The Henry Wellcome Building of Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN, UK
* Author for correspondence (e-mail: pjr{at}well.ox.ac.uk)
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Summary |
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Key words: Hypoxia inducible factor-, Prolyl hydroxylation, Asparaginyl hydroxylation, von Hippel-Lindau protein, Ubiquitylation
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Introduction |
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HIF binds to a core pentanucleotide DNA sequence (RCGTG) in the
hypoxia-response elements (HREs) of target genes. The DNA-binding complex is a
heterodimer of HIF- and HIF-ß subunits
(Wang et al., 1995
).
HIF-ß subunits are constitutive nuclear proteins that have different
dimerisation partners in other systems of gene regulation (for a review, see
Gu et al., 2000
). HIF-
subunits have a specific function in hypoxia-inducible gene regulation and are
the targets of the oxygen-sensitive signalling pathway.
As was originally observed in studies of erythropoiesis and erythropoietin,
induction of HIF and HIF-target genes by hypoxia is closely mimicked by
exposure of cells to cobaltous ions (for a review, see
Ebert and Bunn, 1999) and by
exposure to specific iron chelators (Wang
and Semenza, 1993
). Together with the specificity of the response
to hypoxia, as opposed to other metabolic stresses, these findings led to the
concept of a specific oxygen sensor, and different types of ferroprotein were
postulated to perform this function (for reviews, see
Bunn and Poyton, 1996
;
Semenza, 1999
). Interestingly,
HIF is also activated by growth factors, oncogenes and tumour suppressor
mutations that promote cell survival or proliferation, thus effecting a
potential link between the growth of metabolizing tissues and the provision of
an oxygen supply (reviewed by Maxwell et
al., 1999
).
In keeping with the complexity of this task, HIF- exists as multiple
isoforms with different biological properties. Three principal isoforms
(HIF-1
, HIF-2
and HIF-3
) are encoded by distinct genetic
loci, further diversity being enerated by alternative promoter usage and
splicing patterns (Makino et al.,
2002
; Wenger,
2002
). Assembly of an active HIF complex is a multi-step process
involving regulated synthesis, processing and stabilization of HIF-
,
nuclear localization, dimerisation and interaction with transcriptional
coactivators (for reviews, see Semenza,
2000b
; Wenger,
2002
). To date, analyses of the regulatory mechanisms underlying
HIF activation by hypoxic and non-hypoxic stimuli have emphasized the
involvement of different types of pathway and different modes of HIF
activation. Proteolysis of HIF-
subunits is strikingly oxygen dependent
(Huang et al., 1996
;
Huang et al., 1998
;
Pugh et al., 1997
;
Sutter et al., 2000
). In
contrast, the rate of HIF-1
translation appears largely independent of
oxygen (Gorlach et al., 2000
)
but is responsive to growth factor and oncogenic stimulation
(Karni et al., 2002
;
Laughner et al., 2001
;
Treins et al., 2002
).
Phosphorylation cascades such as the mitogen-activated protein kinase (MAPK)
and phosphoinositide 3-kinase (PI3K) pathways are activated by growth factor
stimulation, and amplify the HIF response to hypoxia by post-translational
(Conrad et al., 1999
;
Richard et al., 1999
;
Zundel et al., 2000
) as well
as translational controls (Karni et al.,
2002
; Laughner et al.,
2001
; Treins et al.,
2002
). However, the exact sites of regulated phosphorylation in
the HIF system have not yet been defined and most analyses have suggested that
these pathways do not directly mediate the response to hypoxia. In contrast,
studies focused specifically on the regulation of HIF by oxygen have led to
the recognition of different modes of signal transduction involving
oxygen-dependent protein hydroxylation of HIF-
(Ivan et al., 2001
;
Jaakkola et al., 2001
;
Lando et al., 2002b
;
Yu et al., 2001
). Here, we
focus primarily on these recent insights into the oxygen-sensing response.
An important early step in defining oxygen-regulated HIF hydroxylase
pathways was the recognition that several steps in the activation process are
independently regulated by oxygen and that discrete HIF- domains can
transfer these properties onto heterologous proteins
(Huang et al., 1998
;
Jiang et al., 1997
;
Kallio et al., 1998
;
Pugh et al., 1997
).
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Oxygen-dependent proteolysis of HIF-![]() |
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Recognition that the HIF-pVHL protein interaction is
suppressed by the classical HIF-activating stimuli of cobaltous ions, iron
chelation and hypoxia led to a detailed biochemical analysis of this
interaction. These studies demonstrated the existence of two interaction sites
for pVHL within the HIF-
ODD, corresponding to the NODD and CODD
subdomains, and showed that interaction is regulated by enzymatic
hydroxylation at specific prolyl residues (for human HIF-1
, at Pro 402
in the NODD and at Pro 564 in the CODD)
(Ivan et al., 2001
;
Jaakkola et al., 2001
;
Masson et al., 2001
;
Yu et al., 2001
). Since the
only previously characterized mammalian prolyl hydroxylases (pro-collagen
prolyl hydroxylases) were 2-oxoglutarate-dependent oxygenases (reviewed by
Kivirikko and Myllyharju,
1998
), it was predicted that the HIF prolyl hydroxylases would
also belong to this family of enzymes. Based on conserved structural features
(a ß-barrel jelly-roll conformation that aligns a
2-histidine-1-carboxylate Fe (II) co-ordination motif at the catalytic site)
(Schofield and Zhang, 1999
;
Valegard et al., 1998
), a
candidate approach was used to define the HIF-modifying enzymes. This
identified the HIF prolyl hydroxylases as the products of genes related to
C.elegans egl-9, a gene that was first described in the context of an
egg-laying abnormal (EGL) phenotype (Bruick
and McKnight, 2001
; Epstein et
al., 2001
).
In mammalian cells, three isoforms were identified, termed
prolyl hydroxylase domain (PHD) enzymes
(PHD1-PHD3), and shown to hydroxylate HIF- in vitro
(Bruick and McKnight, 2001
;
Epstein et al., 2001
). These
enzymes have an absolute requirement for dioxygen as co-substrate. The overall
reaction results in insertion of one oxygen atom into the HIF-
peptide
substrate at the prolyl residue, the other generating succinate from 2-OG with
the release of CO2. Relatively labile binding of Fe(II) at the
2-his-1-carboxylate centre results in striking sensitivity to inhibition by
iron chelators and metals such as Co(II) that can exchange for Fe(II) at this
site. As predicted, the activity of the recombinant PHD enzymes is strongly
inhibited by cobaltous ions, and iron chelation. Furthermore, reactions
conducted in a controlled oxygen environment showed that the activity of the
purified enzyme is strikingly sensitive to graded levels of hypoxia in vitro
(Epstein et al., 2001
). Thus
the properties of these non-haem iron enzymes fit those of the postulated
ferroprotein sensor underlying the classic characteristics of the
erythropoietin/HIF response.
