–14. doi:10.1083/jcb.200212104. PMC 2172757. PMID 12654899.
  64. ^ Roisin-Bouffay C, Luciani MF, Klein G, Levraud JP, Adam M, Golstein P (2004). "Developmental cell death in dictyostelium does not require paracaspase". Journal of Biological Chemistry. 279 (12): 11489–94. doi:10.1074/jbc.M312741200. PMID 14681218.
  65. ^ Deponte, M (2008). "Programmed cell death in protists". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1783 (7): 1396–1405. doi:10.1016/j.bbamcr.2008.01.018. PMID 18291111.
  66. ^ Kaczanowski S, Sajid M and Reece S E 2011 Evolution of apoptosis-like programmed cell death in unicellular protozoan parasites Parasites Vectors 4 44
  67. ^ Proto, W. R.; Coombs, G. H.; Mottram, J. C. (2012). "Cell death in parasitic protozoa: regulated or incidental?" (PDF). Nature Reviews Microbiology. 11 (1): 58–66. doi:10.1038/nrmicro2929. PMID 23202528. Archived from the original (PDF) on 2016-03-03. Retrieved 2014-11-14.
  68. ^ Szymon Kaczanowski; Mohammed Sajid; Sarah E Reece (2011). "Evolution of apoptosis-like programmed cell death in unicellular protozoan parasites". Parasites & Vectors. 4: 44. doi:10.1186/1756-3305-4-44.
  69. ^ de Duve C (1996). "The birth of complex cells". Scientific American. 274 (4): 50–7. doi:10.1038/scientificamerican0496-50. PMID 8907651.
  70. ^ Dyall SD, Brown MT, Johnson PJ (2004). "Ancient invasions: from endosymbionts to organelles". Science. 304 (5668): 253–7. doi:10.1126/science.1094884. PMID 15073369.
  71. ^ Chiarugi A, Moskowitz MA (2002). "Cell biology. PARP-1--a perpetrator of apoptotic cell death?". Science. 297 (5579): 200–1. doi:10.1126/science.1074592. PMID 12114611.
  72. ^ Kaczanowski, S. Apoptosis: its origin, history, maintenance and the medical implications for cancer and aging. Phys Biol 13,
  73. ^ a b c Srivastava, Rakesh (2007). Apoptosis, Cell Signaling, and Human Diseases. Humana Press.

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Anoikis is a form of programmed cell death that occurs in anchorage-dependent cells when they detach from the surrounding extracellular matrix (ECM). Usually cells stay close to the tissue to which they belong since the communication between proximal cells as well as between cells and ECM provide essential signals for growth or survival. When cells are detached from the ECM, there is a loss of normal cell–matrix interactions, and they may undergo anoikis. However, metastatic tumor cells may escape from anoikis and invade other organs.

Autolysis (biology)

In biology, autolysis, more commonly known as self-digestion, refers to the destruction of a cell through the action of its own enzymes. It may also refer to the digestion of an enzyme by another molecule of the same enzyme.

The term derives from the Greek words αὐτο- ("self") and λύσις ("splitting").


"Autoschizis" is a term derived from the Greek αὐτο- auto-, meaning "self", and σχίζειν skhizein, "to split". It was introduced in 1998 to describe a novel form of cancer cell death characterized by a reduction in cell size that occurs due to the loss of cytoplasm through self-excision (the cell splits open) without the loss of cell organelles, morphologic degradation of the cells nucleus and nucleolus without the formation of apoptotic bodies and destruction of the cell membrane. The cell death results from karyorrhexis and karyolysis. Autoschizis can be initiated via in vivo treatment with vitamin C (VC), synthetic vitamin K (VK3) or, better, a combination of both. The treatment has been tested on various types of cancer cells in vitro and in vivo with positive results.


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. 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.

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. Fas was first identified using a monoclonal antibody generated by immunizing mice with the FS-7 cell line. Thus, the name Fas is derived from FS-7-associated surface antigen.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.


Karyolysis (from Greek κάρυον karyon—kernel, seed, or nucleus), and λύσις lysis from λύειν lyein, "to separate") is the complete dissolution of the chromatin of a dying cell due to the enzymatic degradation by endonucleases. The whole cell will eventually stain uniformly with eosin after karyolysis. It is usually associated with karyorrhexis and occurs mainly as a result of necrosis, while in apoptosis after karyorrhexis the nucleus usually dissolves into apoptotic bodies.Disintegration of the cytoplasm, pyknosis of the nuclei, and karyolysis of the nuclei of scattered transitional cells may be seen in urine from healthy individuals as well as in urine containing malignant cells. Cells with an attached tag of partially preserved cytoplasm were initially described by Papanicolaou and are sometimes called comet or decoy cells. They may have some of the characteristics of malignancy, and it is therefore important that they be recognized for what they are.


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.


Neurotrophins are a family of proteins that induce the survival, development, and function of neurons.

They belong to a class of growth factors, secreted proteins that are capable of signaling particular cells to survive, differentiate, or grow. Growth factors such as neurotrophins that promote the survival of neurons are known as neurotrophic factors. Neurotrophic factors are secreted by target tissue and act by preventing the associated neuron from initiating programmed cell death – thus allowing the neurons to survive. Neurotrophins also induce differentiation of progenitor cells, to form neurons.

Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain (for example, the hippocampus) retain the ability to grow new neurons from neural stem cells, a process known as neurogenesis. Neurotrophins are chemicals that help to stimulate and control neurogenesis.


Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.Programmed death-ligand 1 (PD-L1) is a 40kDa type 1 transmembrane protein that has been speculated to play a major role in suppressing the adaptive arm of immune system during particular events such as pregnancy, tissue allografts, autoimmune disease and other disease states such as hepatitis. Normally the adaptive immune system reacts to antigens that are associated with immune system activation by exogenous or endogenous danger signals. In turn, clonal expansion of antigen-specific CD8+ T cells and/or CD4+ helper cells is propagated. The binding of PD-L1 to the inhibitory checkpoint molecule PD-1 transmits an inhibitory signal based on interaction with phosphatases (SHP-1 or SHP-2) via Immunoreceptor Tyrosine-Based Switch Motif (ITSM) motif . This reduces the proliferation of antigen-specific T-cells in lymph nodes, while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells) - further mediated by a lower regulation of the gene Bcl-2.


Programmed cell death 1 ligand 2 (also known as PD-L2, B7-DC) is a protein that in humans is encoded by the PDCD1LG2 gene. PDCD1LG2 has also been designated as CD273 (cluster of differentiation 273).


Paraptosis (from the Greek παρά para, "related to" and apoptosis) is a type of programmed cell death, morphologically distinct from apoptosis and necrosis. The defining features of paraptosis are cytoplasmic vacuolation, independent of caspase activation and inhibition, and lack of apoptotic morphology. Paraptosis lacks several of the hallmark characteristics of apoptosis, such as membrane blebbing, chromatin condensation, and nuclear fragmentation. Like apoptosis and other types of programmed cell death, the cell is involved in causing its own death, and gene expression is required. This is in contrast to necrosis, which is non-programmed cell death that results from injury to the cell.

Paraptosis has been found in some developmental and neurodegenerative cell deaths, as well as induced by several cancer drugs.


Perforin-1 is a protein that in humans is encoded by the PRF1 gene and the Prf1 gene in mice.


Phenoptosis (pheno – showing or demonstrating, ptosis – programmed death), designated by V.P. Skulachev in 1999, signifies the phenomenon of programmed death of an organism, i.e. that an organism's genes include features that under certain circumstances will cause the organism to rapidly degenerate and die off. Recently this has been referred to as "fast phenoptosis" as aging is being explored as "slow phenoptosis". Phenoptosis is a common feature of living species, whose ramifications for humans is still being explored.

Poly (ADP-ribose) polymerase

Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death.

Programmed cell death protein 1

Programmed cell death protein 1, also known as PD-1 and CD279 (cluster of differentiation 279), is a protein on the surface of cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.PD-1 is an immune checkpoint and guards against autoimmunity through two mechanisms. First, it promotes apoptosis (programmed cell death) of antigen-specific T-cells in lymph nodes. Second, it reduces apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells).PD-1 inhibitors, a new class of drugs that block PD-1, activate the immune system to attack tumors and are used to treat certain types of cancer.The PD-1 protein in humans is encoded by the PDCD1 gene. PD-1 is a cell surface receptor that belongs to the immunoglobulin superfamily and is expressed on T cells and pro-B cells. PD-1 binds two ligands, PD-L1 and PD-L2.


Pyknosis, or karyopyknosis, is the irreversible condensation of chromatin in the nucleus of a cell undergoing necrosis or apoptosis. It is followed by karyorrhexis, or fragmentation of the nucleus.

Pyknosis (from Greek pyknono meaning "to thicken up, to close or to condense") is also observed in the maturation of erythrocytes (a red blood cell) and the neutrophil (a type of white blood cell). The maturing metarubricyte (a stage in RBC maturation) will condense its nucleus before expelling it to become a reticulocyte. The maturing neutrophil will condense its nucleus into several connected lobes that stay in the cell until the end of its cell life.

Pyknotic nuclei are often found in the zona reticularis of the adrenal gland. They are also found in the keratinocytes of the outermost layer in parakeratinised epithelium.


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 this process, immune cells recognize foreign danger signals within themselves, release pro-inflammatory cytokines, swell, burst and die. The released cytokines attract other immune cells to fight the infection and contribute to inflammation in the tissue. Pyroptosis promotes the rapid clearance of various bacterial and viral infections by removing intracellular replication niches and enhancing the host's defensive responses. However, in pathogenic chronic diseases, the inflammatory response does not eradicate the primary stimulus, as would normally occur in most cases of infection or injury, and thus a chronic form of inflammation ensues that ultimately contributes to tissue damage. Some examples of pyroptosis include Salmonella-infected macrophages and abortively HIV-infected T helper cells.The initiation of pyroptosis in infected macrophages is caused by the recognition of flagellin components of Salmonella and Shigella species (and similar pathogen-associated molecular patterns (PAMPs) in other microbial pathogens) by NOD-like receptors (NLRs). These receptors function like plasma membrane toll-like receptors (TLRs), but recognize antigens located within the cell rather than outside of it.

In contrast to apoptosis, pyroptosis requires the function of the enzyme caspase-1. Caspase-1 is activated during pyroptosis by a large supramolecular complex termed the pyroptosome (also known as an inflammasome). Only one large pyroptosome is formed in each macrophage, within minutes after infection. Biochemical and mass spectroscopic analysis revealed that this pyroptosome is largely composed of dimers of the adaptor protein ASC (apoptosis-associated speck protein containing a CARD or Caspase activation and recruitment domain).

Unlike apoptosis, cell death by pyroptosis results in plasma-membrane rupture and the release of damage-associated molecular pattern (DAMP) molecules such as ATP, DNA and ASC oligomers (specks) into the extracellular milieu, including cytokines that recruit more immune cells and further perpetuate the inflammatory cascade in the tissue. These processes are in marked contrast to the packaging of cellular contents and non-inflammatory phagocytic uptake of membrane-bound apoptotic bodies that characterizes apoptosis.

Senescence (biology of ageing)
Related topics
Fas path
TNF path
Human embryogenesis in the first three weeks
Week 1
Week 2
Week 3

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