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PHYSIOLOGY 29: 168 –176, 2014; doi:10.1152/physiol.00016.2013
Apoptotic Cell Death Under Hypoxia
Eukaryotic life depends largely on molecular oxygen. During evolution, ingenious mechanisms have evolved that allow organisms to adapt when oxygen
Ataman Sendoel,
and Michael O. Hengartner
Institute of Molecular Life Sciences, University of Zurich, Zurich,
Switzerland
[email protected]
levels decrease. Many of these adaptional responses to low oxygen are
orchestrated by the heterodimeric transcription factor hypoxia-inducible factor (HIF). Here, we review the link between HIF and apoptosis.
168
is typically characterized by a core of necrosis (56,
104), a passive, uncontrolled type of cell death. By
contrast, the hypoxic stress experienced by cells in
the penumbra region that surround the core necrotic region is not sufficient to kill them. These
moderately hypoperfused cells, however, subsequently die by apoptosis, a programmed and
highly controlled type of cell death that can be
pharmacologically blocked (104). Similar cascades
are thought to occur during myocardial infarction,
which is also characterized by a core of necrosis
and a border zone of the ischemic region, where
cells undergo apoptosis (12, 52).
Why should a hypoxic cell that is not lethally
damaged activate apoptosis? What are the molecular mechanisms underlying this decision? Are
there adaptational mechanisms to hypoxia that
protect from apoptosis? In this review, we cover
the effects of hypoxia at the cellular level, discuss
adaptational mechanisms to hypoxia, and describe
the consequences with regard to apoptotic cell
death induction.
Two Paths to Rome: The Intrinsic
and the Extrinsic Apoptosis
Signaling Pathways
Apoptosis is a cell-intrinsic cell suicide program used
by multicellular organisms to eliminate unneeded or
potentially dangerous cells in an organism. Whereas
apoptosis was initially defined based on characteristic morphological hallmarks, the identification and
characterization of the proteins mediating apoptotic
cell death led to a more molecular definition (26, 45).
At the molecular level, we can distinguish two major
pathways: the intrinsic and extrinsic signaling pathways. The two pathways activate different initiator
caspases but converge at the level of effector
caspases (FIGURE 1).
The extrinsic signaling pathway is initiated by
binding of a death ligand to a death receptor on the
cell surface. These death receptors belong to the family of tumor necrosis factor receptor and include
TNF-R1, CD95 (Fas), TRAIL-R1, and TRAIL-R2. Binding of CD95 ligand to the CD95, for instance, results
in the formation of the CD95 death-inducing signaling complex (DISC) comprised of the FAS-associated
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Two to 2.5 billion years ago, earth’s atmosphere
shifted from an anoxic state to an oxic state, a
transition known as the great oxygenation event (5,
24). This event built the basis of biological diversification as oxygen provided now free energy supply
to living organisms. Today’s eukaryotes from the
humble yeast to highly evolved humans, depend
largely on molecular oxygen. Humans for instance
can survive only a few minutes without oxygen (47).
Cellular respiration is not only a central but also one
of the most sophisticated and elegant aspects of biology. It allows the cell to make use of oxygen’s
physical properties to exploit the thermodynamic
potential of oxidation for energy production.
The key organelle for energy production is the
mitochondrion. Mitochondria integrate various metabolic pathways to produce energy for the cell,
including the tricarboxylic acid cycle (TCA), betaoxidation, and oxygen metabolism. These metabolic
pathways synergize to convert the biochemical energy of nutrients into the cellular energy currency,
adenosine triphosphate (ATP). ATP is the main energy form for a variety of cellular processes, including
DNA, RNA, and protein synthesis, maintenance of
the cytoskeleton, signaling, and ion transport. Moreover, the mitochondrial outer membrane is also critical in the regulation of apoptotic cell death. Thus
mitochondria constitute an important crossway between energy production and cell death signaling.