Functional studies of PHD enzymes
In C. elegans the hif-1 gene product is completely
stabilized by inactivating mutations in egl-9, providing genetic
evidence for the critical function of EGL-9 in the HIF response
(Epstein et al., 2001).
Similarly, in Drosophila melanogaster, abrogation of a single PHD
homologue, termed fatiga, by RNAi or chromosomal deletion leads to
striking upregulation of the HIF-1
homologue Similar
(Bruick and McKnight, 2001
;
Lavista-Llanos et al., 2002
).
Interestingly, among the mammalian enzymes PHD2, but not PHD1 and PHD3,
contains an N-terminal zinc finger `MYND' putative protein-interaction domain
that is distinct from the catalytic domain and conserved in EGL-9, which
suggests that PHD2 is most closely related to the C.elegans gene
product (Taylor, 2001
). When
over-expressed in culture cells each of the mammalian PHD enzymes has the
capacity to reduce the HIF transcriptional response in modest hypoxia,
presumably by compensating for oxygen-limited hydroxylation
(Bruick and McKnight, 2001
).
However, further studies are required to define the relative importance of the
PHD enzymes in the physiological regulation of HIF.
Pharmacological inactivation of the PHDs by 2-OG analogues is sufficient to
stabilize HIF- (Ivan et al.,
2002
; Jaakkola et al.,
2001
), but this action is nonspecific with respect to the PHD
isoforms. In vitro studies do suggest significant differences in substrate
specificity. For instance, PHD3 does not appear to hydroxylate the NODD site
in HIF-1
(Epstein et al.,
2001
), and comparison of enzyme activity in vitro showed that the
CODD sequence is hydroxylated most efficiently by PHD2
(Huang et al., 2002
).
Interestingly, biochemical purification from rabbit reticulocyte extract
identified PHD2 but not the other enzymes, using hydroxylation of the human
HIF-1
CODD as the activity assay
(Ivan et al., 2002
).
The three enzymes have different tissue distributions
(Lieb et al., 2002;
Oehme et al., 2002
) and, at
least under conditions of over-expression, have distinct patterns of
sub-cellular localisation (Huang et al.,
2002
; Metzen et al.,
2003
). PHD2 mRNA is widely expressed, but is particularly abundant
in adipose tissue (Oehme et al.,
2002
). PHD3 mRNA is also expressed in many tissues, but is most
abundant in the heart and placenta (Lieb
et al., 2002
; Oehme et al.,
2002
). Likewise, PHD1 mRNA is expressed in many tissues but
expression is much increased in the testis
(Lieb et al., 2002
).
The HIF- ODD sequences are quite distinct from the typical
Pro-Pro-Glyn repeats that are targeted by pro-collagen prolyl
hydroxylases. Sequence alignment of mammalian HIF-1
and HIF-2
,
at both the NODD and CODD regions, and the Caenorhabditis elegans
HIF-1 ODD, reveals a conserved LxxLAP motif
(Masson et al., 2001
).
However, the functional basis for this conservation remains unclear. Analyses
of individual mutations at Leu559, Leu562 and Ala563 in the context of the
human HIF-1
CODD indicate that all are tolerated at least to some
degree in assays of hydroxylation by each PHD enzyme, suggesting that, with
the exception of the target prolyl residue, the substrate-recognition
determinants are relatively non-stringent
(Huang et al., 2002
).
Interaction of hydroxylated HIF- with VHL E3
The mechanism by which insertion of a single oxygen atom into proline
governs recognition by pVHL has been analysed in crystallographic studies of
the HIF-pVHL interaction. The hydroxylated HIF-1
CODD
peptide binds the ß-domain of pVHL in an extended conformation, making
contact at two distinct sites: HIF-1
residues 560-567 containing
hydroxyproline (Hyp) residue 564 (site 1), and residues 571-577 (site 2)
(Hon et al., 2002
;
Min et al., 2002
). At site 1
the Hyp residue is buried within a pocket in pVHL, the oxygen atom hydrogen
bonding with pVHL residues Ser111 and His115 in the floor of the pocket.
Although proline would fit into this pocket, it would not permit the hydrogen
bonding and would exclude a water molecule that hydrogen bonds to these
residues in the unliganded structure. This mechanism is central to the
specificity of pVHL for hydroxylated HIF-
. In keeping with this,
solution binding assays using peptides of varying length confirm the
importance of site 1; site 2 providing only a modest increase in the binding
affinity (Hon et al., 2002
;
Min et al., 2002
). Kinetic and
competition studies indicate that the NODD binds at the same site with similar
affinity (Hon et al., 2002
),
although more efficient binding of the NODD to the VHL-E3 complex retrieved
from cultured cells versus pVHL produced by programmed reticulocyte lysate
suggests that there are significant differences between NODD and CODD binding
to pVHL that are not yet understood
(Masson et al., 2001
).
Although the physiological role of pVHL as a critical component of the
hypoxia response is clear, the role of HIF dysregulation in the tumour
predisposition associated with pVHL inactivation is less clear
(Kaelin, 2002). It is
therefore of interest that all of the five pVHL residues lining the
Hyp-binding pocket are sites for tumour-associated missense mutations
(Beroud et al., 1998
). This
strongly suggests that loss of capture either of HIF-
or of another
hydroxylated pVHL substrate directly contributes to the oncogenic process. In
keeping with this, overexpression of a peptide containing the hydroxylation
site from the HIF-1
CODD at a level sufficient to overwhelm
hydroxyproline substrate recognition by pVHL was found to block pVHL tumour
suppressor function (Maranchie et al.,
2002
). In contrast, the same authors found that expression of a
transcriptionally active HIF-1
polypeptide, which is stabilized by
mutations within the CODD that prevent recognition by pVHL, does not block
tumour suppression (Maranchie et al.,
2002
). This suggests that recognition of a hydroxylated substrate
other than HIF-1
is important for pVHL tumour suppressor function.
Using a similar strategy, other workers found that stabilized HIF-2
does prevent pVHL tumour suppression
(Kondo et al., 2002
). Taken
together, these findings suggest that pVHL tumour suppression is dependent on
its ability to capture hydroxylated substrates that include, but are not
necessarily confined to, HIF-2
polypeptides. In this regard, the recent
identification of the RNA polymerase II large subunit as a prolyl-hydroxylated
substrate of pVHL is of interest
(Kuznetsova et al., 2003
).
