Life, 52: 49 53, 2001

c 2001 IUBMB
Copyright
1521-6543/01 $12.00 + .00
IUBMB

Critical Review
HIF-1 and AP-1 Cooperate to Increase Gene Expression
in Hypoxia: Role of MAP Kinases
Carine Michiels, Emmanuel Minet, Gaetan Michel, Denis Mottet,
Jean-Pascal Piret, and Martine Raes
Laboratory of Biochemistry and Cellular Biology, University of Namur, Namur, Belgium

Summary
HIF-1 is the main transcription factor responsible for increased
gene expression in hypoxia: VEGF, erythropoietin, GLUT-1, and
glycolytic enzymes are such target genes and all participate in the
adaptative response of cells to hypoxia. AP-1 activation by hypoxia
has also been demonstrated in several cell lines and it cooperates
with HIF-1 for increasing VEGF gene transcription in hypoxia.
Both HIF-1 and AP-1 activation by hypoxia seems to involve members of the MAP kinase family. Here, we summarize the data indicating that ERK and JNK are needed for activation of HIF-1 and
AP-1, respectively.
IUBMB Life, 52: 49 53, 2001
Keywords

AP-1; HIF-1; hypoxia; MAP kinases; VEGF.

INTRODUCTION
Hypoxicconditions are associated with differential expression of genes allowing cells and tissues to adapt to low oxygen
concentration (1, 2). Speci c increased expression of glycolytic
enzymes, glucose tranporter GLUT-1 (3), VEGF (4), tyrosine
hydroxylase (5 ), transferrin (6 ), and erythropoietin is observed,
all proteins involved in the adaptative response of cells to hypoxia. The modi cation of gene expression is dependent on
the activation of speci c transcription factors: HIF-1, HIF-2,
NF-B, Egr-1, and AP-1 have been reported to be activated by
hypoxia (for a review, see 7 ).

Hypoxia-Inducible Factor-1
HIF-1 is a heterodimeric transcription factor consisting of
HIF-1 and HIF-1/ARNT (aryl hydrocarbon receptor nuclear
Received 7 July 2001; accepted 10 July 2001.
Address correspondence to Carine Michiels, Laboratory of Biochemistry and Cellular Biology, University of Namur, 61 rue de
Bruxelles, 5000 Namur, Belgium. Fax: 32-81-724135. E-mail: carine.
michiels@fundp.ac.be

translocator). Both subunits belong to the Per-ARN/Ahr-Sim

family of the bHLH (basic helix-loop-helix) transcription factors (8). HIF-1 as well as ARNT are constitutively expressed.
However, HIF-1 appears to be the HIF-1 subunit regulated by
hypoxia, as in this condition, HIF-1 degradation is inhibited,
whereas in contrast in normoxia, HIF-1 is rapidly degraded by
the ubiquitin-proteosome system (9 11). It has to be noted that,
besides the fact that overall protein synthesis is diminished in
hypoxia, ARNT and HIF-1 proteins are ef ciently translated
in normoxia and in hypoxia (12) and that HIF-1 translation
may be enhanced, for example by HER2 signaling (13). HIF-1
contains an oxygen-dependen t degradation domain (10) within
which there is a highly conserved binding domain for the tumor suppressor von Hippel-Lindau protein (pVHL) (14 16 ).
pVHL organizes the assembly of a complex that activates the
E3 ubiquitin ligase which then ubiquitinylates HIF-1, targeting its degradation. Inactivation of pVHL is associated with the
von Hippel-Lindau cancer syndrome. pVHL mutations prevent
its binding to HIF-1, leading to constitutive expression of this
transcription factor and its target genes. Such mutations increase
the potential for angiogenesis, probably through continuous synthesis of VEGF (17, 18). Recent data showed that the interaction
between HIF-1 and pVHL is regulated through hydroxylation
of a proline residue of HIF-1 by a prolyl hydroxylase enzyme.
In the absence of oxygen, this enzyme is no longer active: the
unmodi ed prolyl-HIF-1 no longer interacts with pVHL and
accumulates (19, 20). The absolute requirement for oxygen of
this prolyl hydroxylase indicates that this enzyme may function
as a direct oxygen sensor.
Other data showed that stabilization of HIF-1 is also dependent on the PI-3kinase/Akt pathway. Indeed, the use of PI-3K inhibitors inhibits the accumulation of HIF-1 in hypoxia (21). As
well, dominant negative mutants for PI-3K or for Akt decrease
the hypoxia-induced overexpression of VEGF (22). Moreover,
disruption of PTEN, a phosphatidylinositol triphosphate phosphatase that inactivates Akt, leads to increased VEGF expression in normoxia (23). However, it is currently unclear how the
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MICHIELS ET AL.

