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Programmed Cell Death Definition Essay

For the protein, see Programmed cell death protein 1.

Programmed cell death (or PCD) is the death of a cell in any form, mediated by an intracellular program.[1][2] 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 are both forms of programmed cell death, but necrosis was long seen as a non-physiological process that occurs as a result of infection or injury.[3]

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,[4] has been recognized as an alternate 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.[5]


The concept of "programmed cell-death" was used by Lockshin & Williams[6] 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 chromosometranslocations 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.[7]

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).[8]



Apoptosis is the process of programmed cell death (PCD) that may occur in multicellular organisms.[10]Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomalDNA 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.[11]


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, neurodegenerativediseases, stress, infection and cancer.


A critical regulator of autophagy induction is the kinasemTOR, 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 ATGgenes 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[edit]

Besides the above two types of PCD, other pathways have been discovered.[12] 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[13] 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.[14]

Aponecrosis is a hybrid of apoptosis and necrosis and refers to an incomplete apoptotic process that is completed by necrosis.[15]

NETosis is the process of cell-death generated by NETs.[16]

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[edit]

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.[by whom?] Common types of atrophic factors are:[17]

  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[edit]

The initial expansion of the developing nervous system is counterbalanced by the removal of neurons and their processes.[18] During the development of the nervous system almost 50% of developing neurons are naturally removed by programmed cell death (PCD).[19] PCD in the nervous system was first recognized in 1896 by John Beard.[20] Since then several theories were proposed to understand its biological significance during neural development.[21]

Role in neural development[edit]

PCD in the developing nervous system has been observed in proliferating as well as post-mitotic cells.[18] 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.[22] 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.[21] At gestational weeks 19-23, PCD is observed in post-mitotic cells.[23] 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.[21] 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.[24] 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.[21]

The neurotrophic theory[edit]

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.[22] 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.[25]

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.[26] 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.[26] 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.[27][28] Experiments that further supported this theory led to the identification of the first neurotrophic factor, nerve growth factor (NGF).[29]

Peripheral versus central nervous system[edit]

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.[30][31] Expression of neurotrophin receptors, TrkA and TrkC, is sufficient to induce apoptosis in the absence of their ligands.[19] 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.[31] Supporting evidence came from an experiment where interneuron progenitors were either transplanted into the mouse neocortex or cultured in vitro.[32] 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.[32] 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[edit]

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.[21] Excess progenitor cell proliferation that leads to gross brain abnormalities is often lethal, as seen in caspase-3 or caspase-9knockout mice which develop exencephaly in the forebrain.[33][34] 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.[35] Knockout or inhibition of apoptotic protease activating factor 1 (APAF1), also results in malformations and increased embryonic lethality.[36][37][38] 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.[39][40][41][42][43][44][45] 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.[46][47][48] The normal behavioral phenotypes of these mice suggest that an adaptive mechanism may be involved to compensate for the excess neurons.[21]

Invertebrates and vertebrates[edit]

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.[49] In the nematode, PCD occurs in the first hour of development leading to the elimination of 12% of non-gonadal cells including neuronal lineages.[50] 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.[51] Furthermore, sex targeted cell death leads to different neuronal innervation of specific organs in males and females.[52] 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.[21] 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.[53] Although synaptic refinement in vertebrate systems is largely dependent on PCD, other evolutionary mechanisms also play a role.[21]

In plant tissue[edit]

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.[54]

In "APL regulates vascular tissue identity in Arabidopsis",[55] 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.[56] It should be noted, however, that 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.[57]

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.[58]

PCD in pollen prevents inbreeding[edit]

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.[59]

In slime molds[edit]

The social slime moldDictyostelium 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.[60]

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.[61] 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-chromosomeD. discoideum has additional significance: It permits the study of a developmental PCD path that does not depend on caspases characteristic of apoptosis.[62]

Evolutionary origin of mitochondrial apoptosis[edit]

The occurrence of programmed cell death in protists is possible,[63][64] but it remains controversial. Some categorize death in those organisms as unregulated apoptosis-like cell death.[65][66]

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.[67] 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.[68]

Mitochondriate eukaryotic cells live poised between life and death, because mitochondria still retain their repertoire of molecules that can trigger cell suicide.[69] 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.[70] 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.