Function of the intact HIF- ODD
In addition to the minimal NODD and CODD, other sequences have been
implicated in proteolytic regulation either because their inclusion amplifies
regulation manifest by the minimal domain or because their deletion or
mutation impairs proteolytic regulation of the native HIF- polypeptide
(Huang et al., 1998
). Such
sequences could affect conformation so as to optimise the presentation of the
hydroxylase-recognition or pVHL-binding sites. Alternatively, they may
represent points of interaction with other pathways that regulate HIF-
.
In this context it is of interest that at least two other post-translation
modifications of the HIF-
ODD are known to occur. First, the
HIF-1
ODD is heavily phosphorylated, although the functional
significance of this remains unclear. For instance, in in vitro assays of VHL
E3 binding and ubiquitylation at the NODD, phosphorylation-dependent shifts in
NODD mobility can be observed but do not appear to affect its properties as a
hydroxylaseVHL-E3 substrate (Masson
et al., 2001
). Nevertheless, mutational studies at other sites
within the ODD have implicated certain phosphoacceptor residues as
functionally important. One study examined a HIF-1
polypeptide that was
disabled at the NODD, and showed that, in this context, phosphoacceptor
mutations near the CODD (S551G/T552A) have a stabilizing effect in normoxic
cells that is not observed in the case of the phosphomimetic mutations
(S551D/T552D) (Sutter et al.,
2000
). Although this site is outside the minimal functional CODD,
it is possible that, in the native molecule, phosphorylation alters the
characteristics of hydroxylaseVHL-E3 interaction so as to enhance
degradation. Nevertheless, to date, the sites of phosphorylation within the
ODD have not been precisely mapped, and it is unclear whether these particular
residues are in fact phosphorylated.
Recently, further insights into the function of the ODD have been provided
by the recognition of ARD-1 as an ODD-interacting acetyl transferase that
acetylates Lys 532 (Jeong et al.,
2002). This process apparently promotes interaction of the CODD
with VHL, increasing the efficiency of ubiquitylation and degradation,
although at present it is not clear whether the effect is to enhance
hydroxylation or VHL capture of hydroxylated HIF CODD. ARD-1 mRNA is
downregulated by hypoxia, and it has been proposed that resulting
downregulation of ODD acetylation in hypoxia inhibits VHL-mediated proteolysis
(Jeong et al., 2002
).
Interestingly, it has also been demonstrated that hypoxia upregulates histone
deacetylase mRNAs (Kim et al.,
2001
). However, it is not yet clear whether oxygen regulation of
acetylation pathways represents a distinct interface with oxygen, or whether
these pathways connect back in some way to the HIF transcriptional
cascade.
Other recent studies have demonstrated the potential for HIF-
carboxylate residues surrounding the CODD to bind metal ions such as Co(II).
Although in vitro studies have indicated that binding of cobalt to this site
could reduce capture of hydroxylated HIF by pVHL, potentially providing a
further explanation for stabilization of HIF-
by cobalt, whether this
occurs in vivo, and how it fits with the activity of cobalt on other
regulatory domains of HIF-
is unclear
(Yuan et al., 2003
). Indeed
overexpression of PHD3 in vivo appears sufficient to ablate Co(II)-induced
stabilization of HIF-1
, suggesting that the dominant mode of action of
cobalt in vivo is through inhibition of hydroxylase activity
(Cioffi et al., 2003
).
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Oxygen-dependent transcriptional activation of HIF-![]() |
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Characterization of isolated C-TAD activity showed that, as with the ODD,
the action of hypoxia can be mimicked by cobaltous ions, iron chelators, and
the inhibitory 2-OG analogue dimethyl oxalylglycine, indicating the operation
of an independent but closely similar oxygen-sensing signal
(Pugh et al., 1997;
Sang et al., 2002
). Mass
spectrometric analysis of a HIF-2
C-TAD polypeptide, which was
overexpressed and purified from 293T cells, again revealed an oxidative
modification, in this case hydroxylation of an asparaginyl residue (Asn851 in
human HIF-2
, corresponding to Asn803 in human HIF-1
)
(Lando et al., 2002b
). The
relevant asparaginyl hydroxylase was rapidly demonstrated to be a molecule
termed factor inhibiting HIF (FIH)
(Hewitson et al., 2002
;
Lando et al., 2002a
) that had
first been identified as a protein that can interact with the HIF-
C-TAD and suppress transcription (Mahon et
al., 2001
). Studies of recombinant protein have established that
FIH can hydroxylate the HIF-
C-TAD directly, that the site of
hydroxylation is the ß-carbon of the asparginyl residue
(McNeill et al., 2002
), and
that this modification prevents interaction of the HIF-
CAD with the
CH-1 domain of the coactivator p300
(Hewitson et al., 2002
;
Lando et al., 2002a
).
It has also been reported that FIH interacts with pVHL and forms a ternary
complex with the HIF- C-TAD (Mahon
et al., 2001
). Although interaction with pVHL is not an absolute
requirement for FIH activity (Hewitson et
al., 2002
; Sang et al.,
2002
), these findings fit well with studies of HIF-dependent
transcription in pVHL-defective cells. Upregulation of HIF-target gene
expression in such cells is essentially complete
(Gnarra et al., 1996
;
Iliopoulos et al., 1996
;
Maxwell et al., 1999
), which
implies that all oxygen-dependent controls of HIF, and not just proteolytic
regulation, are disabled in the absence of VHL. This suggests that VHL is
intimately involved with the hypoxia response, its functions extending beyond
those of an E3 ligase.
Structural analyses of FIH and the C-TADCH-1 interaction
NMR studies indicate that the non-hydroxylated HIF-1 C-TAD is
disordered in solution but becomes structured on binding to CH-1; HIF-1
C-TAD forming
-helices that interact with each side of CH-1
(Dames et al., 2002
;
Freedman et al., 2002
). Asn803
forms part of the helical conformation, and is buried in the interface between
the two proteins. Thus it is predicted that ß-hydroxylation at this site
would destabilise the helix and place the hydroxyl group in an energetically
unfavourable hydrophobic environment with no hydrogen-bonding partner, and
thus effectively disrupt the CH-1 interaction.
For FIH itself, recently solved crystallographic structures show a dimeric
structure that conforms to the predicted ß-barrel jelly-roll conformation
(Bae et al., 2002;
Dann et al., 2002
;
Hewitson et al., 2002
).
