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Blood, Vol. 94 No. 6 (September 15), 1999:
pp. 1864-1877
REVIEW ARTICLE
Regulation of the Erythropoietin Gene
By
Benjamin L. Ebert and
H. Franklin Bunn
From the Division of Hematology, Brigham and Women's Hospital, and
Harvard-MIT Division of Health Science and Technology, Harvard Medical
School, Boston, MA.
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INTRODUCTION |
IN HUMANS AND OTHER mammals, decreased
oxygen tension triggers specific and tightly regulated cellular,
vascular, and erythropoietic responses. An association between
polycythemia and people living at high altitudes was first reported in
1863.1 Erythropoietin (Epo), a 34.4-kD glycoprotein
hormone, was subsequently identified as the humoral regulator of red
blood cell production. Decreased tissue oxygen tension modulates Epo
levels by increasing expression of the Epo gene. Since the
cloning of the Epo gene in 1985,2,3 considerable
progress has been made in understanding the molecular mechanisms by
which the Epo gene is regulated by environmental,
tissue-specific, and developmental cues.
Erythropoiesis, which normally proceeds at a low basal level to replace
aged red blood cells, is highly induced by loss of red blood cells,
decreased ambient oxygen tension, increased oxygen affinity for
hemoglobin, and other stimuli that decrease delivery of oxygen to the
tissues. In states of severe hypoxia, production of Epo is increased up
to 1,000-fold. The secreted hormone circulates in the blood and binds
to receptors expressed specifically on erythroid progenitor cells,
thereby promoting the viability, proliferation, and terminal
differentiation of erythroid precursors, resulting in an increase in
red blood cell mass. The oxygen carrying capacity of the blood is thus
enhanced, increasing tissue oxygen tension, thereby completing the
negative feedback loop (Fig 1).4,5
Research on the regulation of the Epo gene has shown a general
system of oxygen-sensing, signaling, and transcriptional regulation of
a broad range of physiologically relevant genes, including those
encoding angiogenic growth factors, glucose transporters, and enzymes
involved in adaptation to hypoxia.
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TISSUE SPECIFICITY |
Temporal and tissue-specific signals limit expression of the Epo
gene primarily to specific cells in the fetal liver and the adult kidney.
Localization of Epo production to the kidneys was first demonstrated by
Jacobsen et al,6 who showed that, after bilateral nephrectomy, rats and rabbits do not respond to hemorrhage with an
appropriate increase in plasma Epo levels. Erslev et al7 have proposed that the peritubular region of the renal cortex is the
ideal location for Epo production. Oxygen consumption in the kidney is
determined largely by sodium reabsorption, which in turn depends on the
filtered load. Because the glomerular filtration rate is roughly
proportional to renal blood flow, renal oxygen consumption is linked to
renal blood flow. Therefore, oxygen tension at the site of the
Epo-producing cells is relatively independent of changes in renal blood
flow. At high hematocrit levels, viscosity increases to the point that
blood flow to tissues is compromised. If the primary site of Epo
production were in an organ other than the kidney, the resultant
decrease in tissue oxygen tension would lead to a vicious cycle of
increasing erythropoiesis causing worsening hypoxia.
When kidney cells were separated into glomerular and tubular fractions,
Epo mRNA was found only in the tubular fraction that included
the peritubular interstitium.8 Consistent with these findings, in situ hybridization studies with 35S-labeled
Epo RNA9,10 or DNA11 probes on kidney
tissue from anemic mice showed Epo mRNA in peritubular
interstitial cells. The number of these cells expressing Epo
mRNA increased with a decreasing hematocrit level.12 In
contrast to these studies, other investigators have demonstrated Epo
production by renal tubular cells using in situ hybridization for
Epo mRNA,13 immunohistochemistry with Epo-specific
antibodies,13 and detection of  -galactosidase in
transgenic mice bearing a 7-kb fragment of the Epo gene linked to the lacZ gene.14 Human renal tumor cells of
tubular origin can express Epo.15
Immunohistochemistry using Epo-specific antibodies is confounded by the
reabsorption of circulating Epo by renal tubular cells.
Two studies have demonstrated the colocalization of Epo-producing cells
and immunoreactivity to 5'-ectonucleotidase, suggesting that the
cells are likely to be fibroblasts.16,17 Maxwell et al17 prepared transgenic mice using regulatory sequences
from the mouse Epo gene flanking the SV40 T antigen as a marker
gene. In one line of these transgenic mice, the transgene was
fortuitously integrated into the endogenous Epo locus by
homologous recombination. This provided a model in which the marker
gene, inserted into the Epo locus, is subject to all of the
same tissue-specific controls as the endogenous Epo gene.
Consequently, expression of the SV40 T antigen permitted
immunohistochemical identification of the Epo-producing cells to be the
fibroblast-like type I interstitial cells.17 When all of
the somewhat contradictory studies cited above are carefully weighed,
the bulk of convincing evidence favors a peritubular interstitial cell
as the primary site of regulated Epo production in the kidney.