Programmed death of entire organisms[edit]

Main article: Phenoptosis

Clinical significance[edit]


The BCR-ABL oncogene has been found to be involved in the development of cancer in humans.[71]


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.[71]


A molecular characteristic of metastatic cells is their altered expression of several apoptotic genes.[71]

See also[edit]

Notes and references[edit]

  • Srivastava, R. E. in Molecular Mechanisms (Humana Press, 2007).
  • Kierszenbaum, A. L. & Tres, L. L. (ed Madelene Hyde) (ELSEVIER SAUNDERS, Philadelphia, 2012).
  1. ^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. 
  2. ^Green, Douglas (2011). Means To An End. New York: Cold Spring Harbor Laboratory Press. ISBN 978-0-87969-887-4. 
  3. ^Kierszenbaum, Abraham (2012). Histology and Cell Biology - An Introduction to Pathology. Philadelphia: ELSEVIER SAUNDERS. 
  4. ^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. 
  5. ^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. 
  6. ^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. 
  7. ^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. 
  8. ^"The Nobel Prize in Physiology or Medicine 2002". The Nobel Foundation. 2002. Retrieved 2009-06-21. 
  9. ^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. 
  10. ^Green, Douglas (2011). Means To An End. New York: Cold Spring Harbor Laboratory Press. ISBN 978-0-87969-888-1. 
  11. ^D. Bowen, Ivor (1993). Cell Biology International 17. Great Britain: Portland Press. pp. 365–380. ISSN 1095-8355. 
  12. ^Kroemer G, Martin SJ (2005). "Caspase-independent cell death". Nature Medicine. 11 (7): 725–30. doi:10.1038/nm1263. PMID 16015365. 
  13. ^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. "Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death". Cell. 149 (5): 1060–1072. doi:10.1016/j.cell.2012.03.042. 
  14. ^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. 
  15. ^Formigli, L; et al. (2000). "aponecrosis: morphological and biochemical exploration of a syncretic process of cell death sharing apoptosis and necrosis". Journal Cellular Physiology. 182 (1): 41–49. doi:10.1002/(sici)1097-4652(200001)182:1<41::aid-jcp5>3.0.co;2-7. 
  16. ^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: 1–8. doi:10.1016/j.numecd.2015.11.008. PMID 26719220. 
  17. ^Chapter 10: All the Players on One Stage from PsychEducation.org
  18. ^ abTau, GZ (2009). "Normal development of brain circuits". Neuropsychopharmacology. 35 (1): 147–168. doi:10.1038/npp.2009.115. PMC 3055433. PMID 19794405. 
  19. ^ abDekkers, 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. 
  20. ^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. 
  21. ^ abcdefghBuss, 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. 
  22. ^ abDe 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. 
  23. ^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. 
  24. ^Finlay, BL (1989). "Control of cell number in the developing mammalian visual system". Progress in Neurobiology. 32: 207–234. doi:10.1016/0301-0082(89)90017-8. 
  25. ^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. 
  26. ^ abConstantino, Sotelo (2002). "The chemotactic hypothesis of Cajal: a century behind". Progress in Brain Research. 136: 11–20. doi:10.1016/s0079-6123(02)36004-7. 
  27. ^
Overview of signal transduction pathways involved in apoptosis.
Dying cells in the proliferate zone
Cell death in the peripheral vs central nervous system
A conserved apoptotic pathway in nematodes, mammals and fruitflies

The cells of a multicellular organism are members of a highly organized community. The number of cells in this community is tightly regulated—not simply by controlling the rate of cell division, but also by controlling the rate of cell death. If cells are no longer needed, they commit suicide by activating an intracellular death program. This process is therefore called programmed cell death, although it is more commonly called apoptosis (from a Greek word meaning “falling off,” as leaves from a tree).

The amount of apoptosis that occurs in developing and adult animal tissues can be astonishing. In the developing vertebrate nervous system, for example, up to half or more of the nerve cells normally die soon after they are formed. In a healthy adult human, billions of cells die in the bone marrow and intestine every hour. It seems remarkably wasteful for so many cells to die, especially as the vast majority are perfectly healthy at the time they kill themselves. What purposes does this massive cell death serve?

In some cases, the answers are clear. Mouse paws, for example, are sculpted by cell death during embryonic development: they start out as spadelike structures, and the individual digits separate only as the cells between them die (Figure 17-35). In other cases, cells die when the structure they form is no longer needed. When a tadpole changes into a frog, the cells in the tail die, and the tail, which is not needed in the frog, disappears (Figure 17-36). In many other cases, cell death helps regulate cell numbers. In the developing nervous system, for example, cell death adjusts the number of nerve cells to match the number of target cells that require innervation. In all these cases, the cells die by apoptosis.