However, structures of FIH complexed with substrates and inhibitors reveal a
number of unusual features (Hewitson et
al., 2002
). The 2-OG 5-carboxylate binding site differs from the
characteristic Arg, Ser/Thr site on the eighth strand of the jelly-roll
employed by most previously characterized 2-OG dioxygenases and involves
hydrogen bonding to Lys214 (on the fourth strand of the jelly-roll), Thr196,
and Tyr145 (Dann et al., 2002
;
Elkins et al., 2003
).
Co-crystallisation with HIF-
C-TAD peptides reveals a two-site
interaction, changes in the FIH structure upon binding indicating an induced
fit (Elkins et al., 2003
). The
HIF-
C-TAD hydroxylation site itself adopts a largely extended
conformation that includes a tight turn, stabilised by hydrogen bonding
between the backbone carbonyl of HIF-1
Val802 and NH of Ala804, that
projects the side chain of the target Asn 803 towards the active site Fe(II)
(Elkins et al., 2003
). These
unusual structural features of FIH at both the HIF-
C-TAD and 2-OG
binding sites may assist design of selective inhibitors. The structure of the
FIHC-TAD complex also suggests a potential interaction with protein
phosphorylation. It has been proposed that phosphorylation at a conserved
threonine residue (Thr796 in human HIF-1
) promotes transactivation by
directly facilitating interaction with p300/CBP
(Gradin et al., 2002
). The
relationship of this residue to the active site of the HIF-
CADFIH complex suggests that phosphorylation might also inhibit
HIF-
asparaginyl hydroxylation.
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Oxygen-dependent subcellular localization of HIF-![]() |
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Oxygen-dependent splicing of HIF-![]() |
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Perspectives |
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Some enzymes of this class also require the presence of ascorbate for full
catalytic activity, and the PHD enzymes may have a similar requirement.
Although the mechanism is incompletely understood, one action of ascorbate on
pro-collagen prolyl hydroxylase is to reconstitute active enzyme following
oxidation of the iron in uncoupled cycles in which 2-OG is decarboxylated
without subsequent hydroxylation of the prime substrate; ascorbate may also
act to augment an intracellular Fe(II) pool that can replenish the active site
Fe(II) (for reviews, see Kivirikko and
Myllyharju, 1998; Prescott and
Lloyd, 2000
). Whether limiting availability of iron or ascorbate
contributes to the physiological regulation of HIF is unclear. However, using
antisera that recognise the hydroxylated HIF-1
CODD specifically, it
has been shown that under conditions of oncogenic stimulation of HIF,
hydroxylation at this site is often not complete even in fully oxygenated cell
cultures (Chan et al., 2002
).
Among potential explanations is the possibility that intracellular iron or
ascorbate deficiency in proliferating tissue culture cells effectively limits
hydroxylase activity. It has been noted that supplementation of cultures with
iron or ascorbate strikingly reduces oncogenic activation of HIF in normoxic
cells, by promotion of prolyl hydroxylase activity
(Knowles et al., 2003
). The
position of two Krebs cycle intermediates, 2-OG and succinate, as
HIF-hydroxylase co-substrate and product, respectively, is also of interest,
allowing potential links to mitochondrial energy metabolism. A future focus
will therefore be to understand factors affecting the availability of Fe(II)
and 2-OG at the sites of hydroxylation.
As HIF hydroxylation is not an equilibrium reaction, the extent of
modification at a given oxygen concentration will also be affected by the
quantity of available enzyme. Since the PHD enzymes are the products of genes
that are strongly inducible and expressed in a tissue-specific manner, this is
likely to have an important effect in shaping cellular responses to hypoxia.
For instance, both PHD2 and PHD3 mRNAs are strongly induced by hypoxia itself
(Epstein et al., 2001). In
keeping with this, prior exposure of cells to hypoxia enhances the HIF prolyl
hydroxylase activity found in cell extracts, and the rate of HIF-
degradation following a return to normoxia
(Berra et al., 2001
).
Interestingly, PHD1 mRNA has also been reported to be an oestrogen-inducible
transcript (Seth et al.,
2002
), whereas PHD3 has previously been identified in different
cell types as a gene that is induced by p53
(Madden et al., 1996
), by
stimuli inducing smooth muscle differentiation
(Wax et al., 1994
) and by
nerve growth factor withdrawal (Lipscomb
et al., 2001
). In future work it will be important to determine
whether and in what way these effects on hydroxylase expression patterns
affect cellular responses to hypoxia.
Delineation of these HIF-hydroxylation pathways provides new targets for
therapeutic intervention. There is increasing evidence that activation of HIF
is protective in ischemic/hypoxic disease, and can generate a productive
angiogenic response (Elson et al.,
2001; Vincent et al.,
2000
). Direct induction of HIF-1 in vivo has been achieved both by
use of NODD and CODD polypeptides that block VHL-mediated degradation
(Maranchie et al., 2002
;
Willam et al., 2002
) and by
2-OG analogues that inhibit the HIF hydroxylases
(Ivan et al., 2002
;
Jaakkola et al., 2001
). Given
the extent of the 2-OG superfamily, it is likely that particular attention to
the design of specific inhibitors will be required. Nevertheless, emerging
structural information defining unusual and specific features of particular
hydroxylases suggests that this should be possible.
Finally, it will be of particular interest to determine whether protein
hydroxylation has a broad role in signalling responses to hypoxia. Recent
evidence suggests that both HIF-3 and the large subunit (Rpb1) of RNA
polymerase II are also targeted for VHL-dependent ubiquitylation via prolyl
hydroxylation (Kuznetsova et al.,
2003
; Maynard et al.,
2003
). Previous studies of PHD1 and PHD3 have implicated these
gene products in the regulation of a variety of cellular growth,
differentiation and apoptotic pathways, and it is possible that prolyl
hydroxylation of non-HIF-
substrates is involved in such responses
(Erez et al., 2002
;
Lipscomb et al., 2001
;
Madden et al., 1996
;
Seth et al., 2002
;
Wax et al., 1994
). In
addition, more effective database searching enabled by new structural insights
suggests the existence of a much larger 2-OG oxygenase family than has been
previously recognised (Elkins et al.,
2003
), raising the possibility that other members of this family
function in oxygen-regulated pathways that involve protein hydroxylation.
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References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Bae, M.-Y., Ahn, M.-Y., Jeong, J.-W., Bae, M.-H., Lee, Y. M.,
Bae, S.-Y., Park, J.-W., Kim, K.-R. and Kim, K.-W. (2002).