During evolution, oxygen availability became so
important that complex anatomical structures
were developed to maintain appropriate oxygen
delivery to all tissues within an organism. The
complex circulatory, respiratory, and neuroendocrine systems were accompanied by mechanisms
to sense oxygen levels and adapt to hypoxia at the
cellular as well as systemic levels.
Hypoxia is a broad term used for a condition
where oxygen demand exceeds oxygen supply. As a
result of hypoxia, ATP levels drop, cellular functions cannot be maintained, and–if the insult lasts
long enough– cells die. A classical example for an
acute hypoxic event is stroke, caused by an occlusion of a brain artery (ischemia: restriction in blood
supply) or hemorrhage. A stroke lesion can lead to
both types of cell death, necrosis and apoptosis. It
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agents. Three interacting subgroups of proteins
from the Bcl-2 family control the intrinsic signaling pathway at the mitochondrial membrane (14).
The first group consists of the antiapoptotic Bcl-2
proteins. Members of this subgroup share four
conserved Bcl-2 homologous (BH) domains and
are essential for cell survival. By contrast, the
multi-BH domain pro-apoptotic subfamily members BAX, BAK, and BOK are critical for the effector
phase of apoptosis. The third group, the pro-apoptotic BH3-only proteins, shares only the BH3 domain with the other family members. BH3-only
proteins are important players in the activation
of apoptosis and mediate the response to proapoptotic stimuli such as DNA damage. Upon activation of BH3-only proteins, the balance between
antiapoptotic and proapoptotic members shifts.
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death domain (FADD), procaspase-8/procaspase-10,
and cellular FLICE-inhibitory protein (c-FLIP) (4)
(FIGURE 1).
In some type of cells (type I cells) that are characterized by high caspase-8 levels, active caspase-8
directly cleaves and activates caspase-3 and other
effector caspases. In type II cells, however,
caspase-8 levels are lower and the proapoptotic
signals need to be amplified by caspase-8 mediated cleavage of the Bcl-2 family member Bid.
Truncated (tBid) activates the intrinsic signaling
pathway and results in release of cytochrome c
from mitochondria (4, 23).
Intrinsic apoptotic signaling occurs in response to a wide variety of stimuli or cellular
stresses such as DNA damage and cytokine deprivation or in response to chemotherapeutic
FIGURE 1. Overview of the intrinsic and extrinsic apoptotic signaling pathways
The binding of a death ligand to the death receptor initiates the extrinsic pathway and results in activation of the death-inducing signaling complex (DISC). Caspase-8 then either directly activates the downstream caspase (type I cells) or needs an amplification step
(type II cells) via cleavage of Bid. Intrinsic apoptotic signaling occurs in response to physiological signals or cellular stresses such as
DNA damage. Upon activation, the balance between antiapoptotic and proapoptotic Bcl-2 members on the mitochondrial membrane
shifts and results in outer mitochondrial membrane permeabilization and cytochrome c release. Bcl-2 family members targeted by HIF
are highlighted in red. Cytosolic cytochrome c binds to the apoptotic caspase activating factor (Apaf1) and recruits procaspase-9 to
form the apoptosome. Activated caspase-9 within the apoptosome can then promote activation of downstream caspases.
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Reprogramming Apoptosis Under
Hypoxia?
