What is the oxygen sensor for mammals? HIF1a. and. Prolyl hydroxylase (PHD): Non heme iron oxygen sensor
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1 What is the oxygen sensor for mammals? HIF1a and Prolyl hydroxylase (PHD): Non heme iron oxygen sensor
2 Biochem. J. 405, 1 (2007) Scheme 1 The biochemical circle of life Through the process of photosynthesis, plants and cyanobacteria ( blue green algae ) use solar energy to synthesize glucose (C 6 H 12 O 6 ) from CO 2 and water, with O 2 produced as a side product. Glucose and O 2 are used by most organisms to convert ADP into ATP, through the process of oxidative phosphorylation, which yields CO 2 and water as side products. hv represents solar energy [where h is Planck's constant ( J s) and v is the frequency of the photons in Hz].
3 Complex IV: Cytochrome c oxidase (Cox) Scheme 2 Mitochondrial oxidative phosphorylation The respiratory-chain complexes are as follows: I, NADH:ubiquinone oxidoreductase; II, succinate:ubiquinone oxidoreductase; III, cytochrome bc 1 complex; IV, COX. IMM and OMM refer to the mitochondrial (Mito) inner and outer membranes respectively. -
4 Scheme 3 Oxygen homoeostasis The O 2 partial pressure ( tension ; PO 2 ) in each mammalian cell is determined by the supply of O 2 by diffusion from the vasculature and the local consumption of O 2 by the cell and those surrounding it. In each cell, a set point is established at which consumption of O 2 and production of ATP and ROS are optimized. Changes in PO 2 result in decreased ATP production and/or increased ROS production, which, if uncorrected by homoeostatic mechanisms, can result in cell death.
5 HIF-1 [alpha] controls metabolic and ph-regulating pathways. Cells respond to hypoxia by HIF- 1 [alpha] -mediated upregulation of glucose transporters (Glut-1 and Glut-3) and enzymes of glycolysis. Conversion of pyruvate to lactic acid is facilitated by the induction of lactate dehydrogenase (LDH). HIF-1 [alpha] also induces pyruvate dehydrogenase kinase-1 (PDK-1), which inhibits the conversion of pyruvate into acetyl-coa by pyruvate dehydrogenase (PDH), thus preventing entry of pyruvate into the TCA cycle. Subunit composition of cytochrome c oxidase (COX4) is influenced by HIF-1 [alpha] in hypoxia: COX4-2 is induced and COX4-1 is reciprocally reduced by induction of the protease LON that degrades COX4-1. Switching the COX subunits ensures optimal efficiency of mitochondrial respiration in hypoxia. Furthermore, ph homeostasis is maintained by induction of carbonic anhydrase IX (CAIX) and the monocarboxylate transporter MCT 4 and the Na [plus] [sol] H [plus] exchanger NHE1
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7 Biochem. J. 405, 1 (2007) Scheme 5 COX subunit composition in regulated by O 2 in yeast and human cells
8 Mol. Cell 30 (4), 393 (2012)
9 HIF-1 [alpha] regulates factors involved in developmental and pathological angiogenesis. The steps of angiogenesis involve multiple gene products expressed by different cell types (e.g. endothelial cells and pericytes). A coordinated sequence of events is necessary with a tight balance of activators and inhibitors of angiogenesis. HIF-1 [alpha] directly regulates genes involved in steps such as vasodilation, increased vascular permeability, extracellular matrix remodeling and proliferation (bold). Other genes (underlined) are also hypoxiaresponsive; however, direct binding of HIF to regulatory regions in those genes has still to be defined.
10 HIF-1 [alpha] in cancer. In malignant tissue, different stimuli activate HIF-1 [alpha] : local hypoxia due to increased proliferation or insufficient oxygen supply, inactivation of tumor suppressors such as VHL, oncogenes, growth factors, accumulation of TCA intermediates such as fumarate or succinate and therapeutic irradiation. Together with other cell types such as macrophages these factors contribute to a tumor microenvironment that is capable of modulating the HIF response itself. These complex interactions together influence the phenotype and the behavior of the tumor in terms of progression, invasiveness or metastatic potential.