Before birth, Epo is primarily produced in the liver. The primary site
of Epo production switches from liver to kidney shortly after
birth,18,19 but the signals governing this change are poorly understood. In the liver, an oxygen gradient is established as
oxygen-rich blood from the portal triads becomes depleted of oxygen as
it flows towards the central vein. Consequently, in transgenic mice,
both the Epo transgene and the endogenous Epo gene are
preferentially expressed near the central vein where oxygen tension is
lowest.10
Two Epo-producing cell types were identified in the liver: hepatocytes
and a nonparenchymal cell type.10,20 The identity of the
nonparenchymal cells was established using transgenic mice bearing the
SV40 T antigen homologously recombined into the Epo locus. In
these mice, SV40 T antigen expression was observed in a subset of
nonparenchymal cells, identified as Ito cells, as well as in a subset
of hepatocytes.21
Highly sensitive assays have shown low levels of Epo mRNA in
the kidneys and livers of unstimulated mice and
rats,9,22-24 consistent with low basal levels of Epo in
serum. Low levels of Epo expression have also been detected in
the lung, spleen, brain, and testis of rats.23,24
Expression and production of both Epo and Epo-receptors has been
demonstrated in the brain.23,25-27 Oxygen-regulated
expression of Epo has been observed in astrocytes both in vitro in
cultured astrocytes25,27 and in vivo.23,27 The
presence of Epo receptors, the inability of Epo to cross the
blood-brain barrier, and the regulated expression of Epo in the brain
have led researchers to propose a paracrine function for Epo in neural
tissue. Recent evidence demonstrates that Epo can protect neurons from
ischemic damage in vivo.28
The discovery that both Epo mRNA and Epo protein are expressed
in erythroid progenitors29,30 has raised the intriguing possibility that tonic low-level erythropoiesis may be supported by
autocrine stimulation, whereas circulating (hormonal) Epo provides a
more robust stimulus to erythropoiesis during hypoxic stress.
For decades, a tissue culture model eluded investigators studying the
regulation of Epo. Some cells, such as rat kidney mesangial cells,31 the renal cell line RC-1,32 and
hepatic carcinomas,33 produced Epo at very low levels with
minimal induction by hypoxia. Cell lines that produce significant
amounts of Epo in a regulated fashion were discovered by screening a
range of renal and hepatic cells in culture.34 Two human
hepatoma cell lines, Hep3B and HepG2, were shown to produce significant
amounts of Epo constitutively, with marked induction by hypoxia. The
magnitude and time course of the induction of Epo mRNA
paralleled Epo protein production. The discovery of a tissue culture
model demonstrated that individual cells contain the apparatus
necessary for oxygen sensing and the consequent regulation of gene
expression. Hep3B and HepG2 cells have proved to be an invaluable tool
in exploring the molecular basis of Epo gene regulation.
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REGULATION OF Epo GENE EXPRESSION |
In addition to tissue-specific and developmental signals, Epo
gene expression is modulated by a number of physiological and pharmacological agents (Table 1).
Regulation of Epo by hypoxia and other stimuli occurs at
the mRNA level. In the kidneys of mice made anemic by blood loss,
Epo mRNA was increased approximately 200-fold over the level in
the kidneys of normal control mice.35 Epo mRNA was
induced in the liver as well, but at a lower level of expression. The
increase in Epo mRNA reached a maximum at 4 to 8 hours after
induction. The magnitude of induction was proportional to the degree of
anemia. Similarly, injection of cobalt chloride into rats induced
Epo expression in the kidney and, to a lesser degree, in the
liver.36 The time course and level of induction of Epo
mRNA paralleled induction of Epo in serum measured by
radioimmunoassay.36
Nuclear run-on assays using nuclei prepared from the kidneys of rats
that had been made hypoxic or treated with cobalt showed an increase in
transcription of the Epo gene.8 Similar results were obtained with Hep3B cells.37 Transcriptionally active
nuclear extracts from hypoxic Hep3B cells were compared with extracts from cells cultured in normoxia.38 The hypoxic nuclear
extracts supported a higher rate of Epo transcription in vitro,
demonstrating the presence of hypoxically inducible trans-acting
factors capable of interacting with cis-acting sequences from the
Epo gene.
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REGULATORY DOMAINS IN THE Epo GENE |
Comparison of the human and murine Epo genes provided clues to
the location of key regulatory domains in the Epo
gene.39-41 Three noncoding segments of the Epo
gene are highly conserved between human and mouse sequences: the
promoter, the first intron, and a 120-bp region 100 bp 3' to the
polyadenylation site.
Both transient transfection experiments and studies with transgenic
mice have been used to identify functionally important cis-acting
elements. Experiments with transgenic mice mapped broad regions of the
Epo gene that regulate Epo expression in response to
tissue-specific and developmental signals. Transient transfections of
cultured cells have been used to characterize cis-acting sequences that
are critical for the response to hypoxia. Conserved sequences both
5' and 3' of the Epo gene proved to be important
for regulation of the Epo gene, but deletion of the conserved
sequences in the first intron did not influence hypoxic
induction.42 Regulatory elements in the Epo gene
are portrayed in Fig 2.
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| Fig 2.
Structure of the human Epo gene. Exons are indicated by
solid black boxes; 5' and 3' untranslated regions are
indicated by open rectangles. Areas of homology between human and
murine noncoding sequences are shown with blue rectangles, and the
region of liver specific DNase I hypersensitivity is shown with a green
rectangle. The 3' enhancer is expanded for greater detail. Sites
that are functionally critical for hypoxic induction are underscored in
red. Binding of HIF-1, HNF-4, and p300 is illustrated. As indicated by
the arrow, p300 is capable of interacting with the basal
transcriptional machinery in the promoter.
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Transgenic experiments.
Transgenic mice were initially produced containing a 4-kb fragment that
included the human Epo gene, 400 bp of 5'-flanking sequence, and 700 bp of 3'-flanking sequence. The transgene was widely expressed, causing the mice to become polycythemic, indicating that additional cis-acting sequences, required for tissue-specific and
developmental regulation, lie outside this construct. Nevertheless, in
the liver, the transgene was upregulated by anemia and cobalt chloride.