Hypoxia-Inducible Factor, the Master
Regulator of the Hypoxic World
Hypoxia-inducible factor (HIF) is a heterodimeric
transcription factor that orchestrates cellular and
systemic adaptive responses to maintain oxygen
homeostasis and adapt to low oxygen levels. HIF
was initially identified as a regulator of erythropoietin gene expression in response to a decrease in
oxygen availability in the kidney (94, 95). The HIF
heterodimer consists of an oxygen-dependent
␣-subunit (HIF-1␣, HIF-2␣, or HIF-3␣) and a constitutively expressed ␤-subunit, both of which
are basic helix-loop-helix (bHLH) transcription
factors. Under normal oxygen levels, prolyl hydroxylases (PHD1–3) utilize oxygen as a substrate
to hydroxylate two proline residues of HIF␣ (10,
21, 40, 42). Hydroxylated HIF␣ is recognized by
the von Hippel-Lindau (VHL) protein, which is
the substrate recognition subunit of the VCBCul2 ubiquitin-ligase, which ubiquitinates HIF␣
and targets it for proteasomal degradation (103)
(FIGURE 2). Under hypoxic conditions, PHD activity decreases, HIF␣ proline residues are not hydroxylated, and the protein can accumulate. Once
stabilized, HIF␣ can rapidly enter the nucleus and
joins HIF-1␤ to generate the heterodimeric transcription factor HIF, which then promotes the expression of dozens to hundreds of target genes by
binding to hypoxia response elements [HRE; minimal core sequence 5=-RCGTG-3= (R is A or G)]
present in their regulatory region (98). A decrease
in oxygen levels also leads to impairment of the
factor inhibiting HIF (FIH), an asparagine hydroxylase. This impairment results in a decrease in
N-803 hydroxylation, which enables recruitment of
FIGURE 2. Oxygen-dependent regulation of the heterodimeric transcription factor
HIF Under normal oxygen levels, prolyl hydroxylases (PHD) hydroxylate two proline residues (P402 and P564 of HIF-1␣) within
the oxygen-dependent degradation domain (ODD) of HIF␣, which allows the binding of the von Hippel Lindau protein (VHL).
VHL is the recognition subunit of the VCB-Cul2 ubiquitin ligase, which ubquitinates HIF␣ and results in its rapid degradation.
Under low oxygen levels, PHD is not active, and HIF␣ enters the nucleus and activates together with HIF␤ transcription of target genes. A decrease in oxygen levels also leads to impairment of the factor inhibiting HIF (FIH). Impairment of this asparagine hydroxylase results in a decrease in N-803 hydroxylation, which enables recruitment of the transcriptional coactivators
p300 and CREB binding protein (p300/CBP).
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Together, these activities ultimately lead to the activation of Bax and Bak. Some BH3-only proteins
such as Bid and Bim directly induce a conformational change of Bax and Bak to form oligomerization (18, 75). Other BH3 domain proteins bind
to and inhibit prosurvival Bcl-2 proteins (102)
(FIGURE 1).
Once activated, Bax and Bak mediate mitochondrial outer membrane permeabilization (MOMP)
(48, 78, 96). Mitochondrial outer membrane permeabilization results in the release of a variety of
apoptogenic molecules, the most important of
which is cytochrome c (57, 70). Once released to
the cytosol, cytochrome c binds in the presence of
2=-deoxyadenosine triphosphate (dATP) or adenosine triphosphate (ATP) to the apoptotic protease
activating factor (Apaf1), promoting its oligomerization and the recruitment of the initiator procaspase-9 to form the apoptosome, a wheel-like
particle with sevenfold symmetry. Active caspase
within the apoptosome then promotes efficient
activation of the downstream caspases 3 and 7
that are responsible for the execution phase of
apoptosis (1).
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the transcriptional coactivators p300 and CREB
binding protein (p300/CBP) (54, 59).
Depending on the cellular context, HIF induces
the expression of a vast array of genes involved in
angiogenesis, cellular metabolism, proliferation,
extracellular matrix formation, or the regulation of
apoptosis (98).
HIF␣-Dependent Responses
Family Member
Pro-apoptotic
BNIP
Noxa
Bcl-2
Anti-apoptotic
Bcl-2
Bcl-xL
Bax
Bak
Mcl-1
Bid
Bad
Reference(s)
11, 32, 90
46
13
83
16, 83, 92
22, 83
83
58, 71, 73a, 89
22
22
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The effects of a drop in oxygen partial pressure can
be basically subdivided in HIF␣-dependent and
-independent effects. We start our discussion first
with HIF␣-dependent responses.