11 Abstract Hypoxia-inducible factors (HIFs) are broadly expressed in human cancers, and HIF1α and HIF2α were previously suspected to promote tumour progression through largely overlapping functions. However, this relatively simple model has now been challenged in light of recent data from various approaches that reveal unique and sometimes opposing activities of these HIFα isoforms in both normal physiology and disease. These effects are mediated in part through the regulation of unique target genes, as well as through direct and indirect interactions with important oncoproteins and tumour suppressors, including MYC and p53. As HIF inhibitors are currently undergoing clinical evaluation as cancer therapeutics, a more through understanding of the unique roles performed by HIF1α and HIF2α in human neoplasia is warranted. Nature Rev. Cancer 12, 9 (2012) HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
12 Physiol. Rev. 89, 481 (2009) Hypoxia inducible factor (HIF)-1α stabilization in normoxia vs. HIF-1α degradation under hypoxia. Top: prolyl hydroxylase (PHD) in the presence of O 2 hydroxylates HIF-1α, which can then bind to von Hippel Lindau protein (pvhl). This event promotes the polyubiquitination of HIF-1α followed by 26-Sproteasomal degradation. Bottom: the lack of oxygen prevents the hydroxylation of HIF-1α by PHD, leading to its stabilization. HIF-1α can then migrate to the nucleus and associate with HIF-1β and the cofactor p300/cbp. The HIF-1 complex binds to and induces the transcription of genes containing hypoxia-responsive elements (HRE) with core sequence 5 -ACGTG-3 in their promoter region.
13 Summary Hypoxia-inducible factor 1α (HIF1α) and HIF2α are broadly expressed in many human cancers, and expression of these proteins frequently correlate with poor patient prognosis. Although HIF1α and HIF2α share some redundant functions, they also exhibit unique and even opposing activities in cell growth, metabolism, angiogenesis, nitric oxide homeostasis and other processes that affect tumour growth. A careful genetic dissection of Hif1a versus Epas1 (which encodes HIF2α) in autochthonous mouse models of cancer is underway, but is only in its infancy. Given that recent results have revealed unanticipated roles for the HIFα subunits in these assays, more work is clearly needed. The HIFs affect many key aspects of tumour initiation, progression, invasion, inflammatory cell recruitment and metastasis; therefore, they represent attractive targets for novel targeted therapies. Surprisingly, HIF1α can function as a tumour suppressor in renal cell carcinoma, whereas HIF2α functions as a tumour suppressor in lung adenocarcinoma. Because HIF inhibitors are being developed for therapeutic benefit, possible tumour-suppressive roles for the HIFs in a minority of human cancers should be carefully assessed. Nature Rev. Cancer 12, 9 (2012)
14 Box 1 O2-dependent regulation of HIF Using molecular oxygen (O 2 ) and 2-oxoglutarate as substrates, hypoxia-inducible factor (HIF) prolylhydroxylase (PHD) enzyme hydroxylate two specific proline residues in the O 2 -dependent degradation domain (ODD) of HIFα proteins (see the figure). These hydroxylation events occur on Pro402 and Pro564 in HIF1α, and Pro405 and Pro531 in HIF2α, and are required for the von Hippel Lindau (VHL) tumour suppressor protein the recognition component of an E3 ubiquitin ligase complex to bind and degrade HIFα subunits under normoxic conditions. Hypoxia inhibits PHD activity through various mechanisms, including substrate limitation (reviewed in Ref. 4), which results in HIFα subunit stabilization, heterodimerization with HIF1β (also known as ARNT), and increased HIF transcriptional activity. Hypoxic conditions also inhibit hydroxylation by factor inhibiting HIF (FIH) of a conserved carboxy-terminal asparagine residue in the HIFα subunits, an event that blocks the interaction between HIFα subunits and the transcriptional co-activators p300 and CREB binding protein (CBP)149, 150, 151. Thus, whereas PHD-mediated hydroxylation destabilizes HIFα subunits, FIH-mediated hydroxylation inhibits their transcriptional activity. bhlh, basic helix-loop-helix; PAS, PER-ARNT-SIM; TAD, transactivation domain. Prolyl hydroxydase (PHD) Non-heme iron protein. The hypoxia mimetic CoCl2 Co2+ substitutes with Fe2+, resulting in no activity of PHD
15 Physiol. Rev. 89, 481 (2009) Hypoxia inducible factor (HIF)-1α stabilization in normoxia vs. HIF-1α degradation under hypoxia. Top: prolyl hydroxylase (PHD) in the presence of O 2 hydroxylates HIF-1α, which can then bind to von Hippel Lindau protein (pvhl). This event promotes the polyubiquitination of HIF-1α followed by 26-Sproteasomal degradation. Bottom: the lack of oxygen prevents the hydroxylation of HIF-1α by PHD, leading to its stabilization. HIF-1α can then migrate to the nucleus and associate with HIF-1β and the cofactor p300/cbp. The HIF-1 complex binds to and induces the transcription of genes containing hypoxia-responsive elements (HRE) with core sequence 5 -ACGTG-3 in their promoter region.