Jab1 interacts directly with HIF-1 and regulates its stability.
J. Biol. Chem. 277,9
-12.
Beroud, C., Joly, D., Gallou, C., Staroz, F., Orfanelli, M. T.
and Junien, C. (1998). Software and database for the analysis
of mutations in the VHL gene. Nucleic Acids Res
26,256
-258.
Berra, E., Richard, D. E., Gothie, E. and Pouyssegur, J.
(2001). HIF-1-dependent transcriptional activity is required for
oxygen-mediated HIF-1 degradation. FEBS Lett.
491, 85-90.[CrossRef][Medline]
Bhattacharya, S., Michels, C. L., Leung, M.-K., Arany, Z. P.,
Kung, A. L. and Livingston, D. M. (1999). Functional role of
p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1.
Genes Dev. 13,64
-75.
Brahimi-Horn, C., Berra, E. and Pouyssegur, J. (2001). Hypoxia, the tumour's gateway to progression along the angiogenic pathway. Trends Cell Biol. 11,S32 -S36.[CrossRef][Medline]
Bruick, R. K. and McKnight, S. L. (2001). A
conserved family of prolyl-4-Hydroxylases that modify HIF.
Science 294,1337
-1340.
Bunn, H. F. and Poyton, R. O. (1996). Oxygen
sensing and molecular adaptation to hypoxia. Physiological
Rev. 76,839
-885.
Chan, D. A., Sutphin, P. D., Denko, N. C. and Giaccia, A. J.
(2002). Role of prolyl hydroxylation in oncogenically stabilized
hypoxia-inducible factor-1. J. Biol. Chem.
277,40112
-40117.
Cioffi, C. L., Qin Liu, X., Kosinski, P. A., Garay, M. and
Bowen, B. R. (2003) Differential regulation of HIF-1
prolyl-4-hydroxylase genes by hypoxia in human cardiovascular cells.
Biochem. Biophys. Res. Commun.
303,947
-953.[CrossRef][Medline]
Cockman, M. E., Masson, N., Mole, D. R., Jaakkola, P., Chang, G.
W., Clifford, S. C., Maher, E. R., Pugh, C. W., Ratcliffe, P. J. and Maxwell,
P. H. (2000). Hypoxia inducible factor- binding and
ubiquitylation by the von Hippel-Lindau tumor suppressor protein.
J. Biol. Chem. 275,25733
-25741.
Conrad, P. W., Freeman, T. L., Beitner-Johnson, D. and Millhorn,
D. E. (1999). EPAS1 trans-activation during hypoxia
requires p42/p44 MAPK. J. Biol. Chem.
274,33709
-33713.
Dames, S. A., Martinez-Yamout, M., Guzman, R. N. D., Dyson, H.
J. and Wright, P. E. (2002). Structural basis for
hif-1/CBP recognition in the cellular hypoxic response.
Proc. Natl. Acad. Sci. USA
99,5271
-5276.
Dann, C. E. I., Bruick, R. K. and Deisenhofer, J.
(2002). Structure of factor-inhibiting hypoxia-inducible factor
1: an asparaginyl hydroxylase involved in the hypoxic response pathway.
Proc. Natl. Acad. Sci. USA
99,15351
-15356.
Ebert, B. L. and Bunn, H. F. (1999). Regulation
of the Erythropoietin Gene. Blood
94,1864
-1877.
Elkins, J. M., Hewitson, K. S., McNeill, L. A., Seibel, J. F.,
Schlemminger, I., Pugh, C. W., Ratcliffe, P. J. and Schofield, C. J.
(2003). Structure of factor-inhibiting hypoxia-inducible factor
(HIF) reveals mechanism of oxidative modification of HIF-1.
J. Biol. Chem. 278,1802
-1806.
Elson, D. A., Thurston, G., Huang, L. E., Ginzinger, D. G.,
McDonald, D. M., Johnson, R. S. and Arbeit, J. M. (2001).
Induction of hypervascularity without leakage or inflammation in transgenic
mice overexpressing hypoxia-inducible factor-1. Genes
Dev. 15,2520
-2532.
Ema, M., Hirota, K., Mimura, J., Abe, H., Yodoi, J., Sogawa, K.,
Poellinger, L. and Fujii-Kuriyama, Y. (1999). Molecular
mechanisms of transcription activation by HLF and HIF1alpha in response to
hypoxia: their stabilization and redox signal-induced interaction with
CBP/p300. EMBO J. 18,1905
-1914.
Epstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A. et al. (2001). C. elegans EGL-9 and mammalian homologues define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43-54.[Medline]
Erez, N., Milyavsky, M., Goldfinger, N., Peles, E., Gudkov, A. V. and Rotter, V. (2002). Falkor, a novel cell growth regulator isolated by a functional genetic screen. Oncogene 21,6713 -6721.[CrossRef][Medline]
Freedman, S. J., Sun, Z.-Y. J., Poy, F., Kung, A. L.,
Livingston, D. M., Wagner, G. and Eck, M. J. (2002).
Structural basis for recruitment of CBP/p300 by hypoxia-inducible
factor-1. Proc. Natl. Acad. Sci. USA
99,5367
-5372.
Gnarra, J. R., Zhou, S., Merrill, M. J., Wagner, J. R., Krumm,
A., Papavassiliou, E., Oldfield, E. H., Klausner, R. D. and Linehan, W. M.
(1996). Post-transcriptional regulation of vascular endothelial
growth factor mRNA by the product of the VHL tumor suppressor gene.
Proc. Natl. Acad. Sci. USA
93,10589
-10594.
Gorlach, A., Camenisch, G., Kvietikova, I., Vogt, L., Wenger, R. H. and Gassmann, M. (2000). Efficient translation of mouse hypoxia-inducible factor-1alpha under normoxic and hypoxic conditions. Biochim. Biophys. Acta 1493,125 -134.[Medline]
Gradin, K., Takasaki, C., Fujii-Kuriyama, Y. and Sogawa, K.
(2002). The transcriptional activation function of the HIF-like
factor requires phosphorylation at a conserved threonine. J. Biol.
Chem. 277,23508
-23514.
Groulx, I. and Lee, S. (2002). Oxygen-dependent
ubiquitination and degradation of hypoxia-inducible factor requires
nuclear-cytoplasmic trafficking of the von Hippel-Lindau tumor suppressor
protein. Mol. Cell. Biol.
22,5319
-5336.
