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Apoptosis is a pathway of cell death in which cells activate enzymes that degrade the cells
own nuclear DNA and nuclear and cytoplasmic proteins. Fragments of the apoptotic cells
then break off, giving the appearance that is responsible for the name (apoptosis, falling
off). The plasma membrane of the apoptotic cell remains intact, but the membrane is altered
in such a way that the cell and its fragments become avid targets for phagocytes. The dead
cell and its fragments are rapidly cleared before cellular contents have leaked out, so
apoptotic cell death does not elicit an inflammatory reaction in the host. Apoptosis differs in
this respect from necrosis, which is characterized by loss of membrane integrity, enzymatic
digestion of cells, leakage of cellular contents, and frequently a host reaction (Fig. 16 and
Table 11). However, apoptosis and necrosis sometimes coexist, and apoptosis induced by
some pathologic stimuli may progress to necrosis.
Causes of Apoptosis
Apoptosis occurs in many normal situations and serves to eliminate potentially harmful cells
and cells that have outlived their usefulness. It also occurs as a pathologic event when cells
are damaged beyond repair, especially when the damage affects the cells DNA or proteins; in
these situations, the irreparably damaged cell is eliminated.
Cell loss in proliferating cell populations, such as intestinal crypt epithelia, in order
to maintain a constant number
Elimination of cells that have served their useful purpose, such as neutrophils in an
acute inflammatory response and lymphocytes at the end of an immune response. In
these situations, cells undergo apoptosis because they are deprived of necessary
survival signals, such as growth factors.
Cell injury in certain infections, particularly viral infections, in which loss of infected
cells is largely due to apoptotic death that may be induced by the virus (as in
adenovirus and human immunodeficiency virus infections) or by the host immune
response (as in viral hepatitis).
Morphology
Figure 121 Morphologic appearance of apoptotic cells. Apoptotic
In H&E-stained tissue sections, the nuclei of apoptotic cells show various stages of chromatin
condensation and aggregation and, ultimately, karyorrhexis (Fig. 121); at the molecular level
this is reflected in fragmentation of DNA into nucleosome-sized pieces. The cells rapidly
shrink, form cytoplasmic buds, and fragment into apoptotic bodies composed of membranebound vesicles of cytosol and organelles (Fig. 16). Because these fragments are quickly
extruded and phagocytosed without eliciting an inflammatory response, even substantial
apoptosis may be histologically undetectable.
Mechanisms of Apoptosis
Apoptosis results from the activation of enzymes called caspases (so named because they are
cysteine proteases that cleave proteins after aspartic residues). The activation of caspases
depends on a finely tuned balance between production of pro- and anti-apoptotic proteins.
Two distinct pathways converge on caspase activation: the mitochondrial pathway and the
death receptor pathway (Fig. 122). Although these pathways can intersect, they are
generally induced under different conditions, involve different molecules, and serve distinct
roles in physiology and disease.
Figure 122 Mechanisms of apoptosis. The two pathways of
and activate caspase-8. In many cell types caspase-8 may cleave and activate a pro-apoptotic
member of the Bcl-2 family called Bid, thus feeding into the mitochondrial pathway. The
combined activation of both pathways delivers a lethal blow to the cell. Cellular proteins,
notably a caspase antagonist called FLIP, block activation of caspases downstream of death
receptors. Interestingly, some viruses produce homologues of FLIP, and it is suggested that
this is a mechanism that viruses use to keep infected cells alive. The death receptor pathway
is involved in elimination of self-reactive lymphocytes and in killing of target cells by some
cytotoxic T lymphocytes.
Examples of Apoptosis
Cell death in many situations is caused by apoptosis. The examples listed next illustrate the
role of the two pathways of apoptosis in normal physiology and in disease.
Growth Factor Deprivation
Hormone-sensitive cells deprived of the relevant hormone, lymphocytes that are not
stimulated by antigens and cytokines, and neurons deprived of nerve growth factor die by
apoptosis. In all these situations, apoptosis is triggered by the mitochondrial pathway and is
attributable to activation of pro-apoptotic members of the Bcl-2 family and decreased
synthesis of Bcl-2 and Bcl-xL.
DNA Damage
Exposure of cells to radiation or chemotherapeutic agents induces DNA damage, which if
severe may trigger apoptotic death. When DNA is damaged, the p53 protein accumulates in
cells. It first arrests the cell cycle (at the G1 phase) to allow the DNA to be repaired before it
is replicated (Chapter 5). However, if the damage is too great to be repaired successfully, p53
triggers apoptosis, mainly by stimulating sensors that ultimately activate Bax and Bak, and by
increasing the synthesis of pro-apoptotic members of the Bcl-2 family. When p53 is mutated
or absent (as it is in certain cancers), cells with damaged DNA that would otherwise undergo
apoptosis survive. In such cells, the DNA damage may result in mutations or DNA
rearrangements (e.g., translocations) that lead to neoplastic transformation (Chapter 5).
Accumulation of Misfolded Proteins: ER Stress
During normal protein synthesis, chaperones in the ER control the proper folding of newly
synthesized proteins, and misfolded polypeptides are ubiquitinated and targeted for
proteolysis. If, however, unfolded or misfolded proteins accumulate in the ER because of
inherited mutations or environmental perturbations, they induce a protective cellular response
that is called the unfolded protein response (Fig. 124). This response activates signaling
pathways that increase the production of chaperones and retard protein translation, thus
reducing the levels of misfolded proteins in the cell. In circumstances in which the
accumulation of misfolded proteins overwhelms these adaptations, the result is ER stress,
which leads to the activation of caspases and ultimately apoptosis. Intracellular accumulation
of abnormally folded proteins, caused by mutations, aging, or unknown environmental
factors, may cause diseases by reducing the availability of the normal protein or by inducing
cell injury (Table 12). Cell death as a result of protein misfolding is now recognized as a
feature of a number of neurodegenerative diseases, including Alzheimer, Huntington, and
Parkinson diseases, and possibly type 2 diabetes. Deprivation of glucose and oxygen and
stresses such as infections also result in protein misfolding, culminating in cell injury and
death.
Figure 124 The unfolded protein response and ER stress. A Table 12 Diseases Caused by
Misfolding of Proteins
Apoptosis of Self-Reactive Lymphocytes
Lymphocytes capable of recognizing self antigens are normally produced in all individuals. If
these lymphocytes encounter self antigens, the cells die by apoptosis. Both the mitochondrial
pathway and the Fas death receptor pathway have been implicated in this process (Chapter 4).
Failure of apoptosis of self-reactive lymphocytes is one of the causes of autoimmune
diseases.
Cytotoxic T LymphocyteMediated Apoptosis
Regulated mechanism of cell death that serves to eliminate unwanted and irreparably
damaged cells, with the least possible host reaction
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.
Contents
1 Types
o 1.1 Apoptosis
o 1.2 Autophagy
1.2.1 Mechanism
2 Atrophic factors
3 History
4 In plant tissue
o 4.1 PCD in pollen prevents inbreeding
5 In slime molds
6 Evolutionary origin
8 Clinical significance
o 8.1 ABL
o 8.2 c-Myc
o 8.3 Metastasis
9 See also
11 External links
Types
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 Atg12Atg5 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 prosurvival 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 "nonapoptotic 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.[by whom?] Common types of
atrophic factors are:[9]
1. Decreased workload
2. Loss of innervation
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 apoptosisfor
instance, nuclear DNA degradationbut 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]
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.
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
Netosis
Anoikis
Aponecrosis
Apoptosis-inducing factor
Apoptosome
Autolysis (biology)
Autophagy
Autoschizis
Bcl-2
Calpains
Caspases
Cell damage
Cornification
Cytochrome c
Cytotoxicity
Diablo homolog
Entosis
Eryptosis
Etosis or Netosis
Excitotoxicity
Inflammasome
Mitotic catastrophe
Necrobiology
Necroptosis
Necrosis
NET
Parthanatos
Pyroptosis
RIP kinases
Wallerian degeneration
1.
