The known target genes of the HIF-1 complex are involved in a wide spectrum of cellular events (Tables 9.1 and 9.2; Manalo et al., 2005), including angiogenesis-related genes (Berra et al., 2000; Conway et al., 2001; Eckhart et al., 1997; Josko et al., 2000); red blood cell metabolism-related genes (Lok and Ponka, 1999; Tacchini et al., 1999; Wang and Semenza, 1996;
Wanner et al., 2000); glucose metabolism-related genes (Chen et al., 2001; Gatenby and Gillies, 2004; Ullah et al., 2006;
Wenger, 2000; Wykoff et al., 2000); apoptosis-related genes (Carmeliet et al., 1998; Krick et al., 2005); and cell growth, proliferation, and differentiation-associated genes (Feldser et al., 1999; Krishnamachary et al., 2003). Vascular endothelial cell growth factor (VEGF) is one of the major angiogenesis-related target genes. Specifically, VEGF promotes prolifera- tion of endothelial cells and increases the number and density of blood vessels (Berra et al., 2000; Conway et al., 2001;
TABLE 9.1 Selected Genes Induced by Hypoxia-Inducible Factor-1
Gene Name Symbol Gene Name Symbol
Oxidoreductases
Prostaglandin I2 (prostacyclin) synthase PTGIS Inositol-1,4,5-triphosphate receptor, type 2 ITPR2 Prolyl hydroxylase domain-containing protein-3 EGLN3 AXL receptor tyrosine kinase AXL
N-myc downstream regulated gene-1 NDRG1 Leptin receptor LEPR
Prostaglandin-endoperoxide synthase-1 PTGS1 G-protein–coupled receptor kinase-5 GRK5 Prolyl hydroxylase domain-containing protein-2 EGLN1 Other signal transduction
Peptidylglycine α-amidating monooxygenase PAM Cyclin-dependent kinase inhibitor-1C (p57, Kip2)
CDKN1C
ERO1-like ERO1L Phospholipase C, γ2 PLCG2
Thioredoxin interacting protein TXNIP AMP-activated protein kinase family member 5 ARK5
Lysyl oxidase-like-2 LOXL2 PDZ domain containing-3 PDZK3
Collagens/modifying enzymes Ectonucleotide
pyrophosphatase/phosphodiesterase-1
ENPP1
Lysyl oxidase LOX SPRY domain-containing SOCS box
protein SSB-1
SSB1
Procollagen proline 4-hydroxylase, α2 P4HA2 Dual specificity phosphatase-6 DUSP6
Collagen, type 1, α2 COL1A2 Pellino homolog-2 PELI2
Procollagen lysine hydroxylase-2 PLOD2 Ribosomal protein S6 kinase, 90 kDa, poly- peptide-2
RPS6KA2
Collagen, type V, α1 COL5A1 Adenylate kinase-3 AK3
Procollagen lysine hydroxylase-2 PLOD2 Rho-related BTB domain containing-1 RHOBTB1
Collagen, type XVIII, α1 COL18A1 Calcium/calmodulin-dependent serine protein kinase
CASK
Collagen, type IX, α1 COL9A1 CK2 interacting protein-1 CKIP-1
Collagen, type IV, α1 COL4A1 Regulator of G-protein signalling-3 RGS3
Collagen, type IV, α2 COL4A2 LIM and senescent cell antigen-like domains-1 LIMS1
Procollagen lysine hydroxylase PLOD Ras association (RalGDS/AF-6) domain fam- ily-2
RASSF2
Protein tyrosine phosphatase, receptor type, F PTPRF Growth factors/cytokines
Angiopoietin-like-4 ANGPTL4 WAS protein family, member-2 WASF2
Stanniocalcin-1 STC1 Growth arrest and DNA-damage-inducible, β GADD45B
Copper and HIF Regulation of Gene Expression Chapter | 9 103
Gene Name Symbol Gene Name Symbol
Inhibin, β A (activin A, activin AB α) INHBA Cyclin G2 CCNG2
Vascular endothelial growth factor VEGF Cyclin-dependent kinase (CDC2-like)-11 CDK11
Inhibin, βE INHBE Triple functional domain (PTPRF interacting) TRIO
Stanniocalcin-2 STC2 Related RAS viral (r-ras) oncogene homolog RRAS
Endothelin-1 EDN1 Myocytic induction/differentiation originator MIDOR1
Growth differentiation factor-10 GDF10 FK506 binding protein-9, 63 kDa FKBP9
Insulin-like growth factor binding protein-3 IGFBP3 Transcription factors
Chemokine (C-X3-C motif) ligand-1 CX3CL1 V-maf oncogene homolog F MAFF
Vascular endothelial growth factor C VEGFC Peroxisome proliferative activated receptor, γ PPARG
Relaxin-1 RLN1 Transcription factor-8 TCF8
Platelet-derived growth factor B polypeptide PDGFB Jumonji domain containing-1 JMJD1
Placental growth factor PGF Zinc finger and BTB domain containing-1 ZBTB1
