Cell Science at a Glance
BH3-only proteins in
apoptosis at a glance
Lina Happo1,2, Andreas Strasser1,2
and Suzanne Cory1,2,*
1
The Walter and Eliza Hall Institute of Medical
Research, 1G Royal Parade, Parkville, Melbourne,
VIC 3052, Australia
2
Department of Medical Biology, The University of
Melbourne, Melbourne, VIC 3010 Australia
*Author for correspondence ([email protected])
Journal of Cell Science 125, 1081–1087
ß 2012. Published by The Company of Biologists Ltd
doi: 10.1242/jcs.090514
engulfed by phagocytes (for reviews,
see Hotchkiss et al., 2009; Strasser et al.,
2011). Defects in apoptosis contribute to
many diseases, ranging from cancer and
autoimmunity to degenerative disorders.
This Poster focuses on key initiators
of apoptosis: the BH3-only proteins.
Certain BH3-only proteins have also been
implicated in non-apoptotic processes (see
Elgendy et al., 2011; Yeretssian et al., 2011).
The two mammalian apoptosis
pathways
In mammalian cells, there are two pathways
to apoptosis (Hotchkiss et al., 2009; Strasser
et al., 2011) (see Poster): the ‘extrinsic’
pathway, which is triggered by engagement
of cell surface ‘death receptors’ of the
tumour necrosis factor receptor family with
their ligands, and the ‘intrinsic’ (or
mitochondrial) pathway, which is triggered
by diverse cellular stresses, such as cytokine
deprivation, DNA damage or oncogene
activation. These pathways are largely
independent (Strasser et al., 1995), each
activating different initiator caspases, but
they converge at the level of effector
caspases.
The intrinsic pathway is controlled
by interactions between proteins related to
BCL2, the oncoprotein activated by
chromosome translocation in follicular
lymphoma (Tsujimoto et al., 1985). BCL2
inhibits apoptosis (Vaux et al., 1988), as do
four close homologues – BCL-XL, BCL-W,
MCL1 and A1 – which share four BCL2
homology (BH) domains (see Poster). Other
relatives that are similar in sequence and
structure – BAX, BAK (and possibly BOK)
– instead promote apoptosis, as do distant
relatives (BIM, PUMA, NOXA, BID, BMF,
BAD, BIK and HRK), which have only the
Journal of Cell Science
Apoptosis is a genetically programmed
process for the elimination of damaged or
redundant cells by activation of caspases
(aspartate-specific cysteine proteases).
Caspases cleave vital proteins, leading the
cell to fragment into vesicles that are rapidly
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(See poster insert)
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Journal of Cell Science 125 (5)
BH3 domain in common with BCL2 or each
other. Induction of apoptosis requires the
activation of members of both of these
death-promoting families (Cheng et al.,
2001; Zong et al., 2001). Exposure to
stress results in the induction of BH3-only
proteins, which neutralise the pro-survival
proteins. Subsequent activation of BAX and
BAK, which involves their conformational
change and homo-oligomerisation on the
mitochondrial outer membrane, leads to its
permeabilisation. The consequent release of
cytochrome c into the cytoplasm promotes
the formation of the apoptosome complex,
which activates initiator caspase-9.
The ,26-residue BH3 domain is an
amphipathic a-helix that binds with high
affinity to a hydrophobic groove on the
surface of pro-survival BCL2 family
members (Sattler et al., 1997). Individual
BH3-only proteins have varying affinities for
different pro-survival proteins (Opferman
et al., 2003; Chen et al., 2005; Kuwana et al.,
2005; Certo et al., 2006; Ku et al., 2011).
Whereas BIM, tBID (the cleaved active form
of BID; see below) and PUMA bind with high
affinity to all pro-survival proteins, others are
more selective; for example, BAD binds with
high affinity only to BCL2, BCL-XL and
BCL-W, and NOXA only to MCL1 and A1.
Importantly, the ‘promiscuous’ binders are
more potent killers than the more selective
binders, but co-expression of ‘selective
binders’ that have complementary specificity
(e.g. BAD plus NOXA), kills cells as potently
as the ‘promiscuous’ BIM (Chen et al., 2005).
This suggests that efficient apoptosis requires
neutralisation of all pro-survival BCL2 family
members expressed within a given cell.