Gu, Y.-Z., Hogenesch, J. B. and Bradfield, C. A. (2000). The PAS superfamily: sensors of environmental and developmental signals. Annu. Rev. Pharm. Toxicol. 40,519 -561.[CrossRef][Medline]
Hewitson, K. S., McNeill, L. A., Riordan, M. V., Tian, Y.-M.,
Bullock, A. N., Welford, R. W., Elkins, J. M., Oldham, N. J., Bhattacharya,
S., Gleadle, J. M. et al. (2002). Hypoxia inducible factor
(HIF) asparagine hydroxylase is identical to Factor Inhibiting HIF (FIH) and
is related to the cupin structural family. J. Biol.
Chem. 277,26351
-26355.
Hofer, T., Desbaillets, I., Hopfl, G., Gassmann, M. and Wenger,
R. H. (2001). Dissecting hypoxia-dependent and
hypoxia-independent steps in the HIF-l activation cascade: implications
for HIF-1
gene therapy. FASEB J.
15,2715
-2717.
Hon, W. C., Wilson, M. I., Harlos, K., Claridge, T. D.,
Schofield, C. J., Pugh, C. W., Maxwell, P. H., Ratcliffe, P. J., Stuart, D. I.
and Jones, E. Y. (2002). Structural basis for the recognition
of hydroxyproline in HIF-1 by pVHL. Nature
417,975
-978.[CrossRef][Medline]
Huang, L. E., Arany, Z., Livingston, D. M. and Bunn, H. F.
(1996). Activation of hypoxia-inducible transcription factor
depends primarily on redox-sensitive stabilization of its subunit.
J. Biol. Chem. 271,32253
-32259.
Huang, L. E., Gu, J., Schau, M. and Bunn, H. F.
(1998). Regulation of hypoxia-inducible factor 1 is
mediated by an oxygen-dependent domain via the ubiquitin-proteasome pathway.
Proc. Natl. Acad. Sci. USA
95,7987
-7992.
Huang, J., Zhao, Q., Mooney, S. M. and Lee, F. S.
(2002). Sequence determinants in hypoxia inducible
factor-1a for hydroxylation by the prolyl hydroxylases PHD1, PHD2 and
PHD3. J. Biol. Chem.
277,39792
-39800.
Iliopoulos, O., Levy, A. P., Jiang, C., Kaelin, W. G., Jr and
Goldberg, M. A. (1996). Negative regulation of
hypoxia-inducible genes by the von Hippel-Lindau protein. Proc.
Natl. Acad. Sci. USA 93,10595
-10599.
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M.,
Salic, A., Asara, J. M., Lane, W. S. and Kaelin, W. G. J.
(2001). HIF targeted for VHL-mediated destruction by
proline hydroxylation: implications for O2 sensing.
Science 292,464
-468.
Ivan, M., Haberberger, T., Gervasi, D. C., Michelson, K. S.,
Gunzler, V., Kondo, K., Yang, H., Sorokina, I., Conaway, R. C., Conaway, J. W.
et al. (2002). Biochemical purification and pharmacological
inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible
factor. Proc. Natl. Acad. Sci. USA
99,13459
-13464.
Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert,
J., Gaskell, S. J., von Kriegsheim, A., Hebestreit, H. F., Mukherji, M.,
Schofield, C. J. et al. (2001). Targeting of HIF- to
the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl
hydroxylation. Science
292,468
-472.
Jeong, J.-W., Bae, M.-K., Ahn, M.-Y., Kim, S.-H., Sohn, T.-K.,
Bae, M.-H., Yoo, M.-A., Song, E. J., Lee, K.-J. and Kim, K.-W.
(2002). Regulation and destabilization of HIF-1 by
ARD1-mediated acetylation. Cell
111,709
-720.[Medline]
Jewell, U. R., Kvietikova, I., Scheid, A., Bauer, C., Wenger, R.
H. and Gassmann, M. (2001). Induction of HIF-1alpha in
response to hypoxia is instantaneous. FASEB J.
15,1312
-1314.
Jiang, B.-H., Semenza, G. L., Bauer, C. and Marti, H. H. (1996). Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am. J. Physiol. 271,C1172 -C1180.[Medline]
Jiang, B.-H., Zheng, J. Z., Leung, S. W., Roe, R. and Semenza,
G. L. (1997). Transactivation and inhibitory domains of
hypoxia-inducible factor 1. Modulation of transcriptional activity by
oxygen tension. J. Biol. Chem.
272,19253
-19260.
Kaelin, W. G. (2002). Molecular Basis of the VHL Hereditary Cancer Syndrome. Nature Rev. Cancer 2, 673-682.[CrossRef][Medline]
Kallio, P. J., Okamoto, K., O'Brien, S., Carrero, P., Makino,
Y., Tanaka, H. and Poellinger, L. (1998). Signal transduction
in hypoxic cells: inducible nuclear translocation and recruitment of the
CBP/p300 coactivator by the hypoxia-inducible factor-1. EMBO
J. 17,6573
-6586.
Kallio, P. J., Wilson, W. J., O'Brien, S., Makino, Y. and
Poellinger, L. (1999). Regulation of the hypoxia-inducible
transcription factor 1 by the ubiquitin-proteasome pathway.
J. Biol. Chem. 274,6519
-6525.
Karni, R., Dor, Y., Keshet, E., Meyuhas, O. and Levitzki, A.
(2002). Activated pp60c-Src leads to elevated
hypoxia-inducible factor (HIF)-1 expression under normoxia.
J. Biol. Chem. 277,42919
-42925.
Kim, M. S., Kwon, H. J., Lee, Y. M., Baek, J. H., Jang, J.-E., Lee, S.-W., Moon, E.-J., Kim, H.-S., Lee, S.-K., Chung, H. Y. et al. (2001). Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat. Med. 7, 437-443.[CrossRef][Medline]
Kivirikko, K. I. and Myllyharju, J. (1998). Prolyl 4-hydroxylases and their protein disulfide isomerase subunit. Matrix Biol. 16,357 -368.[CrossRef][Medline]
Knowles, H. J., Raval, R. R., Harris, A. L. and Ratcliffe, P. J. (2003). Effect of ascorbate on the activity of hypoxia inducible factor (HIF) in cancer cells. Cancer Res. 270,1900 -1915.
Kondo, K., Kico, J., Nakamura, E., Lechpammer, M. and Kaelin, W. G. J. (2002). Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 1,237 -246.[CrossRef][Medline]
Kuznetsova, A. V., Meller, J., Schnell, P. O., Nash, J. A.,
Ignacak, M. L., Sanchez, Y., Conaway, J. W., Conaway, R. C. and
Czyzyk-Krzeska, M. F. (2003). von Hippel-Lindau protein binds
hyperphosphorylated large subunit of RNA polymerase II through a proline
hydroxylation motif and targets it for ubiquitination. Proc. Natl.