The consequences of HIF␣ stabilization on apoptosis are complex, exemplified by many opposing
reports suggesting that HIF-1␣ can induce as well
as antagonize apoptosis. Part of this complexity is
due to the existence of three HIF␣ subunits in
mammals. HIF-1␣ and HIF-2␣ have overlapping
but distinct functions. Depending on the cell type,
the two HIF␣ subunits can also have completely
opposing effects on apoptosis. Furthermore, HIF␣
subunits can have suppressive interactions as
shown in renal cell carcinomas, where enhanced
expression of HIF-1␣ suppressed HIF-2␣ and viceversa. Experiments in which expression of one
HIF␣ subunit is altered could induce compensatory effects of the other HIF␣ subunits (74, 77) and
make it more difficult to draw conclusions. Moreover, the role of HIF-3␣ is less clear. A short splice
variant of this gene, the inhibitory PAS protein
(iPAS), functions predominantly as transcriptional
repressor (62, 63). HIF-3␣ contains an oxygen-dependent degradation (ODD) domain but no
COOH-terminal transactivation domain (CAD).
Similar to HIF-1␣ and HIF-2␣, HIF-3␣ is targeted
for proteasomal degradation by VHL in an oxygendependent manner (30, 63). Interestingly, HIF-3␣
can be induced by HIF-1␣, which could be part of
a negative feedback loop to attenuate the hypoxia
response (60).
Mitochondria not only contain the electron
transport chain but also lie at the center of the
intrinsic apoptotic signaling pathway. The two processes overlap at the level of cytochrome c, which
not only function in electron transfer between the
complexes III and IV but is also released during
apoptosis from the mitochondrial intermembrane
space (70). Given the importance of mitochondria
in apoptosis regulation, we will start our discussion
on HIF␣-mediated effects on apoptosis with the
Bcl-2 family members.
HIF␣ subunits have been implicated in the regulation of a variety of Bcl-2 family members with
both pro- and antiapoptotic consequences and are
summarized in Table 1. The importance of each of
these reported regulatory effects are likely dependent on the cellular context. Proapoptotic changes
Table 1. Bcl-2 family members targeted by
HIF-␣
by HIF-1␣ include downregulation of Bcl-2 (13),
induction of BH3-only domain proteins BNIP3
(Bcl2/adenovirus EIB 19kD-interacting protein 3),
its homolog Nip-3-like protein 3 (11, 32, 90), and
the BH3-only domain protein Noxa (46).
In contrast, a large body of evidence suggests
that HIF-1␣ can also protect from apoptotic cell
death induction (Table 1). Antiapoptotic changes
include increase in Bcl-2 (83) and Mcl-1 levels (58,
71, 89), Bcl-xL induction (16, 64, 83) (through
HIF-1␣ binding to a hypoxia-response element in
the Bcl-xL promoter), and decreases in pro-apoptotic Bid (22), Bax (22, 83), and Bak levels (83).
Mitochondria could also be directly targeted by
HIF-1␣. HIF-1␣ can, for instance, induce mitofusin-1, which changes mitochondrial morphology
from a tubular to an enlarged network. Hypoxic
cells that were initially resistant to etoposide-induced cell death were resensitized to apoptosis
through silencing mitofusin, BNIP3, or BNIP3L
(17). HIF-1␣ has also been linked to mitochondria
via hexokinases. Beyond catalyzing the first step of
glycolysis, hexokinase II has been reported to shift
the apoptotic balance by binding to the voltagedependent anion channel (VDAC) on the mitochondrial membrane (72, 73). As with many other
glycolytic enzymes, hexokinase II can be induced
by HIF-1␣, and a recent study indicated that
hexokinase II is crucial for the Warburg effect in
glioblastoma multiforme (101). This direct interaction, most probably independent of Bax and Bak
(53, 61, 79, 101), could therefore integrate the preferential use of aerobic glycolysis (Warburg effect)
with the inhibition of apoptosis.
The impact of HIF-2␣ on apoptotic cell death
induction has been studied to a smaller extent but
points clearly to an antiapoptotic function. Raval
and colleagues have shown that HIF-2, in contrast
to HIF-1, negatively regulates pro-apoptotic BNIP3
in VHL-deficient renal cell carcinomas cells (77).