However, there is still vigorous debate
on how the BH3-only proteins trigger
activation of BAX and BAK (Chipuk et al.,
2010; Strasser et al., 2011). The ‘direct
activation’ model (Letai et al., 2002;
Kuwana et al., 2005; Chipuk et al., 2010)
(see Poster) proposes that certain BH3-only
proteins termed ‘activators’ – for example
BIM, tBID and perhaps PUMA (Cartron
et al., 2004) – bind transiently with low
affinity to BAX and BAK (‘hit and run’),
thereby triggering their conformational
change and subsequent oligomerisation
on the mitochondrial outer membrane.
According to this model, the other BH3only proteins, termed ‘sensitisers’ (for
example, BAD, BIK, HRK), bind only to
pro-survival BCL2 family members, but
in doing so they liberate any complexed
‘activator’ BH3-only proteins to activate
BAX or BAK. Recently, the distinction
between ‘activator’ and ‘sensitiser’
BH3-only proteins has become more
blurred, with claims that NOXA (Dai et al.,
2011) and BMF (Du et al., 2011) can act as
direct activators.
The ‘indirect activation’ model (see
Poster) posits that the primary role of all
BH3-only proteins is to bind to pro-survival
BCL2 family members, thereby preventing
them from binding to and neutralising any
activated BAX or BAK molecules (Chen
et al., 2005; Willis et al., 2005; Willis et al.,
2007; Uren et al., 2007). This model
envisages that activation of a BAX or BAK
protein is the result of a conformational
change that exposes its BH3 domain, which,
if not bound by a pro-survival BCL2like protein, would catalyse self homooligomerisation (see Dewson and Kluck,
2009). The two models are not mutually
exclusive; indeed, they might act in parallel
during developmentally programmed death
of haematopoietic cells (Merino et al., 2009).
Variations of these models have also been
proposed (Chipuk et al., 2010; Lovell et al.,
2008; Strasser et al., 2011).
Regulation and function of
individual BH3-only proteins
BH3-only proteins are regulated by
diverse transcriptional and post-translational
mechanisms (see Poster). Loss of individual
BH3-only proteins, except BIM, results in a
relatively normal phenotype in the absence of
stress conditions (see Table in Poster),
indicative of functional overlap. Different
cytotoxic conditions induce distinctive, albeit
overlapping, expression patterns that can
vary with cell type.
BIM
There are three major splice variants of BIM
(BIMS, BIML and BIMEL), the most potent
being BIMS, which is extremely hard to detect
in vivo (O’Connor et al., 1998). Transcription
of Bim is reportedly induced by the forkhead
transcription factor FOXO3a, in response to
cytokine withdrawal (Dijkers et al., 2000); by
CHOP, a member of the C/EBP transcription
factor family, during endoplasmic reticulum
(ER) stress (Puthalakath et al., 2007); and by
MYC, possibly indirectly (Egle et al., 2004).
Bim transcription is repressed by the miR-1792 microRNA cluster (Ventura et al., 2008),
which in turn is repressed by glucocorticoids
(Molitoris et al., 2011). BIMEL and
BIML are also thought to be regulated
post-translationally by sequestration to
the microtubule-associated dynein motor
complex (Puthalakath and Strasser, 2002).
Phosphorylation of BIM can either be
activating or inactivating, depending on the
site. Phosphorylation by extracellular signalregulated kinase (ERK) lowers the affinity of
BIM for MCL1 and BCL-XL, and targets it for
ubiquitylation and proteasomal degradation
(Ewings et al., 2007). By contrast,
phosphorylation by Jun N-terminal kinase
(JNK) increases the pro-apoptotic activity of
BIM (Lei and Davis, 2003; Putcha et al.,
2003). Dephosphorylation by protein
phosphatase 2A (PP2A) following ER stress
also enhances its activity (Puthalakath et al.,
2007).
BIM is prominent in lymphoid cells, but is
also readily detectable in many other cell
types (O’Reilly et al., 2000). Bim–/– mice
exhibit prominent lymphoid hyperplasia,
indicating that BIM is a major regulator
of lymphoid homeostasis (Bouillet et al.,
1999). BIM is crucial for the deletion of
autoreactive thymocytes (Bouillet et al.,
2002) and B cells (Enders et al., 2003), and
for the termination of acute (Pellegrini et al.,
2003) and chronic (Hughes et al., 2008)
immune responses. Bim–/– mice develop
excessive antibody levels which, depending
on the genetic background, can lead to
autoimmune kidney disease (Bouillet et al.,
1999). Remarkably, loss of even only a
single allele of Bim can prevent the fatal
polycystic kidney disease that afflicts Bcl2–/–
mice (Bouillet et al., 2001), indicating that
BCL2 and BIM are the principal regulators
of apoptosis in developing nephrons.