16 Prolyl hydroxydase (PHD) Non-heme iron protein. The hypoxia mimetic CoCl2 Co2+ substitutes with Fe2+, resulting in no activity of PHD Biochem. J. 405, 1 (2007) Oxygen-dependent regulation of mitochondria respiration by hypoxia-inducible factor 1
17 J. Biol. Inorg. Chem. 8, 1 (2003) Mechanisms of ligand discrimination by heme proteins Fig. 3 A Structure of the heme domain of BjFixL. The FG loop is shown in green. B Comparison of the structure of FG loop and conformation of Arg220 in the unliganded on (blue) and liganded off (tan) state [32, 33] PAS Structure Fruit basket structure Hand structure PAS (Per-ARNT-Sim)
18 TABLE 1 Correlation of prognosis and HIFα expression in human cancers *
19 Box2 HIFs in normal and cancer stem cells Stem cells reside in complex microenvironments, or niches, and multiple studies have revealed that oxygen (O 2 ) concentrations influence the ability of stem and/or progenitor cells to remain quiescent or to undergo differentiation, depending on the cell type.. Hypoxia-inducible factor 1α (HIF1α) and HIF2α exhibit distinct roles in stem cell regulation. HIF1α seems to have a dominant role in modulating WNT β-catenin signalling in hypoxic embryonic stem cells and isolated neural stem cells (NSCs) of the embryonic mesencephalon and adult hippocampus153. WNT β-catenin activity is closely associated with regions of low O 2 concentrations in the subgranular zone of the hippocampus, an important NSC niche, and Hif1a deletion impairs WNT-dependent processes, such as NSC proliferation, differentiation and neuronal maturation. It should be noted that the opposite result has been reported for colon cancer cells, in which HIF1α inhibits WNT β-catenin activity154, indicating that the interaction between HIF1α and WNT in stem cells is functionally distinct from more differentiated cells, including neoplastic cells. However, the basis for this difference is currently unknown. HIF1α has also been proposed to increase the intracellular stability of activated NOTCH1 and to promote the induction of NOTCH target genes in myogenic and neural precursor cells155. This has been extended to thymic lymphomas in p53 mutant mice in which HIF1α promotes NOTCH1 activation and target gene expression156. However, data from neuroblastoma stem cells suggest that both HIF1α and HIF2α can augment NOTCH pathway signalling157. By contrast, HIF2α (but not HIF1α) regulates the POU transcription factor OCT4 (also known as POU5F1)158. OCT4 is essential for maintaining an undifferentiated cell fate in embryonic stem cells, the embryonic epiblast and primordial germ cells. Finally, HIF2α is selectively expressed in CD133 + glioblastoma 'cancer stem cells', whereas HIF1α is detected in both tumorigenic (that is, stem) and non-tumorigenic populations, suggesting that HIF2α has a unique role in the CD133 + subpopulation69. Similarly, human neuroblastomas have small numbers of tumour-initiating or stem-like cells that express neural crest markers (ID2, NOTCH1, HES1 and vimentin) and HIF2α157. On HIF2α inhibition, these cells undergo early differentiation into sympathetic neuronal cells and express markers such as achaete scute homologue 1 (ASH1), ISL1 and stathmin-like 2 (also known as SCG10). It is noteworthy that the CD133 + glioblastoma and putative neuroblastoma tumour initiating or stem-like cells express high levels of HIF2α, although they reside in peri-endothelial niches159. Although the extent of O 2 saturation within these capillaries is unknown, the data are consistent with the idea that HIF2α accumulates at higher concentrations of O 2 than does HIF1α. Alternatively, the expression of HIFα subunits in distinct cancer cell subpopulations could be controlled by non-hypoxic stimuli, such as aberrant metabolism160.