Although the impact on apoptosis has not been
tested in this study, the authors elegantly showed
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that the two HIF␣ subunits have contrasting biological properties, with HIF-1␣ retarding and
HIF-2␣ enhancing renal cell tumor growth, a feature that could be partly due to differential apoptosis regulation. Another study dissected the
HIF-1␣ and HIF-2␣ network in hepatocellular carcinoma cells. In this system, HIF-1␣ knockdown
also increased expression of HIF-2␣ and vice-versa.
Moreover, HIF-2␣ expression shifted the balance
of the Bcl-2 family members toward survival (64).
Finally, the short splice variant of HIF-3 (IPAS)
has been been implicated in exerting a proapoptotic activity by direct binding to Bcl-x(L) (92).
p53 is a tumor suppressor that can signal to the
intrinsic apoptosis pathway. Following activation,
p53 can induce proapoptotic BH3-only proteins such
as Puma and Noxa to trigger apoptosis. The interaction between HIF␣ and p53 has been the source of
much controversy in the past. As is the case for VHL
and HIF␣, p53 is tightly controlled and targeted for
proteasomal degradation by its ubiquitin ligase
Mdm2. Activation of p53 includes posttranslational
modifications at the NH2 terminus that disrupt the
interaction with Mdm2 and results in p53 accumulation and transcriptional activation of p53 target
genes by recruitment of p300/CBP (67, 69, 93).
At least three different types of interaction have
been proposed between HIF-1␣ and p53. First, direct protein-protein interaction has been proposed
as the underlying mechanism for hypoxia-induced
p53 stabilization (3). Two different studies have
provided in vitro data suggesting a direct binding
of the ODD (oxygen-dependent degradation) domain of HIF-1␣ to p53 (37, 82). Moreover, direct in
vitro and in vivo interactions between HIF-1␣ and
Mdm2 to modulate p53 function (15) and VHL and
p53 association to stabilize p53 have been reported
(81). Thus, if HIF␣ and p53 were simultaneously
stabilized, direct interaction between these two
proteins could affect transcription of p53 target
genes. However, these data have been challenged
by a report that HIF-1␣ was not required for p53
induction under hypoxia (97). Another controversy
to this scenario has been that HIF-1 is induced at
relatively modest hypoxia levels, whereas p53 is
only stabilized under severe hypoxia, restricting
possible interactions. Moreover, although phosphorylated HIF-1 is bound to HIF-1␤, only dephosphorylated HIF-1␣ seems to be able to bind p53
and promote apoptosis (91).
Second, given that both transcription factors require p300/CBP as coactivator, it has been suggested that p53 and HIF␣ compete for p300/CBP
(85). In such a scenario, stabilized HIF␣ could outcompete p53 from p300 and attenuate the tran172
PHYSIOLOGY • Volume 29 • May 2014 • www.physiologyonline.org
HIF␣-Independent Responses
During hypoxia, reactive oxygen species can be
generated (33) due to electron release before transfer to complex IV (87). This leads to DNA damage
(34), opening of the mitochondrial permeability
transition pore (20, 38), and release of apoptogenic
proteins such as cytochrome c. Furthermore, ATM
and ATR kinases are phosphorylated under low
oxygen levels independently of DNA damage and
HIF-1 (6), with the possible result that these ki-
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p53 and HIF: Communications Among
Master Regulators
scriptional response to p53. Third, the network of
HIF-1␣ target genes could directly or indirectly
affect p53 response. A number of HIF-1 targets,
including homeodomain-interacting protein kinase-2 (HIPK2) (68) or nucleophosmin (55), have
been implicated in negatively regulating p53-induced apoptosis. Of course, all these processes
could occur simultaneously, further complicating
the picture.
