ENTRY ko04066 Pathway NAME HIF-1 signaling pathway DESCRIPTION Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis. It consists of two subunits: an inducibly-expressed HIF-1alpha subunit and a constitutively-expressed HIF-1beta subunit. Under normoxia, HIF-1 alpha undergoes hydroxylation at specific prolyl residues which leads to an immediate ubiquitination and subsequent proteasomal degradation of the subunit. In contrast, under hypoxia, HIF-1 alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Eventually, HIF-1 acts as a master regulator of numerous hypoxia-inducible genes under hypoxic conditions. The target genes of HIF-1 encode proteins that increase O2 delivery and mediate adaptive responses to O2 deprivation. Despite its name, HIF-1 is induced not only in response to reduced oxygen availability but also by other stimulants, such as nitric oxide, or various growth factors. CLASS Environmental Information Processing; Signal transduction PATHWAY_MAP ko04066 HIF-1 signaling pathway ORTHOLOGY K05405 interleukin 6 K05055 interleukin 6 receptor K04692 signal transducer and activator of transcription 3 K10160 toll-like receptor 4 K04687 interferon gamma K05132 interferon gamma receptor 1 K05133 interferon gamma receptor 2 K04735 transcription factor p65 K02580 nuclear factor NF-kappa-B p105 subunit K04526 insulin K04357 epidermal growth factor K05459 insulin-like growth factor 1 K04527 insulin receptor [EC:2.7.10.1] K04361 epidermal growth factor receptor [EC:2.7.10.1] K05087 insulin-like growth factor 1 receptor [EC:2.7.10.1] K05083 receptor tyrosine-protein kinase erbB-2 [EC:2.7.10.1] K04368 mitogen-activated protein kinase kinase 1 [EC:2.7.12.2] K04369 mitogen-activated protein kinase kinase 2 [EC:2.7.12.2] K04371 mitogen-activated protein kinase 1/3 [EC:2.7.11.24] K04372 MAP kinase interacting serine/threonine kinase [EC:2.7.11.1] K00922 phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153] K02649 phosphoinositide-3-kinase regulatory subunit alpha/beta/delta K04456 RAC serine/threonine-protein kinase [EC:2.7.11.1] K07203 serine/threonine-protein kinase mTOR [EC:2.7.11.1] K07205 eukaryotic translation initiation factor 4E binding protein 1 K03259 translation initiation factor 4E K04688 ribosomal protein S6 kinase beta [EC:2.7.11.1] K02991 small subunit ribosomal protein S6e K08268 hypoxia-inducible factor 1 alpha K03871 von Hippel-Lindau disease tumor supressor K03868 E3 ubiquitin-protein ligase RBX1 [EC:2.3.2.32] K03872 elongin-C K03873 elongin-B K03870 cullin 2 K09592 hypoxia-inducible factor prolyl hydroxylase [EC:1.14.11.29] K09097 aryl hydrocarbon receptor nuclear translocator K04498 E1A/CREB-binding protein [EC:2.3.1.48] K21421 NADPH oxidase 2 [EC:1.-.-.-] K01116 phosphatidylinositol phospholipase C, gamma-1 [EC:3.1.4.11] K05859 phosphatidylinositol phospholipase C, gamma-2 [EC:3.1.4.11] K02677 classical protein kinase C alpha type [EC:2.7.11.13] K19662 classical protein kinase C beta type [EC:2.7.11.13] K19663 classical protein kinase C gamma type [EC:2.7.11.13] K04515 calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:2.7.11.17] K16451 metalloproteinase inhibitor 1 K03159 lymphotoxin beta receptor TNFR superfamily member 3 K05437 erythropoietin K14736 transferrin K06503 transferrin receptor K05448 vascular endothelial growth factor A K05096 FMS-like tyrosine kinase 1 [EC:2.7.10.1] K03982 plasminogen activator inhibitor 1 K05465 angiopoietin 1 K05466 angiopoietin 2 K05467 angiopoietin 4 K05121 endothelial-specific receptor tyrosine kinase [EC:2.7.10.1] K16366 endothelin-1 K13241 nitric-oxide synthase, inducible [EC:1.14.13.39] K13242 nitric-oxide synthase, endothelial [EC:1.14.13.39] K00510 heme oxygenase 1 [EC:1.14.14.18] K12334 natriuretic peptide A K07299 MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 1 K12077 pyruvate dehydrogenase kinase isoform 1 [EC:2.7.11.2] K00844 hexokinase [EC:2.7.1.1] K00850 6-phosphofructokinase 1 [EC:2.7.1.11] K00134 glyceraldehyde 3-phosphate dehydrogenase (phosphorylating) [EC:1.2.1.12] K01623 fructose-bisphosphate aldolase, class I [EC:4.1.2.13] K01689 enolase 1/2/3 [EC:4.2.1.11] K00927 phosphoglycerate kinase [EC:2.7.2.3] K01103 