Caspases are the central components of the apoptotic response. The apoptotic caspases
are generally divided into two classes: the initiator caspases, which include
-9 and -10 and the effector
caspases, which include caspases-3,
-6 and -7. All caspases are
produced in cells as catalytically inactive zymogenes and must undergo proteolytic
activation during apoptosis. Activation of effector caspases is carried out by an
initiator caspases . Once activated, the effector caspases
are responsible for the proteolytic cleavage of a broad spectrum of cellular targets,
which ultimately leads to cell death .
The apoptotic response is activated through either the
intrinsic or the extrinsic
pathway, depending on the origin of the death stimuli.
The intrinsic pathway is triggered in response to a wide
range of death stimulus that are generated from within the cell, such as oncogene
activation and DNA damage.
The intrinsic pathway is mediated by mitochondria: In
response to apoptotic stimuli several proteins, such as cytochrome
c, are released from the intermembrane space of mitochondria into the
cytoplasm. Cytochrome c binds to and activates the protein
APAF1 in the cytoplasm that allows
APAF1 to bind to ATP/dATP and to form the apoptosome, which
mediates activation of caspase-9, thereby triggering a
cascade of caspase activation.
The extrinsic pathway is initiated by binding of an
extracellular death ligand, such as FasL and TNF-alpha, to
its cell-surface death receptor, such as FasR and
TNFR. Adaptor protein FADD,
transmit activating signal to effector caspases
caspase-2, -8, and
Caspase-10 can function independently of
caspase-8 in initiating Fas- and tumor necrosis
factor-related apoptosis-inducing ligand-receptor-mediated apoptosis .
IGF-1 (insulin-like growth factor 1) exhibits strong
anti-apoptotic activity. IGF-1 stimulates activation
of AKT (RAC serine/threonine-protein kinase) and AKT-induced
inhibitory phosphorylation of caspase-9. Thereby
IGF-1 inhibits caspase-9 mediated apoptosis .
Activation of caspase-2 occurs in a complex that contains
death domain-containing protein PIDD and the adaptor protein
The extrinsic pathway can crosstalk to the
intrinsic pathway through the caspase-8-mediated cleavage of
BID (a BH3-ONLY member of the BCL2 FAMILY of proteins),
which then triggers the release of mitochondrial proteins.
The conserved IAP family of proteins can potently inhibit the enzymatic activity of
active caspases. Caspases-3, -7
and -9 are subject to inhibitory action of
XIAP (X-linked inhibitor of apoptosis), which is a member of
IAP family .
Caspase-3 and caspase-6 are
necessary for cleavage of a large number of nuclear proteins essential for
apoptosis-associated chromatin margination, DNA fragmentation, and nuclear collapse
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Molecular mechanisms of caspase regulation during apoptosis.
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