2.
Jump up ^ Green, Douglas (2011). Means To An End. New York: Cold Spring
Harbor Laboratory Press. ISBN 978-0-87969-888-1.
3.
4.
Jump up ^ Schwartz LM, Smith SW, Jones ME, Osborne BA (1993). "Do all
programmed cell deaths occur via apoptosis?". PNAS 90 (3): 9804.
doi:10.1073/pnas.90.3.980. PMC 45794. PMID 8430112.;and, for a more recent view,
see Bursch W, Ellinger A, Gerner C, Frhwein U, Schulte-Hermann R (2000).
"Programmed cell death (PCD). Apoptosis, autophagic PCD, or others?". Annals of
the New York Academy of Sciences 926: 112. doi:10.1111/j.17496632.2000.tb05594.x. PMID 11193023.
5.
Jump up ^ Green, Douglas (2011). Means To An End. New York: Cold Spring
Harbor Laboratory Press. ISBN [[Special:BookSources/978879698881|
978879698881 [[Category:Articles with invalid ISBNs]]]] Check |isbn= value
(help).
6.
7.
8.
Jump up ^ 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): 10601072.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
23.
24.
25.
External links
Mitochondria
Cellular senescence
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Apoptosis
Apoptosis
In contrast to necrosis, which is a form of traumatic cell death that results from acute cellular
injury, in general apoptosis confers advantages during an organism's lifecycle. For example,
the separation of fingers and toes in a developing human embryo occurs because cells
between the digits apoptose. Unlike necrosis, apoptosis produces cell fragments called
apoptotic bodies that phagocytic cells are able to engulf and quickly remove before the
contents of the cell can spill out onto surrounding cells and cause damage.[5]
Between 50 and 70 billion cells die each day due to apoptosis in the average human adult. For
an average child between the ages of 8 and 14, approximately 20 billion to 30 billion cells die
a day.[6]
Research in and around apoptosis has increased substantially since the early 1990s. In
addition to its importance as a biological phenomenon, defective apoptotic processes have
been implicated in an extensive variety of diseases. Excessive apoptosis causes atrophy,
whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer.
Contents
2 Process
o 2.1 Mitochondrial regulation
o 2.2 Direct signal transduction
2.2.2.1 Caspases
o 2.3 Execution
o 2.4 Removal of dead cells
3 Pathway knock-outs
5 Implication in disease
o 5.1 Defective pathways
o 5.2 Inhibition
5.2.2 Treatments
5.3.1 Treatments
6 Plants
7 Caspase-independent apoptosis
9 See also
10 References
11 External links
John E. Sulston won the Nobel Prize in Medicine in 2002, for his pioneering research on
apoptosis.
In Greek, apoptosis translates to the "dropping off" of petals or leaves from plants or trees.
Cormack, professor of Greek language, reintroduced the term for medical use as it had a
medical meaning for the Greeks over two thousand years before. Hippocrates used the term
to mean "the falling off of the bones". Galen extended its meaning to "the dropping of the
scabs". Cormack was no doubt aware of this usage when he suggested the name. Debate
continues over the correct pronunciation, with opinion divided between a pronunciation with
the second p silent (/ptoss/ ap--TOH-sis[2][11]) and the second p pronounced (/pp
toss/),[2][12] as in the original Greek.[citation needed] In English, the p of the Greek -pt- consonant
cluster is typically silent at the beginning of a word (e.g. pterodactyl, Ptolemy), but
articulated when used in combining forms preceded by a vowel, as in helicopter or the orders
of insects: diptera, lepidoptera, etc.
In the original Kerr Wyllie and Currie paper, British Journal of Cancer, 1972 Aug;26(4):23957, there is a footnote regarding the pronunciation:
"We are most grateful to Professor James Cormack of the Department of Greek, University of
Aberdeen, for suggesting this term. The word "apoptosis" () is used in Greek to
describe the "dropping off" or "falling off" of petals from flowers, or leaves from trees. To
show the derivation clearly, we propose that the stress should be on the penultimate syllable,
the second half of the word being pronounced like "ptosis" (with the "p" silent), which comes
from the same root "to fall", and is already used to describe the drooping of the upper eyelid."
Process
Mitochondrial regulation
The mitochondria are essential to multicellular life. Without them, a cell ceases to respire
aerobically and quickly dies. This fact forms the basis for some apoptotic pathways.
Apoptotic proteins that target mitochondria affect them in different ways. They may cause
mitochondrial swelling through the formation of membrane pores, or they may increase the
permeability of the mitochondrial membrane and cause apoptotic effectors to leak out.[13]
These are very closely related to intrinsic pathway, and tumors arise more frequently through
intrinsic pathway than the extrinsic pathway because of sensitivity.[16] There is also a growing
body of evidence indicating that nitric oxide is able to induce apoptosis by helping to
dissipate the membrane potential of mitochondria and therefore make it more permeable.[17]
Nitric oxide has been implicated in initiating and inhibiting apoptosis through its possible
action as a signal molecule of subsequent pathways that activate apoptosis.[18][citation needed]
Mitochondrial proteins known as SMACs (small mitochondria-derived activator of caspases)
are released into the cytosol following an increase in permeability. SMAC binds to inhibitor
of apoptosis proteins (IAPs) and deactivates them, preventing the IAPs from arresting the
apoptotic process and therefore allowing apoptosis to proceed. IAP also normally suppresses
the activity of a group of cysteine proteases called caspases,[19] which carry out the
degradation of the cell, therefore the actual degradation enzymes can be seen to be indirectly
regulated by mitochondrial permeability.
Cytochrome c is also released from mitochondria due to formation of a channel, the
mitochondrial apoptosis-induced channel (MAC), in the outer mitochondrial membrane,[20]
and serves a regulatory function as it precedes morphological change associated with
apoptosis.[13] Once cytochrome c is released it binds with Apoptotic protease activating factor
- 1 (Apaf-1) and ATP, which then bind to pro-caspase-9 to create a protein complex known as
an apoptosome. The apoptosome cleaves the pro-caspase to its active form of caspase-9,
which in turn activates the effector caspase-3.
MAC (not to be confused with the Membrane Attack Complex formed by complement
activation, also commonly denoted as MAC), also called "Mitochondrial Outer Membrane
Permeabilization Pore" is regulated by various proteins, such as those encoded by the
mammalian Bcl-2 family of anti-apoptopic genes, the homologs of the ced-9 gene found in
C. elegans.[21][22] Bcl-2 proteins are able to promote or inhibit apoptosis by direct action on
MAC/MOMPP. Bax and/or Bak form the pore, while Bcl-2, Bcl-xL or Mcl-1 inhibit its
formation.
Overview of TNF (left) and Fas (right) signalling in apoptosis, an example of direct signal
transduction.
Two theories of the direct initiation of apoptotic mechanisms in mammals have been
suggested: the TNF-induced (tumour necrosis factor) model and the Fas-Fas ligand-mediated
model, both involving receptors of the TNF receptor (TNFR) family[23] coupled to extrinsic
signals.
TNF path
TNF is a cytokine produced mainly by activated macrophages, and is the major extrinsic
mediator of apoptosis. Most cells in the human body have two receptors for TNF: TNF-R1
and TNF-R2. The binding of TNF to TNF-R1 has been shown to initiate the pathway that
leads to caspase activation via the intermediate membrane proteins TNF receptor-associated
death domain (TRADD) and Fas-associated death domain protein cIAP1/2 inhibit TNF-
signaling by binding to TRAF2. FLIP inhibits the activation of caspase-8 (FADD).[24] Binding
of this receptor can also indirectly lead to the activation of transcription factors involved in
cell survival and inflammatory responses.[25] However, signalling through TNF-R1 might also
induce apoptosis in a Caspase-independent manner.[26] The link between TNF and apoptosis
shows why an abnormal production of TNF plays a fundamental role in several human
diseases, especially in autoimmune diseases.