Loss of BIM increases the resistance of
many haematopoietic cell types to diverse
cytotoxic conditions, including cytokine
deprivation and exposure to abnormal
calcium flux, taxol and glucocorticoids
(Bouillet et al., 1999). Although BIM is
not a direct transcriptional target of the
DNA damage response protein P53, loss of
BIM renders normal (Bouillet et al., 1999;
Erlacher et al., 2005) and transformed
(Happo et al., 2010) lymphoid cells more
resistant to DNA-damage-inducing agents,
including chemotherapeutics. BIM cooperates with PUMA to mediate apoptosis
triggered by cytokine deprivation and
exposure to c-irradiation, dexamethasone
and ER stressors (Ekoff et al., 2007;
Erlacher et al., 2006).
PUMA and NOXA
Noxa (Oda et al., 2000) and Puma (Nakano
and Vousden, 2001; Yu et al., 2001) are
both direct transcriptional targets of
p53. However, although lymphocytes and
fibroblasts lacking PUMA are highly
resistant to c-irradiation and DNA-damageinducing chemotherapeutics (Jeffers et al.,
2003; Villunger et al., 2003a), those lacking
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NOXA remain relatively sensitive (Shibue
et al., 2003; Villunger et al., 2003b).
Conversely, loss of NOXA renders
fibroblasts and keratinocytes more resistant
to UV radiation than does loss of PUMA
(Naik et al., 2007). Thus, different DNA
lesions might modulate the target gene
preferences of P53.
E2F1 also targets both Noxa and Puma
for transcription (Hershko and Ginsberg,
2004) and the hypoxia-inducible factor
HIF1a targets Noxa (Kim et al., 2004).
Puma transcription is induced when cells
are deprived of cytokines or treated with
glucocorticoids, staurosporine or phorbol
esters (Ekoff et al., 2007; Erlacher et al.,
2005; Jeffers et al., 2003; Kieran et al.,
2007; Michalak et al., 2008; Villunger
et al., 2003b). NOXA is reportedly
inhibited by cytosolic sequestration
following phosphorylation by cyclindependent kinase 5 (CDK5) (Lowman
et al., 2010).
BID
Unlike most BH3-only proteins, which are
relatively unstructured until they are bound
to pro-survival proteins (Hinds et al., 2007),
BID is structurally similar to BAX and
BAK (Chou et al., 1999; McDonnell et al.,
1999). Full-length BID is expressed in
most tissues, but is inactive until
cleaved proteolytically. Because BID can
be cleaved by caspase-8, its active form,
tBID, can link the extrinsic and
intrinsic apoptosis pathways (see Poster).
Hepatocytes from Bid–/– mice are resistant
to killing through the death receptor FAS,
but their lymphocytes remain sensitive
(Kaufmann et al., 2007; Yin et al., 1999),
implying that apoptosis signal amplification
through the mitochondrial pathway is
essential for killing in certain cell types,
but not in others.
BMF
There are two major isoforms of BMF,
produced from different initiation sites on a
common transcript (Grespi et al., 2010).
BMF can be negatively regulated by
sequestration to the cytoskeleton through
binding to the myosin V motor complex
(Puthalakath et al., 2001). Although studies
in cell lines implicated BMF in detachmentmediated apoptosis (anoikis) (Puthalakath
et al., 2001), endothelial cells and
fibroblasts from Bmf–/– mice remain
sensitive (Labi et al., 2008), suggesting
that other BH3-only proteins are also
triggered by anoikis. BMF activity might
be regulated by JNK phosphorylation (Lei
and Davis, 2003). Bmf–/– mice develop
progressive B cell hyperplasia (Labi et al.,
2008), indicating that BMF regulates
lymphoid
homeostasis.
Lymphocytes
lacking BMF have increased resistance to
dexamethasone and to inhibitors of histone
deacetylases (HDACs) (Labi et al., 2008),
which prevent transcription by promoting
chromatin compaction.
BAD
Phosphorylation of BAD by the protein
kinase AKT during cytokine signalling
reportedly results in its binding and
sequestration by 14-3-3 scaffold proteins
(del Peso et al., 1997). Bad–/– mice appear
normal (Ranger et al., 2003), except for a
mild thrombocytosis (Kelly et al., 2010)
that is probably caused by reduced
inhibition of BCL-XL in the absence
of BAD (Mason et al., 2007). Mouse
embryonic fibroblasts (MEFs) lacking
BAD remain sensitive to many apoptotic
stimuli (Ranger et al., 2003). Combined loss
of BIM and BAD enhances the survival of
activated B cells that are deprived of
cytokines and accelerates c-radiationinduced thymic lymphomagenesis, which
is indicative of functional overlap (Kelly
et al., 2010).