Figure 1. Schematic representation of HIF-1 regulation. ARNT: aryl receptor nuclear translocator; HIF-1: hypoxia-inducible
factor-1; hsp 90: heat shock protein 90; PH: prolyl hydroxylase; pol II: polymerase II; VHL: von Hippel Lindau protein.
PI-3K/Akt pathway would interact with the prolyl hydroxylasepVHL system in order to regulate HIF-1 protein level. Stabilization of HIF-1 is only the rst step of HIF-1 activation:
adequate redox conditions (24), dissocation from the chaperone
hsp90 (25), association with co-activators such as CBP/p300
(26 ), or SRC-1 (27) as well as phosphorylation are also required
(Fig. 1).
In order to be fully transcriptionally active, HIF-1 must be
phosphorylated. The rst evidence indicating that HIF-1 is a
phosphoprotein was produced by Wang and coworkers (28). Using EMSA, they showed that when nuclear extracts of hypoxic
Hep3B cells were treated with phosphatase, the HIF-1/DNA
complex is disrupted. Then, Salceda et al. (29) went on to demonstrate that PD98059, an inhibitor of the ERK pathway, inhibits
HIF-1 transcriptional activity but not its stabilization by hypoxia. Consistent with these results, we demonstrated that in
HMEC-1, an endothelial cell line, hypoxia activates ERK1 and
ERK2 (30). Using PD98059 or ERK dominant-negative mutant
together with a HIF-1 reporter gene, we showed that in hypoxic
HMEC-1, the transcriptional activity of HIF-1 is dependent on
the MEK1/ERK transduction pathway. These results were con rmed using HepG2 cells (Fig. 2A). On the other hand, the
JNK pathway does not seem to be involved because MEKK1
dominant-negative mutant did not inhibit the hypoxia-induced
increase in the reporter gene expression (Fig. 2B). Thanks to
an in vitro kinase assay, the carboxy terminal domain of HIF1 that encompasses the transactivation domains of the protein
was demonstrated to be directly phosphorylated by ERK1 (30).

Similarly, Richards et al. showed, in an in vitro kinase assay,

that the HIF-1 subunit was phosphorylated by active ERK1
or ERK2 but not by active JNK or p38 (31). Moreover, activation of the raf-1-MEK1-ERK pathway leads to the induction of HIF-1 reporter gene expression without an increase in
HIF-1 protein level. However, when measuring ERK activity
in serum-deprived cells incubated in hypoxia, no activation of
these kinases was detected in this cell line. HIF-2 or EPAS1 is a
protein that shares 48% sequence identity with HIF-1 (32). As
for HIF-1, ERK pathway is also a critical mediator of EPAS-1
activation regulating its transcriptional activity without affecting protein stabilization upon hypoxia (33). Taken together, all
these results indicate that ERK could directly participate in the
activation of the HIF-1 transcriptional activity in hypoxia.

AP-1
AP-1 is a transcription factor belonging to the leucine zipper family (for a review, see 34, 35). This factor is a dimer
composed of jun/jun (c-jun, junB, junD) or jun/fos (s-fos, fosB,
fra-1, fra-2, ATF-2, CREB) subunits. It has been demonstrated
that environmental stresses such as heat shock, UV irradiation,
ionizing radiations, or cytokines can induce the synthesis of jun
and fos proteins, leading to an increase in AP-1 binding activity. Furthermore, phosphorylation of jun by c-jun N-terminal
kinase (JNK) and/or of fos by the FRK MAP kinase is required
for AP-1 transcriptional activity (36, 37 ). Restricted dimer combinations of these subunits, including mainly the c-jun homodimer and c-jun/c-fos heterodimer recognize the TRE consensus