Figure 17-35

Sculpting the digits in the developing mouse paw by apoptosis. (A) The paw in this mouse embryo has been stained with a dye that specifically labels cells that have undergone apoptosis. The apoptotic cells appear as bright green dots between the developing (more...)

Figure 17-36

Apoptosis during the metamorphosis of a tadpole into a frog. As a tadpole changes into a frog, the cells in the tadpole tail are induced to undergo apoptosis; as a consequence, the tail is lost. All the changes that occur during metamorphosis, including (more...)

In adult tissues, cell death exactly balances cell division. If this were not so, the tissue would grow or shrink. If part of the liver is removed in an adult rat, for example, liver cell proliferation increases to make up the loss. Conversely, if a rat is treated with the drug phenobarbital—which stimulates liver cell division (and thereby liver enlargement)—and then the phenobarbital treatment is stopped, apoptosis in the liver greatly increases until the liver has returned to its original size, usually within a week or so. Thus, the liver is kept at a constant size through the regulation of both the cell death rate and the cell birth rate.

In this short section, we describe the molecular mechanisms of apoptosis and its control. In the final section, we consider how the extracellular control of cell proliferation and cell death contributes to the regulation of cell numbers in multicellular organisms.

Apoptosis Is Mediated by an Intracellular Proteolytic Cascade

Cells that die as a result of acute injury typically swell and burst. They spill their contents all over their neighbors—a process called cell necrosis—causing a potentially damaging inflammatory response. By contrast, a cell that undergoes apoptosis dies neatly, without damaging its neighbors. The cell shrinks and condenses. The cytoskeleton collapses, the nuclear envelope disassembles, and the nuclear DNA breaks up into fragments. Most importantly, the cell surface is altered, displaying properties that cause the dying cell to be rapidly phagocytosed, either by a neighboring cell or by a macrophage (a specialized phagocytic cell, discussed in Chapter 24), before any leakage of its contents occurs (Figure 17-37). This not only avoids the damaging consequences of cell necrosis but also allows the organic components of the dead cell to be recycled by the cell that ingests it.

Figure 17-37

Cell death. These electron micrographs show cells that have died by (A) necrosis or (B and C) apoptosis. The cells in (A) and (B) died in a culture dish, whereas the cell in (C) died in a developing tissue and has been engulfed by a neighboring cell. (more...)

The intracellular machinery responsible for apoptosis seems to be similar in all animal cells. This machinery depends on a family of proteases that have a cysteine at their active site and cleave their target proteins at specific aspartic acids. They are therefore called caspases. Caspases are synthesized in the cell as inactive precursors, or procaspases, which are usually activated by cleavage at aspartic acids by other caspases (Figure 17-38A). Once activated, caspases cleave, and thereby activate, other procaspases, resulting in an amplifying proteolytic cascade (Figure 17-38B). Some of the activated caspases then cleave other key proteins in the cell. Some cleave the nuclear lamins, for example, causing the irreversible breakdown of the nuclear lamina; another cleaves a protein that normally holds a DNA-degrading enzyme (a DNAse) in an inactive form, freeing the DNAse to cut up the DNA in the cell nucleus. In this way, the cell dismantles itself quickly and neatly, and its corpse is rapidly taken up and digested by another cell.

Figure 17-38

The caspase cascade involved in apoptosis. (A) Each suicide protease is made as an inactive proenzyme (procaspase), which is usually activated by proteolytic cleavage by another member of the caspase family. As indicated, two of the cleaved fragments (more...)

Activation of the intracellular cell death pathway, like entry into a new stage of the cell cycle, is usually triggered in a complete, all-or-none fashion. The protease cascade is not only destructive and self-amplifying but also irreversible, so that once a cell reaches a critical point along the path to destruction, it cannot turn back.

Procaspases Are Activated by Binding to Adaptor Proteins

All nucleated animal cells contain the seeds of their own destruction, in the form of various inactive procaspases that lie waiting for a signal to destroy the cell. It is therefore not surprising that caspase activity is tightly regulated inside the cell to ensure that the death program is held in check until needed.