BIK
BIK was the first BH3-only protein to be
identified (Boyd et al., 1995; Chittenden
et al., 1995). Bik transcription can be
activated by E2F1 and P53 (see
Chinnadurai et al., 2008) and Bik activity
is postulated to be inhibited by
phosphorylation mediated by casein
kinase II (CSNK2) (Verma et al., 2000).
Although BIK is widely expressed, Bik–/–
mice display no overt abnormalities and
Bik–/– haematopoietic cells and fibroblasts
remain sensitive to diverse apoptotic
stimuli (Coultas et al., 2004). Defects in
spermatogenesis in Bik–/–Bim–/– mice
suggest that BIK and BIM share the role
of eliminating supernumerary germ cells
(Coultas et al., 2005).
HRK
HRK activity is enhanced by JNKmediated phosphorylation (Ma et al.,
2007). HRK expression is restricted to the
central and peripheral nervous systems and
contributes to apoptosis of certain neuronal
cells induced by cytokine deprivation
(Coultas et al., 2007; Imaizumi et al.,
1997). Although HRK expression in
human hematopoietic cells has also been
reported (Inohara et al., 1997), loss of
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HRK has no impact on mouse
haematopoietic cells (Coultas et al., 2007).
BH3-only proteins as tumour suppressors
Inhibition of apoptosis is a fundamental
step in tumour development (Hanahan
and Weinberg, 2000) and, conversely,
induction of apoptosis might be important
for tumour suppression. Mutations crippling
genes encoding BH3-only proteins have
been detected in a range of human cancers
(see Table in Poster) and direct tests using
mice in which certain genes have been
knocked out have provided experimental
evidence that certain BH3-only proteins can
indeed serve as tumour suppressors.
BIM was the first BH3-only protein
shown to be a tumour suppressor. Using
Em-Myc transgenic mice, in which Myc
expression is driven by the immunoglobulin
heavy chain (IgH) enhancer, modelling
the chromosome translocation in Burkitt
lymphoma (Adams et al., 1985), loss
of only a single allele of Bim was
found to accelerate MYC-driven B
lymphomagenesis (Egle et al., 2004). Loss
of BIM also accelerates renal cancers
induced in mice by mutant Ras (Tan et al.,
2005). Homozygous deletion of BIM is
evident in many mantle cell lymphomas
(Tagawa et al., 2005) and silencing of BIM
by promoter methylation and mutation is
common in B cell lymphomas (MestreEscorihuela et al., 2007). Certain Burkitt
lymphomas carry point mutations in MYC
that prevent MYC from activating BIM
(Hemann et al., 2005). The miR-17-92
cluster, which represses BIM expression,
is often overexpressed or amplified in
human cancers (Xiao et al., 2008).
As a result of P53 mutations, over 50% of
human tumours exhibit impaired ability to
induce PUMA or NOXA in response to
genotoxic damage or oncogenic stress
(for examples see Table in Poster). Loss
or knock-down of PUMA accelerated
B lymphomagenesis in Em-Myc mice
(Garrison et al., 2008; Hemann et al.,
2004; Michalak et al., 2009) and loss of
NOXA accelerated c-radiation-induced
thymic lymphomagenesis (Michalak et al.,
2010). However, Noxa–/–Puma–/– mice do
not develop tumours (Michalak et al., 2008)
and, although the combined loss of
PUMA and NOXA accelerated MYCdriven lymphomagenesis, the effect is not
as great as that provoked by loss of
P53 (Michalak et al., 2009). Therefore,
induction of apoptosis through PUMA and
NOXA constitutes only one mechanism by
which P53 suppresses tumour development;
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Journal of Cell Science 125 (5)
Journal of Cell Science
others include cell cycle arrest, DNA repair
and cellular senescence. Loss of BMF or
BAD also accelerates lymphomagenesis in
mouse model systems (Labi et al., 2008;
Frenzel et al., 2010; Kelly et al., 2010).
BH3-only proteins and cancer
therapy
BH3-only proteins play a crucial role in the
killing of tumour cells by anti-cancer agents
(see Strasser et al., 2011). Efficient killing
of MYC-driven lymphomas in mice by
DNA-damaging agents requires the P53
targets PUMA and NOXA, and also,
unexpectedly, BIM (Happo et al., 2010).
