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(The FASEB Journal. 2002;16:1151-1162.)
© 2002 FASEB

Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression

ROLAND H. WENGER

Carl-Ludwig-Institute of Physiology, University of Leipzig, Leipzig, Germany

1Correspondence: Carl-Ludwig-Institute of Physiology, University of Leipzig, Liebigstrasse 27, D-04103 Leipzig, Germany. E-mail: wenr{at}medizin.uni-leipzig.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 HYPOXIA-INDUCIBLE TRANSCRIPTION...
 OXYGEN SENSING AND REGULATION...
 REGULATION OF HIF-1 ACTIVITY
 O2-REGULATED GENES
 CONCLUSIONS
 REFERENCES
 
Although it was known for a long time that oxygen deprivation leads to the transcriptional induction of the gene encoding erythropoietin, the molecular mechanisms behind this process remained enigmatic. The cloning of the hypoxia-inducible factors (HIFs), the finding that HIF-1 regulates the expression of many more genes apart from erythropoietin, and the elucidation of the oxygen-dependent mechanisms degrading the HIF {alpha} subunits recently led to the spectacular discovery of the molecular principles of oxygen sensing. This review aims to summarize our current knowledge of oxygen-regulated gene expression.—Wenger, R. H. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression.


Key Words: environmental adaptation • erythropoietin • oxygen • transcriptional regulation • vascular endothelial growth factor


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
HYPOXIA-INDUCIBLE TRANSCRIPTION...
 OXYGEN SENSING AND REGULATION...
 REGULATION OF HIF-1 ACTIVITY
 O2-REGULATED GENES
 CONCLUSIONS
 REFERENCES
 
IN MULTICELLULAR SPECIES, highly complex organs have evolved for the uptake (lung), transport (blood), and tissue distribution (cardiovascular system) of oxygen. Ingeniously, local oxygen partial pressure itself, rather than a genetically encoded developmental program or a central oxygen-measuring regulator, represents the main functional regulator of oxygen homeostasis. Autonomous oxygen regulation has its advantages because it provides a high level of plasticity to the function of these organs in high altitude or during wound healing. However, it can also be detrimental because in solid tumor growth, intrinsic tumor cell-borne mechanisms regulate tumor oxygenation rather than extrinsic host-controlled mechanisms. Many processes involved in oxygen homeostasis are mediated by hypoxia-inducible factors (HIFs), which transcriptionally regulate the expression of several dozens of target genes. Thus, HIFs represent the link between oxygen sensors and effectors at the cellular, local, and systemic level. Pioneering studies of the regulation of the gene encoding erythropoietin eventually led to the discovery of HIF-1, followed by an avalanche of novel insights into oxygen-regulated gene expression far beyond the regulation of erythropoiesis.


   HYPOXIA-INDUCIBLE TRANSCRIPTION FACTORS
TOP
 ABSTRACT
 INTRODUCTION
 HYPOXIA-INDUCIBLE TRANSCRIPTION...
OXYGEN SENSING AND REGULATION...
 REGULATION OF HIF-1 ACTIVITY
 O2-REGULATED GENES
 CONCLUSIONS
 REFERENCES
 
HIF-1, a DNA binding activity at the erythropoietin 3' enhancer
The initial step toward the discovery of HIF-1 came from studies of DNA–protein interactions at the 3' hypoxia response element (HRE) of the erythropoietin gene (for reviews of identification of the erythropoietin HRE, see refs 1 , 2 ). These studies revealed that several factors interact with the erythropoietin 3' HRE, one of which bound solely after hypoxic exposure. Semenza and Wang hence designated this DNA binding activity ‘hypoxia-inducible factor 1’ or ‘HIF-1’ (3) . Apart from human hepatoma cell lines, HIF-1 DNA binding activity was detected in nuclear extracts derived from phenylhydrazine-treated mice, confirming that the in vitro cultured cell lines reflect the in vivo situation (4) . HIF-1 activity was detected in various non-erythropoietin-producing cell lines cultured under hypoxic conditions (5 , 6) , providing the first evidence that HIF-1 not only activates the erythropoietin gene, but is part of a widespread oxygen-sensing and signal transduction mechanism.

The cloning of the HIF-1{alpha}- and ß subunits
Functional analyses revealed that HIF-1 is a phosphorylation-dependent and redox-sensitive protein, contacting DNA in the major groove (7) . Biochemical purification of this protein yielded a heterodimer composed of a 120 kDa {alpha} subunit and a 91–94 kDa ß subunit (8) . These subunits were partially sequenced and the comparison with sequence databases allowed Wang and Semenza (9) to identify HIF-1{alpha} as a novel protein and HIF-1ß as being identical to the previously identified heterodimerization partner of the dioxin receptor/aryl hydrocarbon receptor (AhR), called AhR nuclear translocator (ARNT) (10) . The HIF-1{alpha} cDNA was cloned and fully sequenced, revealing that HIF-1{alpha} belongs to the same class of proteins as ARNT, containing a basic helix-loop-helix (bHLH) DNA binding domain and a common domain called PAS, an acronym for the first three members of this family, namely, Sim/ARNT/Per (for a review on the PAS protein family, see ref 11 ). Later on, HIF-1{alpha} cDNA was independently cloned in a search for new heterodimerization partners of ARNT (12) and by its capability to bind the transcriptional coactivator p300/CBP (13) .

Additional HIFs
In addition to the ubiquitously expressed HIF-1{alpha}, two other members of this family, HIF-2{alpha} (14 15 16 17) and HIF-3{alpha} (18) , were identified that show a more restricted tissue expression pattern. Functional comparison between HIF-1{alpha} and HIF-2{alpha} in vitro revealed many similarities concerning genomic organization, modular protein structure, hypoxic protein stabilization, heterodimerization with ARNT, DNA recognition, DNA binding, and trans-activation of reporter genes (19 20 21 22 23) . The three HIF {alpha} subunits show partially overlapping expression patterns in vitro and in vivo (20 , 24 , 25) . Thus, HIF-2 and HIF-3 potentially might interact with the DNA binding site of HIF-1 target genes. However, further experiments are required to define the precise role of each member of the HIF family.