The Fas receptor (also known as Apo-1 or CD95) binds the Fas ligand (FasL), a
transmembrane protein part of the TNF family.[23] The interaction between Fas and FasL
results in the formation of the death-inducing signaling complex (DISC), which contains the
FADD, caspase-8 and caspase-10. In some types of cells (type I), processed caspase-8
directly activates other members of the caspase family, and triggers the execution of
apoptosis of the cell. In other types of cells (type II), the Fas-DISC starts a feedback loop that
spirals into increasing release of proapoptotic factors from mitochondria and the amplified
activation of caspase-8.[27]
Common components
Following TNF-R1 and Fas activation in mammalian cells a balance between proapoptotic
(BAX,[28] BID, BAK, or BAD) and anti-apoptotic (Bcl-Xl and Bcl-2) members of the Bcl-2
family is established. This balance is the proportion of proapoptotic homodimers that form in
the outer-membrane of the mitochondrion. The proapoptotic homodimers are required to
make the mitochondrial membrane permeable for the release of caspase activators such as
cytochrome c and SMAC. Control of proapoptotic proteins under normal cell conditions of
nonapoptotic cells is incompletely understood, but in general, Bax or Bak are activated by the
activation of BH3-only proteins, part of the Bcl-2 family.
Caspases
Caspases play the central role in the transduction of DR apoptotic signals. Caspases are
proteins that are highly conserved, cysteine-dependent aspartate-specific proteases. There are
two types of caspases: initiator caspases, caspase 8,10,9,2, and effector caspases, caspase
3,7,6. The activation of initiator caspases requires binding to specific oligomeric adaptor
protein. Effector caspases are then activated by these active initiator caspases through
proteolytic cleavage. The active effector caspases then proteolytically degrade a host of
intracellular proteins to carry out the cell death program.
Caspase-independent apoptotic pathway
Execution
Many pathways and signals lead to apoptosis, but there is only one mechanism that actually
causes the death of a cell.[citation needed] After a cell receives stimulus, it undergoes organized
degradation of cellular organelles by activated proteolytic caspases. A cell undergoing
apoptosis shows a characteristic morphology:
1. Cell shrinkage and rounding are shown because of the breakdown of the
proteinaceous cytoskeleton by caspases.[30]
2. The cytoplasm appears dense, and the organelles appear tightly packed.
3. Chromatin undergoes condensation into compact patches against the nuclear envelope
(also known as the perinuclear envelope) in a process known as pyknosis, a hallmark
of apoptosis.[31][32]
4. The nuclear envelope becomes discontinuous and the DNA inside it is fragmented in a
process referred to as karyorrhexis. The nucleus breaks into several discrete
chromatin bodies or nucleosomal units due to the degradation of DNA.[33]
5. The cell membrane shows irregular buds known as blebs.
6. The cell breaks apart into several vesicles called apoptotic bodies, which are then
phagocytosed.
Apoptosis progresses quickly and its products are quickly removed, making it difficult to
detect or visualize. During karyorrhexis, endonuclease activation leaves short DNA
fragments, regularly spaced in size. These give a characteristic "laddered" appearance on agar
gel after electrophoresis. Tests for DNA laddering differentiate apoptosis from ischemic or
toxic cell death.[34]
Pathway knock-outs
Many knock-outs have been made in the apoptosis pathways to test the function of each of
the proteins. Several caspases, in addition to APAF-1 and FADD, have been mutated to
determine the new phenotype. In order to create a tumor necrosis factor (TNF) knockout, an
exon containing the nucleotides 3704-5364 was removed from the gene. This exon encodes a
portion of the mature TNF domain, as well as the leader sequence, which is a highly
conserved region necessary for proper intracellular processing. TNF-/- mice develop
normally and have no gross structural or morphological abnormalities. However, upon
immunization with SRBC (sheep red blood cells), these mice demonstrated a deficiency in
the maturation of an antibody response; they were able to generate normal levels of IgM, but
could not develop specific IgG levels. Apaf-1 is the protein that turns on caspase 9 by
cleavage to begin the caspase cascade that leads to apoptosis. Since a -/- mutation in the
APAF-1 gene is embryonic lethal, a gene trap strategy was used in order to generate an
APAF-1 -/- mouse. This assay is used to disrupt gene function by creating an intragenic gene
fusion. When an APAF-1 gene trap is introduced into cells, many morphological changes
occur, such as spina bifida, the persistence of interdigital webs, and open brain. In addition,
after embryonic day 12.5, the brain of the embryos showed several structural changes. APAF1 cells are protected from apoptosis stimuli such as irradiation. A BAX-1 knock-out mouse
exhibits normal forebrain formation and a decreased programmed cell death in some neuronal
populations and in the spinal cord, leading to an increase in motor neurons.
The caspase proteins are integral parts of the apoptosis pathway, so it follows that knock-outs
made have varying damaging results. A caspase 9 knock-out leads to a severe brain
malformation. A caspase 8 knock-out leads to cardiac failure and thus embryonic lethality.
However, with the use of cre-lox technology, a caspase 8 knock-out has been created that
exhibits an increase in peripheral T cells, an impaired T cell response, and a defect in neural
tube closure. These mice were found to be resistant to apoptosis mediated by CD95, TNFR,
etc. but not resistant to apoptosis caused by UV irradiation, chemotherapeutic drugs, and
other stimuli. Finally, a caspase 3 knock-out was characterized by ectopic cell masses in the
brain and abnormal apoptotic features such as membrane blebbing or nuclear fragmentation.
A remarkable feature of these KO mice is that they have a very restricted phenotype: Casp3,
9, APAF-1 KO mice have deformations of neural tissue and FADD and Casp 8 KO showed
defective heart development, however in both types of KO other organs developed normally
and some cell types were still sensitive to apoptotic stimuli suggesting that unknown
proapoptotic pathways exist.
Implication in disease
Defective pathways
The many different types of apoptotic pathways contain a multitude of different biochemical
components, many of them not yet understood.[40] As a pathway is more or less sequential in
nature, it is a victim of causality; removing or modifying one component leads to an effect in
another. In a living organism, this can have disastrous effects, often in the form of disease or
disorder. A discussion of every disease caused by modification of the various apoptotic
pathways would be impractical, but the concept overlying each one is the same: The normal
functioning of the pathway has been disrupted in such a way as to impair the ability of the
cell to undergo normal apoptosis. This results in a cell that lives past its "use-by-date" and is
able to replicate and pass on any faulty machinery to its progeny, increasing the likelihood of
the cell's becoming cancerous or diseased.
A recently described example of this concept in action can be seen in the development of a
lung cancer called NCI-H460.[41] The X-linked inhibitor of apoptosis protein (XIAP) is
overexpressed in cells of the H460 cell line. XIAPs bind to the processed form of caspase-9,
and suppress the activity of apoptotic activator cytochrome c, therefore overexpression leads
to a decrease in the amount of proapoptotic agonists. As a consequence, the balance of antiapoptotic and proapoptotic effectors is upset in favour of the former, and the damaged cells
continue to replicate despite being directed to die.
Dysregulation of p53
The tumor-suppressor protein p53 accumulates when DNA is damaged due to a chain of
biochemical factors. Part of this pathway includes alpha-interferon and beta-interferon, which
induce transcription of the p53 gene, resulting in the increase of p53 protein level and
enhancement of cancer cell-apoptosis.[42] p53 prevents the cell from replicating by stopping
the cell cycle at G1, or interphase, to give the cell time to repair, however it will induce
apoptosis if damage is extensive and repair efforts fail. Any disruption to the regulation of the
p53 or interferon genes will result in impaired apoptosis and the possible formation of
tumors.