20 TABLE 2 Representative shared and unique target genes regulated by HIF1α and HIF2α
21 TABLE 3 Mouse models testing altered expression of HIFα proteins in tumour growth and progression
22 FIGURE 1 HIF1α and HIF2α exhibit antagonistic functions in NO production. Under conditions of low interferon-γ (IFNγ), hypoxia-inducible factor 2α (HIF2α) is more abundant and induces the expression of arginase 1, thus reducing the production of nitric oxide (NO). Under conditions of high IFNγ concentrations, levels of HIF2α are diminished and HIF1α dominates so that inducible nitric oxide synthase (inos) can use arginine for the generation of NO. These physiologically antagonistic functions allow the HIFα subunits to coordinately regulate the production of NO in a cytokine-induced and transcriptiondependent fashion.
23 FIGURE 2 HIF1α and HIF2α are post-translationally modified and differentially regulated by multiple mechanisms. a Multiple mechanisms differentially regulate hypoxia-inducible factor 1α (HIF1α) and HIF2α at the levels of transcription or mrna stability (shown in orange), mrna translation (shown in blue) and protein stability (shown in purple). In most cases, these regulatory events have opposite effects on HIF1α and HIF2α expression, or seem to be specific for only one HIFα isoform. b A summary of phosphorylations (P), acetylations (A) and hydroxylations (OH) of HIF1α and HIF2α by casein kinase 1 (CK1), arrest defective 1 (ARD1), prolyl hydroxylases (PHDs), factor inhibiting HIF (FIH), MAPK, sirtuin 1 (SIRT1), protein kinase D1 (PKD1) and ataxia-telangiectasia mutated (ATM). It should be noted that ARD1 acetylates HIF1α, whereas SIRT1 deacetylates both HIF1α and HIF2α. c Sequence alignment of HIF2α residues with a similar region of HIF1α; shaded residues are unique to HIF2α and allow the selective phosphorylation of HIF2α Thr324 by PKD1. BAF57, BRG1- associated factor 57; bhlh, basic helix-loop-helix; CHIP, carboxyl terminus of HSP70-interaction protein; HAF, HIF-associated factor; HSP70, heat shock protein 70; IFNγ, interferon-γ; IL-4, interleukin-4; IREBP1, iron response element binding protein 1; mtorc, mtor complex; ODD, O 2 -dependent degradation domain; PAS, PER ARNT SIM; TAD, transactivation domain.
24 Prolyl hydroxydase (PHD) Non-heme iron protein. The hypoxia mimetic CoCl2 Co2+ substitutes with Fe2+, resulting in no activity of PHD Biochem. J. 405, 1 (2007) Oxygen-dependent regulation of mitochondria respiration by hypoxia-inducible factor 1
25 FIGURE 3 Differential regulation of HIF1α and HIF2α by SIRT1. High levels of NAD + activate sirtuin 1 (SIRT1), which results in decreased hypoxia-inducible factor 1α (HIF1α) transcriptional activity and enhanced HIF2α-mediated stimulation of target genes, including erythropoietin. Sirtuins, a family of redox-sensitive, NAD + -dependent deacetylases and/or ADPribosyltransferases. Mammalian cells express a family of sirtuins (SIRT1 7) that regulate complex changes in gene expression, metabolism and the cellular redox status; they have also been implicated in controlling longevity, although this idea remains highly controversial.
26 IGURE 4 Distinct effects of HIF1α and HIF2α on MYC complex formation and promoter occupancy. Hypoxic cells that exclusively express hypoxia-inducible factor 1α (HIF1α) exhibit decreased MYC activity owing to diminished association of MYC with MAX and SP1, and reduced stability of MYC. HIF1α also induces the expression of MAX interactor 1 (MXI1), which inhibits MYC target gene expression (not shown). Cells expressing HIF2α exhibit increased MYC complex formation and target gene activation, although the mechanisms involved are not fully understood. MYC, a bhlh leucine zipper (LZ) transcription factor that is overexpressed in >40% of human cancers. MYC controls the G1/S cell cycle transition by forming heterodimers with a related protein MAX. This heterodimer binds to conserved E-box sequences (CTCGAG), thus promoting the expression of genes such as cyclin D2 (CCND2), E2F1 and ornithine decarboxylase 1 (ODC1).