6-phosphofructo-2-kinase / fructose-2,6-biphosphatase 3 [EC:2.7.1.105 3.1.3.46] K00016 L-lactate dehydrogenase [EC:1.1.1.27] K02161 apoptosis regulator Bcl-2 K06625 cyclin-dependent kinase inhibitor 1A K06624 cyclin-dependent kinase inhibitor 1B K00161 pyruvate dehydrogenase E1 component subunit alpha [EC:1.2.4.1] K00162 pyruvate dehydrogenase E1 component subunit beta [EC:1.2.4.1] COMPOUND C00002 ATP C00007 Oxygen C00022 Pyruvate C00024 Acetyl-CoA C00026 2-Oxoglutarate C00031 D-Glucose C00072 Ascorbate C00076 Calcium cation C00165 Diacylglycerol C00186 (S)-Lactate C00338 Lipopolysaccharide C00533 Nitric oxide C00704 Superoxide C01245 D-myo-Inositol 1,4,5-trisphosphate C14818 Fe2+ REFERENCE PMID:20836033 AUTHORS Semenza GL TITLE Oxygen homeostasis. JOURNAL Wiley Interdiscip Rev Syst Biol Med 2:336-61 (2010) DOI:10.1002/wsbm.69 REFERENCE PMID:17955264 AUTHORS Mole DR, Ratcliffe PJ TITLE Cellular oxygen sensing in health and disease. JOURNAL Pediatr Nephrol 23:681-94 (2008) DOI:10.1007/s00467-007-0632-x REFERENCE PMID:18498744 AUTHORS Kaelin WG Jr, Ratcliffe PJ TITLE Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. JOURNAL Mol Cell 30:393-402 (2008) DOI:10.1016/j.molcel.2008.04.009 REFERENCE PMID:22205687 AUTHORS Palazon A, Aragones J, Morales-Kastresana A, de Landazuri MO, Melero I TITLE Molecular pathways: hypoxia response in immune cells fighting or promoting cancer. JOURNAL Clin Cancer Res 18:1207-13 (2012) DOI:10.1158/1078-0432.CCR-11-1591 REFERENCE PMID:20965423 AUTHORS Majmundar AJ, Wong WJ, Simon MC TITLE Hypoxia-inducible factors and the response to hypoxic stress. JOURNAL Mol Cell 40:294-309 (2010) DOI:10.1016/j.molcel.2010.09.022 REFERENCE PMID:22562152 AUTHORS Greer SN, Metcalf JL, Wang Y, Ohh M TITLE The updated biology of hypoxia-inducible factor. JOURNAL EMBO J 31:2448-60 (2012) DOI:10.1038/emboj.2012.125 REFERENCE PMID:15448722 AUTHORS Zagorska A, Dulak J TITLE HIF-1: the knowns and unknowns of hypoxia sensing. JOURNAL Acta Biochim Pol 51:563-85 (2004) REFERENCE PMID:19364912 AUTHORS Semenza GL TITLE Regulation of oxygen homeostasis by hypoxia-inducible factor 1. JOURNAL Physiology (Bethesda) 24:97-106 (2009) DOI:10.1152/physiol.00045.2008 REFERENCE PMID:16234508 AUTHORS Wenger RH, Stiehl DP, Camenisch G TITLE Integration of oxygen signaling at the consensus HRE. JOURNAL Sci STKE 2005:re12 (2005) DOI:10.1126/stke.3062005re12 REFERENCE PMID:15031665 AUTHORS Lee JW, Bae SH, Jeong JW, Kim SH, Kim KW TITLE Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. JOURNAL Exp Mol Med 36:1-12 (2004) DOI:10.1038/emm.2004.1 REFERENCE PMID:18259201 AUTHORS Weidemann A, Johnson RS TITLE Biology of HIF-1alpha. JOURNAL Cell Death Differ 15:621-7 (2008) DOI:10.1038/cdd.2008.12 REFERENCE PMID:11902584 AUTHORS Harris AL TITLE Hypoxia--a key regulatory factor in tumour growth. JOURNAL Nat Rev Cancer 2:38-47 (2002) DOI:10.1038/nrc704 REFERENCE PMID:19147540 AUTHORS Knaup KX, Jozefowski K, Schmidt R, Bernhardt WM, Weidemann A, Juergensen JS, Warnecke C, Eckardt KU, Wiesener MS TITLE Mutual regulation of hypoxia-inducible factor and mammalian target of rapamycin as a function of oxygen availability. JOURNAL Mol Cancer Res 7:88-98 (2009) DOI:10.1158/1541-7786.MCR-08-0288 REFERENCE PMID:18505681 AUTHORS Kaluz S, Kaluzova M, Stanbridge EJ TITLE Regulation of gene expression by hypoxia: integration of the HIF-transduced hypoxic signal at the hypoxia-responsive element. JOURNAL Clin Chim Acta 395:6-13 (2008) DOI:10.1016/j.cca.2008.05.002 REFERENCE PMID:20679415 AUTHORS Cadenas S, Aragones J, Landazuri MO TITLE Mitochondrial reprogramming through cardiac oxygen sensors in ischaemic heart disease. JOURNAL Cardiovasc Res 88:219-28 (2010) DOI:10.1093/cvr/cvq256 REFERENCE PMID:19861159 AUTHORS Berchner-Pfannschmidt U, Tug S, Kirsch M, Fandrey J TITLE Oxygen-sensing under the influence of nitric oxide. JOURNAL Cell Signal 22:349-56 (2010) DOI:10.1016/j.cellsig.2009.10.004 REL_PATHWAY ko00020 Citrate cycle (TCA cycle) ko04010 MAPK signaling pathway ko04020 Calcium signaling pathway ko04120 Ubiquitin mediated proteolysis ko04150 mTOR signaling pathway ko04151 PI3K-Akt signaling pathway ko04370 VEGF signaling pathway ///