Inhibition
Inhibition of apoptosis can result in a number of cancers, autoimmune diseases, inflammatory
diseases, and viral infections. It was originally believed that the associated accumulation of
cells was due to an increase in cellular proliferation, but it is now known that it is also due to
a decrease in cell death. The most common of these diseases is cancer, the disease of
excessive cellular proliferation, which is often characterized by an overexpression of IAP
family members. As a result, the malignant cells experience an abnormal response to
apoptosis induction: Cycle-regulating genes (such as p53, ras or c-myc) are mutated or
inactivated in diseased cells, and further genes (such as bcl-2) also modify their expression in
tumors.
HeLa cell
Apoptosis in HeLa cells is inhibited by proteins produced by the cell; these inhibitory
proteins target retinoblastoma tumor-suppressing proteins.[43] These tumor-suppressing
proteins regulate the cell cycle, but are rendered inactive when bound to an inhibitory protein.
[43]
HPV E6 and E7 are inhibitory proteins expressed by the human papillomavirus, HPV
being responsible for the formation of the cervical tumor from which HeLa cells are derived.
[44]
HPV E6 causes p53, which regulates the cell cycle, to become inactive.[45] HPV E7 binds
to retinoblastoma tumor suppressing proteins and limits its ability to control cell division.[45]
These two inhibitory proteins are partially responsible for HeLa cells' immortality by
inhibiting apoptosis to occur.[46] CDV (Canine Distemper Virus) is able to induce apoptosis
despite the presence of these inhibitory proteins. This is an important oncolytic property of
CDV: this virus is capable of killing canine lymphoma cells. Oncoproteins E6 and E7 still
leave p53 inactive, but they are not able to avoid the activation of caspases induced from the
stress of viral infection. These oncolytic properties provided a promising link between CDV
and lymphoma apoptosis, which can lead to development of alternative treatment methods for
both canine lymphoma and human non-Hodgkin lymphoma. Defects in the cell cycle are
thought to be responsible for the resistance to chemotherapy or radiation by certain tumor
cells, so a virus that can induce apoptosis despite defects in the cell cycle is useful for cancer
treatment.[46]
Treatments
The main method of treatment for death signaling-related diseases involves either increasing
or decreasing the susceptibility of apoptosis in diseased cells, depending on whether the
disease is caused by either the inhibition of or excess apoptosis. For instance, treatments aim
to restore apoptosis to treat diseases with deficient cell death, and to increase the apoptotic
threshold to treat diseases involved with excessive cell death. To stimulate apoptosis, one can
increase the number of death receptor ligands (such as TNF or TRAIL), antagonize the antiapoptotic Bcl-2 pathway, or introduce Smac mimetics to inhibit the inhibitor (IAPs). The
addition of agents such as Herceptin, Iressa, or Gleevec works to stop cells from cycling and
causes apoptosis activation by blocking growth and survival signaling further upstream.
Finally, adding p53-MDM2 complexes displaces p53 and activates the p53 pathway, leading
to cell cycle arrest and apoptosis. Many different methods can be used either to stimulate or
to inhibit apoptosis in various places along the death signaling pathway.[47]
Apoptosis is a multi-step, multi-pathway cell-death programme that is inherent in every cell
of the body. In cancer, the apoptosis cell-division ratio is altered. Cancer treatment by
chemotherapy and irradiation kills target cells primarily by inducing apoptosis.
Hyperactive apoptosis
On the other hand, loss of control of cell death (resulting in excess apoptosis) can lead to
neurodegenerative diseases, hematologic diseases, and tissue damage. The progression of
HIV is directly linked to excess, unregulated apoptosis. In a healthy individual, the number of
CD4+ lymphocytes is in balance with the cells generated by the bone marrow; however, in
HIV-positive patients, this balance is lost due to an inability of the bone marrow to regenerate
CD4+ cells. In the case of HIV, CD4+ lymphocytes die at an accelerated rate through
uncontrolled apoptosis, when stimulated.
Treatments
Treatments aiming to inhibit apoptosis work to simultaneously inhibit the expression of
proapoptotic factors and promote the expression of anti-apoptotic factors. Fas-induced
apoptosis can be blocked by use of FLIPs (FLICE-inhibitory proteins, which inhibit caspases8 and -10), Bcl-2 (which prevents cytochrome c release and the subsequent activation of
caspase 9), and CrmA (Cytokine response modifier A). Increasing the concentration of IAPs
works to block specific caspases. Finally, the Akt protein kinase promotes cell survival
through two pathways. Akt phosphorylates and inhibits Bas (a Bcl-2 family member), causing
Bas to interact with the 14-3-3 scaffold, resulting in Bcl dissociation and thus cell survival.
Akt also activates IKK, which leads to NF-B activation and cell survival. Active NF-B
induces the expression of anti-apoptotic genes such as Bcl-2, resulting in inhibition of
apoptosis. NF-B has been found to play both an antiapoptotic role and a proapoptotic role
depending on the stimuli utilized and the cell type.[48]
HIV progression
The progression of the human immunodeficiency virus infection into AIDS is due primarily
to the depletion of CD4+ T-helper lymphocytes in a manner that is too rapid for the body's
bone marrow to replenish the cells, leading to a compromised immune system. One of the
mechanisms by which T-helper cells are depleted is apoptosis, which results from a series of
biochemical pathways:[49]
1. HIV enzymes deactivate anti-apoptotic Bcl-2. This does not directly cause cell death
but primes the cell for apoptosis should the appropriate signal be received. In parallel,
these enzymes activate proapoptotic procaspase-8, which does directly activate the
mitochondrial events of apoptosis.
2. HIV may increase the level of cellular proteins that prompt Fas-mediated apoptosis.
3. HIV proteins decrease the amount of CD4 glycoprotein marker present on the cell
membrane.
4. Released viral particles and proteins present in extracellular fluid are able to induce
apoptosis in nearby "bystander" T helper cells.
5. HIV decreases the production of molecules involved in marking the cell for apoptosis,
giving the virus time to replicate and continue releasing apoptotic agents and virions
into the surrounding tissue.
6. The infected CD4+ cell may also receive the death signal from a cytotoxic T cell.
Cells may also die as a direct consequence of viral infection. HIV-1 expression induces
tubular cell G2/M arrest and apoptosis.[50] The progression from HIV to AIDS is not
immediate or even necessarily rapid; HIV's cytotoxic activity toward CD4+ lymphocytes is
classified as AIDS once a given patient's CD4+ cell count falls below 200.[51]
Viral infection
Viral induction of apoptosis occurs when one or several cells of a living organism are infected
with a virus, leading to cell death. Cell death in organisms is necessary for the normal
development of cells and the cell cycle maturation.[52] It is also important in maintaining the
regular functions and activities of cells.