27 Prolyl hydroxydase (PHD) Non-heme iron protein. The hypoxia mimetic CoCl2 Co2+ substitutes with Fe2+, resulting in no activity of PHD Physiol. Rev. 89, 481 (2009) Hypoxia inducible factor (HIF)-1α stabilization in normoxia vs. HIF-1α degradation under hypoxia. Top: prolyl hydroxylase (PHD) in the presence of O 2 hydroxylates HIF-1α, which can then bind to von Hippel Lindau protein (pvhl). This event promotes the polyubiquitination of HIF-1α followed by 26-S-proteasomal degradation. Bottom: the lack of oxygen prevents the hydroxylation of HIF-1α by PHD, leading to its stabilization. HIF-1α can then migrate to the nucleus and associate with HIF- 1β and the cofactor p300/cbp. The HIF-1 complex binds to and induces the transcription of genes containing hypoxia-responsive elements (HRE) with core sequence 5 -ACGTG-3 in their promoter region.
28 Figure 3. HIF-1a regulation by proline hydroxylation. (a) In normoxia, hypoxiainducible factor (HIF)-1a is hydroxylated by proline hydroxylases (PHD1, 2 and 3) in the presence of O2, Fe2+, 2- oxoglutarate (2-OG) and ascorbate. Hydroxylated HIF-1a (OH) is recognised by pvhl (the product of the von Hippel Lindau tumour suppressor gene), which, together with a multisubunit ubiquitin ligase complex, tags HIF-1a with polyubiquitin; this allows recognition by the proteasome and subsequent degradation. Acetylation of HIF-1a (OAc) also promotes pvhl binding. (b) In response to hypoxia, proline hydroxylation is inhibited. VHL is no longer able to bind and target HIF-1a for proteasomal degradation, which leads to HIF-1a accumulation and translocation to the nucleus. There, HIF-1a dimerises with HIF-1b, binds to hypoxia-response elements (HREs) within the promoters of target genes and recruits transcriptional coactivators such as p300/cbp for full transcriptional activity. A range of cell functions are regulated by the target genes, as indicated. Abbreviation: CBP, CREBbinding protein; Ub, ubiquitin.
29 Prolyl hydroxydase (PHD) Non-heme iron protein. The hypoxia mimetic CoCl2 Co2+ substitutes with Fe2+, resulting in no activity of PHD Cell Death & Differentiation 15, 621 (2008) Regulation of HIF-1 [alpha] protein by prolyl hydroxylation and proteasomal degradation. There are three hydroxylation sites in the HIF-1 [alpha] subunit: two prolyl residues in the oxygen-dependent degradation domain (ODDD) and one asparaginyl residue in the C-terminal transactivation domain (C-TAD). In the presence of oxygen, prolyl hydroxylation is catalyzed by the Fe(II)-, oxygen- and 2-oxoglutarate-dependent PHDs. The hydroxylated prolyl residues allow capture of HIF-1 [alpha] by the von Hippel [ndash] Lindau protein (pvhl), leading to ubiquitination and subsequent proteasomal degradation. Asparaginyl hydroxylation is catalyzed by an enzyme termed as factor-inhibiting HIF (FIH) at a single site in the C-TAD. This hydroxylation prevents cofactor recruitment. In the absence of hydroxylation due to hypoxia or PHD inhibition, HIF-1 [alpha] translocates to the nucleus, heterodimerizes with HIF-1 [beta] and binds to hypoxia-response elements (HREs) in the regulatory regions of target genes.
30 Nature Rev. Mol. Cell Biol. 5, 343 (2004) In the presence of oxygen, active hypoxia-inducible factor (HIF) hydroxylases that is, prolyl hydroxylase domains (PHDs) and factor inhibiting HIF (FIH) downregulate and inactivate HIF subunits. PHDs hydroxylate a prolyl residue in the amino- and the carboxy-terminal oxygen-dependent degradation domains (NODDD and CODDD, respectively; seefig. 2), which promotes von-hippel Lindau-tumour-suppressor (pvhl)-dependent proteolysis and results in the destruction of HIF subunits. FIH, on the other hand, hydroxylates an asparaginyl residue in the carboxy-terminal activation domain (CAD; see Fig. 2), which blocks p300 co-activator recruitment and results in the inactivation of HIF-subunit transcriptional activity. In hypoxia, HIF hydroxylases are inactive and these processes are suppressed, which allows the formation of a transcriptionally active complex.
