KEGG   PATHWAY: ko04066Help
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
BRITE hierarchy
Pathway map
HIF-1 signaling pathway
ko04066

All organismsOrtholog table
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 [EC:2.7.1.153]
K02649  
phosphoinositide-3-kinase, regulatory subunit
K04456  
RAC serine/threonine-protein kinase [EC:2.7.11.1]
K07203  
FKBP12-rapamycin complex-associated protein
K07205  
eukaryotic translation initiation factor 4E binding protein 1
K03259  
translation initiation factor 4E
K04688  
p70 ribosomal S6 kinase [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  
RING-box protein 1
K03872  
transcription elongation factor B, polypeptide 1
K03873  
transcription elongation factor B, polypeptide 2
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]
K08008  
NADPH oxidase
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 [EC:2.7.11.13]
K04515  
calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:2.7.11.17]
K16451  
metallopeptidase 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]
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]
K00134  
glyceraldehyde 3-phosphate dehydrogenase [EC:1.2.1.12]
K01689  
enolase [EC:4.2.1.11]
K01103  
6-phosphofructo-2-kinase / fructose-2,6-bisphosphatase [EC:3.1.3.46 2.7.1.105]
K02161  
apoptosis regulator BCL-2
K06625  
cyclin-dependent kinase inhibitor 1A
K06624  
cyclin-dependent kinase inhibitor 1B
K00161  
pyruvate dehydrogenase E1 component alpha subunit [EC:1.2.4.1]
K00162  
pyruvate dehydrogenase E1 component beta subunit [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  
O2.-
C01245  
D-myo-Inositol 1,4,5-trisphosphate
C14818  
Fe2+
Reference
  Authors
Semenza GL
  Title
Oxygen homeostasis.
  Journal
Wiley Interdiscip Rev Syst Biol Med 2:336-61 (2010)
Reference
  Authors
Mole DR, Ratcliffe PJ
  Title
Cellular oxygen sensing in health and disease.
  Journal
Pediatr Nephrol 23:681-94 (2008)
Reference
  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)
Reference
  Authors
Majmundar AJ, Wong WJ, Simon MC
  Title
Hypoxia-inducible factors and the response to hypoxic stress.
  Journal
Mol Cell 40:294-309 (2010)
Reference
  Authors
Greer SN, Metcalf JL, Wang Y, Ohh M
  Title
The updated biology of hypoxia-inducible factor.
  Journal
EMBO J 31:2448-60 (2012)
Reference
  Authors
Zagorska A, Dulak J
  Title
HIF-1: the knowns and unknowns of hypoxia sensing.
  Journal
Acta Biochim Pol 51:563-85 (2004)
Reference
  Authors
Semenza GL
  Title
Regulation of oxygen homeostasis by hypoxia-inducible factor 1.
  Journal
Physiology (Bethesda) 24:97-106 (2009)
Reference
  Authors
Wenger RH, Stiehl DP, Camenisch G
  Title
Integration of oxygen signaling at the consensus HRE.
  Journal
Sci STKE 2005:re12 (2005)
Reference
  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)
Reference
  Authors
Weidemann A, Johnson RS
  Title
Biology of HIF-1alpha.
  Journal
Cell Death Differ 15:621-7 (2008)
Reference
  Authors
Harris AL
  Title
Hypoxia--a key regulatory factor in tumour growth.
  Journal
Nat Rev Cancer 2:38-47 (2002)
Reference
  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)
Reference
  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)
Reference
  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)
Reference
  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)

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