Thus, cis-acting sequences capable of mediating oxygen-regulated gene
expression in liver cells lie between 400 bp 5' and 700 bp 3' of the Epo gene.43
Tissue-specific regulatory domains were mapped in subsequent transgenic
experiments by use of constructs with varying lengths of Epo
upstream flanking sequence. Promiscuous expression of the Epo
gene, seen in transgenic constructs with 300 bp44 or
400 bp43 of 5' flanking sequence, was extinguished in
constructs containing 6 kb of 5' flanking sequence.45
In constructs containing 9.5 kb or less of 5' flanking sequence,
inducible expression of the Epo transgene was observed in the
liver but not in the kidney.44 However, physiological
expression of the Epo transgene with inducible expression in
the kidney was seen in transgenic mice containing 14 kb of 5'
flanking sequence.46 Thus, transgenic experiments indicate
that a repressive element(s) exists between 0.4 and 6 kb upstream of
the Epo gene, and a kidney-specific inducible element(s) exists
between 9.5 and 14 kb upstream of the Epo gene.
Epo 3' enhancer.
A liver-specific DNase I hypersensitivity site was discovered in the
3' flanking sequence of an Epo transgene.47
Analysis of this region of the Epo gene by transient
transfections of reporter constructs led to the identification of a
hypoxically inducible enhancer.47-50 In both the mouse and
human Epo genes, this enhancer lies in a highly conserved
region 120 bp 3' to the polyadenylation site. As is typical of
eukaryotic transcriptional enhancers, activity was independent of
orientation and distance from the promoter. The enhancer demonstrated
the same stimulus specificity as the Epo gene with responses to
hypoxia, cobaltous chloride, and iron chelation, but not to cyanide and
2-deoxyglucose.
Detailed characterization of the Epo 3' enhancer defined
3 sites that are critical for regulation by hypoxia.50-52
On the 5' side, the sequence CACGTGCT was the first response
element to be characterized for the transcription factor, hypoxia
inducible factor-1 (HIF-1).51 Binding of HIF-1 to this site
is induced by hypoxia, and an intact HIF-1 binding site is necessary
for hypoxically inducible function of the Epo enhancer. In
addition to the hypoxically inducible DNA-binding activity, HIF-1, this site also binds another complex constitutively. The transcription factors ATF-1 and CREB-1 have been shown to be involved in this complex
in vitro, but it is not clear whether these factors play a functional
role in the Epo enhancer.53 Further details
concerning the function and activation of HIF-1 are discussed below.
A second site, 7 bp 3' to the HIF-1 site, has the sequence CACA
in the human Epo gene. No proteins are known to bind to this site, but mutation of this site abrogates hypoxia inducible activity of
the enhancer. A similar sequence has been found adjacent to HIF-1 sites
in other genes.54 These first 2 sites (HIF-1 and CACA)
require the presence of a third site for hypoxically inducible transcription, unless the enhancer is directly upstream from the promoter.52
The sequence of the third site in the Epo enhancer is a direct
repeat of 2 steroid hormone receptor half sites separated by 2 bp,
termed a DR-2 site.50 Mutations of this site ablate or markedly inhibit hypoxic induction.50-52 Nuclear proteins
from a broad range of cell types bind strongly to this site, as
demonstrated by both electrophoretic mobility shift assays and DNase I
footprinting experiments. However, binding of proteins to this site is
not oxygen-dependent either in vivo or in vitro.50-52,55 In
some non-Epo-producing cells, a complex does not form at this site in
vivo.55 Hormones whose biological actions depend on binding
to nuclear receptors had no effect on the hypoxic induction of a
reporter gene containing the Epo promoter and Epo
enhancer.50 These results suggested that the DR-2 site
might bind an orphan nuclear receptor, a DNA-binding protein that
shares structural homology with hormone binding nuclear receptors but
lacks a known ligand. Screening a variety of in vitro-translated orphan
receptors showed that HNF-4 bound specifically to this
site.56 Hypoxic induction of Epo is abolished in
Hep3B cells expressing a dominant negative mutant of HNF-4. HNF-4 is expressed in the renal cortex and liver, like Epo, as well as in the intestine. Thus, HNF-4 may contribute to the tissue specificity of Epo gene expression.
Promoter.