A novel inhibitory PAS protein (IPAS), a splice variant of HIF-3{alpha}, has recently been discovered by Poellinger and co-workers (26) . IPAS lacks a trans-activation domain, thus serving as a natural HIF antagonist. IPAS is strongly expressed in the corneal epithelium of the eye, an organ in which HIF-dependent angiogenesis is suppressed despite profound tissue hypoxia. Three other naturally occurring potential HIF-1 antagonists were reported: aHIF, an antisense RNA complementary to the 3' untranslated region of HIF-1{alpha} (27) ; HIF-1{alpha}Z, a zinc-inducible isoform lacking exon 12 (28) ; and a dominant-negative HIF-1{alpha} isoform lacking exons 11 and 12 (29) . The physiological relevance of these transcripts still needs to be defined.

Expression and physiological functions of HIFs in vivo
The existence of several HIFs, partially overlapping in expression and function, suggested that they might be functionally redundant. However, embryonic lethal phenotypes were found in mouse gene targeting experiments at both the HIF-1{alpha} and HIF-2{alpha} loci. These experiments demonstrated that HIF-1{alpha} is required for mesenchymal cell survival during embryonic development. HIF-1{alpha} knockout embryos die around midgestation, showing cardiovascular malformations and open neural tube defects (30 31 32) . Mice containing only one mutant HIF-1{alpha} allele develop normally but show impaired physiological responses to chronic hypoxia such as reduced polycythemia, right ventricular hypertrophy, pulmonary hypertension, pulmonary vascular remodeling, and electrophysiological responses (33 , 34) . Carotid bodies isolated from these mice show a defective neural activity after exposure to hypoxia (35) . Finally, although the ventilatory response to acute hypoxia was normal, ventilatory adaptation to chronic hypoxia was impaired in partially HIF-1{alpha}-deficient mice (35) . These results clearly demonstrate the central role of HIF-1 in the adaptation to hypoxia not only at the cellular but at the systemic level.

Diverse phenotypes related to the cardiovascular system were reported for HIF-2{alpha} knockout embryos. On one genetic background, the organ of Zuckerkandl (the major catecholamine source during development) does not produce sufficient amounts of catecholamines, leading to embryonic lethality, presumably because of bradycardia (36) . On a different genetic background, HIF-2{alpha} was found to play an important role for remodeling of the primary vascular network (37) . The expression pattern and functional role of HIF-3{alpha} still have to be elucidated.

Several tissues are naturally hypoxic despite normoxic-inspired oxygen fractions. This tissue hypoxia often serves as an important, HIF-mediated developmental signal. For example, conditional knockout mice lacking HIF-1{alpha} expression specifically in the cartilaginous growth plate of the developing bone show gross skeletal malformations and die perinatally, probably due to tracheal abnormalities (38) . In these mice, cells in the hypoxic interior of the growth plate die as a result of defective HIF-1{alpha}-mediated growth arrest. During placenta development, hypoxia maintains trophoblast proliferation and prevents differentiation toward an invasive phenotype (39) . Indeed, ARNT knockout mice revealed that HIF-1 is essential for mammalian placentation (40) . In addition, least part of this developmental process is regulated by HIF-1-mediated TGF-ß3 expression (41) . HIF-1-regulated TGF-ß3 expression is involved in the scarless wound healing in hypoxic embryonic skin (42) .

Expression studies in healthy mice revealed that the function of HIF-1 might reach far beyond hypoxia adaptation: HIF-1{alpha} was found to be expressed in diverse normoxic organs within distinct cell types (43) , suggesting that additional factors such as cellular differentiation and response to growth factors regulate HIF-1{alpha} expression. Expression of HIF-1{alpha} in normoxic mouse brain, for example, appears to be involved in the regulation of the circadian rhythm, as HIF-1 was shown to interact with the clock component Per1 (44) . A novel isoform of HIF-1{alpha} whose expression is regulated by an alternative promoter/first exon combination is expressed in postmeiotic spermatids of the mouse testis; the corresponding HIF-1{alpha} protein is located in the midpiece of the spermatozoal tail (45) . The same isoform was reported to be up-regulated in activated T cells (46) . However, further studies will have to reveal the function of this alternative HIF-1{alpha} isoform at these specific locations.

A recent report demonstrated HIF-1{alpha} induction by exposing mice to heat, leading to an increase in core body temperature as found in fever. As shown by the different modification pattern of HIF-1{alpha}, this effect is not due to tissue hypoxia secondary to heat but occurs rather by direct protein stabilization involving HSP90 (47) . Myocardial mechanical stress was reported to induce HIF-1{alpha} via stress-activated channels (48) . This effect seems to be mediated via common kinase signaling pathways (see below).

HIFs are expressed in a multitude of diseases associated with tissue hypoxia, including ischemia and tumorigenesis. However, this review focuses on the physiological functions of HIFs; pathophysiological functions were reviewed previously (49) .


   OXYGEN SENSING AND REGULATION OF HIF {alpha} SUBUNITS
TOP
 ABSTRACT
 INTRODUCTION
 HYPOXIA-INDUCIBLE TRANSCRIPTION...
 OXYGEN SENSING AND REGULATION...
REGULATION OF HIF-1 ACTIVITY
 O2-REGULATED GENES
 CONCLUSIONS
 REFERENCES
 
The oxygen sensor: a family of novel protein hydroxylases
The nature of the oxygen sensor responsible for HIF-1 activation has remained enigmatic for a long time; many interesting hypotheses were proposed, that have been discussed elsewhere (50) . The breakthrough experiments were performed by two research groups, headed by Ratcliffe (51) and Kaelin (52) , who discovered that an oxygen-dependent enzymatic activity covalently modifies a domain of HIF-1{alpha} known as the oxygen-dependent degradation (ODD) domain (53) . To the surprise of all researchers involved in the hunt for the oxygen sensor, this modification turned out to be the hydroxylation of two proline residues (Pro402 and Pro564) by a prolyl-4-hydroxylase, similar to the proline modification known from the collagens (51 , 52 , 54 , 55) .