Acad. Sci. USA 100,2706
-2711.
Lando, D., Peet, D. J., Gorman, J. J., Whelan, D. A., Whitelaw,
M. L. and Bruick, R. K. (2002a). FIH-1 is an asparaginyl
hydroxylase enzyme that regulates the transcriptional activity of
hypoxia-inducible factor. Genes Dev.
16,1466
-1471.
Lando, D., Peet, D. J., Whelan, D. A., Gorman, J. J. and
Whitelaw, M. L. (2002b). Asparagine hydroxylation of the HIF
transactivation domain: a hypoxic switch. Science
295,858
-861.
Laughner, E., Taghavi, P., Chiles, K., Mahon, P. C. and Semenza,
G. L. (2001). HER2 (neu) signaling increases the rate of
hypoxia-inducible factor 1 (HIF-1
) synthesis: novel mechanism
for HIF-1-mediated vascular endothelial growth factor expression.
Mol. Cell. Biol. 21,3995
-4004.
Lavista-Llanos, S., Centanin, L., Irisarri, M., Russo, D. M.,
Gleadle, J. M., Bocca, S. N., Muzzopappa, M., Ratcliffe, P. J. and Wappner,
P. (2002). Control of the hypoxic reponse in Drosophila
melanogaster by the basic helix-loop-helix PAS protein Similar.
Mol. Cell. Biol. 22,6842
-6853.
Lieb, M. E., Menzies, K., Moschella, M. C., Ni, R. and Taubman, M. B. (2002). Mammalian EGLN genes have distinct patterns of mRNA expression and regulation. Biochem. Cell Biol. 80,421 -426.[Medline]
Lipscomb, E. A., Sarmiere, P. D. and Freeman, R. S.
(2001). SM-20 is a novel mitochondrial protein that causes
caspase-dependent cell death in nerve growth factor-dependent neurons.
J. Biol. Chem. 276,5085
-5092.
Luo, J. C. and Shibuya, M. (2001). A variant of
nuclear localization signal of bipartite-type is required for the nuclear
translocation of hypoxia inducible factors (1, 2
and 3
).
Oncogene 20,1435
-1444.[CrossRef][Medline]
Madden, S. L., Galella, E. A., Riley, D., Bertelsen, A. H. and Beaudry, G. A. (1996). Induction of cell growth regulatory genes by p53. Cancer Res. 56,5384 -5390.[Abstract]
Mahon, P. C., Hirota, K. and Semenza, G. L.
(2001). FIH-1: a novel protein that interacts with HIF-1alpha and
VHL to mediate repression of HIF-1 transcriptional activity. Genes
Dev. 15,2675
-2686.
Makino, Y., Cao, R., Svensson, K., Bertilsson, G., Asman, M., Tanaka, H., Cao, Y., Berkenstam, A. and Poellinger, L. (2001). Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414,550 -554.[CrossRef][Medline]
Makino, Y., Kanopka, A., Wilson, W. J., Tanaka, H. and
Poellinger, L. (2002). IPAS is an hypoxia-inducible splicing
variant of the HIF-3a locus. J. Biol. Chem.
277,32405
-32408.
Maranchie, J. K., Vasselli, J. R., Riss, J., Bonifacino, J. S.,
Linehan, W. M. and Klausner, R. D. (2002). The contribution
of VHL substrate binding and HIF1- to the phenotype of VHL loss in
renal cell carcinoma. Cancer Cell
1, 247-255.[CrossRef][Medline]
Masson, N., Willam, C., Maxwell, P. H., Pugh, C. W. and
Ratcliffe, P. J. (2001). Independent function of two
destruction domains in hypoxia-inducible factor- chains activated by
prolyl hydroxylation. EMBO J.
20,5197
-5206.
Maxwell, P. H., Pugh, C. W. and Ratcliffe, P. J. (1993). Inducible operation of the erythropoietin 3' enhancer in multiple cell lines: evidence for a widespread oxygen sensing mechanism. Proc. Natl. Acad. Sci. USA 90,2423 -2427.[Abstract]
Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R. and Ratcliffe, P. J. (1999). The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399,271 -275.[CrossRef][Medline]
Maxwell, P. H., Pugh, C. W. and Ratcliffe, P. J. (2001). Activation of the HIF pathway in cancer. Curr. Opin. Genet. Dev. 11,293 -299.[CrossRef][Medline]
Maynard, M. A., Qi, H., Chung, J., Lee, E. H. L., Kondo, Y.,
Hara, S., Conaway, R. C., Conaway, J. W. and Ohh, M. (2003).
Multiple splice variants of the human HIF-3 locus are targets of the
VHL E3 ubiquitin ligase complex. J. Biol. Chem.
278,11032
-11040.
McNeill, L. A., Hewitson, K. S., Claridge, T. D., Seibel, J. F., Horsfall, L. E. and Schofield, C. J. (2002). Hypoxia-inducible factor asparaginyl hydroxylase (FIH-1) catalyses hydroxylation at the ß-carbon of asparagine-803. J. Biochem. 367,571 -575.
Metzen, E., Berchner-Pfannschmidt, U., Stengel, P., Marxsen, J.
H., Stolze, I., Klinger, M., Huang, W. Q., Wotzlaw, C., Hellwig-Burgel, T.,
Jelkmann, W., Acker, H. and Fandrey, J. (2003). Intracellular
localisation of human HIF-1 alpha hydroxylases: implications for oxygen
sensing. J. Cell Sci.
116,1319
-1326.
Min, J.-H., Yang, H., Ivan, M., Gertler, F., Kaelin, W. G. J.
and Pavletich, N. P. (2002). Structure of an
HIF-1-pVHL complex: hydroxyproline recognition in signaling.
Science 296,1886
-1889.
O'Rourke, J. F., Tian, Y.-M., Ratcliffe, P. J. and Pugh, C.
W. (1999). Oxygen-regulated and transactivating domains in
endothelial PAS protein 1: comparison with hypoxia inducible factor-1.
J. Biol. Chem. 274,2060
-2071.