31 Prolyl hydroxydase (PHD) Non-heme iron protein. The hypoxia mimetic CoCl2 Co2+ substitutes with Fe2+, resulting in no activity of PHD
32 Nature Medicine 16, 641 (2010) Shifting HIFs in osteroarthritis HIF1a and HIF2a have different functions in the cartilage. In the articular chondrocytes in the synovial joint, HIF-1α promotes homeostatic pathways, and HIF-2α promotes degradative pathways that foster osteoarthritis. The articular cartilage resides in hypoxic, avascular conditions within the synovial joint (left). Chondrocytes, cells of the articular cartilage, are affected by various forms of stress (biomechanical, inflammatory and aging), as well as the loss of synovial fluid boundary lubricants and the increase of certain factors released from subchondral bone and synovium. Four studies published in Nature Medicine have provided details for the emerging chondrocyte-centered osteoarthritis model depicted here.
33 New England J. Med. 360, 813 (2009)
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36 Prolyl hydroxydase (PHD) Non-heme iron protein. The hypoxia mimetic CoCl2 Co2+ substitutes with Fe2+, resulting in no activity of PHD Under aerobic conditions, the hydroxylation of both HIF-1α and HIF-2α by prolyl hydroxylases facilitates the binding of the pvhl E3 ligase complex (pvhl E3L) to HIF-1α and HIF-2α. This results in the poly-ubiquitination of HIF-1α and HIF-2α and their proteasomal degradation. Under hypoxic conditions, HIF- 1α and HIF-2α are stabilized and they enter the nucleus where they heterodimerize with HIF-1β and initiate downstream transcription. The presence of growth factors or specific extracellular stimuli promote the binding of HAF to HIF-1α by a new oxygen-independent mechanism recently described in our laboratory. This promotes the poly-ubiquitination and degradation of HIF- 1α while HIF-2α is allowed remain to activate downstream transcription.
37 Important pathways regulating HIF-1α translation. During normoxic conditions HIF1A mrna is translated by capdependent mechanisms (green background). Under certain cellular contexts, HIF-1α translation can be stimulated by growth factors (GFs), oncoproteins or cytokines that activate the PtdIns3K Akt mtor and the MAPK (RAS MEK ERK) pathways. Cellular stress such as hypoxia or the absence of nutrients can inhibit cap- dependent translation by two mechanisms. In the first, the ER kinase PERK phosphorylates eif2-α (2α) and prevents its assembly with the ternary complex (TC). In the second, TSC1- and/or TSC2-mediated mtor inhibition results in 4E-BP hypophosphorylation leading to its interaction with eif4e (4E) and blocking eif4f-complex formation and subsequent translation initiation. mtor inhibition also prevents S6K activation and the regulation of downstream translation components. It has been suggested that during hypoxia HIF-1α is also translated via a cap-independent mechanism (blue background), possibly through the IRES. The RNA-binding proteins PTB and HuR have been proposed to bind to HIF1A mrna at the 3 UTR and 5 UTR, respectively, and enhance HIF-1α translation in response to the hypoxia mimetic CoCl2. Abbreviations: PI3K, phosphatidylinositol 3-kinase.
38 The cellular response to O2 (oxygen) is a central process in animal cells and figures prominently in the pathophysiology of several diseases, including cancer, cardiovascular disease, and stroke. This process is coordinated by the HIF (Hypoxia- Inducible Factor) and its regulator, the pvhl (Von Hippel-Lindau tumor suppressor protein). HIF1 is a basic helix-loop-helix transcription factor that transactivates genes encoding proteins that participate in homeostatic responses to hypoxia. It induces expression of proteins controlling glucose metabolism, cell proliferation, and vascularization. Several genes involved in cellular differentiation are directly or indirectly regulated by hypoxia. These include Epo (Erythropoietin), LDHA (Lactate Dehydrogenase-A), ET1 (Endothelin-1), transferrin, transferrin receptor, VEGF (Vascular Endothelial Growth Factor), Flk1, FLT1 (Fms-Related Tyrosine Kinase-1), PDGF-Beta (Platelet-Derived Growth Factor-Beta), bfgf (basic Fibroblast Growth Factor), and others genes affecting glycolysis (Ref.1). HIF1 consists of a heterodimer of two basic helixloop-helix PAS (Per-ARNT-Sim) proteins, HIF1-Alpha, and HIF1-Beta. HIF1-Alpha accumulates under hypoxic conditions whereas HIF1-Beta is constitutively expressed. HIF1-Alpha is an important mediator of the hypoxic response of tumor cells and controls the up-regulation of a number of factors important for solid tumor expansion including the angiogenic factor VEGF. HIF1-Beta is the ARNT (Aryl hydrocarbon Receptor Nuclear Translocator), an essential component of the xenobiotic response (Ref.2).
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