The Epo promoter does not have consensus TATA or CAAT elements
in either the mouse or human genes. Comparison of the 5' flanking sequences of the human and murine Epo genes shows 73% overall sequence identity and 8 areas of even higher homology.39,40
The Epo promoter contributes to the hypoxic inducibility of the
Epo gene.57 After deletion of the 3'
enhancer, expression of a stably transfected marked Epo gene
was induced approximately 10-fold in response to hypoxia.42
The minimal promoter acts synergistically with the 3' enhancer to
confer a 40-fold induction in response to hypoxia.50
The minimal Epo promoter capable of induction by hypoxia
encompasses 117 bp 5' to the transcription initiation
site.50 A segment of 17 bp ( 61 to 45) is
responsible for this upregulation by hypoxia.58 There is no
HIF-1 consensus sequence at this site. Using computer homology
matching, a HIF-1 site was identified at position 180 in the
Epo 5' flanking sequence.59 However, reporter
gene experiments suggest that this site is not a functional hypoxia
response element.50 GATA sites60,61 and a
ribonucleoprotein binding site62 have also been described,
but the role of these proteins in the response to hypoxia is not
proven. Addition of antisense oligonucleotides to GATA elements
increased Epo gene expression, whereas the addition of
antisense oligonucleotides to CACCC elements decreased Epo gene
expression, indicating that the Epo promoter is regulated
negatively by GATA sites and positively by CACCC sites.60
L-NMMA, a nitric oxide synthase inhibitor, was recently demonstrated to
increase binding of GATA factors in the Epo promoter and
decrease Epo expression.63
Methylation of CpG sites in the Epo promoter varies between
Epo-producing and non-Epo-producing cells. By inhibiting the formation of DNA-binding complexes and by the binding of inhibitory methyl-CpG binding proteins, methylation may contribute to tissue-specific activity of the Epo promoter.64
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mRNA STABILITY |
Enhanced transcription accounts for most, but probably not all, of the
hypoxic induction of the Epo gene. In Hep3B cells, nuclear
run-on experiments showed about a 10-fold increase in transcription of
Epo mRNA during exposure to 1% O2 in the setting of a 50- to 100-fold increase in the steady-state level of Epo mRNA.37 In 2 other hypoxically regulated genes,
tyrosine hydroxylase (TH)65,66 and VEGF,67,68
approximately 50% of the enhanced gene expression in response to
hypoxia is due to increased mRNA stability. For both genes, specific
mRNA binding proteins have been demonstrated in cytosolic extracts of
hypoxic cells.66,68
In comparison to TH and VEGF, less is known about posttranscriptional
regulation of the Epo gene. Inhibitors of transcription markedly prolong the half-life of Epo mRNA, thus making
actinomycin chase experiments uninterpretable.37 Two
proteins, 70 and 135 kD, which have been designated Epo
mRNA-binding protein (ERBP), bind to a 120-bp pyrimidine-rich
region in the 3' UTR of Epo mRNA.69 This
interaction does not seem to be regulated by oxygen
tension,69 but binding is subject to redox
control.70 Heat shock protein 70 participates in a complex
with ERBP and Epo mRNA.71 Deletion of the ERBP
binding site prolongs the half-life of Epo mRNA and eliminates
hypoxically induced stabilization.72 Deletion of a 50-bp
segment lying 70 bp downstream of the binding site for these proteins
causes a 7-fold increase in the half-life of a transfected marked
Epo gene.42 Epo, VEGF, and TH mRNA can
cross-compete for binding in mobility shift assays, suggesting common
features to the regulation of mRNA stability in these 3 genes.67,73
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HIF-1 |
The transcription factor HIF-1 mediates hypoxically inducible
transcription of oxygen-regulated genes. The HIF-1 site in the Epo
3' enhancer is the primary element in the Epo gene
that mediates the transcriptional response to hypoxia. The time course
of HIF-1 activation mimics the induction of the Epo
gene.74 Hypoxia, cobalt, and DFO, stimuli that trigger
Epo gene expression, also activate HIF-1 DNA binding. The HIF-1
site in the Epo 3' enhancer was the first hypoxia
response element (HRE) to be identified and was used for the affinity
purification of HIF-1.75 HIF-1 is a heterodimer composed of
120-kD and 91- to 94-kD subunits, both of which are basic
helix-loop-helix (bHLH) proteins in the PAS (Per-AHR-ARNT-SIM) family
of transcription factors.76 HIF-1 is the previously
cloned and characterized aryl hydrocarbon receptor nuclear translocator
(ARNT), which forms a heterodimer with the aryl hydrocarbon receptor
(AHR), mediating regulation of genes involved in the transcriptional
response to xenobiotics and oxidant stress.77,78
Both HIF-179 and ARNT80 have basic domains
that are critical for DNA binding and PAS domains that are crucial for
dimerization. The domain structure of HIF-1 is shown in
Fig 3. Interaction between HIF-1 and
ARNT requires both bHLH and PAS domains.81 Deletion of both
the basic domain and the carboxy-terminal activation domains results in
a dominant negative form of HIF-1.79 Transactivation by
the HIF-1 heterodimer requires the N-terminal DNA-binding and heterodimerization domains of ARNT, but not its C-terminal activation domain.82
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| Fig 3.
Structure of HIF-1 . Open rectangles represent the PAS
A and B domains. Solid black rectangles within the oxygen-dependent
degradation domain indicate the location of PEST sequences.
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HIF-1 activity has been demonstrated in a wide variety of cells by both
electrophoretic mobility shift assays83 and transfections of a reporter gene containing HIF-1 sites.84 Steady-state
levels of HIF-1 and ARNT mRNA are not significantly affected by
oxygen tension.81,85,86 At the protein level, ARNT
abundance is also not dependent on oxygen tension. In contrast, the
HIF-1 subunit is only detectable in cells treated with hypoxia or
stimuli that mimic hypoxia, such as cobalt or iron chelators. In
normoxic cells or in cells pretreated with H2O2
before deoxygenation, HIF-1 protein is barely
detectable.86 Thus, HIF-1 activation correlates with the
oxygen-dependent accumulation of HIF-1 protein. Under normoxic
conditions, HIF-1 is rapidly degraded by the ubiquitin-proteasome pathway.87,88 Specific inhibitors of this pathway markedly increase HIF-1 abundance. Hypoxia and iron chelation dramatically increase the half-life of HIF-1, permitting the formation of functionally active HIF-1/ARNT heterodimers. A domain from the central region of HIF-1 was identified that is critical for
oxygen-regulated protein degradation.88 This region spans
amino acids 401-603 with further deletions causing a diminution of the
magnitude of hypoxic inducibility.88 Sequences from within
this region mediate hypoxically inducible
transactivation.89,90 Deletion of this oxygen-dependent
degradation (ODD) domain resulted in stabilization of HIF-1 and
constitutive HIF-1 DNA-binding activity independent of oxygen
tension.88 Furthermore, the ODD domain is transportable, ie, it is capable of conferring oxygen-dependent degradation on a
heterologous protein.88 Both carbon monoxide and nitric
oxide donors suppress degradation of HIF-1 via the ODD
domain.91
A second domain at the C-terminus of the HIF-1 protein (amino acids
775-826) was also shown to mediate hypoxically inducible trans-activation.82,89,90 This C-terminal region is not
associated with changes in levels of HIF-1 protein. Therefore,
hypoxia must activate this C-terminal domain by some form of
posttranslational modification such as phosphorylation.