Oehme, F., Ellinghaus, P., Kolkhof, P., Smith, T. J., Ramakrishnan, S., Hutter, J., Schramm, M. and Flamme, I. (2002). Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors. Biochem. Biophys. Res. Commun. 296,343 -349.[CrossRef][Medline]
Ohh, M., Park, C. W., Ivan, M., Hoffman, M. A., Kim, T. Y., Huang, L. E., Pavletich, N., Chau, V. and Kaelin, W. G. (2000). Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat. Cell. Biol. 2,423 -427.[CrossRef][Medline]
Prescott, A. G. and Lloyd, M. D. (2000). The iron(II) and 2-oxoacid-dependent dioxygenases and their role in metabolism. Natural Product Reports 17,367 -383.[CrossRef][Medline]
Pugh, C. W., O'Rourke, J. F., Nagao, M., Gleadle, J. M. and
Ratcliffe, P. J. (1997). Activation of hypoxia inducible
factor-1; definition of regulatory domains within the subunit.
J. Biol. Chem. 272,11205
-11214.
Richard, D. E., Berra, E., Gothie, E., Roux, D. and
Pouysségur, J. (1999). p42/p44 mitogen-activated
protein kinases phosphorylate hypoxia-inducible factor 1 (HIF-1
)
and enhance the transcriptional activity of HIF-1. J. Biol.
Chem. 274,32631
-32637.
Sang, N., Fang, J., Srinivas, V., Leshchinsky, I. and Caro,
J. (2002). Carboxyl-terminal transactivation activity of
hypoxia-inducible factor 1alpha is governed by a von Hippel-Lindau
protein-independent, hydroxylation-regulated association with p300/CBP.
Mol. Cell. Biol. 22,2984
-2992.
Schofield, C. J. and Zhang, Z. (1999). Structural and mechanistic studies on 2-oxoglutarate-dependent oxygenases and related enzymes. Curr. Opin. Struct. Biol. 9, 722-731.[CrossRef][Medline]
Semenza, G. L. (1999). Perspectives on oxygen sensing. Cell 98,281 -284.[Medline]
Semenza, G. L. (2000a). HIF-1 and human
disease: one highly involved factor. Genes Dev.
14,1983
-1991.
Semenza, G. L. (2000b). HIF-1: mediator of
physiological and pathophysiological responses to hypoxia. J. Appl.
Physiol. 88,1474
-1480.
Semenza, G. L. and Wang, G. L. (1992). A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol. Cell. Biol. 12,5447 -5454.[Abstract]
Seth, P., Krop, I., Porter, D. and Polyak, K. (2002). Novel estrogen and tamoxifen induced genes identified by SAGE (serial analysis of gene expression). Oncogene 21,836 -843.[CrossRef][Medline]
Sutter, C. H., Laughner, E. and Semenza, G. L.
(2000). Hypoxia-inducible factor 1a protein expression
is controlled by oxygen-regulated ubiquitination that is disrupted by
deletions and missense mutations. Proc. Natl. Acad. Sci.
USA 97,4748
-4753.
Taylor, M. S. (2001). Characterization and comparative analysis of the EGLN gene family. Gene 275,125 -132.[CrossRef][Medline]
Treins, C., Giorgetti-Peraldi, S., Murdaca, J., Semenza, G. L.
and Van Obberghen, E. (2002). Insulin stimulates
hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of
rapamycin-dependent signaling pathway. J. Biol. Chem.
277,27975
-27981.
Valegard, K., van Scheltinga, A. C. T., Lloyd, M. D., Hara, T., Ramaswamy, S., Perrakis, A., Thompson, A., Lee, H. J., Baldwin, J. E., Schofield, C. J. et al. (1998). Structure of a cephalosporin synthase. Nature 394,805 -809.[CrossRef][Medline]
Vincent, K. A., Shyu, K. G., Luo, Y., Magner, M., Tio, R. A.,
Jiang, C., Goldberg, M. A., Akita, G. Y., Gregory, R. J. and Isner, J. M.
(2000). Angiogenesis is induced in a rabbit model of hindlimb
ischemia by naked DNA encoding an HIF-1alpha/VP16 hybrid transcription factor.
Circulation 102,2255
-2261.
Wang, G. L. and Semenza, G. L. (1993). Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. Blood 82,3610 -3615.[Abstract]
Wang, G. L., Jiang, B.-H., Rue, E. A. and Semenza, G. L. (1995). Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. USA 92,5510 -5514.[Abstract]
Wax, S. D., Rosenfield, C. L. and Taubman, M. B.
(1994). Identification of a novel growth factor-responsive gene
in vascular smooth muscle cells. J. Biol. Chem.
269,13041
-13047.
Wenger, R. H. (2000). Mammalian oxygen sensing, signalling and gene regulation. J. Exp. Biol. 20,1253 -1263.
Wenger, R. H. (2002). Cellular adaptation to
hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible
transcription factors, and O2-regulated gene expression.
FASEB J. 16,1151
-1162.
Willam, C., Masson, N., Tian, Y. M., Mahmood, S. A., Wilson, M.
I., Bicknell, R., Eckardt, K. U., Maxwell, P. H., Ratcliffe, P. J. and Pugh,
C. W. (2002). Peptide blockade of HIFalpha degradation
modulates cellular metabolism and angiogenesis. Proc. Natl. Acad.
Sci. USA 99,10423
-10428.
Yu, F., White, S. B., Zhao, Q. and Lee, F. S.
(2001). HIF-1 binding to VHL is regulated by
stimulus-sensitive proline hydroxylation. Proc. Natl. Acad. Sci.
USA 98,9630
-9635.
Yuan, Y., Hilliard, G., Ferguson, T. and Millhorn, D. E.
(2003). Cobalt inhibits the interaction between hypoxia inducible
factor- and von Hippel-Lindau protein by direct binding to hypoxia
inducible factor-
. J. Biol. Chem.
278,15911
-15916.
Zhang, Z. H., Ren, J. S., Stammers, D. K., Baldwin, J. E., Harlos, K. and Schofield, C. J. (2000). Structural origins of the selectivity of the trifunctional oxygenase clavaminic acid synthase. Nat. Struct. Biol. 7,127 -133.[CrossRef][Medline]
Zhou, J., Gunsior, M., Bachmann, B. O., Townsend, C. A. and Solomon, E. I. (1998). Substrate binding to the alpha-ketoglutarate-dependent non-heme iron enzyme clavaminate synthase 2: coupling mechanism of oxidative decarboxylation and hydroxylation. J. Am. Chem. Soc. 120,13539 -13540.[CrossRef]
Zundel, W., Schindler, C., Haas-Kogan, D., Koong, A., Kaper, F.,
Chen, E., Gottschalk, A. R., Ryan, H. E., Johnson, R. S., Jefferson, A. B. et
al. (2000). Loss of PTEN facilitates HIF-1-mediated
gene expression. Genes Dev.
14,391
-396.
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