Whereas HIF-1␣ seems to have context-dependent pro- and antiapoptotic functions, HIF-2␣ predominantly inhibits p53. First, unlike HIF-1␣,
HIF-2␣ does not bind Mdm2 (7). In renal cell carcinoma cells, inhibition of HIF-2␣ has been shown
to promote p53 phosphorylation and stabilization
likely due to an increase in ROS generation and
DNA damage. Another mechanism for HIF-2␣-induced p53 inhibition in renal cell carcinomas
might include phosphorylation and nuclear accumulation of Mdm2, resulting in enhanced degradation of p53 (80). This antiapoptotic function of
HIF-2␣ is indirectly mediated through AKT-mediated phosphorylation of Mdm2, suggesting that
HIF-2␣ could negatively affect clinical response to
radiotherapy and chemotherapy (80).
Interestingly, stabilization of p53 under low oxygen conditions results in a different type of activity than when induced by DNA damage. Extensive
microarray analyses showed that, unlike DNA
damage, hypoxia resulted in stabilized p53 with
mainly transrepression activity (35, 51). The proapoptotic p53 targets such as Puma, Noxa, and Bax
are elevated in response to DNA damage, but not
hypoxia, likely due to interaction with mSin3A instead of p300 (35, 51).
In summary, the net effects of HIF stabilization on
apoptosis signaling are clearly context-dependent.
Although HIF-1␣ can either have pro- or antiapoptotic properties, HIF-2␣ seems to predominantly activate a signaling network antagonizing apoptosis.
These distinct outcomes could be explained by different cellular contexts in which HIF is stabilized:
although it might be beneficial to eliminate a damaged, potentially harmful cell under hypoxia, an endothelial cell under low oxygen levels, for instance,
needs to proliferate and be protected from apoptosis
to ensure neovascularization.
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Hypoxia-Inducible Factor and
Apoptosis in Lower Organisms
The roundworm C. elegans has been a powerful
model to elucidate the molecular basis of apoptosis. The core apoptotic machinery in C. elegans
consists of the Bcl-2 homolog CED-9, which prevents, under normal conditions, CED-4 (Apaf1)
from activating the effector caspase CED-3 (31).
Apoptosis is triggered by the BH3-only domain
protein EGL-1, which binds to the CED-9-CED-4
complex at the mitochondrial membrane, thereby
releasing CED-4 (19, 39). Once released from the
complex, CED-4 forms an octamer to facilitate autocatalytic activation of CED-3 (76). Of the 1,090
cells generated during development, 131 die by
apoptosis. In the adult hermaphrodite germ line,
the same apoptotic execution machinery mediates
the removal of approximately half of all presumptive oocytes (31). Apoptosis in the germ line can be
induced by DNA damage through a conserved signaling pathway that leads to activation of the p53
homolog CEP-1 and transcriptional upregulation
of EGL-1 by CEP-1/p53 (27).
Although this tiny nematode consists of only 959
somatic cells and contains no specialized system
for oxygen delivery, it still expresses a single isoform of the hypoxia-inducible factor HIF-1 (43). C.
elegans might need an efficient hypoxia response
system since it inhabits the soil environment,
where oxygen levels can vary from 21% to virtually
0%. Thus C. elegans is exposed to the whole spectrum of oxygen levels and will require efficient
adaptational mechanisms to protect its cells.
HIF-1 in C. elegans is clearly an antiapoptotic
factor. vh-1 or egl-9 mutant worms, both of which
show constitutively stabilized HIF-1 levels, completely fail to induce DNA damage-induced germline apoptosis (88). HIF-1 inhibits either directly or
indirectly CEP-1/p53, whereas the function of the
BH3-only domain protein EGL-1 and the Bcl-2
member CED-9 is not affected. Thus the various
levels of interaction seen in mammals (Bcl-2 family, BH3-only domain proteins, p53) is reduced and
simplified in the worm to the inhibition of p53.