HIF-1 has been shown to interact with the transcriptional
coactivators, p300 and CBP,92 highly homologous proteins
that are functionally and immunologically
indistinguishable.93,94 Expression of the adenovirus
protein, E1A, which binds to p300/CBP blocking functional activity,
prevents hypoxic induction of the genes encoding Epo,
VEGF,92 and LDH-A.95 Functional activity of the
C-terminal transactivation domain of HIF-1 requires interactions with the CH1 domain of p300/CBP.96,97 p35srj, an
alternatively spliced form of MRG-1,98 also binds to the
CH1 domain of p300/CBP, competing with HIF-1 for binding to
p300/CBP.97 Induction of p35srj by hypoxia may contribute
to a negative feedback on HIF-1 activation97 and perhaps
explains the prompt decrease in Epo expression after the peak mRNA
levels 4 to 6 hours after hypoxic induction.24 p300 and CBP
are large proteins with several domains for interacting with multiple
proteins. P300/CBP has been shown to interact with HNF-499
and other nuclear hormone receptors,100,101 CREB,102 TATA binding protein,103 and
TFIIB.104 By simultaneously interacting with HIF-1,
adjacent transcription factors, and the basal transcriptional
machinery, p300/CBP likely acts as a scaffold for the construction of a
transcriptionally active, hypoxically inducible complex. Formation of
such a complex may explain the requirement of an HNF-4 site, adjacent
to the HIF-1 site, for hypoxically inducible activity of the Epo
3' enhancer.95
A plethora of additional members of the bHLH-PAS family have been
cloned recently, including ARNT2, HIF-2, MOP3, MOP4, and CLOCK.105-109 HIF-2 (also known as EPAS-1, MOP2, HRF,
and HLF) has a broad tissue distribution and, like HIF-1,
accumulates only under hypoxic conditions.110 MOP3-HIF-1
and MOP3-HIF-2 heterodimers are capable of binding an HIF consensus
site and activating transcription in response to
hypoxia.111 ARNT is capable of forming homodimers as well
as heterodimers with HIF-1, AHR, and SIM. The requirement of ARNT
for the responses to both hypoxia and aryl hydrocarbons can lead to a
functional interference between the 2 pathways.81
Insulin and insulin-like growth factor I (IGF-1) activate HIF-1
DNA-binding activity, HIF-1-mediated transcriptinal activation of a
reporter gene,112 and expression of several oxygen
regulated genes, including Epo.113 The signalling
pathways for hypoxia, insulin, and IGF-1 appear to converge, all
leading to stabilization of HIF-1.
Activition of HIF-1 is modulated by a complex set of mechanisms likely
to include not only protein stability, but also
phosphorylation,114,115 redox
chemistry,86,87,116 and nuclear localization.96
Subsequent to binding of HIF-1 to its cognate cis-acting sequence,
interaction with adjacent transcription factors and coactivator
proteins are necessary for hypoxic induction of transcription.
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MECHANISM OF OXYGEN SENSING AND SIGNAL TRANSDUCTION |
Despite a great deal of attention and experimental data, the precise
nature of the mammalian oxygen sensor remains elusive. However, the
synthesis of evidence obtained to date provides an outline of the
likely characteristics of the oxygen sensor that signals the activation
of gene expression via HIF-1. A plausible model is shown in
Fig 4.
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| Fig 4.
Proposed model of oxygen sensing and signaling. In
oxygenated cells, a flavo-heme protein functions as an NADPH oxidase,
transferring electrons through the flavin (FAD) and heme to molecular
oxygen, generating superoxide (O2 ), which,
in the presence of iron, is converted to hydroxyl radical
(OH·) and other reactive oxygen species (ROS). As a
result, HIF-1 is oxidatively modified so that it is recognized by
the proteasome and rapidly degraded. Cobalt (Co2+) as
well as other transition metals (Ni2+ and
Mn2+) may block the iron-dependent degradation of
HIF-1. At low oxygen tension, as well as in the presence of an iron
chelator or one of the above-mentioned transition metals, HIF-1 is
stable and can form a heterodimer with constitutively
expressed HIF-1, thereby activating HIF-1, which translocates to the
nucleus and binds to response elements in hypoxia inducible genes.
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Oxygen sensors in bacteria and yeast have been well characterized, and
in these systems heme proteins play a central role.117 Similarly, several lines of evidence indicate that a heme protein is
involved in mammalian oxygen sensing.118 CO binds
specifically and noncovalently to heme proteins, causing the heme
moiety to be maintained in an "oxy" conformation. CO blocks the
activation of HIF-1 by hypoxia and the hypoxically regulated expression
of VEGF, PDGF, ET-1, and PEPCK.117 CO binds with a lower
affinity than oxygen to the putative heme protein sensor, with a
Haldane coefficient of approximately 0.5.91 The transition
metals Co2+, Ni2+, and Mn2+ mimic
the effect of hypoxia on Epo, HIF-1, and other oxygen-regulated genes.118,119 A possible mechanism for the action of these
transition metals is that they can substitute for iron in heme
proteins, locking the heme moiety in the "deoxy" conformation.
