KEGG   PATHWAY: oas04066
Entry
oas04066                    Pathway                                
Name
HIF-1 signaling pathway - Ovis aries (sheep)
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
oas04066  HIF-1 signaling pathway
oas04066

Organism
Ovis aries (sheep) [GN:oas]
Gene
443406  IL6; interleukin-6 precursor [KO:K05405]
101103369  IL6R; interleukin-6 receptor subunit alpha isoform X1 [KO:K05055]
100294659  STAT3; signal transducer and activator of transcription 3 isoform X10 [KO:K04692]
554263  TLR4; toll-like receptor 4 precursor [KO:K10160]
443396  IFNG; interferon gamma precursor [KO:K04687]
101112907  IFNGR1; interferon gamma receptor 1 isoform X2 [KO:K05132]
101122484  IFNGR2; interferon gamma receptor 2 isoform X2 [KO:K05133]
101102191  RELA; transcription factor p65 [KO:K04735]
101108228  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X2 [KO:K02580]
114110121  INS; insulin [KO:K04526]
443318  IGF1; insulin-like growth factor I precursor [KO:K05459]
443431  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
780479  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
443515  IGF1R; insulin-like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
780519  ERBB2; receptor tyrosine-protein kinase erbB-2 isoform X2 [KO:K05083] [EC:2.7.10.1]
101123635  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X2 [KO:K04368] [EC:2.7.12.2]
101113846  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
101115485  MAPK1; mitogen-activated protein kinase 1 isoform X2 [KO:K04371] [EC:2.7.11.24]
101123008  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
101104102  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
101122519  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X1 [KO:K04372] [EC:2.7.11.1]
101109759  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
101110015  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101117348  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X3 [KO:K00922] [EC:2.7.1.153]
101123247  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101111546  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X2 [KO:K02649]
101121455  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X3 [KO:K02649]
101118462  AKT3; RAC-gamma serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
101119242  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100294652  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100271659  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
101111426  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 isoform X6 [KO:K07205]
101103218  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X2 [KO:K03259]
101112730  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
101106260  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
101107371  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
101109574  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
100037665  RPS6; small ribosomal subunit protein eS6 [KO:K02991]
106991797  small ribosomal subunit protein eS6-like [KO:K02991]
101105666  small ribosomal subunit protein eS6-like [KO:K02991]
101116863  small ribosomal subunit protein eS6-like [KO:K02991]
105602663  small ribosomal subunit protein eS6-like [KO:K02991]
114116599  small ribosomal subunit protein eS6-like [KO:K02991]
114118688  small ribosomal subunit protein eS6-like [KO:K02991]
121819715  small ribosomal subunit protein eS6-like [KO:K02991]
443519  HIF1A; hypoxia-inducible factor 1-alpha isoform X1 [KO:K08268]
101122897  VHL; von Hippel-Lindau disease tumor suppressor [KO:K03871]
101109871  RBX1; E3 ubiquitin-protein ligase RBX1 isoform X2 [KO:K03868] [EC:2.3.2.32]
101107798  ELOC; elongin-C [KO:K03872]
105616454  elongin-C [KO:K03872]
101105146  elongin-C-like [KO:K03872]
101120329  elongin-C-like [KO:K03872]
101118496  ELOB; elongin-B [KO:K03873]
101110527  elongin-B [KO:K03873]
101122714  CUL2; cullin-2 isoform X1 [KO:K03870]
101114163  EGLN1; egl nine homolog 1 isoform X1 [KO:K09592] [EC:1.14.11.29]
101120517  EGLN2; prolyl hydroxylase EGLN2 [KO:K09592] [EC:1.14.11.29]
101117367  EGLN3; prolyl hydroxylase EGLN3 isoform X2 [KO:K09592] [EC:1.14.11.29]
443285  ARNT; aryl hydrocarbon receptor nuclear translocator [KO:K09097]
101110136  EP300; histone acetyltransferase p300 isoform X1 [KO:K04498] [EC:2.3.1.48]
101123600  CREBBP; CREB-binding protein [KO:K04498] [EC:2.3.1.48]
100036757  CYBB; cytochrome b-245 heavy chain [KO:K21421] [EC:1.-.-.-]
101103341  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
101122126  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 isoform X1 [KO:K05859] [EC:3.1.4.11]
101110074  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
101118410  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