Molecular cloning of the HIF-prolyl hydroxylases was greatly supported by C. elegans genetics. The egl-9 gene encoded an orphan prolyl hydroxylase and, indeed, egl-9-mutant C. elegans constitutively expressed HIF-1{alpha} (56) . Using the egl-9 sequence as an electronic bait in database searches, Ratcliffe and co-workers identified three mammalian homologs designated ‘prolyl hydroxylase domain containing’ (PHD) 1, 2, and 3 (56) . The same three HIF-prolyl hydroxylases (termed HPH 3, 2, and 1, respectively) were cloned by Bruick and McKnight based on sequence similarity to collagen-modifying prolyl hydroxylases (57) .

The PHDs/HPHs are dioxygenases requiring oxygen and 2-oxoglutarate as cosubstrates. PHDs/HPHs contain iron liganded by two histidine and one aspartic acid residues. Oxygen binding to this central moiety requires the vitamin C-dependent maintenance of iron in its ferrous state. The PHDs/HPHs transfer one oxygen atom onto the proline residues of the HIF {alpha} subunits; the second oxygen atom reacts with 2-oxoglutarate, yielding succinate and carbon dioxide as products. Under oxygen-deprived conditions or when the PHDs/HPHs are inactivated by competitive substrate analogs, the HIF prolines remain unmodified. The same effects were obtained by iron chelation, oxidation, or replacement by transition metal ions such as cobalt, treatments known to mimic hypoxia-inducible expression. The most convincing proof for the role of PHDs/HPHs as oxygen sensors was the demonstration that HIF {alpha} subunit modification was reduced under hypoxic conditions similar to those known to induce HIF-1{alpha} (56 , 58) .

Whitelaw and co-workers recently discovered that the carboxyl-terminal trans-activation region of HIF {alpha} subunits is hydroxylated in an oxygen-dependent manner (59) . In contrast to proline modification, regulating stability, the carboxyl-terminal hydroxylation modifies asparagine residues (Asn803 and Asn851 in HIF-1{alpha} and HIF-2{alpha}, respectively), regulating activity rather than stability by interfering with the recruitment of the transcriptional coactivator CBP/p300 (59) . Although the corresponding asparaginyl hydroxylase has not been identified, these results are consistent with the observation that stabilization alone is not sufficient to fully activate HIFs under normoxic conditions (60) .

The von Hippel-Lindau tumor suppressor protein (pVHL) mediates HIF-1{alpha} protein degradation under normoxic conditions
Hydroxylation of the HIF-1{alpha} ODD domain confers rapid degradation to the constitutively translated protein (58 , 61) . In fact, the HIF-1{alpha} protein usually remains undetectable under normoxic conditions. Proteasomal inhibitors or mutation of the ubiquitin-activating enzyme E1 stabilize HIF-1{alpha}, demonstrating that under normoxic conditions HIF-1{alpha} is degraded by ubiquitinylation and proteasomal degradation (53 , 62 63 64 65 66) . As discovered by Maxwell and co-workers (23) , this degradation is mediated by pVHL, binding to the hydroxylated but not to the nonhydroxylated HIF-1{alpha} ODD domain (51 , 52) . pVHL is part of an ubiquitin ligase linking the HIF {alpha} subunits via elongin C and a complex composed of several not completely characterized proteins to the ubiquitinylation machinery. Cells deficient in functional pVHL show constitutively high HIF {alpha} subunit levels and expression of many oxygen-regulated genes, leading to highly vascularized hemangioblastoma tumor formation, the most frequent manifestation of hereditary VHL disease. Tumor mutations of pVHL affect either binding to HIF-1{alpha} or binding to elongins C and B, consistent with a role of HIFs in the tumorigenesis of hemangioblastoma and renal cell carcinoma (67 68 69 70 71 72 73 74) .

Alternative mechanisms stabilizing HIF-1{alpha} under normoxic conditions
Apart from the relatively well-characterized mechanisms of hypoxic HIF {alpha} subunit stabilization, many growth factors and cytokines are known to stabilize HIF-1{alpha} under normoxic conditions, including insulin, insulin-like growth factors 1 and 2, epidermal growth factor, fibroblast growth factor 2, interleukin 1ß, tumor necrosis factor {alpha}, angiotensin II, thrombin, transforming growth factor ß1, platelet-derived growth factor, and hepatocyte growth factor (75 76 77 78 79 80 81 82 83 84) . Despite this great diversity, most of these growth factors might stabilize HIF-1{alpha} via common cellular kinase pathways (see below) activated by cell type-specific receptors. However, so far it is not known how HIF-1{alpha} is finally stabilized by these signaling pathways.

Nitric oxide (NO) has been reported to normoxically stabilize HIF-1{alpha} (85 86 87 88 89) . Contradictory reports have been published showing that treatment with NO (as well as carbon monoxide) or ectopic expression of inducible NO synthase (which is itself a HIF-1 target) abrogated HIF-1 activity (90 91 92 93) . This discrepancy might be explained by the finding that NO effects seem to be transient because initial NO treatment increased, but prolonged NO treatment decreased, HIF-1{alpha} protein and hypoxic erythropoietin expression (94) . As with the growth factors and cytokines, these in vitro data might be restricted to the cell culture models used and do not necessarily reflect the physiological situation in vivo.