Many experiments have indicated that a decrease in levels of oxygen
free radicals after hypoxic stimulus leads to the accumulation of
HIF-1 and the activation of HIF-1. Addition of
H2O2 or agents that increase intracellular
peroxide concentration block the induction of Epo and the
accumulation of HIF-1.86 Desferrioxamine (DFO), an iron
chelator, mimics the effect of hypoxia on oxygen-regulated genes and
HIF-1 activity.120 Intracellular iron probably functions as
a Fenton reagent, catalyzing the formation of reactive oxygen species.
Therefore, iron chelation, like hypoxia, is likely to effect a
reduction in intracellular levels of hydroxyl radical and singlet
oxygen. A substantial number of enzymes are inactivated by
oxygen-dependent and iron-dependent oxidation at specific residues, rendering them targets for proteolytic degradation.121,122
This modification is inhibited by Mn2+ and also by
Co2+ and Ni2+ (W. Willmore, R. Levine, and H.F.
Bunn, unpublished observations). If this degradative pathway applies to
HIF-1 (as shown in Fig 4), it would explain the stabilization of
HIF-1 by these 3 transition metals.
Spectrophotometric evidence points to the involvement of a cytochrome
b-like protein in oxygen sensing.123-126
Furthermore, diphenyl iodonium (DPI), which inhibits NAD(P)H oxidases
and other flavoproteins, impairs oxygen sensing.127,128 DPI
also inhibits the response to hypoxia in the carotid
body129 and pulmonary neuroepithelial bodies.130 However, it is unlikely that the oxygen sensor
is identical to the NAD(P)H oxidase in neutrophils and macrophages, which is dedicated to the oxidative burst, necessary for the
destruction of engulfed microorganisms.131 Patients with
chronic granulomatous disease, who have a genetic defect in 1 of the 4 subunits of neutrophil/macrophage NAD(P)H oxidase, do not have
phenotypic evidence of disordered oxygen sensing. The oxygen sensor
must be present in a wide range of tissues, and the generation of free
radicals involved in the signaling process is likely to be within a
specific cell compartment and highly regulated by tissue oxygen
tension. (Many experiments have indicated that the oxygen-sensing
pathway that regulates Epo is unaffected by inhibitors of
mitochondrial respiration.49,132-134 However, Schumacker et
al135 have recently presented evidence suggesting that
mitochondrial cytochrome oxidase [complex IV] serves as an oxygen
sensor in hepatocytes and cardiac myocytes. Their evidence is based on
measurements of HIF-1 activation in Hep3B cells treated with
mitochondrial inhibitors and in  o Hep3B cells lacking
functional mitochondria.)
In the nitrogen-fixing bacteria, Rhizobium, oxygen-regulated
gene expression is mediated by hypoxically inducible phosphorylation of
a transcription factor.136,137 Phosphorylation may play a role in signaling the hypoxic stimulus and regulation of HIF-1 activity
in mammalian cells as well. Treatment of nuclear extracts from hypoxic
cells with alkaline phosphatase abolishes HIF-1 DNA-binding activity.138 Inhibitors of both serine/threonine and
tyrosine kinases block activation of HIF-1.114 Multiple
compounds that interfere with phosphorylation cascades have complex
effects on HIF-1 activation and oxygen-regulated gene
expression,115 but the role of a particular phosphorylation
pathway in the activation of HIF-1 has not been conclusively proven.
The role of src kinase was proposed to play a critical role in the
hypoxia signaling pathway.139 Although subsequent
experiments indicate that c-src is not necessary for activation of
HIF-1,128,140 expression of v-src increases HIF-1
expression in both normoxia and hypoxia.140 In the HIF-1
protein, mutation of phosphoacceptor sites in the hypoxically inducible
domain between amino acids 549-672 did not have a major influence on
the magnitude hypoxic induction.89
In the current model of oxygen sensing, the preponderance of evidence
supports the role of a heme protein, likely a cytochrome b-like
protein, which signals a decrease in oxygen tension by a decrease in
the levels of free radicals. Many gaps in knowledge and areas of
conflicting data await future elucidation of the oxygen sensing
mechanism responsible for the activation of HIF-1 and the regulation of
Epo and other oxygen-responsive genes.
| |
REGULATION OF OTHER GENES BY HYPOXIA |
The Epo gene provided an apt model system for identification of
HIF-1 and investigation of the mechanism of oxygen sensing. An
understanding of oxygen-regulated expression of other genes has
provided insight into diverse areas of physiology. Genes shown to be
regulated by hypoxia are listed in Table 2.
Hypoxia activates angiogenesis by inducing the genes encoding VEGF and
other growth factors with angiogenic properties.119,141-145 HIF-1-mediated regulation of blood vessel growth appears to be of
critical importance, because HIF-1/ and
ARNT/ knockout mice do not live beyond
embryonic day 8.5 to 9.5, likely owing to a failure of vascular
development.146-148 In neoplasms, angiogenesis is essential
for tumor growth and metastasis. Solid tumor xenografts composed of
ARNT-deficient cells have reduced VEGF expression and grow more slowly
than xenografts that can form an intact HIF-1
heterodimer.149
When oxygen is limited, the rate of glycolysis increases to compensate
for a decrease in ATP production via mitochondrial respiration.
