KEGG   PATHWAY: hsa04066
Entry
hsa04066                    Pathway                                
Name
HIF-1 signaling pathway - Homo sapiens (human)
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
hsa04066  HIF-1 signaling pathway
hsa04066

Network
  Element
N00079  HIF-1 signaling pathway
Drug
D09926  Icrucumab (USAN/INN)
D10334  Rebastinib (USAN)
D10386  Cindunistat (USAN/INN)
D10395  Nesvacumab (USAN/INN)
D10399  Rebastinib Tosylate (USAN)
D10419  Cindunistat hydrochloride maleate (USAN)
D10464  Firtecan pegol (USAN/INN)
D10593  Roxadustat (JAN/USAN/INN)
D10874  Daprodustat (JAN/USAN/INN)
D11078  Vadadustat (JAN/USAN/INN)
D11273  Molidustat sodium (JAN/USAN)
D11452  Tomivosertib (USAN/INN)
D11481  Tomivosertib hydrochloride (USAN)
D11523  Enarodustat (JAN)
D11540  Razuprotafib (USAN)
D11812  Pabinafusp alfa (genetical recombination) (JAN)
D12122  Molidustat (USAN/INN)
D12394  Inobrodib (USAN)
D12509  Trontinemab (USAN/INN)
D12806  Tividenofusp alfa (USAN/INN)
D12924  Pocenbrodib (USAN/INN)
D12925  Pocenbrodib hydrochloride (USAN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
3569  IL6; interleukin 6 [KO:K05405]
3570  IL6R; interleukin 6 receptor [KO:K05055]
6774  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
7099  TLR4; toll like receptor 4 [KO:K10160]
3458  IFNG; interferon gamma [KO:K04687]
3459  IFNGR1; interferon gamma receptor 1 [KO:K05132]
3460  IFNGR2; interferon gamma receptor 2 [KO:K05133]
5970  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
4790  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
3630  INS; insulin [KO:K04526]
1950  EGF; epidermal growth factor [KO:K04357]
3479  IGF1; insulin like growth factor 1 [KO:K05459]
3643  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
1956  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
3480  IGF1R; insulin like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
2064  ERBB2; erb-b2 receptor tyrosine kinase 2 [KO:K05083] [EC:2.7.10.1]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
8569  MKNK1; MAPK interacting serine/threonine kinase 1 [KO:K04372] [EC:2.7.11.1]
2872  MKNK2; MAPK interacting serine/threonine kinase 2 [KO:K04372] [EC:2.7.11.1]
5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5295  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
5296  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
8503  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
110117499  P3R3URF-PIK3R3; P3R3URF-PIK3R3 readthrough [KO:K02649]
207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
2475  MTOR; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1]
1978  EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205]
1977  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
9470  EIF4E2; eukaryotic translation initiation factor 4E family member 2 [KO:K03259]
253314  EIF4E1B; eukaryotic translation initiation factor 4E family member 1B [KO:K03259]
6198  RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:2.7.11.1]
6199  RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:2.7.11.1]
6194  RPS6; ribosomal protein S6 [KO:K02991]
3091  HIF1A; hypoxia inducible factor 1 subunit alpha [KO:K08268]
7428  VHL; von Hippel-Lindau tumor suppressor [KO:K03871]
9978  RBX1; ring-box 1 [KO:K03868] [EC:2.3.2.32]
6921  ELOC; elongin C [KO:K03872]
6923  ELOB; elongin B [KO:K03873]
8453  CUL2; cullin 2 [KO:K03870]
54583  EGLN1; egl-9 family hypoxia inducible factor 1 [KO:K09592] [EC:1.14.11.29]
112399  EGLN3; egl-9 family hypoxia inducible factor 3 [KO:K09592] [EC:1.14.11.29]
112398  EGLN2; egl-9 family hypoxia inducible factor 2 [KO:K09592] [EC:1.14.11.29]
405  ARNT; aryl hydrocarbon receptor nuclear translocator [KO:K09097]
1387  CREBBP; CREB binding protein [KO:K04498] [EC:2.3.1.48]
2033  EP300; E1A binding protein p300 [KO:K04498] [EC:2.3.1.48]
1536  CYBB; cytochrome b-245 beta chain [KO:K21421] [EC:1.-.-.-]
