Programmed cell death

Programmed cell-death (or PCD) is death of a cell in any form, mediated by an intracellular program.^[1][2] PCD is carried out in a regulated process, which usually confers advantage during an organism's life-cycle. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose; the result is that the digits are separate. PCD serves fundamental functions during both plant and metazoa (multicellular animals) tissue development. Apoptosis and autophagy are both forms of programmed cell death, but necrosis is 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, 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.

Types

Overview of signal transduction pathways involved in apoptosis.

• Apoptosis or Type I cell-death. See Apoptosis
• Autophagic or Type II cell-death. (Cytoplasmic: characterized by the formation of large vacuoles that eat away organelles in a specific sequence prior to the destruction of the nucleus.)^[4]

Apoptosis

Apoptosis is the process of programmed cell death (PCD) that may occur in multicellular organisms.^[5] 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.^[6]

Autophagy

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 (physiology), Infection and cancer.

Mechanism

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.^[7] 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^[8] and Wallerian degeneration.

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

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:^[9]

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

History

The concept of "programmed cell-death" was used by Lockshin & Williams^[10] 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.^[11]

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).^[12]

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.^[13]

In "APL regulates vascular tissue identity in Arabidopsis",^[14] 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.^[15] 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.^[16]

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.^[17]

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.^[18]

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.^[19]

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.^[20] 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.^[21]

Evolutionary origin

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.^[22] 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.^[23]

Mitochondriate eukaryotic cells live poised between life and death, because mitochondria still retain their repertoire of molecules that can trigger cell suicide.^[24] This process has now been evolved to happen only when programmed.^{[citation needed]} Given certain signals 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

Clinical significance

ABL

The BCR-ABL oncogene has been found to be involved in the development of cancer in humans.^[25]

c-Myc

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.^[25]

Metastasis

A molecular characteristic of metastatic cells is their altered expression of several apoptotic genes.^[25]

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).

External links

• Apoptosis and Cell Death Labs
• International Cell Death Society
• The Bcl-2 Family Database