101116423  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
443453  CAMK2A; calcium/calmodulin-dependent protein kinase type II subunit alpha isoform X1 [KO:K04515] [EC:2.7.11.17]
101113850  CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X4 [KO:K04515] [EC:2.7.11.17]
101108884  CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X10 [KO:K04515] [EC:2.7.11.17]
101118870  CAMK2B; calcium/calmodulin-dependent protein kinase type II subunit beta isoform X1 [KO:K04515] [EC:2.7.11.17]
443331  TIMP1; metalloproteinase inhibitor 1 precursor [KO:K16451]
101114509  LTBR; tumor necrosis factor receptor superfamily member 3 [KO:K03159]
443302  EPO; erythropoietin precursor [KO:K05437]
443000  TF; LOW QUALITY PROTEIN: serotransferrin [KO:K14736]
101117129  inhibitor of carbonic anhydrase-like isoform X2 [KO:K14736]
100885768  TFRC; transferrin receptor protein 1 isoform X2 [KO:K06503]
443103  VEGFA; vascular endothelial growth factor A precursor [KO:K05448]
443088  FLT1; vascular endothelial growth factor receptor 1 isoform X1 [KO:K05096] [EC:2.7.10.1]
100381267  SERPINE1; plasminogen activator inhibitor 1 precursor [KO:K03982]
497271  ANGPT1; angiopoietin-1 [KO:K05465]
497273  ANGPT2; angiopoietin-2 [KO:K05466]
101107460  ANGPT4; angiopoietin-4 [KO:K05467]
497272  TEK; angiopoietin-1 receptor isoform X4 [KO:K05121] [EC:2.7.10.1]
443498  EDN1; endothelin-1 precursor [KO:K16366]
443078  NOS2; nitric oxide synthase, inducible isoform X2 [KO:K13241] [EC:1.14.13.39]
443077  NOS3; nitric oxide synthase 3 isoform X1 [KO:K13242] [EC:1.14.13.39]
101120910  HMOX1; heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]
100294648  NPPA; natriuretic peptides A precursor [KO:K12334]
443461  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
101113205  PDK1; pyruvate dehydrogenase (acetyl-transferring) kinase isozyme 1, mitochondrial isoform X2 [KO:K12077] [EC:2.7.11.2]
101107841  HKDC1; hexokinase HKDC1 isoform X2 [KO:K00844] [EC:2.7.1.1]
100036759  HK1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
101107690  HK2; hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
101119209  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
101108592  PFKP; ATP-dependent 6-phosphofructokinase, platelet type isoform X1 [KO:K00850] [EC:2.7.1.11]
443164  PFKL; ATP-dependent 6-phosphofructokinase, liver type [KO:K00850] [EC:2.7.1.11]
443489  PFKM; ATP-dependent 6-phosphofructokinase, muscle type isoform X2 [KO:K00850] [EC:2.7.1.11]
443005  GAPDH; glyceraldehyde-3-phosphate dehydrogenase [KO:K00134] [EC:1.2.1.12]
114110581  glyceraldehyde-3-phosphate dehydrogenase-like [KO:K00134] [EC:1.2.1.12]
101105422  ALDOC; fructose-bisphosphate aldolase C [KO:K01623] [EC:4.1.2.13]
443085  ALDOA; fructose-bisphosphate aldolase A isoform X2 [KO:K01623] [EC:4.1.2.13]
443440  ALDOB; fructose-bisphosphate aldolase B [KO:K01623] [EC:4.1.2.13]
443086  ENO3; beta-enolase isoform X1 [KO:K01689] [EC:4.2.1.11]
101118119  ENO1; alpha-enolase [KO:K01689] [EC:4.2.1.11]
101109164  ENO2; gamma-enolase [KO:K01689] [EC:4.2.1.11]
100216440  PGK1; phosphoglycerate kinase 1 [KO:K00927] [EC:2.7.2.3]
101102678  PGK2; phosphoglycerate kinase 2 [KO:K00927] [EC:2.7.2.3]
101107621  PFKFB3; 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 isoform X1 [KO:K01103] [EC:2.7.1.105 3.1.3.46]
101118315  L-lactate dehydrogenase C chain isoform X2 [KO:K00016] [EC:1.1.1.27]
443089  LDHA; L-lactate dehydrogenase A chain isoform X1 [KO:K00016] [EC:1.1.1.27]
101118261  LDHB; L-lactate dehydrogenase B chain [KO:K00016] [EC:1.1.1.27]
101107202  LDHAL6B; L-lactate dehydrogenase A-like 6B [KO:K00016] [EC:1.1.1.27]
114118359  L-lactate dehydrogenase B chain-like [KO:K00016] [EC:1.1.1.27]
101119602  BCL2; apoptosis regulator Bcl-2 isoform X1 [KO:K02161]
100302083  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
100127219  CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624]
101103029  pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial-like [KO:K00161] [EC:1.2.4.1]
101110118  PDHA1; pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial [KO:K00161] [EC:1.2.4.1]
101113677  PDHA2; pyruvate dehydrogenase E1 component subunit alpha, testis-specific form, mitochondrial isoform X1 [KO:K00161] [EC:1.2.4.1]
101121975  PDHB; pyruvate dehydrogenase E1 component subunit beta, mitochondrial [KO:K00162] [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
Related
pathway
oas00020  Citrate cycle (TCA cycle)
oas04010  MAPK signaling pathway
oas04020  Calcium signaling pathway
oas04120  Ubiquitin mediated proteolysis
oas04150  mTOR signaling pathway
oas04151  PI3K-Akt signaling pathway
oas04370  VEGF signaling pathway
KO pathway
ko04066   
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