Viruses can trigger apoptosis of infected cells via a range of mechanisms including:
Receptor binding
Expression of viral proteins coupled to MHC proteins on the surface of the infected
cell, allowing recognition by cells of the immune system (such as Natural Killer and
cytotoxic T cells) that then induce the infected cell to undergo apoptosis.[53]
Canine distemper virus (CDV) is known to cause apoptosis in central nervous system and
lymphoid tissue of infected dogs in vivo and in vitro.[54] Apoptosis caused by CDV is
typically induced via the extrinsic pathway, which activates caspases that disrupt cellular
function and eventually leads to the cells death.[43] In normal cells, CDV activates caspase-8
first, which works as the initiator protein followed by the executioner protein caspase-3.[43]
However, apoptosis induced by CDV in HeLa cells does not involve the initiator protein
caspase-8. HeLa cell apoptosis caused by CDV follows a different mechanism than that in
vero cell lines.[43] This change in the caspase cascade suggests CDV induces apoptosis via the
intrinsic pathway, excluding the need for the initiator caspase-8. The executioner protein is
instead activated by the internal stimuli caused by viral infection not a caspase cascade.[43]
The Oropouche virus (OROV) is found in the family Bunyaviridae. The study of apoptosis
brought on by Bunyaviridae was initiated in 1996, when it was observed that apoptosis was
induced by the La Crosse virus into the kidney cells of baby hamsters and into the brains of
baby mice.[55]
OROV is a disease that is transmitted between humans by the biting midge (Culicoides
paraensis).[56] It is referred to as a zoonotic arbovirus and causes febrile illness, characterized
by the onset of a sudden fever known as Oropouche fever.[57]
The Oropouche virus also causes disruption in cultured cells - cells that are cultivated in
distinct and specific conditions. An example of this can be seen in HeLa cells, whereby the
cells begin to degenerate shortly after they are infected.[55]
With the use of gel electrophoresis, it can be observed that OROV causes DNA fragmentation
in HeLa cells. It can be interpreted by counting, measuring, and analyzing the cells of the
Sub/G1 cell population.[55] When HeLA cells are infected with OROV, the cytochrome C is
released from the membrane of the mitochondria, into the cytosol of the cells. This type of
interaction shows that apoptosis is activated via an intrinsic pathway.[52]
In order for apoptosis to occur within OROV, viral uncoating, viral internalization, along with
the replication of cells is necessary. Apoptosis in some viruses is activated by extracellular
stimuli. However, studies have demonstrated that the OROV infection causes apoptosis to be
activated through intracellular stimuli and involves the mitochondria.[55]
Many viruses encode proteins that can inhibit apoptosis.[58] Several viruses encode viral
homologs of Bcl-2. These homologs can inhibit proapoptotic proteins such as BAX and
BAK, which are essential for the activation of apoptosis. Examples of viral Bcl-2 proteins
include the Epstein-Barr virus BHRF1 protein and the adenovirus E1B 19K protein.[59] Some
viruses express caspase inhibitors that inhibit caspase activity and an example is the CrmA
protein of cowpox viruses. Whilst a number of viruses can block the effects of TNF and Fas.
For example the M-T2 protein of myxoma viruses can bind TNF preventing it from binding
the TNF receptor and inducing a response.[60] Furthermore, many viruses express p53
inhibitors that can bind p53 and inhibit its transcriptional transactivation activity. As a
consequence, p53 cannot induce apoptosis, since it cannot induce the expression of
proapoptotic proteins. The adenovirus E1B-55K protein and the hepatitis B virus HBx protein
are examples of viral proteins that can perform such a function.[61]
Viruses can remain intact from apoptosis in particular in the latter stages of infection. They
can be exported in the apoptotic bodies that pinch off from the surface of the dying cell, and
the fact that they are engulfed by phagocytes prevents the initiation of a host response. This
favours the spread of the virus.[60]
Plants
Programmed cell death in plants has a number of molecular similarities to that of animal
apoptosis, but it also has differences, notable ones being the presence of a cell wall and the
lack of an immune system that removes the pieces of the dead cell. Instead of an immune
response, the dying cell synthesizes substances to break itself down and places them in a
vacuole that ruptures as the cell dies. Whether this whole process resembles animal apoptosis
closely enough to warrant using the name apoptosis (as opposed to the more general
programmed cell death) is unclear.[62]
Caspase-independent apoptosis
The characterization of the caspases allowed the development of caspase inhibitors, which
can be used to determine whether a cellular process involves active caspases. Using these
inhibitors it was discovered that cells can die while displaying a morphology similar to
apoptosis without caspase activation.[63] Later studies linked this phenomenon to the release
of AIF (apoptosis-inducing factor) from the mitochondria and its translocation into the
nucleus mediated by its NLS (nuclear localization signal). Inside the mitochondria, AIF is
anchored to the inner membrane. In order to be released, the protein is cleaved by a calciumdependent calpain protease.
See also
Anoikis
Apaf-1
Apo2.7
Autolysis
Autophagy
Cisplatin
Entosis
Immunology
Necrosis
Necrobiosis
p53
cytotoxicity
Pseudoapoptosis
References
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External links
Apoptosis (Programmed Cell Death) - The Virtual Library of Biochemistry and Cell
Biology
Apoptosis Video
Cell signaling
Death
Immune system
Apoptosis
Cellular senescence
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Apoptosis
From Wikipedia, the free encyclopedia
Apoptosis
In contrast to necrosis, which is a form of traumatic cell death that results from acute cellular
injury, in general apoptosis confers advantages during an organism's lifecycle. For example,
the separation of fingers and toes in a developing human embryo occurs because cells
between the digits apoptose. Unlike necrosis, apoptosis produces cell fragments called
apoptotic bodies that phagocytic cells are able to engulf and quickly remove before the
contents of the cell can spill out onto surrounding cells and cause damage.[5]
Between 50 and 70 billion cells die each day due to apoptosis in the average human adult. For
an average child between the ages of 8 and 14, approximately 20 billion to 30 billion cells die
a day.[6]
Research in and around apoptosis has increased substantially since the early 1990s. In
addition to its importance as a biological phenomenon, defective apoptotic processes have
been implicated in an extensive variety of diseases. Excessive apoptosis causes atrophy,
whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer.
Contents
2 Process
o 2.1 Mitochondrial regulation
o 2.2 Direct signal transduction
2.2.2.1 Caspases
o 2.3 Execution
o 2.4 Removal of dead cells
3 Pathway knock-outs
5 Implication in disease
o 5.1 Defective pathways
o 5.2 Inhibition
5.2.2 Treatments
5.3.1 Treatments
6 Plants
7 Caspase-independent apoptosis
9 See also
10 References
11 External links
John E. Sulston won the Nobel Prize in Medicine in 2002, for his pioneering research on
apoptosis.
In Greek, apoptosis translates to the "dropping off" of petals or leaves from plants or trees.
Cormack, professor of Greek language, reintroduced the term for medical use as it had a
medical meaning for the Greeks over two thousand years before. Hippocrates used the term
to mean "the falling off of the bones". Galen extended its meaning to "the dropping of the
scabs". Cormack was no doubt aware of this usage when he suggested the name. Debate
continues over the correct pronunciation, with opinion divided between a pronunciation with
the second p silent (/ptoss/ ap--TOH-sis[2][11]) and the second p pronounced (/pp
toss/),[2][12] as in the original Greek.[citation needed] In English, the p of the Greek -pt- consonant
cluster is typically silent at the beginning of a word (e.g. pterodactyl, Ptolemy), but
articulated when used in combining forms preceded by a vowel, as in helicopter or the orders
of insects: diptera, lepidoptera, etc.
In the original Kerr Wyllie and Currie paper, British Journal of Cancer, 1972 Aug;26(4):23957, there is a footnote regarding the pronunciation:
"We are most grateful to Professor James Cormack of the Department of Greek, University of
Aberdeen, for suggesting this term. The word "apoptosis" () is used in Greek to
describe the "dropping off" or "falling off" of petals from flowers, or leaves from trees. To
show the derivation clearly, we propose that the stress should be on the penultimate syllable,
the second half of the word being pronounced like "ptosis" (with the "p" silent), which comes
from the same root "to fall", and is already used to describe the drooping of the upper eyelid."
Process
Mitochondrial regulation
The mitochondria are essential to multicellular life. Without them, a cell ceases to respire
aerobically and quickly dies. This fact forms the basis for some apoptotic pathways.
Apoptotic proteins that target mitochondria affect them in different ways. They may cause
mitochondrial swelling through the formation of membrane pores, or they may increase the
permeability of the mitochondrial membrane and cause apoptotic effectors to leak out.[13]
These are very closely related to intrinsic pathway, and tumors arise more frequently through
intrinsic pathway than the extrinsic pathway because of sensitivity.[16] There is also a growing
body of evidence indicating that nitric oxide is able to induce apoptosis by helping to
dissipate the membrane potential of mitochondria and therefore make it more permeable.[17]
Nitric oxide has been implicated in initiating and inhibiting apoptosis through its possible
action as a signal molecule of subsequent pathways that activate apoptosis.[18][citation needed]
Mitochondrial proteins known as SMACs (small mitochondria-derived activator of caspases)
are released into the cytosol following an increase in permeability. SMAC binds to inhibitor
of apoptosis proteins (IAPs) and deactivates them, preventing the IAPs from arresting the
apoptotic process and therefore allowing apoptosis to proceed. IAP also normally suppresses
the activity of a group of cysteine proteases called caspases,[19] which carry out the
degradation of the cell, therefore the actual degradation enzymes can be seen to be indirectly
regulated by mitochondrial permeability.