MAPK IN HIF-1 AND AP-1 ACTIVATION IN HYPOXIA

Figure 2. Effect of the inhibition of ERK and JNK pathways on HIF-1 transcriptional activity. (A) HepG2 cells were
transfected with a reporter gene vector containing 6 hypoxiaresponsive elements (HRE) upstream of the luciferase gene as
well as a Renilla plasmid for normalisation. They were then
incubated for 16 h in normoxia or hypoxia, in the presence or
absence of an inhibitor of the ERK pathway, PD98059, at 20
M. Cells were then lysed for luciferase assays. Results are expressed in percentage of normoxic controls as means 1 SD
(n D 3). (B) HepG2 cells were transfected with a MEKK1
dominant-negative vector or a null vector together with a reporter gene vector containing 6 hypoxia-responsive elements
(HRE) upstream of the luciferase gene as well as a Renilla plasmid for normalisation. They were then incubated for 16 h in
normoxia or hypoxia. Cells were then lysed for luciferase assays. Results are expressed in percentage of normoxic controls
as means 1 SD (n D 3).
sequence (TGA(C/G)TCA) and activate the transcription of
target genes (38).
AP-1 activation by hypoxia has already been reported in several cell lines, including BAEC (39), HepG2 (40), HeLa cells
(41), and carcinoma cells (42). bFGF (43) and c-fos (44) are
some of the target genes overexpressed in hypoxia through AP-1
activation. We studied the mechanism of AP-1 activation by hypoxia and demonstrated that in hypoxic HepG2 cells, c-jun is
overexpressed and AP-1 is transcriptionally active, being activated through a JNK-dependent pathway. Moreover, it is involved in the regulation of the c-jun promoter, thus enhancing
c-jun expression and inducing a positive feedback loop on AP-1
activation (45).
Not only does HIF-1 and AP-1 activation in hypoxia increase
expression of speci c target genes, but these two transcription

51

Figure 3. Effect of the inhibition of AP-1 and/or HIF-1 on

the expression of VEGF. HepG2 cells were transfected with
a MEKK1 dominant-negative vector, a HIF-1 dominantnegative vector or a null vector together with a reporter gene
vector containing the authentic hVEGF promoter upstream of
the luciferase gene as well as a Renilla plasmid for normalisation. They were then incubated for 16 h in normoxia or hypoxia
or in the presence of PMA at 100 nM. Cells were then lysed for
luciferase assays. Results are expressed in percentage of normoxic controls as means 1 SD (n D 3).
factors also cooperate to increase VEGF (46) or tyrosine hydroxylase expression (47). This cooperative effect is illustrated
in Fig. 3: hypoxia increased by 19-fold the expression of luciferase driven by the authentic human VEGF promoter. This
induction was inhibited by 73% in the presence of a HIF-1
dominant-negative mutant and by 37% in the presence of the
MEKK1 (a kinase upstream of JNK) dominant-negative mutant.
When both mutants were present, a complete inhibition was observed. On the other hand, only the MEKK1 dominant-negative
mutant could inhibit the PMA-induced expression of the reporter
gene. PMA is a strong activator of AP-1.
CONCLUSIONS
All MAPK family members are not always activated in different cell lines when incubated in hypoxia. For example, ERK
and p38 MAPK but not JNK are activated in PC12 cells (38).
In HMEC-1 (30) and Hela cells (44), ERK activation was also
observed yet in MCF7 cells, activation of JNK was detected, but
not for ERK (43). Hence, dependent on the cell type, only some
of these kinases will be effectively activated under speci c experimental conditions. For a particular set of kinases activated,
it is possible that different sets of transcription factors will be activated, orienting the transcriptional response in different ways,
depending on the tissue and the severity of the hypoxic stress.
Some of these transcription factors may cooperate as it is observed for HIF-1 and AP-1 that VEGF expression in hypoxic
HepG2 increases in an additive way (Fig. 4).

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MICHIELS ET AL.

Figure 4. Schematic representation of the cooperation between HIF-1 and AP-1 for increasing VEGF expression in hypoxia.
The kinases upstream of these transcription factors are also represented.
ACKNOWLEDGMENTS
E. Minet is Research Assistant and C. Michiels is Research
Associate of the FNRS (Fonds National de la Recherche
Scienti que, Belgium). G. Michel, D. Mottet, and J.-P. Piret
are fellows of FRIA (Fonds pour la Recherche dans Industrie et lAgriculture, Belgium). We thank Prof. Frank Brosius
(Department of Internal Medicine, University of Michigan, Ann
Harbor) for providing the pMEKK1 dominant-negative vector, Prof. Gregg Semenza (Institute of Genetic Medicine, John
Hopkins University, Baltimore) for providing the HIF-1
dominant-negative vector, and Prof. J. Poyssegur (Centre de
Biochimie, Universite de Nice, France) for providing the
pVEGF.13 promoter construct. This text presents results of the
Belgian Programme on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Ministers Of ce, Science
Policy Programming. The scienti c responsibility is assumed
by its authors.
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