5335  PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11]
5336  PLCG2; phospholipase C gamma 2 [KO:K05859] [EC:3.1.4.11]
5578  PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
5579  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
5582  PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
815  CAMK2A; calcium/calmodulin dependent protein kinase II alpha [KO:K04515] [EC:2.7.11.17]
817  CAMK2D; calcium/calmodulin dependent protein kinase II delta [KO:K04515] [EC:2.7.11.17]
816  CAMK2B; calcium/calmodulin dependent protein kinase II beta [KO:K04515] [EC:2.7.11.17]
818  CAMK2G; calcium/calmodulin dependent protein kinase II gamma [KO:K04515] [EC:2.7.11.17]
7076  TIMP1; TIMP metallopeptidase inhibitor 1 [KO:K16451]
4055  LTBR; lymphotoxin beta receptor [KO:K03159]
2056  EPO; erythropoietin [KO:K05437]
7018  TF; transferrin [KO:K14736]
7037  TFRC; transferrin receptor [KO:K06503]
7422  VEGFA; vascular endothelial growth factor A [KO:K05448]
2321  FLT1; fms related receptor tyrosine kinase 1 [KO:K05096] [EC:2.7.10.1]
5054  SERPINE1; serpin family E member 1 [KO:K03982]
284  ANGPT1; angiopoietin 1 [KO:K05465]
285  ANGPT2; angiopoietin 2 [KO:K05466]
51378  ANGPT4; angiopoietin 4 [KO:K05467]
7010  TEK; TEK receptor tyrosine kinase [KO:K05121] [EC:2.7.10.1]
1906  EDN1; endothelin 1 [KO:K16366]
4843  NOS2; nitric oxide synthase 2 [KO:K13241] [EC:1.14.13.39]
4846  NOS3; nitric oxide synthase 3 [KO:K13242] [EC:1.14.13.39]
3162  HMOX1; heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]
4878  NPPA; natriuretic peptide A [KO:K12334]
6513  SLC2A1; solute carrier family 2 member 1 [KO:K07299]
5163  PDK1; pyruvate dehydrogenase kinase 1 [KO:K12077] [EC:2.7.11.2]
3101  HK3; hexokinase 3 [KO:K00844] [EC:2.7.1.1]
3098  HK1; hexokinase 1 [KO:K00844] [EC:2.7.1.1]
3099  HK2; hexokinase 2 [KO:K00844] [EC:2.7.1.1]
80201  HKDC1; hexokinase domain containing 1 [KO:K00844] [EC:2.7.1.1]
5213  PFKM; phosphofructokinase, muscle [KO:K00850] [EC:2.7.1.11]
5214  PFKP; phosphofructokinase, platelet [KO:K00850] [EC:2.7.1.11]
5211  PFKL; phosphofructokinase, liver type [KO:K00850] [EC:2.7.1.11]
2597  GAPDH; glyceraldehyde-3-phosphate dehydrogenase [KO:K00134] [EC:1.2.1.12]
230  ALDOC; aldolase, fructose-bisphosphate C [KO:K01623] [EC:4.1.2.13]
226  ALDOA; aldolase, fructose-bisphosphate A [KO:K01623] [EC:4.1.2.13]
229  ALDOB; aldolase, fructose-bisphosphate B [KO:K01623] [EC:4.1.2.13]
2027  ENO3; enolase 3 [KO:K01689] [EC:4.2.1.11]
2026  ENO2; enolase 2 [KO:K01689] [EC:4.2.1.11]
2023  ENO1; enolase 1 [KO:K01689] [EC:4.2.1.11]
5232  PGK2; phosphoglycerate kinase 2 [KO:K00927] [EC:2.7.2.3]
5230  PGK1; phosphoglycerate kinase 1 [KO:K00927] [EC:2.7.2.3]
5209  PFKFB3; 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 [KO:K01103] [EC:2.7.1.105 3.1.3.46]
160287  LDHAL6A; lactate dehydrogenase A like 6A [KO:K00016] [EC:1.1.1.27]
92483  LDHAL6B; lactate dehydrogenase A like 6B [KO:K00016] [EC:1.1.1.27]
3939  LDHA; lactate dehydrogenase A [KO:K00016] [EC:1.1.1.27]
3945  LDHB; lactate dehydrogenase B [KO:K00016] [EC:1.1.1.27]
3948  LDHC; lactate dehydrogenase C [KO:K00016] [EC:1.1.1.27]
596  BCL2; BCL2 apoptosis regulator [KO:K02161]
1026  CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625]
1027  CDKN1B; cyclin dependent kinase inhibitor 1B [KO:K06624]
5161  PDHA2; pyruvate dehydrogenase E1 subunit alpha 2 [KO:K00161] [EC:1.2.4.1]
5160  PDHA1; pyruvate dehydrogenase E1 subunit alpha 1 [KO:K00161] [EC:1.2.4.1]
5162  PDHB; pyruvate dehydrogenase E1 subunit beta [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
hsa00020  Citrate cycle (TCA cycle)
hsa04010  MAPK signaling pathway
hsa04020  Calcium signaling pathway
hsa04120  Ubiquitin mediated proteolysis
hsa04150  mTOR signaling pathway
hsa04151  PI3K-Akt signaling pathway
hsa04370  VEGF signaling pathway
KO pathway
ko04066   
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