   REGULATION OF HIF-1 ACTIVITY
TOP
 ABSTRACT
 INTRODUCTION
 HYPOXIA-INDUCIBLE TRANSCRIPTION...
 OXYGEN SENSING AND REGULATION...
 REGULATION OF HIF-1 ACTIVITY
O2-REGULATED GENES
 CONCLUSIONS
 REFERENCES
 
HIF-1{alpha} protein stabilization alone is not sufficient to activate HIF-1 under normoxic conditions. Solely blocking HIF-1{alpha} ubiquitinylation and proteasomal degradation does not yield transcriptionally active HIF-1 (62 , 65) . Additional, partially hypoxia-inducible mechanisms seem to be involved in HIF activation. Part of this hypoxic activation might be explained by the lack of asparaginyl hydroxylation (see above), but the full HIF-1 activation cascade includes post-translational protein phosphorylation, nuclear translocation, ARNT heterodimerization, DNA binding, recruitment of general and tissue-specific transcriptional cofactors, and target gene trans-activation. Each step may be under the control of the oxygen concentration and other environmental parameters, growth factors, hormones, nutrients, etc. Cross-talk with other signaling pathways allows for the cell type-specific and even target gene-specific fine-tuning of the general hypoxic response. These functions are based on HIF-1{alpha} protein–protein interactions (Table 1 ).


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  		Table 1. HIF-1{alpha} protein–protein interaction partners

Phosphorylation of HIF-1{alpha}
Early reports showed that phosphorylation plays an important role in HIF-1{alpha} activation (95 , 96) , but replacement of potential phosphoacceptor sites in the critical region of the ODD domain does not affect its role in hypoxic protein stabilization (63 , 64) . Thus, protein phosphorylation is secondary to hypoxic stabilization and seems to be required to regulate the transcriptional activity of HIF-1. Several reports showed that the p42/p44 (Erk2/Erk1) mitogen-activated protein kinases (MAPKs) can phosphorylate HIF {alpha} subunits leading to similar electrophoretic migration properties as the hypoxically modified protein (97 98 99 100 101 102) . However, the corresponding phosphoamino acid residues were not identified. MAPK-dependent phosphorylation enhances the transcriptional activity of HIFs, but in nonexcitable cells the p42/p44 MAPKs are not activated by hypoxia (97) . In excitable cells, hypoxia might indirectly activate MAPKs, but HIF {alpha}-protein stabilization is independent of MAPK-dependent phosphorylation (98) . Because many of these growth factor pathways recruit the p42/p44 MAPKs via the receptor tyrosine kinase -> Ras/Raf -> MEK pathway, the results may explain how growth factors activate HIF-1 function. However, they do not explain how growth factor stimulation stabilizes the HIF-1{alpha} protein.

Another important modulator of HIF-1 activity is the receptor tyrosine kinase -> PI3-kinase -> PTEN -> Akt kinase pathway. Specific inhibition of the PI3-kinase was shown to inhibit many of the HIF-1-dependent cellular responses (103 104 105 106) and loss of the tumor suppressor function of PTEN facilitated HIF-1-mediated gene expression (107) . Akt-1 might inhibit glycogen synthase kinase-3-mediated inactivation of HIF-1 (104) . Akt-1 was suggested to induce HIF-1{alpha} protein translation rather than stability (108) , providing a putative mechanism of how this phosphorylation pathway can overcome the oxygen sensor-mediated HIF-1{alpha} degradation under normoxic conditions.

Besides phosphorylation, many studies suggested that reduction oxidation (redox) -dependent processes might trigger HIF-1{alpha} function (22 , 62 , 109 110 111 112 113 114) , probably even by direct protein oxidation (111) . However, the specificity of these effects for the physiological regulation of HIF-1{alpha} in vivo remains obscure.

Nuclear localization of HIF-1{alpha} and the role of ARNT
In contrast to HIF-1{alpha}, ARNT is not regulated by hypoxia. Increases of ARNT sometimes observed in nuclear extracts of hypoxic cells (115) are most likely due to artifacts occurring during extract preparation (116) . In mammalian transcription factors, ARNT serves primarily as a heterodimerization partner of other PAS proteins such as AhR or HIF {alpha} subunits. Formation of the HIF-1 heterocomplex is mandatory for DNA binding and trans-activation (117 118 119 120 121) . However, despite the term ‘nuclear translocator’, ARNT is not required for HIF-1{alpha} (or AhR) translocation into the nucleus (116) . Rather, HIF-1{alpha} autonomously translocates into the nucleus due to the presence of a nuclear localization signal (122) . Hypoxia might activate nuclear translocation of HIF-1{alpha} by a so far unknown mechanism (122) , but overexpressed HIF-1{alpha} constitutively localizes to the nucleus under normoxic conditions (60) . Thus, nuclear translocation might be regulated by normoxic inhibition rather than hypoxic activation, and overexpression of HIF-1{alpha} might saturate this inhibitory mechanism. The p14ARF tumor suppressor protein was reported to sequester HIF-1{alpha} into the nucleolus, thereby inhibiting its trans-activation function (123) .

Transcriptional cofactor recruitment by HIF-1
HIF-1{alpha} contains two trans-activation (TA) domains, one overlapping with the ODD domain and the second at the carboxyl terminus (12 , 53 , 63 , 124) . Regulation of the transcriptional activity of HIF-1 occurs via post-translational hydroxylation, phosphorylation, and redox modifications of these two TA domains. The TA domains confer transcriptional activation of target genes mainly by the recruitment of general transcriptional coactivators including CBP/p300, SRC-1, or TIF2 (13 , 22 , 112 , 122 , 125 , 126) . Modification of the carboxyl-terminal TA domain by asparaginyl hydroxylation inhibits interaction with the CH1 domain of CBP/p300 (59) . The CPB/p300 cofactor is a histone acetyltransferase known to be recruited by many transcription factors. Histone acetylation modulates chromatin structure to ‘open’ the genomic locus for increased transcriptional activity. CBP/p300 is known to directly acetylate some transcription factors; it is tempting to speculate that HIF-1{alpha} might be an acetylation target, which could provide another level of HIF-1 regulation.

