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apoptosis 72 apoptosis
Four caspase pathways involved in apoptosis.
system employs apoptosis for clonal deletion of cortical
thymocytes by antigen in immunologic tolerance. A
healthy organism is an exquisitely integrated collection of
differentiated cells that maintain a balance between life
and death. Some cells are irreplaceable; some complete
Apoptosis signaling.
their functions and are then sacrificed; and some cells
live finite lifetimes to be replaced by subsequent generations.
A failure of cells to fulfill their destiny has catastrophic
consequences for an organism. Apoptosis is the
last phase of cell destiny. It is the controlled disassembly
of a cell. When apoptosis occurs on schedule, neighboring
cells and, more importantly, the total organism are
not adversely affected. Apoptosis gone awry, however,
produces dire effects. When apoptosis occurs in irreplaceable
cells, as in some neurodegenerative disorders,
functions critical to the organism are lost. When cells
fail to undergo apoptosis after serving their purpose, as
in autoimmune disorders, escaped cells adversely affect
the organism. When cells become renegade and resist
apoptosis, as in cancer, the outlaw cells create a dire situation
for the organism. Mistiming of or errors in apoptosis
can exert devastating consequences on development.
Apoptotic fidelity is, therefore, critical to the well-being
of an organism. Mitochondrial cytochrome c is released in
the intrinsic apoptotic pathway, whereas death receptors
such as Fas and TNFR are activated in the extrinsic apoptotic
pathway. The process of apoptosis (programmed cell
death) is regulated by signals generated when cytokines
bind to their receptors. One of the two types of cytokineinduced
signals initiates apoptosis. Cytokines producing
inductive signals include TNF-α, FAS/APO-1 ligand, and
TRAIL/APO-2 ligand. The second is an inhibitory signal
that suppresses apoptosis. Cytokines producing inhibitory
signals include those required for cell survival. Apoptosis
proceeds through cleavage of vital intracellular proteins.
Caspases are inactive until a signal initiates activation of
one, starting a cascade in which a series of other caspases
are proteolytically activated. Although both signaling
processes affect caspase activation, the mechanism
differs. Apoptosis is characterized by degradation of
nuclear DNA, degeneration and condensation of nuclei,
and phagocytosis of cell residue. Proliferating cells often
undergo apoptosis as a natural process and proliferating
lymphocytes manifest rapid apoptosis during development
and during immune responses. In contrast to the internal
death program of apoptosis, necrosis describes death from
without.