Cytochrome c is also released from mitochondria due to formation of a channel, the
mitochondrial apoptosis-induced channel (MAC), in the outer mitochondrial membrane,[20]
and serves a regulatory function as it precedes morphological change associated with
apoptosis.[13] Once cytochrome c is released it binds with Apoptotic protease activating factor
- 1 (Apaf-1) and ATP, which then bind to pro-caspase-9 to create a protein complex known as
an apoptosome. The apoptosome cleaves the pro-caspase to its active form of caspase-9,
which in turn activates the effector caspase-3.
MAC (not to be confused with the Membrane Attack Complex formed by complement
activation, also commonly denoted as MAC), also called "Mitochondrial Outer Membrane
Permeabilization Pore" is regulated by various proteins, such as those encoded by the
mammalian Bcl-2 family of anti-apoptopic genes, the homologs of the ced-9 gene found in
C. elegans.[21][22] Bcl-2 proteins are able to promote or inhibit apoptosis by direct action on
MAC/MOMPP. Bax and/or Bak form the pore, while Bcl-2, Bcl-xL or Mcl-1 inhibit its
formation.
Overview of TNF (left) and Fas (right) signalling in apoptosis, an example of direct signal
transduction.
Two theories of the direct initiation of apoptotic mechanisms in mammals have been
suggested: the TNF-induced (tumour necrosis factor) model and the Fas-Fas ligand-mediated
model, both involving receptors of the TNF receptor (TNFR) family[23] coupled to extrinsic
signals.
TNF path
TNF is a cytokine produced mainly by activated macrophages, and is the major extrinsic
mediator of apoptosis. Most cells in the human body have two receptors for TNF: TNF-R1
and TNF-R2. The binding of TNF to TNF-R1 has been shown to initiate the pathway that
leads to caspase activation via the intermediate membrane proteins TNF receptor-associated
death domain (TRADD) and Fas-associated death domain protein cIAP1/2 inhibit TNF-
signaling by binding to TRAF2. FLIP inhibits the activation of caspase-8 (FADD).[24] Binding
of this receptor can also indirectly lead to the activation of transcription factors involved in
cell survival and inflammatory responses.[25] However, signalling through TNF-R1 might also
induce apoptosis in a Caspase-independent manner.[26] The link between TNF and apoptosis
shows why an abnormal production of TNF plays a fundamental role in several human
diseases, especially in autoimmune diseases.
The Fas receptor (also known as Apo-1 or CD95) binds the Fas ligand (FasL), a
transmembrane protein part of the TNF family.[23] The interaction between Fas and FasL
results in the formation of the death-inducing signaling complex (DISC), which contains the
FADD, caspase-8 and caspase-10. In some types of cells (type I), processed caspase-8
directly activates other members of the caspase family, and triggers the execution of
apoptosis of the cell. In other types of cells (type II), the Fas-DISC starts a feedback loop that
spirals into increasing release of proapoptotic factors from mitochondria and the amplified
activation of caspase-8.[27]
Common components
Following TNF-R1 and Fas activation in mammalian cells a balance between proapoptotic
(BAX,[28] BID, BAK, or BAD) and anti-apoptotic (Bcl-Xl and Bcl-2) members of the Bcl-2
family is established. This balance is the proportion of proapoptotic homodimers that form in
the outer-membrane of the mitochondrion. The proapoptotic homodimers are required to
make the mitochondrial membrane permeable for the release of caspase activators such as
cytochrome c and SMAC. Control of proapoptotic proteins under normal cell conditions of
nonapoptotic cells is incompletely understood, but in general, Bax or Bak are activated by the
activation of BH3-only proteins, part of the Bcl-2 family.
Caspases
Caspases play the central role in the transduction of DR apoptotic signals. Caspases are
proteins that are highly conserved, cysteine-dependent aspartate-specific proteases. There are
two types of caspases: initiator caspases, caspase 8,10,9,2, and effector caspases, caspase
3,7,6. The activation of initiator caspases requires binding to specific oligomeric adaptor
protein. Effector caspases are then activated by these active initiator caspases through
proteolytic cleavage. The active effector caspases then proteolytically degrade a host of
intracellular proteins to carry out the cell death program.
Caspase-independent apoptotic pathway
Execution
Many pathways and signals lead to apoptosis, but there is only one mechanism that actually
causes the death of a cell.[citation needed] After a cell receives stimulus, it undergoes organized
degradation of cellular organelles by activated proteolytic caspases. A cell undergoing
apoptosis shows a characteristic morphology:
1. Cell shrinkage and rounding are shown because of the breakdown of the
proteinaceous cytoskeleton by caspases.[30]
2. The cytoplasm appears dense, and the organelles appear tightly packed.
3. Chromatin undergoes condensation into compact patches against the nuclear envelope
(also known as the perinuclear envelope) in a process known as pyknosis, a hallmark
of apoptosis.[31][32]
4. The nuclear envelope becomes discontinuous and the DNA inside it is fragmented in a
process referred to as karyorrhexis. The nucleus breaks into several discrete
chromatin bodies or nucleosomal units due to the degradation of DNA.[33]
5. The cell membrane shows irregular buds known as blebs.
6. The cell breaks apart into several vesicles called apoptotic bodies, which are then
phagocytosed.
Apoptosis progresses quickly and its products are quickly removed, making it difficult to
detect or visualize. During karyorrhexis, endonuclease activation leaves short DNA
fragments, regularly spaced in size. These give a characteristic "laddered" appearance on agar
gel after electrophoresis. Tests for DNA laddering differentiate apoptosis from ischemic or
toxic cell death.[34]
Pathway knock-outs
Many knock-outs have been made in the apoptosis pathways to test the function of each of
the proteins. Several caspases, in addition to APAF-1 and FADD, have been mutated to
determine the new phenotype. In order to create a tumor necrosis factor (TNF) knockout, an
exon containing the nucleotides 3704-5364 was removed from the gene. This exon encodes a
portion of the mature TNF domain, as well as the leader sequence, which is a highly
conserved region necessary for proper intracellular processing. TNF-/- mice develop
normally and have no gross structural or morphological abnormalities. However, upon
immunization with SRBC (sheep red blood cells), these mice demonstrated a deficiency in
the maturation of an antibody response; they were able to generate normal levels of IgM, but
could not develop specific IgG levels. Apaf-1 is the protein that turns on caspase 9 by
cleavage to begin the caspase cascade that leads to apoptosis. Since a -/- mutation in the
APAF-1 gene is embryonic lethal, a gene trap strategy was used in order to generate an
APAF-1 -/- mouse. This assay is used to disrupt gene function by creating an intragenic gene
fusion. When an APAF-1 gene trap is introduced into cells, many morphological changes
occur, such as spina bifida, the persistence of interdigital webs, and open brain. In addition,
after embryonic day 12.5, the brain of the embryos showed several structural changes. APAF1 cells are protected from apoptosis stimuli such as irradiation. A BAX-1 knock-out mouse
exhibits normal forebrain formation and a decreased programmed cell death in some neuronal
populations and in the spinal cord, leading to an increase in motor neurons.
The caspase proteins are integral parts of the apoptosis pathway, so it follows that knock-outs
made have varying damaging results. A caspase 9 knock-out leads to a severe brain
malformation. A caspase 8 knock-out leads to cardiac failure and thus embryonic lethality.