Long-term adaptation to hypoxia involves the regulation of genes
encoding proteins involved in energy metabolism. An increase in glucose
uptake in hypoxia is associated with increased expression of the genes
encoding 2 glucose transporters, Glut-1 and Glut-3.150,151 Genes encoding specific isoenzymes for most if not all steps in the
glycolytic pathway are upregulated by
hypoxia.59,134,150,152-157 Hypoxia blocks glucagon
induction of PEPCK, the rate-limiting gluconeogenic
enzyme.158-160 Expression of mitochondrially encoded genes
is suppressed by hypoxia,154 but the mechanism of
regulation of these genes appears to be independent of the signaling
pathway that regulates nuclear-encoded genes and HIF-1.150
Hypoxic induction of the tyrosine hydroxylase gene aids in the
regulation of respiration.65,161 HIF-1 has also been
implicated in the regulation of genes encoding type II (inducible)
nitric oxide synthase,162,163 heme
oxygenase-1,164 transferrin,165 and
retrotransposon VL30.166 Oxygen-regulated expression has been demonstrated for endothelin 1,167-169, c-jun,
and c-fos.166 Hypoxic induction of tissue factor
and adenylate kinase 3 were identified by differential display
polymerase chain reaction.151 HIF-1 is involved with
increasing apoptosis and decreasing cellular proliferation in response
to hypoxia, as was demonstrated by use of embryonic stem cells lacking
functional HIF-1
(HIF-1/).170
The importance of HIF-1 in oxygen-regulated gene expression has been
examined in several cell lines, including an ARNT-deficient cell
line,85 an HIF-1-defective cell line created by
mutagenesis and selection,171 and embryonic stem cells from
HIF-1147,148,170 and ARNT knockout mice.146
None of these cells produce Epo, but oxygen-regulated gene expression
is disrupted for a number of other genes having functional HIF-1
response elements. For example, induction of PGK-1 and LDH-A by hypoxia
is abolished in ARNT-deficient cells. For other genes, some hypoxic
induction is retained in the mutant cell lines, for example, heme
oxygenase-1 in HIF-1 mutant cells and VEGF in ARNT-deficient cells.
Possible explanations for retained inducibility include alternative
dimerization partners and regulation at the level of mRNA stability.
The arrangement of sites in hypoxia-responsive regulatory elements in
other genes is similar to that of the Epo 3' enhancer. For example, in the LDH-A promoter, 3 sites are critical for oxygen regulation in arrangement similar to the tripartite structure of the
Epo 3' enhancer.54 Whereas in the Epo
gene 3' enhancer the HIF-1 site is adjacent to an HNF-4 site
that is necessary for hypoxic inducibility, in the LDH-A promoter, the
HIF-1 site is adjacent to a CREB-1/ATF-1 binding site. In both genes,
the necessity of multiple adjacent sites for maximal hypoxia induction is probably due to the formation of a multiprotein complex including p300/CBP.
Comparison of HIF-1 sites characterized in 25 hypoxically inducible
genes has resulted in a consensus recognition sequence for HIF-1
DNA-binding: T/GACGTGCGG.172
| |
CLINICAL STATES ASSOCIATED WITH ABERRANT EXPRESSION OF Epo |
In a variety of pathological states, dysregulation of Epo gene
expression may cause either anemia or polycythemia.
Anemia is a major complication of most forms of renal failure. Because
the anemia of renal failure is due primarily to a decrease in Epo
production,173,174 patients are successfully treated by administration of recombinant human Epo.175,176 In mice
with diverse forms of renal injury, a decreased number of
fibroblast-like interstitial cells express Epo in response to
anemia or hypoxia.177 Damage to the kidneys appears to
change the threshold for Epo gene expression, but the precise
molecular mechanisms have not yet been defined. Renal injury causes an
expansion of interstitial cells and an infiltration of
CD45+ cells, but the phenotype of the Epo-producing
fibroblast-like cells does not appear to change. The sensitivity of
Epo expression to changes in the microenvironment of
Epo-producing cells may explain the difficulty of establishing a renal
cell culture model of inducible Epo expression.
Inappropriately low levels of erythropoietin have been demonstrated in
patients with acquired immunodeficiency syndrome (AIDS),178 rheumatoid arthritis and other chronic inflammatory
diseases,179 and cancer.180 Inflammatory
cytokines have been postulated to play a role in diminishing Epo
gene expression in these disorders and in the anemia of renal
failure. In human hepatoma cell lines and isolated perfused rat
kidneys, the inflammatory cytokines tumor necrosis factor- (TNF-)
and interleukin-1 (IL-1) suppress Epo production.181,182
Patients with Itai-itai disease, caused by long-term cadmium
intoxication, have inappropriately low Epo levels for their degree of
anemia and renal failure.183
Uremia is the predominant and prototypical clinical syndrome for Epo
replacement therapy, but recombinent human Epo (rHuEpo) has been used
in a broad range of clinical settings (for review, see Cazzola et
al184). For example, rHuEpo is efficacious in the treatment
of anemia caused by AZT in human immunodeficiency virus (HIV)-infected
patients, chemotherapy for nonmyeloid malignancies, premature birth,
cancer, rheumatoid arthritis, and inflammatory bowel disease. The
efficacy of rHuEpo is uncertain in patients whose levels of plasma Epo
are elevated in keeping with their degree of anemia.
Primary polycythemia is caused by defects of hematopoietic progenitor
cells and is associated with low levels of circulating erythropoietin.
For example, polycythemia vera (PV) is caused by acquired somatic
mutations in hematopoietic stem cells. IGF-1 and angiotensin II may
increase proliferation of hematopoietic progenitors and thereby
contribute to some forms of polycythemia.185 Familial
congenital polycythemias may be caused by erythropoietin receptor
mutations. In contrast, secondary polycythemia is generally associated
with increased erythropoietin production. Elevated levels of plasma Epo
are encountered in systemic hypoxemia, in certain neoplasms, and, less
commonly, in disorders that impair oxygen delivery to tissues.