BIM (in concert with PUMA) is essential
for inducing apoptosis of tumour
cells following glucocorticoid treatment
(Molitoris et al., 2011), MEK inhibition
(Abrams et al., 2004; Cragg et al., 2008) or
microtubule stabilisation by paclitaxel
(Puthalakath et al., 1999; Sunters et al.,
2003). Inhibitors of oncogenic kinases such
as imatinib, which targets BCR–ABL in
chronic myeloid leukaemia (CML) cells,
require BIM activity and in certain settings
also that of BAD and BMF (Costa et al.,
2007; Cragg et al., 2008; Cragg et al., 2007;
Gong et al., 2007; Kuroda et al., 2006). BIM
and BMF activity mediate the sensitivity of
lymphoid malignancies to glucocorticoids
(Ploner et al., 2008) and HDAC inhibitors
(Lindemann et al., 2007). BMF enhances
the apoptotic response of BCL2overexpressing lymphomas to combined
treatment with the HDAC inhibitor
Vorinostat and the BH3 mimetic ABT-737
(see below) (Wiegmans et al., 2011). BID
contributes to responsiveness to HDAC
inhibitors (Lucas et al., 2004) and
proteasome inhibitors (e.g. bortezomib)
(Duechler et al., 2005), and bortezomib
induces NOXA, BIM and BIK in a variety
of human cancer cells (Fennell et al., 2008).
BH3 mimetics as therapeutics for
cancer
Small-molecule mimics of BH3-only
proteins are being developed for cancer
therapy. ABT-737 (Oltersdorf et al., 2005)
and its orally active derivative ABT-263
(Tse et al., 2008) are both bona fide BH3
mimetics because they kill cells through a
BAX- and BAK-dependent mechanism
(reviewed by Lessene et al., 2008). Both
compounds bind with high affinity to
BCL2, BCL-XL and BCL-W, but do not
interact with MCL1 or A1 (Oltersdorf et al.,
2005). They are relatively well tolerated,
despite the transient thrombocytopaenia
caused primarily by inhibition of BCL-XL,
which is the limiting factor for platelet
survival (Mason et al., 2007; Zhang et al.,
2007). In preclinical studies, ABT-737 was
efficacious as a single agent for treating
certain leukaemias and lymphomas (Del
Gaizo Moore et al., 2007; Del Gaizo Moore
et al., 2008; Konopleva et al., 2006;
Oltersdorf et al., 2005; Shoemaker et al.,
2008; Tse et al., 2008; Vogler et al., 2008),
multiple myelomas (Chauhan et al., 2007;
Kline et al., 2007) and small cell lung
cancers (Oltersdorf et al., 2005), but not for
epithelial cancers (Huang and Sinicrope,
2008; Witham et al., 2007). High levels of
MCL1 confer resistance to ABT-737, but
this could be overcome by reducing MCL1
levels (reviewed by Lessene et al., 2008).
ABT-737 can synergise with conventional
anti-cancer agents, as well as with targeted
inhibitors of oncogenic kinases (reviewed
by Cragg et al., 2009). ABT-263, currently
in early Phase I–II clinical trials, has shown
promising efficacy in chronic lymphocytic
leukaemia (CLL) patients (Gandhi et al.,
2011; Tse et al., 2008; Wilson et al., 2010).
Perspectives
BH3-only proteins are essential for initiating
apoptosis through the mitochondrial
pathway. Elucidating which of the proapoptotic BH3-only proteins are essential
for the killing of malignant cells by
conventional and targeted anti-cancer
agents can provide valuable insights into
why certain therapies succeed in some
patients but fail in others. In the era of
BH3 mimetics, this knowledge will help
tailor the use of rational combination
therapy and increase therapeutic efficacy
whilst limiting collateral damage to normal
tissues.
Acknowledgements
A.S. and S.C. are supported by the National
Health and Medical Research Council [grant
number 461221, Australia Fellowship
(AS)]; the National Institutes of Health
[grant number CA43540]; the Leukemia and
Lymphoma Society [grant number SCOR
7413]; and operational infrastructure grants
through NHMRC IRISS and the Victorian
State Government OIS. L.H. has a Leukaemia
Foundation Australia scholarship. Deposited
in PMC for release after 12 months.
A high-resolution version of the poster is available for
downloading in the online version of this article at
jcs.biologists.org.
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