However, with the use of cre-lox technology, a caspase 8 knock-out has been created that
exhibits an increase in peripheral T cells, an impaired T cell response, and a defect in neural
tube closure. These mice were found to be resistant to apoptosis mediated by CD95, TNFR,
etc. but not resistant to apoptosis caused by UV irradiation, chemotherapeutic drugs, and
other stimuli. Finally, a caspase 3 knock-out was characterized by ectopic cell masses in the
brain and abnormal apoptotic features such as membrane blebbing or nuclear fragmentation.
A remarkable feature of these KO mice is that they have a very restricted phenotype: Casp3,
9, APAF-1 KO mice have deformations of neural tissue and FADD and Casp 8 KO showed
defective heart development, however in both types of KO other organs developed normally
and some cell types were still sensitive to apoptotic stimuli suggesting that unknown
proapoptotic pathways exist.
Implication in disease
Defective pathways
The many different types of apoptotic pathways contain a multitude of different biochemical
components, many of them not yet understood.[40] As a pathway is more or less sequential in
nature, it is a victim of causality; removing or modifying one component leads to an effect in
another. In a living organism, this can have disastrous effects, often in the form of disease or
disorder. A discussion of every disease caused by modification of the various apoptotic
pathways would be impractical, but the concept overlying each one is the same: The normal
functioning of the pathway has been disrupted in such a way as to impair the ability of the
cell to undergo normal apoptosis. This results in a cell that lives past its "use-by-date" and is
able to replicate and pass on any faulty machinery to its progeny, increasing the likelihood of
the cell's becoming cancerous or diseased.
A recently described example of this concept in action can be seen in the development of a
lung cancer called NCI-H460.[41] The X-linked inhibitor of apoptosis protein (XIAP) is
overexpressed in cells of the H460 cell line. XIAPs bind to the processed form of caspase-9,
and suppress the activity of apoptotic activator cytochrome c, therefore overexpression leads
to a decrease in the amount of proapoptotic agonists. As a consequence, the balance of antiapoptotic and proapoptotic effectors is upset in favour of the former, and the damaged cells
continue to replicate despite being directed to die.
Dysregulation of p53
The tumor-suppressor protein p53 accumulates when DNA is damaged due to a chain of
biochemical factors. Part of this pathway includes alpha-interferon and beta-interferon, which
induce transcription of the p53 gene, resulting in the increase of p53 protein level and
enhancement of cancer cell-apoptosis.[42] p53 prevents the cell from replicating by stopping
the cell cycle at G1, or interphase, to give the cell time to repair, however it will induce
apoptosis if damage is extensive and repair efforts fail. Any disruption to the regulation of the
p53 or interferon genes will result in impaired apoptosis and the possible formation of
tumors.
Inhibition
Inhibition of apoptosis can result in a number of cancers, autoimmune diseases, inflammatory
diseases, and viral infections. It was originally believed that the associated accumulation of
cells was due to an increase in cellular proliferation, but it is now known that it is also due to
a decrease in cell death. The most common of these diseases is cancer, the disease of
excessive cellular proliferation, which is often characterized by an overexpression of IAP
family members. As a result, the malignant cells experience an abnormal response to
apoptosis induction: Cycle-regulating genes (such as p53, ras or c-myc) are mutated or
inactivated in diseased cells, and further genes (such as bcl-2) also modify their expression in
tumors.
HeLa cell
Apoptosis in HeLa cells is inhibited by proteins produced by the cell; these inhibitory
proteins target retinoblastoma tumor-suppressing proteins.[43] These tumor-suppressing
proteins regulate the cell cycle, but are rendered inactive when bound to an inhibitory protein.
[43]
HPV E6 and E7 are inhibitory proteins expressed by the human papillomavirus, HPV
being responsible for the formation of the cervical tumor from which HeLa cells are derived.
[44]
HPV E6 causes p53, which regulates the cell cycle, to become inactive.[45] HPV E7 binds
to retinoblastoma tumor suppressing proteins and limits its ability to control cell division.[45]
These two inhibitory proteins are partially responsible for HeLa cells' immortality by
inhibiting apoptosis to occur.[46] CDV (Canine Distemper Virus) is able to induce apoptosis
despite the presence of these inhibitory proteins. This is an important oncolytic property of
CDV: this virus is capable of killing canine lymphoma cells. Oncoproteins E6 and E7 still
leave p53 inactive, but they are not able to avoid the activation of caspases induced from the
stress of viral infection. These oncolytic properties provided a promising link between CDV
and lymphoma apoptosis, which can lead to development of alternative treatment methods for
both canine lymphoma and human non-Hodgkin lymphoma. Defects in the cell cycle are
thought to be responsible for the resistance to chemotherapy or radiation by certain tumor
cells, so a virus that can induce apoptosis despite defects in the cell cycle is useful for cancer
treatment.[46]
Treatments
The main method of treatment for death signaling-related diseases involves either increasing
or decreasing the susceptibility of apoptosis in diseased cells, depending on whether the
disease is caused by either the inhibition of or excess apoptosis. For instance, treatments aim
to restore apoptosis to treat diseases with deficient cell death, and to increase the apoptotic
threshold to treat diseases involved with excessive cell death. To stimulate apoptosis, one can
increase the number of death receptor ligands (such as TNF or TRAIL), antagonize the antiapoptotic Bcl-2 pathway, or introduce Smac mimetics to inhibit the inhibitor (IAPs). The
addition of agents such as Herceptin, Iressa, or Gleevec works to stop cells from cycling and
causes apoptosis activation by blocking growth and survival signaling further upstream.
Finally, adding p53-MDM2 complexes displaces p53 and activates the p53 pathway, leading
to cell cycle arrest and apoptosis. Many different methods can be used either to stimulate or
to inhibit apoptosis in various places along the death signaling pathway.[47]
Apoptosis is a multi-step, multi-pathway cell-death programme that is inherent in every cell
of the body. In cancer, the apoptosis cell-division ratio is altered. Cancer treatment by
chemotherapy and irradiation kills target cells primarily by inducing apoptosis.
Hyperactive apoptosis
On the other hand, loss of control of cell death (resulting in excess apoptosis) can lead to
neurodegenerative diseases, hematologic diseases, and tissue damage. The progression of
HIV is directly linked to excess, unregulated apoptosis. In a healthy individual, the number of
CD4+ lymphocytes is in balance with the cells generated by the bone marrow; however, in
HIV-positive patients, this balance is lost due to an inability of the bone marrow to regenerate
CD4+ cells. In the case of HIV, CD4+ lymphocytes die at an accelerated rate through
uncontrolled apoptosis, when stimulated.
Treatments
Treatments aiming to inhibit apoptosis work to simultaneously inhibit the expression of
proapoptotic factors and promote the expression of anti-apoptotic factors. Fas-induced
apoptosis can be blocked by use of FLIPs (FLICE-inhibitory proteins, which inhibit caspases8 and -10), Bcl-2 (which prevents cytochrome c release and the subsequent activation of
caspase 9), and CrmA (Cytokine response modifier A). Increasing the concentration of IAPs
works to block specific caspases. Finally, the Akt protein kinase promotes cell survival
through two pathways. Akt phosphorylates and inhibits Bas (a Bcl-2 family member), causing
Bas to interact with the 14-3-3 scaffold, resulting in Bcl dissociation and thus cell survival.
Akt also activates IKK, which leads to NF-B activation and cell survival. Active NF-B
induces the expression of anti-apoptotic genes such as Bcl-2, resulting in inhibition of
apoptosis. NF-B has been found to play both an antiapoptotic role and a proapoptotic role
depending on the stimuli utilized and the cell type.[48]
HIV progression
The progression of the human immunodeficiency virus infection into AIDS is due primarily
to the depletion of CD4+ T-helper lymphocytes in a manner that is too rapid for the body's
bone marrow to replenish the cells, leading to a compromised immune system. One of the
mechanisms by which T-helper cells are depleted is apoptosis, which results from a series of
biochemical pathways:[49]
1. HIV enzymes deactivate anti-apoptotic Bcl-2. This does not directly cause cell death
but primes the cell for apoptosis should the appropriate signal be received. In parallel,
these enzymes activate proapoptotic procaspase-8, which does directly activate the
mitochondrial events of apoptosis.