Livingston and co-workers reported that p35srj binds to the CH1 domain of CBP/p300 and blocks the interaction with HIF-1{alpha} resulting in a marked inhibition of trans-activation (127) . Moreover, Semenza and co-workers (128) recently cloned a factor inhibiting HIF-1 (FIH-1). FIH-1 is a transcriptional repressor that interacts with HIF-1{alpha} and pVHL. FIH-1 recruits histone deacetylases, directly or via pVHL, and hence counteracts the recruitment of the histone acetylases CBP/p300 (128) . It will be interesting to determine whether asparaginyl hydroxylation of the carboxyl-terminal TA domain blocks the interaction with CBP/p300 by direct steric hindrance or by hydroxylation-dependent, oxygen-regulated recruitment of transcriptional corepressors.

A reductive environment provided by the redox factor Ref-1 enhances the recruitment of the transcriptional coactivators SRC-1, TIF2 and CBP/p300 (112) . Redox-sensitive cysteine residues that affected trans-activation (in the carboxyl-terminal TA domain) or DNA binding (in the amino-terminal DNA binding domain) of HIF {alpha} subunits were identified (22 , 111) . A model was proposed in which reduced thioredoxin translocates into the nucleus of hypoxic cells and transmits the redox signal to Ref-1, which in turn interacts with the cysteines. Indeed, overexpression of thioredoxin/Ref-1 was shown previously to amplify the hypoxic signal (110) . However, the functional importance of the cysteine residue could not be confirmed in other mutation experiments (19) and a nuclear translocation of thioredoxin under hypoxia was not observed in other reports (58) . Therefore, the specificity of thioredoxin/Ref-1 in maintaining HIF-1{alpha} in a reduced state as part of the hypoxia-signaling mechanism awaits further clarification.

Several negative feedback regulatory pathways apparently limit the hypoxic response. On the mRNA level, a down-regulation of HIF-1{alpha} mRNA concentrations by an unknown mechanism was found after prolonged exposure to hypoxia (121 , 129) . On the protein level, a ‘HIF-1{alpha} proteasome targeting factor’ (HPTF) was proposed (130) . According to this model, HPTF is transcriptionally activated by HIF-1 and in turn targets the HIF-1{alpha} protein for degradation. This factor might be identical to hypoxia-inducible HIF-prolyl hydroxylase family members (56) . Whether these members are by themselves HIF-1 targets is unknown. Finally, on the trans-activation level, HIF-1-dependent induction of p35srj was reported, resulting in a marked inhibition of trans-activation (127) .

HIF-1 DNA binding and transcriptional complex assembly
Once stabilized and activated by hypoxia, HIF-1 binds to the consensus HIF-1 DNA binding site (HBS) A/(G)CGTG present in the HREs of many oxygen-regulated genes (131) . The conserved core HBS contains a CpG dinucleotide, lowering the number of actual HBS sequences found in the genome compared with the frequency of a random tetranucleotide sequence. CpG methylation of the erythropoietin 3' HBS abrogates both HIF-1 DNA binding and gene activation, and endogenous erythropoietin expression in hepatoma cells is inversely related to the degree of CpG methylation of the erythropoietin 3' HBS (132) . In contrast to most HIF-1-dependent genes where the HBSs are located in methylation-free CpG islands, the erythropoietin 3' HBS is present in a locus with average G+C content and suppressed CpG dinucleotide frequency. Such loci are usually methylated and hence ‘silenced’ in mammalian genomes. Thus, there must be a selective pressure to keep this site methylation-free. This could be the constitutive binding of a transcription factor to the HBS. Since HIF-1 activity can be detected only under hypoxic conditions, the specific constitutive binding of ATF-1/CREB-1 (133 , 134) to the HBS might prevent CpG methylation. In support of this model, in vivo footprinting showed that the HBS is occupied in normoxia in the absence of HIF-1 (135) .

An HBS is necessary but not sufficient for efficient hypoxic gene activation. Whereas the HBS is the minimal DNA domain required for the interaction with HIF-1, a functional HRE usually contains neighboring DNA binding sites for additional transcription factors. Although these elements are not hypoxia inducible per se, they might amplify the hypoxic response or confer tissue-restricted activity to a HRE. Examples include HIF-1 cooperation with the ATF-1/CREB-1 factor in thez lactate dehydrogenase A gene (125 , 136) , with AP-1 binding factors in the VEGF gene (137) , and with the orphan receptor hepatic nuclear factor 4 (HNF-4) in the erythropoietin HRE (138) . The molecular mechanism of the interplay between these distinct transcription factors is manifested by the cooperative binding of CBP/p300 because high-affinity binding of CBP/p300 requires more than one protein–protein interaction. Thus, whereas only the HBS confers hypoxic inducibility, other elements are required to form a fully functional transcriptional enhancer complex.

Alternatively, multimerization of HBSs can form a functional HRE. Two adjacent HBSs were detected in the transferrin HRE (139) and two or three adjacent HBSs were found in the HREs of genes encoding several glycolytic enzymes, glucose transporter 1, etc. (50) .


   O2-REGULATED GENES
TOP
 ABSTRACT
 INTRODUCTION
 HYPOXIA-INDUCIBLE TRANSCRIPTION...
 OXYGEN SENSING AND REGULATION...
 REGULATION OF HIF-1 ACTIVITY
 O2-REGULATED GENES
CONCLUSIONS
 REFERENCES
 
HIF-1 acts as a master regulator of oxygen-regulated gene expression, and to date ~ two dozen HIF-1 target genes are known (Table 2 ). However, microarray expression analyses revealed many more potential HIF-1 target genes in pVHL-deficient cells constitutively overexpressing HIF-1{alpha} (140) . Future experiments will show whether these novel genes are direct or indirect HIF-1 targets.