Curiously, HIF-1 controls programmed cell death
in C. elegans non-cell-autonomously by promoting
expression of the tyrosinase family member called
TYR-2. TYR-2 is a secreted protein and acts as a
critical negative regulator of p53-dependent germline apoptosis. It is interesting to note that this
neuronally controlled, systemic hypoxia response
is reminiscent of the mammalian carotid body,
which similarly translates a drop in oxygen partial
pressure into a systemic adaptation. Non-cellautonomous control of apoptosis by hypoxia has
not been reported so far in mammals. Nevertheless, several secreted hypoxia-inducible gene products have been extensively characterized (e.g.,
erythropoietin, VEGF), and it will be very interesting to see whether mammalian tissues have similar
non-cell-autonomous factors to inhibit apoptosis.
In Drosophila, the HIF␣ homolog termed Sima
has also been reported to promote survival. Crystal
cells are a specific type of blood cells produced by
the Drosophila lymph gland, which functions in
clotting and wound healing. These blood cells have
been shown to express even under normoxic conditions the Sima protein, which acts as a critical
factor for hemocyte survival during development
and hypoxic stress. Intriguingly, hemocyte survival
is independent of the HIF␤ homolog Tango, requiring instead activation of Notch signaling (66).
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nases activate the p53 signaling pathway (34) and
other downstream kinases such as Chk2 (25, 28). In
addition, several studies have shown that DNA repair mechanisms such as mismatch repair proteins
(MMR) (49, 65, 100) or homologous recombination
proteins (8, 9) are inhibited under hypoxia. The
resulting genetic instability can either amplify an
already present proapoptotic signal or independently trigger apoptosis. These responses are likely
dependent on the severity of oxygen deprivation
and on the specific cellular context. Some of these
pathways are only activated by severe hypoxia or
anoxia (⬍0.2% O2), as shown, for instance, for p53
activation. For example, although HIF-1␣ was stabilized at 2% O2, p53 only accumulated at 0.02%
O2, suggesting that mild and severe oxygen levels
might activate different signaling networks with
different apoptotic outcomes (2, 34).
Therefore, a drop in oxygen partial pressure can
on one hand activate several upstream players of
the intrinsic apoptosis pathway. On the other
hand, episodes of reoxygenation (ischemia reperfusion injury) following hypoxic exposure can induce additional DNA damage. Together, these
effects result in an activation of apoptotic signaling, which, if not opposed, will ultimately lead to
apoptotic cell death.
HIF and Apoptosis in Physiological
and Pathophysiological Conditions
Although flies and worms mutant in HIF␣ are viable, mice embryos deficient in HIF-1␣ die at day
E11 due to multiple defects, including cell death
within the cephalic mesenchyme as well as within
the endothelial and supporting mesenchyme, which
leads then to vascular defects (41, 50). Although a
direct involvement of apoptotic signaling pathways
has not been reported so far, it is possible that HIF␣
supports survival during development partly also via
protection from apoptosis.
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Implications for Cancer Therapy
Apoptosis is a process that links both cancer genetics and cancer therapy. Evading apoptosis is a
hallmark of cancer (36). Similarily, the ability to
trigger apoptosis is a major determinant of therapy
response since many chemotherapies activate
pathways that ultimately converge on a common
apoptotic signaling pathway (44).
Most solid tumors have heterogenous oxygen
supply and contain regions that are hypoxic. Tumor hypoxia has been associated with radioresistance more than half a century ago (29), and
increased HIF␣ levels have been associated with
increased mortality in many studies since (86).
There are numerous HIF target genes that have
been implicated in tumorigenesis, including CXCR,
VEGF, PDGF, or TGF-␤. In parallel to oncogene
activation, regulation of apoptosis by HIF will have
a major effect on tumorigenesis as well as on cancer therapy. Therefore, a comprehensive analysis
of signaling pathways linking HIF and apoptosis
could help in understanding why HIF stabilization
is associated with higher mortality and treatment
failure in many tumor types. Last but not least,
these signaling pathways could represent interesting targets for cancer therapy. 䡲
No conflicts of interest, financial or otherwise, are declared by the author(s).
Author contributions: A.S. prepared figures; A.S. and
M.O.H. drafted manuscript; A.S. and M.O.H. edited and
revised manuscript; A.S. and M.O.H. approved final version of manuscript.
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