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204 Part IV: Molecular and Cellular Hematology Chapter 15: Apoptosis Mechanisms: Relevance to the Hematopoietic System 205

and natural killer (NK) cells, which introduce apoptosis-inducing promote chromatin condensation and DNA fragmentation. The mito-
proteases, particularly granzyme B (a serine protease), into effective chondrial mechanisms for apoptotic and nonapoptotic cell death are
intracellular compartments of target cells via perforin-dependent mech- activated by myriad stimuli, including growth factor deprivation, oxi-
2+
anisms. Unlike the caspases, granzyme B is a serine protease. However, dants, Ca overload, DNA-damaging agents, microtubule-modifying
6
similar to the caspases, granzyme B specifically cleaves its substrates at drugs, and much more. 17,20 In this sense, mitochondria are sometimes
Asp residues. Granzyme B is capable of cleaving and activating multiple viewed as central integrators of cell stress signals that dictate ultimately
7
caspases and some caspase substrates. Endogenous and viral inhibitors cell life and death decisions.
of granzyme B have been identified, accounting for resistance to this Mitochondria can also participate in cell death pathways induced
apoptotic inducer. 8–10 via TNF family DRs, through crosstalk mechanisms involving proteins
Another caspase-activation pathway is represented by tumor such as Bid, BAR, and Bap31. 21–24 However, mitochondrial (“intrinsic”)
necrosis factor (TNF) family receptors. Eight of the approximately and DR (“extrinsic”) pathways for caspase activation are fully capable of
30 known members of the TNF family in humans contain a so-called independent operation in most types of cells. 25
11
death domain (DD) in their cytosolic tails. Several of these DD- Cell death mechanisms are also linked to endoplasmic reticulum
containing TNF family receptors use caspase activation as a signaling (ER). In most cases, however, these ER-initiated signals ultimately seem
mechanism, including TNF receptor-1 (TNFR1)/CD120a; Fas/APO1/ to impinge on mitochondria as the downstream effectors of the cell
CD95; death receptor (DR)-3 (DR3)/Apo2/Weasle; DR4/ tumor necro- death pathway. In this regard, the ER is a central regulator of intracellu-
sis factor–related apoptosis-inducing ligand receptor 1 (TRAILR1); lar Ca , and ER membranes form close contacts with mitochondria to
2+
DR5/TRAILR2; and DR6. Ligation of these receptors at the cell sur- create structures where Ca effluxes from ER into mitochondria, thereby
2+
face results in receptor clustering and recruitment of several intracel- impacting mitochondrial function in profound ways that can either pro-
lular proteins, including certain procaspases, to the cytosolic domains mote cell life or cause death. Too much Ca entry into mitochondria,
2+
of these receptors, forming a “death-inducing signaling complex” that for instance, triggers a phenomenon called mitochondrial permeability
triggers caspase activation and leads to apoptosis. 12,13 transition (MPT) in which the organelles swell and eventually rupture.
The specific caspases summoned to the DISC are caspase-8 and, in However, in addition to the role of ER Ca and mitochondria-driven
2+
some cases, caspase-10. These caspases contain so-called death effector cell death, another pathway for apoptosis has been linked to accumulation
domains (DEDs) in their N-terminal prodomains that bind to a corre- of unfolded proteins in the ER. Specifically, ER stress induces expression
sponding DED in the Fas-associated death domain (FADD), a bipar- of the proapoptotic transcription factor CHOP, which, in turn, stimulates
tite adapter protein containing a DD and a DED. FADD functions as expression of DR5 (TRAILR2), causing caspase-8-dependent apoptosis.
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a molecular bridge between the DD and DED domain families, and is, Additionally, CHOP has been reported to directly stimulate transcription
in fact, the only protein in the human genome with this dual domain of the gene encoding Bim, a proapoptotic member of the Bcl-2 family (see
structure. Consequently, cells from mice in which the fadd gene has section “Suppressors of Apoptosis” below) that stimulates Cyt-c release
been knocked out are resistant to apoptosis induction by TNF family from mitochondria. Thus, ER stress has multiple potential routes of stim-
cytokines and their receptors. Cells derived from caspase-8 knockout ulating cell death pathways, with the predominant pathway probably
mice also fail to undergo apoptosis in response to ligands or antibodies varying among cell types and pathophysiologic contexts.
that activate TNF family DRs, demonstrating an essential role for this Although diverse mechanisms exist for activating initiator Cas-
caspase in this pathway. However, mice lack the highly homologous pases, as outlined above, in most instances, the biochemical mecha-
14
protease, caspase-10, which is found in humans, having arisen from an nisms appear to be remarkably similar. Much of caspase activation and
apparent gene duplication on chromosome 2. Thus, caspases 8 and 10 can be explained by the “induced proximity model,” in which forcing
27
15
may play redundant roles in human cells. dimerization of procaspases results in conformational states that pro-
Mitochondria also play important roles in apoptosis, releasing cyto- mote protease activation, typically resulting in cleavage events that lock
chrome c (Cyt-c) into the cytosol, which then causes assembly of a multi- the proteases into their fully active state. This mechanism is clearly oper-
protein caspase-activating complex, referred to as the “apoptosome.” 16,17 ative in the caspase-activation pathways induced by TNF family recep-
The central component of the apoptosome is Apaf1, a caspase-activating tors (extrinsic pathway) and Cyt-c/mitochondria (“intrinsic pathway”).
protein that oligomerizes upon binding Cyt-c and which specifically
binds procaspase-9. Apaf1 and procaspase-9 interact with each other
via their caspase recruitment domains (CARDs). Such CARD–CARD SUPPRESSORS OF APOPTOSIS
interactions play important roles in many steps in apoptosis pathways. Given the critical importance of making the correct choices about cell
In addition to Cyt-c, mitochondria also release several other proteins of life–death decisions in complex multicellular organisms, it is not surpris-
relevance to apoptosis, including endonuclease G, AIF (an activator of ing that the pathways governing caspase activation are under exquisite
nuclear endonucleases), and SMAC (Diablo) and Omi (HtrA), antago- control by networks of proteins that directly or indirectly communi-
nists of a family of caspase-inhibitory proteins known as the IAPs (inhib- cate with these proteases. A delicate balance between proapoptotic and
itors of apoptosis) (see section “Inhibitors of Apoptosis” below). antiapoptotic regulators of apoptosis pathways is at play on a continual
The central importance of the Cyt-c–dependent pathway for apop- basis, ensuring the survival of long-lived cells and the proper turnover
tosis is underscored by the observation that cells derived from mice of short-lived cells in a variety of tissues, including the marrow, thymus,
in which either the apaf1 or procaspase-9 genes have been ablated are and peripheral lymphoid tissues. The antiapoptotic proteins responsible
incapable of undergoing apoptosis in response to agents that trigger for creating roadblocks to cell death have been mapped to specific cas-
Cyt-c release from mitochondria. Nevertheless, such cells can die by pase-activation pathways.
18
nonapoptotic routes, demonstrating that mitochondria control both
19
caspase-dependent and caspase-independent cell death pathways.
Moreover, distinguishing mitochondria-driven apoptotic from nonap- BCL-2 FAMILY
optotic cell death can be challenging in many contexts because of the The Bcl-2 family represents a large group of proteins (number >26 in
similar morphologic features caused probably by some of the proteins humans) that control mitochondria-dependent steps in cell-death path-
released from these organelle such as endonuclease G and AIF, which ways, including dictating whether Cyt-c is or is not released from these

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