How are procaspases activated to initiate the caspase cascade? A general principle is that the activation is triggered by adaptor proteins that bring multiple copies of specific procaspases, known as initiator procaspases, close together in a complex or aggregate. In some cases, the initiator procaspases have a small amount of protease activity, and forcing them together into a complex causes them to cleave each other, triggering their mutual activation. In other cases, the aggregation is thought to cause a conformational change that activates the procaspase. Within moments, the activated caspase at the top of the cascade cleaves downstream procaspases to amplify the death signal and spread it throughout the cell (see Figure 17-38B).

Procaspase activation can be triggered from outside the cell by the activation of death receptors on the cell surface. Killer lymphocytes (discussed in Chapter 24), for example, can induce apoptosis by producing a protein called Fas ligand, which binds to the death receptor protein Fas on the surface of the target cell. The clustered Fas proteins then recruit intracellular adaptor proteins that bind and aggregate procaspase-8 molecules, which cleave and activate one another. The activated caspase-8 molecules then activate downstream procaspases to induce apoptosis (Figure 17-39A). Some stressed or damaged cells kill themselves by producing both the Fas ligand and the Fas protein, thereby triggering an intracellular caspase cascade.

Figure 17-39

Induction of apoptosis by either extracellular or intracellular stimuli. (A) Extracellular activation. A killer lymphocyte carrying the Fas ligand binds and activates Fas proteins on the surface of the target cell. Adaptor proteins bind to the intracellular (more...)

When cells are damaged or stressed, they can also kill themselves by triggering procaspase aggregation and activation from within the cell. In the best understood pathway, mitochondria are induced to release the electron carrierproteincytochrome c (see Figure 14-26) into the cytosol, where it binds and activates an adaptor protein called Apaf-1 (Figure 17-39B). This mitochondrial pathway of procaspase activation is recruited in most forms of apoptosis to initiate or to accelerate and amplify the caspase cascade. DNA damage, for example, as discussed earlier, can trigger apoptosis. This response usually requires p53, which can activate the transcription of genes that encode proteins that promote the release of cytochrome c from mitochondria. These proteins belong to the Bcl-2 family.

Bcl-2 Family Proteins and IAP Proteins Are the Main Intracellular Regulators of the Cell Death Program

The Bcl-2 family of intracellular proteins helps regulate the activation of procaspases. Some members of this family, like Bcl-2 itself or Bcl-XL, inhibit apoptosis, at least partly by blocking the release of cytochromec from mitochondria. Other members of the Bcl-2 family are not death inhibitors, but instead promote procaspase activation and cell death. Some of these apoptosis promoters, such as Bad, function by binding to and inactivating the death-inhibiting members of the family, whereas others, like Bax and Bak, stimulate the release of cytochrome c from mitochondria. If the genes encoding Bax and Bak are both inactivated, cells are remarkably resistant to most apoptosis-inducing stimuli, indicating the crucial importance of these proteins in apoptosis induction. Bax and Bak are themselves activated by other apoptosis-promoting members of the Bcl-2 family such as Bid.

Another important family of intracellular apoptosis regulators is the IAP (inhibitor of apoptosis) family. These proteins are thought to inhibit apoptosis in two ways: they bind to some procaspases to prevent their activation, and they bind to caspases to inhibit their activity. IAP proteins were originally discovered as proteins produced by certain insect viruses, which use them to prevent the infected cell from killing itself before the virus has had time to replicate. When mitochondria release cytochromec to activate Apaf-1, they also release a protein that blocks IAPs, thereby greatly increasing the efficiency of the death activation process.

The intracellular cell death program is also regulated by extracellular signals, which can either activate apoptosis or inhibit it. These signal molecules mainly act by regulating the levels or activity of members of the Bcl-2 and IAP families. We see in the next section how these signal molecules help multicellular organisms regulate their cell numbers.


In multicellular organisms, cells that are no longer needed or are a threat to the organism are destroyed by a tightly regulated cell suicide process known as programmed cell death, or apoptosis. Apoptosis is mediated by proteolytic enzymes called caspases, which trigger cell death by cleaving specific proteins in the cytoplasm and nucleus. Caspases exist in all cells as inactive precursors, or procaspases, which are usually activated by cleavage by other caspases, producing a proteolytic caspase cascade. The activation process is initiated by either extracellular or intracellular death signals, which cause intracellular adaptor molecules to aggregate and activate procaspases. Caspase activation is regulated by members of the Bcl-2 and IAP protein families.

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