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  		Table 2. HIF-1 target genesa

HIF-1 target genes involved in iron metabolism
Iron is required for heme formation and is the most common limiting factor in erythropoiesis. Hypoxia was found to increase the expression of transferrin, probably to enhance the iron transport to erythroid tissues (139) . The transferrin receptor is a hypoxia-inducible HIF-1 target gene, enabling cellular transferrin uptake (141 , 142) . Finally, ceruloplasmin was shown to be a HIF-1 target gene (143) . Ceruloplasmin, also known as a ferroxidase, is required to oxidize ferrous to ferric iron. Because only ferric iron can be bound by transferrin, hypoxic ceruloplasmin induction is likely to support iron supply to erythroid tissues.

HIF-1 target genes involved in vascular biology
The vascular system underlies tight oxygen-regulated control. VEGF is the most prominent HIF-1 target gene involved in vascular biology (144 145 146) . HIF-1 seems to regulate flt-1, one of the receptors for VEGF (147) , but this finding was questioned in another report (131) . Recently, an endocrine-gland-derived VEGF (EG-VEGF) was reported that might be a HIF-1 target (148) . The induction of angiogenesis leads to an increase in the vascular density and hence a decrease in the oxygen diffusion distance. However, local blood flow under pathophysiological conditions is controlled by modulation of the vascular tone through production of NO (inducible nitric oxide synthase), CO (heme oxygenase 1), endothelin 1, adrenomedullin, or activation of the {alpha}1B-adrenergic receptor, all of which involve HIF-1 target genes, too (149 150 151 152 153 154) . Transgenic mice expressing HIF-1{alpha} under the control of a keratinocyte-specific promoter develop hypervascularity but, in contrast to VEGF transgenic mice, no vessel leakage or inflammation was observed (155) . This indicates that HIF-1 mediates angiogenesis by mechanisms far more complex than simple VEGF induction, probably by recruiting additional target genes involved in vessel maturation.

HIF-1 target genes involved in glucose metabolism
Under conditions of limited oxygen supply, anaerobic glycolysis becomes the predominant form of cellular ATP generation (Pasteur effect). Many genes involved in glucose uptake and glycolysis were identified as HIF-1 target genes (50) . Enhanced lactate production and hence a decrease in pH results from the increase in anaerobic glycolysis, potentially limiting this source of ATP despite sufficient glucose supply. Transmembrane carbonic anhydrases were reported to be HIF-1 target genes (156) . Carbonic anhydrases regulate the pH by converting protons and bicarbonate to carbon dioxide, which can be taken up by erythrocytes for transportation to the lung.

The constitutive activation of anaerobic metabolism in tumor cells (Warburg effect) provides an explanation for the cell autonomous response to oxygen deficiency (157 , 158) . Thus, HIF-1 function in hypoxic tumor adaptation involves not only VEGF-mediated angiogenesis, but also increased glycolysis, pH buffering, and probably other key steps in tumor progression.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 HYPOXIA-INDUCIBLE TRANSCRIPTION...
 OXYGEN SENSING AND REGULATION...
 REGULATION OF HIF-1 ACTIVITY
 O2-REGULATED GENES
 CONCLUSIONS
REFERENCES
 
Figure 1 schematically summarizes our current knowledge on the functional principles involved in the regulation of HIF-1. Many exciting questions still have to be answered. What are the spatial and temporal functional differences between the three HIF prolyl hydroxylases? What is their preferred oxygen partial pressure? How are they regulated? Will they show a redundant phenotype in knockout mice? What is the nature of the HIF asparaginyl hydroxylase? Where are the HIF phosphoacceptor sites located? How does phosphorylation regulate HIF stability and function? What is the function of HIF-3{alpha}? And how many further HIF target genes will be uncovered by modern gene array technology? Regarding our understanding of the molecular-physiological hypoxia adaptation, the last few years brought us a big step forward. Regarding a possible application of this knowledge in the treatment of major diseases associated with tissue hypoxia, such as stroke, infarction or cancer, we just stand at the beginning.



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  		Figure 1. Simplified schematic model of oxygen sensing and HIF regulation. Under hypoxic conditions, HIF-1{alpha} is stabilized, undergoes modifications, translocates into the nucleus, recruits cofactors, and activates gene expression. Under normoxic conditions, the ODD domain of HIF-1{alpha} is hydroxylated by oxygen-dependent prolyl hydroxylases (targeting HIF-1{alpha} for pVHL-mediated proteolytic destruction) and the carboxyl-terminal TA domain is hydroxylated by an oxygen-dependent asparaginyl hydroxylase (blocking the interaction with the CBP/p300 coactivator). For details. see text. bHLH, basic helix-loop-helix; HBS, HIF-1 binding site; HRE, hypoxia response element; ODD, oxygen-dependent degradation; OH, hydroxylation; P, phosphorylation; PAS, Per-AhR/ARNT-SIM; TA trans-activation; Ub, ubiquitin.