Excessive activation of Epo gene expression can result from
impaired oxygen delivery due to high affinity hemoglobin mutants, methemoglobinemias, and 2,3-bisphosphoglycerate
deficiency.185 Numerous congenital mutations of both -
and -globin genes can result in high-affinity hemoglobin molecules.
Such patients are often asymptomatic, because impaired oxygen delivery
is balanced by polycythemia. Congenital methemoglobinemias also cause
an adaptive erythrocytosis, because the buildup of ferri-hemes
increases the oxygen affinity of the remaining ferro-hemes.
2,3-bisphosphoglycerate is an allosteric regulator of hemoglobin. An
enzymatic defect leading to decreased synthesis of
2,3-bisphosphoglycerate is a rare cause of congenital
polycythemia.186
Chronic arterial hypoxemia often leads to an upregulation of Epo
expression, causing a maladaptive erythrocytosis. Patients with chronic
obstructive pulmonary disease can develop erythrocytosis, which
increases the risk of cor pulmonale. Similarly, patients with right to
left cardiac shunts can have extremely high hematocrit levels.
Specific types of neoplasms can also cause overproduction of Epo.
Elevated Epo levels are found most commonly in patients with renal
carcinomas, Wilms tumor, hepatomas, and cerebellar hemangioblastomas,5 all anatomic sites in which Epo is
normally expressed at low levels; less frequently, these tumors cause
erythrocytosis. Benign renal tumors can also cause erythrocytosis,
possibly due to local ischemia of renal Epo-producing cells.
Mutations in the von Hippel Lindau (VHL) gene are associated with renal
and central nervous system carcinomas, both highly vascular tumors that
overexpress VEGF. In cells in which the von Hippel Lindau protein is
inactivated, the hypoxically inducible genes VEGF, Glut-1, and PDGF-B
are expressed at high levels under both normoxic and hypoxic
conditions. Introduction of wild-type pVHL into these cells causes
expression of these genes to revert to the normal hypoxically inducible
pattern by suppressing normoxic expression.187,188
A congenital and familial polycythemia of unknown etiology has been
characterized in 103 patients from Chuvashia, a region in the Russian
Federation.189 This condition is characterized by an
autosomal recessive pattern of inheritance, high hemoglobin levels
(mean, 23 g/dL), high hematocrit levels (mean, 67%), elevated Epo
levels, and morbidity and mortality secondary to erythrocytosis, including fatal thrombotic and hemorrhagic complications. The polycythemia is not due to high-affinity hemoglobin, methemoglobinemia, 2,3-bisphosphoglycerate deficiency, or systemic hypoxia. Furthermore, the genetic mutation is not linked to either the Epo or Epo
receptor genes. The disorder may therefore be caused by an abnormality in the oxygen sensing-signaling pathway or in a trans-acting factor involved in the regulation of Epo gene expression.
| |
CONCLUSIONS |
Regulation of erythropoiesis and red blood cell mass relies on
modulating Epo gene expression in response to tissue oxygen tension. Developmental, tissue-specific, and environmental signals all
contribute to the precise regulation of the Epo gene. Epo production and gene expression is restricted to specific subsets of
cells: interstitial fibroblast-like cells in the kidney and, in the
liver, Ito cells as well as a subset of hepatocytes. Experiments with
transgenic mice have broadly mapped the cis-acting sequences responsible for tissue-specific expression.
The Epo gene has been a model for the regulation of gene
expression by oxygen tension. The magnitude of hypoxically inducible transcription of the Epo gene is greater than any other gene
known to be regulated by oxygen tension. Human hepatoma cell lines have provided a useful model system for studying inducible expression of the
Epo gene. Regulatory sequences in the Epo gene have
been dissected and characterized in more detail than any other
oxygen-regulated gene. In a plausible model, a cytochrome
b-like flavoheme protein senses oxygen tension and regulates
production of oxygen free radicals.190 In hypoxia, rapid
degradation of HIF-1 by the ubiquitin-proteasome pathway is
prevented, leading to the formation of HIF-1/ARNT heterodimers.
These heterodimers bind to HIF-1 sites, interact with adjacent
DNA-binding proteins and p300/CBP, and activate gene expression.
The Epo gene has been the portal through which a generalized
system of oxygen-regulated gene expression was first identified and
described. This mode of molecular adaptation is more fundamental than
the regulation of Epo in mammals. An HIF-1-like hypoxically inducible
DNA-binding activity was identified in Drosophila
melanogaster.191 In mammals, HIF-1 and the oxygen-sensing
mechanism that regulates Epo are critical for the regulation of
genes involved in angiogenesis, energy metabolism, respiration,
vascular tone, and many other processes.
In humans, regulation of the Epo gene provides an elegant and
precise mechanism for adjusting red blood cell mass to perturbations in
tissue oxygen tension. A more complete understanding of the molecular
mechanisms governing induction of the Epo gene may lead to new
therapeutic agents to treat patients with anemia or polycythemia due to
inappropriate expression of the Epo gene.
| |
ACKNOWLEDGMENT |
The authors thank E. Huang, W. Willmore, P. Hradecky, P. Yachimski, and
M. Vasconcelles for critical review of the manuscript.
| |
FOOTNOTES |
Submitted February 2, 1999; accepted June 17, 1999.
Supported by a National Institutes of Health Grant No. DK41234 to
H.F.B.
Address reprint requests to H. Franklin Bunn, MD, LMRC 223, 221 Longwood Ave, Boston, MA 02115; e-mail: bunn{at}calvin.bwh.harvard.edu.
| |
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TOP
INTRODUCTION
TISSUE SPECIFICITY
