KEGG   PATHWAY: ko04066Help
ko04066                     Pathway                                

HIF-1 signaling pathway
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.
Environmental Information Processing; Signal transduction
BRITE hierarchy
Pathway map
ko04066  HIF-1 signaling pathway

Ortholog table
H01457  Diabetic retinopathy
H01510  Malignant paraganglioma
H01529  Avascular necrosis of femoral head
H01709  Glucocorticoid-induced osteonecrosis
H02044  Cutaneous and mucosal venous malformation
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:]
K04361  epidermal growth factor receptor [EC:]
K05087  insulin-like growth factor 1 receptor [EC:]
K05083  receptor tyrosine-protein kinase erbB-2 [EC:]
K04368  mitogen-activated protein kinase kinase 1 [EC:]
K04369  mitogen-activated protein kinase kinase 2 [EC:]
K04371  mitogen-activated protein kinase 1/3 [EC:]
K04372  MAP kinase interacting serine/threonine kinase [EC:]
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:]
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K04456  RAC serine/threonine-protein kinase [EC:]
K07203  serine/threonine-protein kinase mTOR [EC:]
K07205  eukaryotic translation initiation factor 4E binding protein 1
K03259  translation initiation factor 4E
K04688  ribosomal protein S6 kinase beta [EC:]
K02991  small subunit ribosomal protein S6e
K08268  hypoxia-inducible factor 1 alpha
K03871  von Hippel-Lindau disease tumor supressor
K03868  RING-box protein 1 [EC:]
K03872  transcription elongation factor B, polypeptide 1
K03873  transcription elongation factor B, polypeptide 2
K03870  cullin 2
K09592  hypoxia-inducible factor prolyl hydroxylase [EC:]
K09097  aryl hydrocarbon receptor nuclear translocator
K04498  E1A/CREB-binding protein [EC:]
K21421  NADPH oxidase 2 [EC:1.-.-.-]
K01116  phosphatidylinositol phospholipase C, gamma-1 [EC:]
K05859  phosphatidylinositol phospholipase C, gamma-2 [EC:]
K02677  classical protein kinase C alpha type [EC:]
K19662  classical protein kinase C beta type [EC:]
K19663  classical protein kinase C gamma type [EC:]
K04515  calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:]
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:]
K03982  plasminogen activator inhibitor 1
K05465  angiopoietin 1
K05466  angiopoietin 2
K05467  angiopoietin 4
K05121  endothelial-specific receptor tyrosine kinase [EC:]
K16366  endothelin-1
K13241  nitric-oxide synthase, inducible [EC:]
K13242  nitric-oxide synthase, endothelial [EC:]
K00510  heme oxygenase 1 [EC:]
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:]
K00844  hexokinase [EC:]
K00134  glyceraldehyde 3-phosphate dehydrogenase [EC:]
K01689  enolase [EC:]
K01103  6-phosphofructo-2-kinase / fructose-2,6-biphosphatase 3  [EC:]
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:]
K00162  pyruvate dehydrogenase E1 component beta subunit [EC:]
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+
Semenza GL
Oxygen homeostasis.
Wiley Interdiscip Rev Syst Biol Med 2:336-61 (2010)
Mole DR, Ratcliffe PJ
Cellular oxygen sensing in health and disease.
Pediatr Nephrol 23:681-94 (2008)
Palazon A, Aragones J, Morales-Kastresana A, de Landazuri MO, Melero I
Molecular pathways: hypoxia response in immune cells fighting or promoting cancer.
Clin Cancer Res 18:1207-13 (2012)
Majmundar AJ, Wong WJ, Simon MC
Hypoxia-inducible factors and the response to hypoxic stress.
Mol Cell 40:294-309 (2010)
Greer SN, Metcalf JL, Wang Y, Ohh M
The updated biology of hypoxia-inducible factor.
EMBO J 31:2448-60 (2012)
Zagorska A, Dulak J
HIF-1: the knowns and unknowns of hypoxia sensing.
Acta Biochim Pol 51:563-85 (2004)
Semenza GL
Regulation of oxygen homeostasis by hypoxia-inducible factor 1.
Physiology (Bethesda) 24:97-106 (2009)
Wenger RH, Stiehl DP, Camenisch G
Integration of oxygen signaling at the consensus HRE.
Sci STKE 2005:re12 (2005)
Lee JW, Bae SH, Jeong JW, Kim SH, Kim KW
Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions.
Exp Mol Med 36:1-12 (2004)
Weidemann A, Johnson RS
Biology of HIF-1alpha.
Cell Death Differ 15:621-7 (2008)
Harris AL
Hypoxia--a key regulatory factor in tumour growth.
Nat Rev Cancer 2:38-47 (2002)
Knaup KX, Jozefowski K, Schmidt R, Bernhardt WM, Weidemann A, Juergensen JS, Warnecke C, Eckardt KU, Wiesener MS
Mutual regulation of hypoxia-inducible factor and mammalian target of rapamycin as a function of oxygen availability.
Mol Cancer Res 7:88-98 (2009)
Kaluz S, Kaluzova M, Stanbridge EJ
Regulation of gene expression by hypoxia: integration of the HIF-transduced hypoxic signal at the hypoxia-responsive element.
Clin Chim Acta 395:6-13 (2008)
Cadenas S, Aragones J, Landazuri MO
Mitochondrial reprogramming through cardiac oxygen sensors in ischaemic heart disease.
Cardiovasc Res 88:219-28 (2010)
Berchner-Pfannschmidt U, Tug S, Kirsch M, Fandrey J
Oxygen-sensing under the influence of nitric oxide.
Cell Signal 22:349-56 (2010)

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