   ACKNOWLEDGMENTS
 
The work of the author was supported by the Deutsche Forschungsgemeinschaft (We2672/1–1) and the FSP Oncology (project 22) of the Medical University of Lübeck. I wish to thank D. M. Katschinski, I. Desbaillets, and C. Bauer for helpful discussions and critically reading the manuscript.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 HYPOXIA-INDUCIBLE TRANSCRIPTION...
 OXYGEN SENSING AND REGULATION...
 REGULATION OF HIF-1 ACTIVITY
 O2-REGULATED GENES
 CONCLUSIONS
 REFERENCES
 

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A Single, Mild, Transient Scrotal Heat Stress Causes Hypoxia and Oxidative Stress in Mouse Testes, Which Induces Germ Cell Death
Biol Reprod, May 1, 2009; 80(5): 913 - 919.
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The selective hypoxia inducible factor-1 inhibitor PX-478 provides in vivo radiosensitization through tumor stromal effects
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Cardioprotection by hypoxia-inducible factor 1 alpha transfection in skeletal muscle is dependent on haem oxygenase activity in mice
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S. Puri, D. A. Cano, and M. Hebrok
A Role for von Hippel-Lindau Protein in Pancreatic {beta}-Cell Function
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Mutual Regulation of Hypoxia-Inducible Factor and Mammalian Target of Rapamycin as a Function of Oxygen Availability
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Obesity and the lung: 5 {middle dot} Obesity and COPD
Thorax, December 1, 2008; 63(12): 1110 - 1117.
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Impaired DNA double-strand break repair contributes to chemoresistance in HIF-1{alpha}-deficient mouse embryonic fibroblasts
Carcinogenesis, December 1, 2008; 29(12): 2306 - 2316.
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Tocotrienol Inhibits Secretion of Angiogenic Factors from Human Colorectal Adenocarcinoma Cells by Suppressing Hypoxia-Inducible Factor-1{alpha}
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Brain Protection by Erythropoietin: A Manifold Task
Physiology, October 1, 2008; 23(5): 263 - 274.
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HIF1 transcription factor regulates laminin-332 expression and keratinocyte migration
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Transcriptional Regulation of Serine/Threonine Kinase-15 (STK15) Expression by Hypoxia and HIF-1
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JunD Represses Transcription and Translation of the Tight Junction Protein Zona Occludens-1 Modulating Intestinal Epithelial Barrier Function
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Y. A. Minamishima, J. Moslehi, N. Bardeesy, D. Cullen, R. T. Bronson, and W. G. Kaelin Jr
Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure
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The HIF/VHL Pathway: From Oxygen Sensing to Innate Immunity
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High levels of erythropoietin are associated with protection against neurological sequelae in African children with cerebral malaria
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Oxygen regulation of arterial smooth muscle cell proliferation and survival
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A chemical genomics screen highlights the essential role of mitochondria in HIF-1 regulation
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Hypoxia-inducible Factor Mediates Hypoxic and Tumor Necrosis Factor {alpha}-induced Increases in Tumor Necrosis Factor-{alpha} Converting Enzyme/ADAM17 Expression by Synovial Cells
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Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium
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Hypoxia-induced changes in the expression of rat hepatobiliary transporter genes
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Structural Basis for Depletion of Heat Shock Protein 90 Client Proteins by Deguelin
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M. Nikinmaa and W. Waser
Molecular and cellular studies in evolutionary physiology of natural vertebrate populations: influences of individual variation and genetic components on sampling and measurements
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The Peptidyl Prolyl cis/trans Isomerase FKBP38 Determines Hypoxia-Inducible Transcription Factor Prolyl-4-Hydroxylase PHD2 Protein Stability
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Glycogen Synthase Kinase 3 Phosphorylates Hypoxia-Inducible Factor 1{alpha} and Mediates Its Destabilization in a VHL-Independent Manner
Mol. Cell. Biol., May 1, 2007; 27(9): 3253 - 3265.
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A. A. Kazi and R. D. Koos
Estrogen-Induced Activation of Hypoxia-Inducible Factor-1{alpha}, Vascular Endothelial Growth Factor Expression, and Edema in the Uterus Are Mediated by the Phosphatidylinositol 3-Kinase/Akt Pathway
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Mammalian Tumor Suppressor Int6 Specifically Targets Hypoxia Inducible Factor 2{alpha} for Degradation by Hypoxia- and pVHL-independent Regulation
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Protective Role of Hypoxia-Inducible Factor-2{alpha} against Ischemic Damage and Oxidative Stress in the Kidney
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Lack of Hypoxia-Inducible Factor-1{alpha} Impairs Midbrain Neural Precursor Cells Involving Vascular Endothelial Growth Factor Signaling
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Immunohistochemical Detection of Hypoxia-Inducible Factor-1{alpha} in Human Renal Allograft Biopsies
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Hypoxia-Inducible Factor-1 (HIF-1)
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 GeneticsHome page
C. Shen, Z. Shao, and J. A. Powell-Coffman
The Caenorhabditis elegans rhy-1 Gene Inhibits HIF-1 Hypoxia-Inducible Factor Activity in a Negative Feedback Loop That Does Not Include vhl-1
Genetics, November 1, 2006; 174(3): 1205 - 1214.
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S. R. Walmsley, A. S. Cowburn, M. R. Clatworthy, N. W. Morrell, E. C. Roper, V. Singleton, P. Maxwell, M. K. B. Whyte, and E. R. Chilvers
Neutrophils from patients with heterozygous germline mutations in the von Hippel Lindau protein (pVHL) display delayed apoptosis and enhanced bacterial phagocytosis
Blood, November 1, 2006; 108(9): 3176 - 3178.
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C. Kieda, R. Greferath, C. Crola Da Silva, K. C. Fylaktakidou, J.-M. Lehn, and C. Nicolau
