Porth's Essentials of Pathophysiology, 4e - page 63

C h a p t e r 2
Cellular Responses to Stress, Injury, and Aging
43
It also separates the webbed fingers and toes of the
developing embryo. Apoptotic cell death occurs in the
hormone-dependent involution of endometrial cells dur-
ing the menstrual cycle and in the regression of breast
tissue after weaning from breast-feeding. The control of
immune cell numbers and destruction of autoreactive
T cells in the thymus have been credited to apoptosis.
Cytotoxic T cells and natural killer cells are thought to
destroy target cells by inducing apoptotic cell death.
Apoptosis is linked to many pathologic processes and
diseases. For example, interference with apoptosis is
known to be a mechanism that contributes to carcino-
genesis.
27
Apoptosis is also known to be involved in the
cell death associated with viral infections, such as hepati-
tis B and C.
27,28
Apoptosis may also be implicated in neu-
rodegenerative disorders such as ALS, Alzheimer disease,
and Parkinson disease. However, the exact mechanisms
involved in these diseases remains under investigation.
Two basic pathways for apoptosis have been
described (Fig. 2-9). These are the extrinsic pathway,
which is death receptor dependent, and the intrinsic
pathway, which is death receptor independent. The
execution phase of both pathways is carried out by
proteolytic enzymes called
caspases
(cysteine proteases
that cleave aspartate residues), which are present in the
cell as
procaspases
and are activated by cleavage of an
inhibitory portion of their polypeptide chain.
2,29
The
extrinsic pathway
involves extracellular signaling
proteins that bind to cell surface molecules called
death
receptors
and trigger apoptosis. The prototype death
receptors are tumor necrosis factor (TNF) receptor and
the Fas ligand receptor.
29
Fas ligand may be expressed
on the surface of certain cells, such as cytotoxic T cells,
or appear in a soluble form. When Fas ligand binds to
its receptor, proteins congregate at the cytoplasmic end
of the Fas receptor to form a death-initiating complex.
The complex then converts procaspase-8 to caspase-8.
Caspase-8, in turn, activates a cascade of caspases that
execute the process of apoptosis. The end result includes
activation of endonucleases that cause fragmentation
of DNA and cell death. In addition to TNF and Fas
ligand, primary signaling molecules known to activate
the extrinsic pathway include TNF-related apoptosis-
inducing ligand (TRAIL); the cytokine interleukin-1 (IL-
1); and lipopolysaccharide (LPS), the endotoxin found
in the outer cell membrane of gram-negative bacteria.
The
intrinsic pathway,
or
mitochondrion-induced
pathway,
of apoptosis is activated by conditions such
as DNA damage, ROS, hypoxia, decreased ATP lev-
els, cellular senescence, and activation of the p53 pro-
tein by DNA damage. The intrinsic pathway is tightly
regulated to ensure that cells kill themselves only when
appropriate. A major class of intracellular regulators of
apoptosis is the Bcl-2 family of proteins. Some of these
proteins insert into the mitochondrial membrane open-
ing channels through which proteins escape into the
cytoplasm.
29
A crucial protein released from the mito-
chondria is cytochrome c, a component of the mitochon-
drial electron transport chain (see Chapter 1). When
released into the cytoplasm, cytochrome c binds to a
procaspase-activating protein that activates caspases,
including caspase-3. Caspase-3 activation is a com-
mon step to both the extrinsic and intrinsic pathways.
Activation of caspase-8 in the extrinsic pathway can
also lead to activation of pro-apoptotic proteins, such
as Bid and Bax, thereby bridging the two pathways for
apoptosis.
2,29
While some members of the Bcl-2 family
are pro-apoptotic, others are anti-apoptotic and inhibit
apoptosis by binding to pro-apoptotic proteins, either
on the mitochondrial membranes or in the cytoplasm.
Inhibitors of apoptosis are thought to contribute to
cancer and autoimmune diseases.
29–31
The Bcl-2 gene
Inside cell
Outside cell
ROS
DNA damage
Hypoxia
Senescence
Low ATP level
FADD
Receptor
TRAIL
FasL
TNF
IL-1
LPS
Caspase-8
Caspase-9
Apoptosis
Caspase-3
(–6 or –7)
Cytochrome c
Death domain
Bid
p53
Bax
Mitochondrion
Intrinsic
(mitochondrial-mediated)
pathway
Extrinsic
(death receptor–mediated)
pathway
FIGURE 2-9.
Pathways for apoptosis.The extrinsic pathway
is activated by signals such asTNF-related apoptosis-inducing
ligand (TRAIL) and Fas ligand (FasL) that, upon binding to the
Fas receptor, form a death-inducing complex by joining the
Fas-associated death domain (FADD) to the death domain of
the Fas receptor.The intrinsic pathway is activated by signals,
such as reactive oxygen species (ROS) and DNA damage, which
induce the release of cytochrome c from mitochondria into
the cytoplasm. Both pathways activate caspases to execute
apoptosis, with activation of the pro-apoptotic proteins Bid
and Bax by caspase-8 serving to bridge the two systems. ATP,
adenosine triphosphate; DNA, deoxyribonucleic acid; IL-1,
interleukin-1; LPS, lipopolysaccharide;TNF, tumor necrosis factor.
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