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206 Part IV: Molecular and Cellular Hematology Chapter 15: Apoptosis Mechanisms: Relevance to the Hematopoietic System 207

Bim Bad Bmf such as Bid, Bim, and Bad, lack these membrane-anchoring domains, but
Bik Hrk dynamically target mitochondria in response to specific stimuli. Still oth-
Bcl-G Bcl-X s ers have the membrane-anchoring domain but keep it latched against the
s
body of the protein until stimulated to expose it (e.g., Bax). 31
Based on their predicted (or experimentally determined) three-
dimensional structures, Bcl-2 family proteins can be broadly divided
Bcl-2
Bcl-X L into two groups. One subset of these proteins is probably similar in
Mcl-I structure to the pore-forming domains of bacterial toxins, such as the
Bfl-1 Puma colicins and diphtheria toxin. 32–35 These α-helical pore-like proteins
Bcl-W Noxa include both antiapoptotic proteins (Bcl-2, Bcl-X , Mcl-1, Bfl-1, Bcl-W,
L
Bcl-B Bid Bcl-B) and proapoptotic proteins (Bax, Bak, Bok, and Bid). Most of the
proteins in this subcategory can be recognized by conserved stretches of
amino acid sequence homology, including the presence of Bcl-2 homol-
Bax/Bak ogy (BH) domains, BH1, BH2, BH3, and sometimes BH4. However, this
is not uniformly the case, as the Bid protein contains only a BH3 domain
but has been determined to share the same overall protein-fold with
MOMP Bcl-X , Bcl-2, and Bax. 33,34 Where tested to date, these proteins have all
L
Figure 15–2. Network of interactions among Bcl-2 family proteins. been shown to form ion-conducting channels in synthetic membranes
The functional and physical interactions among proapoptotic and anti- in vitro, including Bcl-2, Bcl-X , Bax, and Bid, 36–40 but the significance of
L
apoptotic Bcl-2 family proteins are depicted. Illustrative members of the this pore activity remains unclear.
Bcl-2 family are shown. The other subset of Bcl-2 family proteins appears to have in com-
mon only the presence of the BH3 domain, including Bad, Bik, Bim,
Hrk, Bcl-G , p193, APR (Noxa), and PUMA. These “BH3-only” pro-
S
organelles (Fig. 15–2). Both proapoptotic and antiapoptotic Bcl-2 family teins are uniformly proapoptotic. Their cell-death–inducing activity
proteins have been delineated. These proteins are best known for their depends, in most cases, on their ability to dimerize with antiapoptotic
28
roles in controlling the intrinsic (mitochondrial) cell-death pathway, Bcl-2 family members, functioning as trans-dominant inhibitors of pro-
20
although effects on the ER-pathway for cell death have also been doc- teins such as Bcl-2 and Bcl-X . 41,42 However, some of these proteins (e.g.,
L
umented. Even though the human genome encodes at least 26 Bcl-2 Bid, PUMA, Bim) can also interact with proapoptotic proteins (e.g.,
29
family proteins, only six of these are antiapoptotic (in humans, Bcl-2, Bax, Bak), functioning as agonists of the killers, in addition to dimeriz-
Bcl-X [BCL2L1], Bcl-W [BCL2L2], Mcl-1 [BCL2L3], Bfl-1 [BCL2L5], ing with antiapoptotics (e.g., Bcl-2; Bcl-X ) to function as antagonists of
L
L
and Bcl-B [BCL2L10]). Several types of animal viruses also harbor Bcl-2 these cell-survival proteins (see Fig. 15–2). 28,43 Binding of Bid to Bax or
family genes within their genomes, including herpes viruses implicated Bak promotes insertion of these proteins into membranes where they
in cancer such as the Epstein-Barr virus (EBV) and Kaposi sarcoma oligomerize, apparently forming large pores through which molecules
virus (KSV). The relative ratios of anti- and proapoptotic Bcl-2 family such as Cyt-c, SMAC, and Omi can escape from mitochondria or caus-
proteins dictate the ultimate sensitivity or resistance of cells to various ing an increase in the permeability of the outer membrane of mitochon-
apoptotic stimuli, including growth factor deprivation, hypoxia, radia- dria through more complex mechanisms. 44,45 Bax and Bak thus induce
tion, anticancer drugs, oxidants, and Ca overload. mitochondrial outer membrane permeabilization (MOMP), which is a
2+
Various Bcl-2 family members play important roles in controlling critical event that not only causes release of death-inducing mitochon-
the life spans of hematopoietic cells, as evidenced by phenotypes gen- drial proteins but also secondarily causes necrosis by uncoupling of oxi-
erated in genetically engineered mice (gene knockouts and transgenics) dative phosphorylation (when Cyt-c becomes limiting) and diversion
and also (in some cases) by human clinical experiences with experi- of electrons from the respiratory chain into production of toxic free
mental therapeutics targeting some of these proteins. For example, anti- radicals. 46,47
apoptotic protein Bcl-2 is required for survival of mature T cells and The BH3 domain mediates dimerization among Bcl-2 family pro-
B cells, with deficiency of Bcl-2 causing lymphopenia. Conversely, the teins. This domain consists of an amphipathic α-helix of approximately
proapoptotic protein Bim is necessary for limiting expansion of T and 16 amino acids that inserts into a hydrophobic crevice on the surface of
B lymphocytes, with deficiency of Bim causing lymphocytosis. Bim also antiapoptotic proteins such as Bcl-2 and Bcl-X . The BH3-only pro-
48
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plays important role in eradicating autoreactive T cells in the thymus teins link a wide variety of environmental stimuli to the mitochondrial
(“negative selection”), having important implications for mechanisms pathway for apoptosis, with some examples outlined below.
of autoimmune diseases. Bcl-X is required for platelet homeostasis, In addition to mitochondria, mechanistic links for Bcl-2 family
30
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such that either genetic or pharmacologically induced Bcl-X deficiency proteins to ER stress and autophagy have also been delineated. For
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causes thrombocytopenia. Antiapoptotic protein Mcl-1 is particularly example, Bax and Bak can bind the ER stress signaling protein, IRE-1,
important for survival of the myeloid lineage in mice, as well as con- thereby stimulating its intrinsic autokinase activity and its endoribo-
tributing to lymphocyte survival. Conversely, antiapoptotic protein nuclease activity. Proapoptotic (Bak/Bax) and antiapoptotic (Bcl-2/
49
Bcl-W is not required for hematopoiesis in mice, despite being widely Bcl-X ) family members also have opposing effects on basal ER Ca
2+
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expressed in myeloid lineage cells. It should be noted that direct com- levels, probably via effects on Ca channel proteins in ER membranes
2+
parisons of gene manipulations in mice with the human circumstance (e.g., IP3Rs, BI-1, and TmBim3). Autophagy protein Beclin contains a
are not always possible because of genomic differences in the Bcl-2 fam- BH3-like domain that mediates interactions with antiapoptotic Bcl-2
ily genes of mice versus humans (e.g., human Bfl-1 versus murine A1; family proteins, which sequester Beclin and thereby reduce autophagic
human Bcl-B versus murine Boo/Diva). flux. Autophagy, which is a lysosome-dependent catabolic pathway,
50
Many members of the Bcl-2 family have a hydrophobic stretch of can either promote cell survival by providing access to nutrients during
amino acids near their carboxyl-terminus that anchors them in the outer times of nutrient insufficiency and hypoxia, or it can cause cell death
mitochondrial membrane. In contrast, other Bcl-2 family members when stimulated to an extreme. 51
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