Suppression of hypoxia-induced HIF-1{alpha} and of angiogenesis in endothelial cells by myo-inositol trispyrophosphate-treated erythrocytes
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A. Cross, T. Barnes, R. C. Bucknall, S. W. Edwards, and R. J. Moots
Neutrophil apoptosis in rheumatoid arthritis is regulated by local oxygen tensions within joints
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R. Nishimura, R. Sakumoto, Y. Tatsukawa, T. J. Acosta, and K. Okuda
Oxygen Concentration Is an Important Factor for Modulating Progesterone Synthesis in Bovine Corpus Luteum
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Increased Prolyl 4-Hydroxylase Domain Proteins Compensate for Decreased Oxygen Levels: EVIDENCE FOR AN AUTOREGULATORY OXYGEN-SENSING SYSTEM
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A. Hubert, S. Paris, J.-P. Piret, N. Ninane, M. Raes, and C. Michiels
Casein kinase 2 inhibition decreases hypoxia-inducible factor-1 activity under hypoxia through elevated p53 protein level
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T. Tanaka, H. Kato, I. Kojima, T. Ohse, D. Son, T. Tawakami, T. Yatagawa, R. Inagi, T. Fujita, and M. Nangaku
Hypoxia and expression of hypoxia-inducible factor in the aging kidney.
J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2006; 61(8): 795 - 805.
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T. Acker, J. Fandrey, and H. Acker
The good, the bad and the ugly in oxygen-sensing: ROS, cytochromes and prolyl-hydroxylases
Cardiovasc Res, July 15, 2006; 71(2): 195 - 207.
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P. Trayhurn, C. Bing, and I. S. Wood
Adipose Tissue and Adipokines--Energy Regulation from the Human Perspective
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J. Wang, M. P. Biju, M.-H. Wang, V. H. Haase, and Z. Dong
Cytoprotective Effects of Hypoxia against Cisplatin-Induced Tubular Cell Apoptosis: Involvement of Mitochondrial Inhibition and p53 Suppression
J. Am. Soc. Nephrol., July 1, 2006; 17(7): 1875 - 1885.
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R. D. Unwin, D. L. Smith, D. Blinco, C. L. Wilson, C. J. Miller, C. A. Evans, E. Jaworska, S. A. Baldwin, K. Barnes, A. Pierce, et al.
Quantitative proteomics reveals posttranslational control as a regulatory factor in primary hematopoietic stem cells
Blood, June 15, 2006; 107(12): 4687 - 4694.
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W. Neuhofer and F.-X. Beck
Survival in Hostile Environments: Strategies of Renal Medullary Cells
Physiology, June 1, 2006; 21(3): 171 - 180.
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O. Aprelikova, M. Wood, S. Tackett, G. V.R. Chandramouli, and J. C. Barrett
Role of ETS Transcription Factors in the Hypoxia-Inducible Factor-2 Target Gene Selection
Cancer Res., June 1, 2006; 66(11): 5641 - 5647.
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U. Hopfer, H. Hopfer, K. Jablonski, R. A. K. Stahl, and G. Wolf
The Novel WD-repeat Protein Morg1 Acts as a Molecular Scaffold for Hypoxia-inducible Factor Prolyl Hydroxylase 3 (PHD3)
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E. Rissanen, H. K. Tranberg, J. Sollid, G. E. Nilsson, and M. Nikinmaa
Temperature regulates hypoxia-inducible factor-1 (HIF-1) in a poikilothermic vertebrate, crucian carp (Carassius carassius)
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E. B. Rankin, J. E. Tomaszewski, and V. H. Haase
Renal cyst development in mice with conditional inactivation of the von hippel-lindau tumor suppressor.
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J.L. James, P.R. Stone, and L.W. Chamley
The regulation of trophoblast differentiation by oxygen in the first trimester of pregnancy
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L. Schaffer, J. Vogel, C. Breymann, M. Gassmann, and H. H. Marti
Preserved placental oxygenation and development during severe systemic hypoxia
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S. Amir, R. Wang, H. Matzkin, J. W. Simons, and N. J. Mabjeesh
MSF-A Interacts with Hypoxia-Inducible Factor-1{alpha} and Augments Hypoxia-Inducible Factor Transcriptional Activation to Affect Tumorigenicity and Angiogenesis
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R. Natarajan, F. N. Salloum, B. J. Fisher, R. C. Kukreja, and A. A. Fowler III
Hypoxia Inducible Factor-1 Activation by Prolyl 4-Hydroxylase-2 Gene Silencing Attenuates Myocardial Ischemia Reperfusion Injury
Circ. Res., January 6, 2006; 98(1): 133 - 140.
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L. A. Palmer
Regulation of respiration and endothelial gene expression by s-nitrosothiols in health and disease.
Proceedings of the ATS, January 1, 2006; 3(2): 166 - 169.
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J. I. Piruat and J. Lopez-Barneo
Oxygen Tension Regulates Mitochondrial DNA-encoded Complex I Gene Expression
J. Biol. Chem., December 30, 2005; 280(52): 42676 - 42684.
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The oxygen sensing signal cascade under the influence of reactive oxygen species
Phil Trans R Soc B, December 29, 2005; 360(1464): 2201 - 2210.
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Induction of the Hypoxia-Inducible Factor System by Low Levels of Heat Shock Protein 90 Inhibitors
Cancer Res., December 1, 2005; 65(23): 11094 - 11100.
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Oxygen-Dependent Modulation of Insulin-Like Growth Factor Binding Protein Biosynthesis in Primary Cultures of Rat Hepatocytes
Endocrinology, December 1, 2005; 146(12): 5433 - 5443.
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Hypoxia inducible factor 1{alpha} regulates T cell receptor signal transduction
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Suppression of Hypoxia-inducible Factor 1{alpha} (HIF-1{alpha}) Transcriptional Activity by the HIF Prolyl Hydroxylase EGLN1
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Errors of measurement for blood volume parameters: a meta-analysis
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Evaluating Hypoxia-Inducible Factor-1{alpha} as a Cancer Therapeutic Target via Inducible RNA Interference In vivo
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Chromatin Immunoprecipitation Analysis of Gene Expression in the Rat Uterus in Vivo: Estrogen-Induced Recruitment of Both Estrogen Receptor {alpha} and Hypoxia-Inducible Factor 1 to the Vascular Endothelial Growth Factor Promoter
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Activation of HIF-prolyl Hydroxylases by R59949, an Inhibitor of the Diacylglycerol Kinase
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Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation
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