Adrenomedullin ADM Hypoxia-inducible factor-3, α subunit HIF3A
Receptors
cAMP responsive element binding protein-3-like 2 CREB3L2 SRY (sex-determining region Y)-box-4 SOX4 γ-Aminobutyric acid (GABA) A receptor, π GABRP Basic helix-loop-helix domain containing,
class B, 2
BHLHB2
Chemokine orphan receptor-1 CMKOR1 RelA-associated inhibitor RAI
Very-low–density lipoprotein receptor VLDLR Neuronal PAS domain protein-2 NPAS2
Protein tyrosine phosphatase, receptor type, R PTPRR Notch homolog-4 NOTCH4
Cubilin (intrinsic factor-cobalamin receptor) CUBN MAX interacting protein-1 MXI1
Chemokine (C-X-C motif) receptor-4 CXCR4 Myocyte enhancer factor-2A MEF2A
Adenosine A2a receptor ADORA2A Transducin-like enhancer of split 1 homolog TLE1
Natriuretic peptide receptor A/guanylate cyclase A NPR1 HIV-1 enhancer binding protein-2 HIVEP2
Insulin receptor INSR Transcription factor-7-like-1 TCF7L1
Protein tyrosine phosphatase, receptor type, B PTPRB Zinc finger protein-292 ZNF292
Activin A receptor, type IB ACVR1B Short stature homeobox-2 SHOX2
Protein tyrosine phosphatase, receptor type, R PTPRR Thioredoxin interacting protein TXNIP
Integral membrane protein-2A ITM2A Hairy and enhancer of split-1 HES1
Erythropoietin receptor EPOR Zinc fingers and homeoboxes-2 ZHX2
Cadherin-2, type 1, N-cadherin (neuronal) CDH2 B-cell CLL/lymphoma-6 (zinc finger pro- tein-51)
BCL6
TNF receptor superfamily, member 10b TNFRSF10B Sirtuin (sir2 homolog)-3 SIRT3
TNF receptor superfamily, member 14 TNFRSF14 MAD, mothers against decapentaplegic homolog-6
MADH6
Opsin 3 (encephalopsin, panopsin) OPN3 Nuclear factor of activated T cells-4 NFATC4
Leptin receptor LEPR
TABLE 9.1 Selected Genes Induced by Hypoxia-Inducible Factor-1—cont’d
TABLE 9.2 Selected Genes Repressed by Hypoxia-Inducible Factor-1
Gene Name Symbol Gene Name Symbol
CDC/cyclins RNA binding/metabolism
Cyclin E2 CCNE2 DEAD/H box polypeptide-11 DDX11
Cyclin E1 CCNE1 Small nuclear ribonucleoprotein polypeptide A′ SNRPA1
Cyclin F CCNF Heterogeneous nuclear ribonucleoprotein U HNRPU
Cell division cycle-2 CDC2 RNA, U3 small nucleolar interacting protein-2 RNU3IP2
Cell division cycle-6 CDC6 DEAD box polypeptide-18 DDX18
Cell division cycle-7 CDC7 Small nuclear ribonucleoprotein polypeptide A′ SNRPA1
MCM proteins POP7 (processing of precursor) homolog RPP20
Minichromosome maintenance deficient-4 MCM4 Small nuclear RNA activating complex-5 SNAPC5 Minichromosome maintenance deficient-2 MCM2 Heterogeneous nuclear ribonucleoprotein D-like HNRPDL
Minichromosome maintenance deficient-5 MCM5 DEAD box polypeptide-23 DDX23
Minichromosome maintenance deficient-6 MCM6 DEAH (Asp-Glu-Ala-his) box polypeptide-35 DHX35 Minichromosome maintenance deficient-10 MCM10 Splicing factor, arginine/serine-rich-2 SFRS2 Minichromosome maintenance deficient-3 MCM3 Heterogeneous nuclear ribonucleoprotein D HNRPD
DNA/RNA polymerases DEAD box polypeptide-21 DDX21
Polymerase (RNA) III polypeptide K POLR3K Small nuclear ribonucleoprotein D1 polypeptide SNRPD1 Polymerase (RNA) II polypeptide L RNAPOL2 Small nuclear ribonucleoprotein D3 polypeptide SNRPD3
Polymerase (DNA directed), ε2 POLE2 Ribonuclease P1 RNASEP1
Polymerase (RNA) III (32kD) RPC32 Ribonuclease P (30 kDa) RPP30
Polymerase (DNA directed), δ2 POLD2 Ubiquitin/proteasome
Polymerase (DNA directed), γ POLG Proteasome activator subunit-3 PSME3
Replication factors Ubiquitin-conjugating enzyme E2S UBE2S
Chromatin assembly factor 1, subunit A CHAF1A Ubiquitin carboxyl-terminal hydrolase L5 UCHL5 DNA replication complex GINS protein PSF2 PFS2 Proteasome 26S subunit, non-ATPase, 11 PSMD11
DNA replication helicase 2-like DNA2L Proteasome activator subunit-4 PSME4
Replication factor C5 RFC5 Ubiquitin specific protease-39 USP39
Replication factor C (activator-1) 3 RFC3 Ubiquitin specific protease-1 USP1