2. HIV may increase the level of cellular proteins that prompt Fas-mediated apoptosis.
3. HIV proteins decrease the amount of CD4 glycoprotein marker present on the cell
membrane.
4. Released viral particles and proteins present in extracellular fluid are able to induce
apoptosis in nearby "bystander" T helper cells.
5. HIV decreases the production of molecules involved in marking the cell for apoptosis,
giving the virus time to replicate and continue releasing apoptotic agents and virions
into the surrounding tissue.
6. The infected CD4+ cell may also receive the death signal from a cytotoxic T cell.
Cells may also die as a direct consequence of viral infection. HIV-1 expression induces
tubular cell G2/M arrest and apoptosis.[50] The progression from HIV to AIDS is not
immediate or even necessarily rapid; HIV's cytotoxic activity toward CD4+ lymphocytes is
classified as AIDS once a given patient's CD4+ cell count falls below 200.[51]
Viral infection
Viral induction of apoptosis occurs when one or several cells of a living organism are infected
with a virus, leading to cell death. Cell death in organisms is necessary for the normal
development of cells and the cell cycle maturation.[52] It is also important in maintaining the
regular functions and activities of cells.
Viruses can trigger apoptosis of infected cells via a range of mechanisms including:
Receptor binding
Expression of viral proteins coupled to MHC proteins on the surface of the infected
cell, allowing recognition by cells of the immune system (such as Natural Killer and
cytotoxic T cells) that then induce the infected cell to undergo apoptosis.[53]
Canine distemper virus (CDV) is known to cause apoptosis in central nervous system and
lymphoid tissue of infected dogs in vivo and in vitro.[54] Apoptosis caused by CDV is
typically induced via the extrinsic pathway, which activates caspases that disrupt cellular
function and eventually leads to the cells death.[43] In normal cells, CDV activates caspase-8
first, which works as the initiator protein followed by the executioner protein caspase-3.[43]
However, apoptosis induced by CDV in HeLa cells does not involve the initiator protein
caspase-8. HeLa cell apoptosis caused by CDV follows a different mechanism than that in
vero cell lines.[43] This change in the caspase cascade suggests CDV induces apoptosis via the
intrinsic pathway, excluding the need for the initiator caspase-8. The executioner protein is
instead activated by the internal stimuli caused by viral infection not a caspase cascade.[43]
The Oropouche virus (OROV) is found in the family Bunyaviridae. The study of apoptosis
brought on by Bunyaviridae was initiated in 1996, when it was observed that apoptosis was
induced by the La Crosse virus into the kidney cells of baby hamsters and into the brains of
baby mice.[55]
OROV is a disease that is transmitted between humans by the biting midge (Culicoides
paraensis).[56] It is referred to as a zoonotic arbovirus and causes febrile illness, characterized
by the onset of a sudden fever known as Oropouche fever.[57]
The Oropouche virus also causes disruption in cultured cells - cells that are cultivated in
distinct and specific conditions. An example of this can be seen in HeLa cells, whereby the
cells begin to degenerate shortly after they are infected.[55]
With the use of gel electrophoresis, it can be observed that OROV causes DNA fragmentation
in HeLa cells. It can be interpreted by counting, measuring, and analyzing the cells of the
Sub/G1 cell population.[55] When HeLA cells are infected with OROV, the cytochrome C is
released from the membrane of the mitochondria, into the cytosol of the cells. This type of
interaction shows that apoptosis is activated via an intrinsic pathway.[52]
In order for apoptosis to occur within OROV, viral uncoating, viral internalization, along with
the replication of cells is necessary. Apoptosis in some viruses is activated by extracellular
stimuli. However, studies have demonstrated that the OROV infection causes apoptosis to be
activated through intracellular stimuli and involves the mitochondria.[55]
Many viruses encode proteins that can inhibit apoptosis.[58] Several viruses encode viral
homologs of Bcl-2. These homologs can inhibit proapoptotic proteins such as BAX and
BAK, which are essential for the activation of apoptosis. Examples of viral Bcl-2 proteins
include the Epstein-Barr virus BHRF1 protein and the adenovirus E1B 19K protein.[59] Some
viruses express caspase inhibitors that inhibit caspase activity and an example is the CrmA
protein of cowpox viruses. Whilst a number of viruses can block the effects of TNF and Fas.
For example the M-T2 protein of myxoma viruses can bind TNF preventing it from binding
the TNF receptor and inducing a response.[60] Furthermore, many viruses express p53
inhibitors that can bind p53 and inhibit its transcriptional transactivation activity. As a
consequence, p53 cannot induce apoptosis, since it cannot induce the expression of
proapoptotic proteins. The adenovirus E1B-55K protein and the hepatitis B virus HBx protein
are examples of viral proteins that can perform such a function.[61]
Viruses can remain intact from apoptosis in particular in the latter stages of infection. They
can be exported in the apoptotic bodies that pinch off from the surface of the dying cell, and
the fact that they are engulfed by phagocytes prevents the initiation of a host response. This
favours the spread of the virus.[60]
Plants
Programmed cell death in plants has a number of molecular similarities to that of animal
apoptosis, but it also has differences, notable ones being the presence of a cell wall and the
lack of an immune system that removes the pieces of the dead cell. Instead of an immune
response, the dying cell synthesizes substances to break itself down and places them in a
vacuole that ruptures as the cell dies. Whether this whole process resembles animal apoptosis
closely enough to warrant using the name apoptosis (as opposed to the more general
programmed cell death) is unclear.[62]
Caspase-independent apoptosis
The characterization of the caspases allowed the development of caspase inhibitors, which
can be used to determine whether a cellular process involves active caspases. Using these
inhibitors it was discovered that cells can die while displaying a morphology similar to
apoptosis without caspase activation.[63] Later studies linked this phenomenon to the release
of AIF (apoptosis-inducing factor) from the mitochondria and its translocation into the
nucleus mediated by its NLS (nuclear localization signal). Inside the mitochondria, AIF is
anchored to the inner membrane. In order to be released, the protein is cleaved by a calciumdependent calpain protease.
See also
Anoikis
Apaf-1
Apo2.7
Autolysis
Autophagy
Cisplatin
Entosis
Immunology
Necrosis
Necrobiosis
p53
cytotoxicity
Pseudoapoptosis
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External links
Apoptosis (Programmed Cell Death) - The Virtual Library of Biochemistry and Cell
Biology
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Int J Oncol. 2002 Jul;21(1):165-70.
Author information
Abstract
Cell death and the subsequent post-mortem changes, called necrosis, are integral parts of
normal development and maturation cycle. Despite the importance of this process, the
mechanisms underlying cell death are still poorly understood. In the recent literature, cell
death is said to occur by two alternative, opposite modes: apoptosis, a programmed, managed
form of cell death, and necrosis, an unordered and accidental form of cellular dying. The
incorrect consequence is the overlapping of: a) the process whereby cells die, cell death; and
b) the changes that the cells and tissues undergo after the cells die. Only the latter process can
be referred to as necrosis and represents a <no return> process in cell life. In this review, we
discuss the excellent basic research developed in this field during last decades and problems
that remain to be resolved in defining both experimentally and mechanicistically the events
that lead to and characterize cell death.
PMID:
12063564
[PubMed - indexed for MEDLINE]
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Review Cell death via apoptosis and its relationship to growth, development and
differentiation of both tumour and normal cells.[Anticancer Res. 1990]
Review Cell death by necrosis, a regulated way to go.[Curr Mol Med. 2008]
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