Origin recognition complex, subunit 6-like ORC6L Transcription factors
Replication factor C (activator-1) 2 RFC2 Myeloid/lymphoid leukemia; translocated to, 10 MLLT10
Other cell cycle BRCA1 associated RING domain-1 BARD1
S-phase kinase-associated protein-2 SKP2 Breast cancer-1, early onset BRCA1
MAD2 mitotic arrest deficient-like-1 MAD2L1 ELK1, member of ETS oncogene family ELK1
Block of proliferation-1 BOP1 Transcription factor A, mitochondrial TFAM
ZW10 interactor ZWINT MYC-associated zinc finger protein MAZ
M-phase phosphoprotein-9 MPHOSPH9 Peroxisome proliferative activated receptor, δ PPARD
Nucleolar and coiled-body phosphoprotein-1 NOLC1 Retinoblastoma-1 RB1
Proliferation-associated-2G4 PA2G4 Thyroid hormone receptor interactor-13 TRIP13
Activator of S-phase kinase ASK Transcription factor 6-like 1 TF6M
Copper and HIF Regulation of Gene Expression Chapter | 9 105
Gene Name Symbol Gene Name Symbol
Protein regulator of cytokinesis-1 PRC1 Inhibitor of DNA binding-1 ID1
NIMA (never in mitosis a)-related kinase-4 NEK4 Ribosomal/mitochondrial biogenesis
Ribonucleotide metabolism Mitochondrial ribosomal protein S12 MRPS12
Ribonucleotide reductase M2 polypeptide RRM2 Ts translation elongation factor, mitochondrial TSFM
Dihydrofolate reductase DHFR Ribosomal RNA processing-4 RRP4
CTP synthase CTPS Ribosome biogenesis regulator homolog RRS1
Phosphoribosyl pyrophosphate synthetase-1 PRPS1 Ribosomal protein L39 RPL39
Uridine monophosphate synthetase UMPS Interleukin enhancer binding protein-3 ILF3
Dihydrofolate reductase DHFR Ribosomal RNA processing-4 RRP4
5-Aminoimidazole-4-carboxamide ribonucle- otide transformylase
ATIC Zinc finger protein-500 ZNF500
Poly(ADP-ribose) polymerase ADPRT Mitochondrial ribosomal protein L40 MRPL40
GTP-binding protein GTPBP4 Nucleolar protein (KKED repeat) NOL5A
ADP-ribosyltransferase (NAD+; poly(ADP- ribose) polymerase)-like-2
ADPRTL2 Mitofusin-2 MFN2
Ribonucleotide reductase M1 polypeptide RRM1 Mitochondrial ribosomal protein L46 MRPL46 TABLE 9.2 Selected Genes Repressed by Hypoxia-Inducible Factor-1—cont’d
Josko et al., 2000). In addition, local blood flow under pathophysiological conditions is controlled by modulation of vascu- lar tone through production of NO (inducible nitric oxide synthase), CO (heme oxygenase-1), endothelin-1, adrenomedulin, or activation of the α1β-adrenergic receptor. All of these events involve HIF-1 target genes (Eckhart et al., 1997; Hu et al., 1998; Lee et al., 1997; Melillo et al., 1995; Nguyen and Claycomb, 1999; Palmer et al., 1998; Wenger, 2002). The red blood cell metabolism-related genes include erythropoietin (Wang and Semenza, 1996; Wanner et al., 2000), ceruloplasmin (Lok and Ponka, 1999; Mukhopadhyay et al., 2000), and the transferrin receptor (Tacchini et al., 1999). Erythropoietin promotes differentiation of stem cells to red blood cells and their proliferation and maturation. Ceruloplasmin is required to oxidize ferrous iron to ferric iron. The transferrin receptor enables cellular uptake of diferric transferrin. Many genes involved in glucose uptake and glycolysis were also identified as HIF-1 target genes (Wenger, 2000), including glucose transporters GLUT1 and GLUT3, which mediate cellular glucose uptake (Chen et al., 2001); transmembrane carbonic anhydrases (Wykoff et al., 2000); lactate dehydrogenase A (Gatenby and Gillies, 2004); and the plasma membrane lactate transporter MCT4 (Ullah et al., 2006). HIF-responsive apoptosis-related genes include caspase-3 and cytochrome c (Carmeliet et al., 1998; Krick et al., 2005; Magnon et al., 2007). Cell growth, proliferation, and differentiation-associated genes targeted by the HIF-1 complex include fibroblast growth factor (FGF), transforming growth factor-α, insulin-like growth factor (IGF)- 2, and epidermal growth factor receptor (Feldser et al., 1999; Krishnamachary et al., 2003; Semenza, 2003).